Next Article in Journal
Efficient Delivery of SARS-CoV-2 Plasmid DNA in HEK-293T Cells Using Chitosan Nanoparticles
Previous Article in Journal
Doxorubicin-Induced Cardiotoxicity and the Emerging Role of SGLT2 Inhibitors: From Glycemic Control to Cardio-Oncology
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Pharmaceuticals
Volume 18
Issue 5
10.3390/ph18050682
pharmaceuticals-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Natural Antidiabetic Agents: Insights into Ericaceae-Derived Phenolics and Their Role in Metabolic and Oxidative Modulation in Diabetes

by
Mihaela Popescu
1,†,
Kristina Radivojevic
2,†,
Diana-Maria Trasca
3,*,
Renata Maria Varut
2,*,
Irina Enache
4 and
Andrei Osman
4
1
Department of Endocrinology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
2
Research Methodology Department, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
3
Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
4
Discipline of Anatomy, Department of Anatomy, University of Medicine and Pharmacy, 200349 Craiova, Romania
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work and Kristina Radivojevic should be consider as main author.
Pharmaceuticals 2025, 18(5), 682; https://doi.org/10.3390/ph18050682
Submission received: 4 April 2025 / Revised: 1 May 2025 / Accepted: 1 May 2025 / Published: 4 May 2025
(This article belongs to the Section Natural Products)
Browse Figures
Versions Notes

Abstract

:
Diabetes mellitus (DM) is a chronic disease with a growing prevalence worldwide, leading to severe health complications. Current treatment relies on antidiabetic medications, which may have adverse effects, highlighting the need for alternative approaches. Natural compounds, such as phenolic compounds, have shown promise in glucose modulation. The Ericaceae family includes several plants with potential antidiabetic properties. This review examines the pathophysiology of diabetes, chemical composition, and specific Ericaceae species that have demonstrated antidiabetic effects. Studies indicate that Vaccinium species and other Ericaceae plants can lower blood glucose levels and improve insulin sensitivity through mechanisms such as enzyme inhibition. These findings suggest that Ericaceae plants may serve as complementary strategies for diabetes management.

1. Introduction

Diabetes mellitus has become a fast-growing global health challenge, with over half a billion people affected worldwide [1].
Diabetes is a heterogeneous syndrome identified by defined hyperglycemia which is classified as type 1 diabetes (T1DM), type 2 diabetes (T2DM), specific types of diabetes, and gestational diabetes mellitus [2]. T2DM is a disease of civilization; based on the latest data from the NCD Risk Factor Collaboration, the number of patients was 828 million [3], out of which T2DM accounts for 96% of the patients, and is one of the important non-communicable chronic diseases that seriously threaten human health, without totally clear cognition on pathogenesis [4]. T2DM is a disease outlined by a nonautoimmune heterogeneously progressive loss of adequate islet β cell insulin secretion frequently in the presence of insulin resistance (IR) and metabolic syndrome (MS). It is important to emphasize that type 2 diabetes mellitus (T2DM) is no longer confined to older adults. In recent years, a concerning two- to three-fold increase in the incidence of T2DM has been reported among younger populations, particularly those under 40 years of age [5]. And while diabetes mellitus (DM) is a multifactorial chronic health syndrome affected by several genetic and/or environmental factors [6], T2DM, in particular, is a complex multifactorial polygenetic disease that can be attributed to many risk factors. Some factors include dietary risks, environmental or occupational risks, tobacco use, low physical activity, and alcohol use, all accounting for part of the risk of T2DM [7]. The complications of T2DM are extensive and diverse, including diabetic kidney disease (DKD) developing in 40% of the people with T2DM [8], diabetic retinopathy (DR) where as many as 60% of the people with T2DM were affected after 20 years of disease duration [9], neuropathy which occurs in almost 45% of T2DM patients [10], Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) [11], coronary artery disease where mortality due to ischemic heart disease is about two to four times more frequently compared to people free of diabetes [12], and stroke [13] where it was discovered that even prediabetes may also be a cause of higher frequency of stroke [14]. The treatment of T2DM involves pharmacological measures, including oral antidiabetic drugs [15], and some non-pharmacological measures, such as regular physical activity and a healthy diet. Additionally, natural therapeutic alternatives, such as plants, have been sought out due to them containing bioactive compounds with pharmacological properties that intervene in antioxidant action or their mechanisms of action that regulate glucose, among other properties [16,17]. Current pharmacological therapies can mitigate hyperglycemia and slow the progression of diabetic complications, but they do not cure the disease and often carry side effects, underscoring an urgent need for safer and more effective interventions [18]. In response, there is increasing interest in plant-derived antidiabetic agents as complementary or alternative therapeutics. Natural phenolic compounds from medicinal plants have shown promise in improving glycemic control through multi-faceted mechanisms (enhancing insulin sensitivity, inhibiting carbohydrate-hydrolyzing enzymes, and mitigating oxidative stress). In particular, members of the Ericaceae family (such as Vaccinium berries) are rich in phenolics and have demonstrated notable antidiabetic potential in recent studies [19,20]. The Ericaceae family comprises about 4000 species across 126 genera, including prominent genera such as Calluna, Erica, Vaccinium, Azelea, Rhododendron, and the Epacrids of Australasia. The Ericaceae, commonly referred to as the heath or heather family, represent a diverse group of flowering plants that predominantly thrive in acidic and nutrient-poor soils. Their remarkable adaptability to such challenging environments has contributed to their widespread distribution across various temperate and subarctic regions [21]. The Ericaceae family has an extensive and diverse range of compounds such as phenolic compounds, pectin, vitamins, sugars [22,23], and anthocyanins (ANTs) [24]. Some of the compounds can be exclusively found in this family, such as grayanane diterpenes [25] which have analgesic [26,27], anti-inflammatory [28], antifeedant [29], and protein tyrosine phosphatase 1B (PTP1B) [30] inhibitory activities. Additionally, studies have found that extracts with phenolic compounds showed powerful α-glucosidase inhibitory activity and it is even more efficacious than the marketed drug acarbose. Moreover, the glucosidase inhibitory activities of Rhododendron arboreum were found to be many-fold higher than those of acarbose [31].
The decision to focus this review on the Ericaceae family is motivated by the unique combination of phytochemical richness and bioactivity exhibited by its members. Ericaceous plants stand out for their exceptional abundance and diversity of phenolic compounds—including anthocyanins, flavonoids, and tannins—which contribute to potent antioxidant effects and multifaceted antidiabetic activities documented in the literature [32,33]. Moreover, many Ericaceae species have a long history of ethnomedicinal use in glycemic control; for example, bilberry (Vaccinium myrtillus) leaf infusions were widely used as a traditional remedy for diabetes before the advent of insulin therapy [34]. This family also produces unique secondary metabolites, such as grayanane diterpenes found almost exclusively in Ericaceae, which display bioactivities relevant to diabetes (notably the inhibition of protein tyrosine phosphatase 1B, a negative regulator of insulin signaling). These attributes, together with robust evidence from both in vitro experiments and in vivo studies, including preliminary clinical trials showing improved glycemic indices with Ericaceae-derived interventions, provide a compelling rationale for prioritizing the Ericaceae family over other plant families in the search for natural antidiabetic agents [35]. Accordingly, the objective of this review is to comprehensively examine Ericaceae-derived phenolics and their roles in modulating metabolic and oxidative pathways, highlighting the links between phytochemical profiles and therapeutic mechanisms in diabetes management.

2. Pathophysiology of Diabetes

T1DM and T2DM are the most common subtypes of DM. Type 1 occurs mainly in children or adolescents [36], while type 2 usually affects middle-aged and elderly adults who have persistent hyperglycemia, mainly due to genetic variants, inappropriate lifestyle, and dietary habits. The pathogenesis of these two types is meaningfully different, so each type is characterized by a distinct etiology, pathophysiology, presentation, and treatment [36,37]. T1DM is characterized by elevated blood glucose levels (hyperglycemia) caused by deficient insulin production due to the destruction of the β-cells of the pancreatic islets of Langerhans, predominantly because of autoimmune inflammation [36]. The traditional understanding posits that autoreactive T cells mistakenly target and destroy healthy pancreatic β-cells, leading to insulin deficiency and consequent hyperglycemia [reference]. This loss of insulin activity not only impairs glucose uptake and metabolism in peripheral tissues such as muscle and adipose tissue, but also promotes excessive hepatic glucose production through enhanced glycogenolysis and gluconeogenesis, processes that are further stimulated by elevated glucagon levels [38]. During the early stages of type 1 diabetes mellitus (T1DM), the seroconversion of islet-specific autoantibodies—targeting insulin, glutamate decarboxylase, insulinoma-associated antigen 2, or zinc transporter 8—represents the earliest notable indicator of autoimmune activity. The simultaneous presence of multiple autoantibodies in the serum remains the most reliable predictor for both the loss of immune tolerance and the eventual clinical onset of T1DM, even though the precise role of these autoantibodies in β-cell destruction is not yet fully understood [39]. As the disease progresses, immune cells infiltrate the pancreatic islets, generating a pro-inflammatory microenvironment characteristic of insulitis. This inflammatory state not only facilitates further β-cell injury but also enhances the presentation of islet antigens via HLA class I molecules, thereby perpetuating autoimmune responses and accelerating the development of T1DM [40]. Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder in which insulin resistance and impaired insulin secretion are primarily driven by the patient’s overweight or obesity status. Epidemiological data indicates that approximately 86% of individuals with T2DM are overweight, underscoring the critical link between excess adiposity and the pathophysiology of the disease. The chronic low-grade inflammation, altered adipokine secretion, and ectopic lipid accumulation associated with obesity collectively contribute to the deterioration of insulin sensitivity and β-cell function [41]. Recent evidence suggests that β-cell dysfunction in type 2 diabetes mellitus (T2DM) arises from a complex interplay between environmental factors and various molecular pathways involved in cellular homeostasis [42]. In states of nutritional excess, such as those observed in obesity, the simultaneous presence of hyperglycemia and hyperlipidemia fosters insulin resistance (IR) and a chronic inflammatory milieu. Under these conditions, β-cells—depending on their genetic susceptibility—are exposed to multiple toxic insults, including inflammatory, endoplasmic reticulum (ER), metabolic, oxidative, and amyloid stresses, ultimately jeopardizing islet integrity and function [43]. An overload of free fatty acids (FFAs) and persistent hyperglycemia promotes ER stress by activating pro-apoptotic branches of the unfolded protein response (UPR) pathways, thereby contributing to β-cell dysfunction [44]. Lipotoxicity, glucotoxicity, and glucolipotoxicity—hallmarks of obesity—further exacerbate metabolic and oxidative stress within β-cells, accelerating their deterioration [42]. Mechanistically, elevated levels of saturated FFAs can impair ER homeostasis by inhibiting the sarco/endoplasmic reticulum Ca2⁺-ATPase (SERCA), activating inositol 1,4,5-triphosphate (IP3) receptors, and disrupting calcium mobilization within the ER. Moreover, chronic hyperglycemia increases proinsulin and islet amyloid polypeptide (IAPP) synthesis in β-cells, leading to the accumulation of misfolded proteins and enhanced generation of reactive oxygen species (ROS) via oxidative protein folding processes [44]. These disturbances further impair ER calcium handling, amplify pro-apoptotic signaling, degrade proinsulin mRNA, and promote interleukin-1β (IL-1β) release, recruiting macrophages and intensifying local islet inflammation [42].
Maintaining proper insulin secretion is vital to meet the body’s metabolic demands, necessitating the preservation of islet architecture and coordinated cell-to-cell communication. The disruption of islet integrity, as driven by the aforementioned stressors, impairs the synchronized secretion of insulin and glucagon, contributing to worsening hyperglycemia. Ultimately, defects in insulin precursor synthesis, insulin production, or secretion mechanisms form the core of β-cell failure, establishing a pathological foundation for T2DM [45].

3. Chemical Composition of Ericaceae Plants with Antidiabetic Potential

The secondary metabolites of the plants protect them from various microbial attacks and have potent medicinal properties. Based on their chemical structures, secondary metabolites are categorized into several classes, such as phenolics, alkaloids, saponins, terpenes, and lipids [46]. Flavonoid content in various plants from the Ericaceae family with antidiabetic effects is shown in Table 1. Table 2 summarizes key phenolic compounds identified in the studied Ericaceae species, providing their IUPAC names, molecular formulas, and corresponding 2D structures. The compounds listed include flavonoids such as quercetin, kaempferol, and myricetin, as well as anthocyanidins such as cyanidin, delphinidin, malvidin, petunidin, and pelargonidin. These bioactive molecules are known for their antioxidant, anti-inflammatory, and potential antidiabetic properties, and their structural diversity underpins their wide range of biological activities. Among these compounds, the phenolic group attracts considerable interest as the most promising secondary metabolite for the treatment of several diseases, including diabetes (Table 3). Recent research has identified several phenolic compounds in Ericaceae plants that exert antidiabetic effects through multi-enzymatic inhibition and the modulation of key metabolic pathways. Among these, anthocyanins such as delphinidin, cyanidin, and malvidin—commonly found in Vaccinium species—demonstrate strong inhibitory effects on α-glucosidase and α-amylase, thereby slowing carbohydrate digestion and blunting postprandial glucose spikes. Flavonols like quercetin and myricetin, present in Arbutus unedo, Rhododendron arboreum, and Gaultheria trichophylla, also inhibit aldose reductase, a key enzyme in the polyol pathway implicated in diabetic complications, as well as protein tyrosine phosphatase 1B (PTP1B), a negative regulator of insulin signaling [47]. Catechins and proanthocyanidins, abundant in Gaultheria and Vaccinium vitis-idaea, inhibit dipeptidyl peptidase-IV (DPP-IV), an enzyme that degrades incretin hormones like GLP-1, thereby prolonging insulin secretion and enhancing glycemic control. Moreover, arbutin, the major phenolic glycoside in Arctostaphylos uva-ursi, has been shown to inhibit glucose-6-phosphatase, thereby suppressing hepatic gluconeogenesis and contributing to lower fasting blood glucose levels. In addition to direct enzyme inhibition, several Ericaceae-derived flavonoids activate AMP-activated protein kinase (AMPK) and upregulate GLUT4 expression, facilitating glucose uptake in skeletal muscle and adipose tissues [48]. This integrative mode of action underscores the therapeutic potential of Ericaceae phenolics, which not only inhibit carbohydrate-digesting enzymes but also modulate intracellular signaling and metabolic enzyme pathways involved in glucose homeostasis. Interestingly, many edible Ericaceae fruits accumulate substantial tannins (condensed proanthocyanidins and hydrolyzable gallo-/ellagitannins), a class under-reported in prior reviews. For example, Vaccinium berries (blueberry, bilberry, cranberry, and lingonberry) are noted as “rich in proanthocyanidins”, and bilberry, in particular, contains both A- and B-type PA oligomers; similarly, the Mediterranean strawberry tree (Arbutus unedo) fruits yield galloyl (gallotannin) and ellagitannin derivatives. Such tannins likely contribute to antidiabetic effects via multiple mechanisms. In vitro, removing tannins greatly weakens the berry-extract inhibition of α-amylase, and isolated A/B-type proanthocyanidin fractions (e.g., from lingonberry) block α-amylase and α-glucosidase while enhancing hepatic glucose uptake. Concurrently, condensed tannins are potent antioxidants/anti-inflammatories: Vaccinium PACs suppress oxidative stress and improve insulin sensitivity, and dietary tannins (e.g., tannic acid or red-wine tannins) markedly blunt postprandial glycemic spikes in humans, akin to acarbose [49]. Chronic hyperglycemia in diabetes drives the excess production of reactive oxygen species (ROS), creating an oxidative environment that damages pancreatic β-cells and impairs insulin signaling. This stress directly oxidizes cellular proteins and lipids and activates stress-sensitive kinases (JNK or NF-κB) that inhibit the insulin receptor signaling cascade, thereby promoting insulin resistance. Because β-cells have intrinsically low antioxidant defenses (e.g., low levels of superoxide dismutase, catalase, and glutathione peroxidase), this ROS-mediated injury particularly impairs insulin secretion [50]. By contrast, antioxidant-rich extracts from Ericaceae plants (for example, anthocyanin- and polyphenol-rich berries) can scavenge excess ROS and reduce inflammation; indeed, Vaccinium extracts have been shown to lower oxidative stress, inflammation, and blood glucose in diabetic models. In this way, the antioxidative properties of these plants help restore redox balance and preserve insulin sensitivity, providing a mechanistic rationale for their dual antidiabetic and antioxidant effects. Out of all phenolic compounds, flavonoids are the most prevalent and well-studied class of polyphenols. Studies have shown that flavonoids possess powerful antidiabetic and antioxidant activities (Table 4) [51,52,53].

4. Ericaceae Phenolic Compounds and Enzyme Inhibition in Diabetes

Figure 1 highlights the key Ericaceae plant sources, major classes of bioactive phenolics, and their mechanistic actions on metabolic pathways such as glucose uptake, insulin secretion, and hepatic gluconeogenesis, ultimately contributing to improved glycemic control and protection against diabetic complications.

4.1. Inhibition of Digestive Enzymes (α-Glucosidase and α-Amylase)

Phenolic compounds from Ericaceae (e.g., blueberries, bilberries, and bearberry) can moderate postprandial glycemia by inhibiting α-glucosidase and α-amylase, the key enzymes that digest dietary carbohydrates. Anthocyanins are particularly effective: a purified anthocyanin extract showed an IC50 ~0.71 mg/mL against α-glucosidase, markedly more potent than acarbose (IC50 ~8.8 mg/mL). The same extract inhibited α-amylase with IC50 ~1.14 mg/mL (comparable to acarbose, ~1.0 mg/mL) [92]. Kinetic analyses indicate a mixed or uncompetitive inhibition mode for these anthocyanins, suggesting they bind to the enzyme-substrate complex or allosteric sites to impede carbohydrate breakdown. In molecular docking studies, flavonols like myricetin (commonly found in Ericaceae berries) can anchor into the α-amylase active site via multiple hydrogen bonds (to catalytic residues Asp197, Asp300, Asp356, etc.) and π–π stacking with Trp59 [93], directly blocking the starch-binding cleft. Likewise, the phenolic glycoside arbutin (abundant in bearberry Arctostaphylos uva-ursi) exhibits direct α-amylase and α-glucosidase inhibition in vitro. Although arbutin alone is slightly less potent than whole plant extracts (which contain synergistic flavonoids and tannins), it contributes to the overall enzyme-inhibitory activity of Ericaceae preparations. Through these mechanisms, berry phenolics slow the release of glucose from complex carbs, flattening postprandial glucose spikes. In vivo, this translates to improved glycemic control and insulin economy, analogous to pharmaceutical α-glucosidase inhibitors but potentially with fewer gastrointestinal side effects [94].

4.2. DPP-IV Inhibition and Incretin Enhancement

Ericaceae phenolics also target dipeptidyl peptidase-IV (DPP-IV), an enzyme that degrades the incretin hormones GLP-1 and GIP. The inhibition of DPP-IV prolongs incretin action, thereby enhancing glucose-stimulated insulin secretion and lowering blood glucose. Several berry-derived polyphenols act as natural DPP-IV inhibitors. Notably, anthocyanins and flavonols can achieve low-micromolar or sub-micromolar potency. For example, cyanidin-3-glucoside (a major anthocyanin in bilberry) inhibits DPP-IV with an IC50 ≈ 0.4 μM, and cyanidin aglycone around 1.4 μM. Quercetin, a flavonol present in blueberries, has an IC₅₀ in the low micromolar range (~2–3 μM). These values approach or even surpass the potency of a known peptidic inhibitor (Diprotin A, IC50 ~4.2 μM). Mechanistically, docking studies reveal that polyphenols like cyanidin-3-glucoside and quercetin fit into the DPP-IV active site, interacting with key subsites S2/S3 via multiple hydrogen bonds and π-interactions. For instance, quercetin’s hydroxyl groups form hydrogen bonds with residues such as Arg356 and Arg358 in the catalytic pocket, while its aromatic rings stack against hydrophobic pocket residues [95]. This mimics how synthetic inhibitors bind DPP-IV, effectively blocking incretin degradation. Consistent with these molecular insights, berry extracts rich in these phenolics have shown DPP-IV inhibitory activity in cell-free assays and even in animal models. One study noted that grape seed procyanidins (structurally similar to berry proanthocyanidins) reduced intestinal DPP-IV activity by ~34% after a single dose, suggesting that dietary polyphenols can acutely elevate circulating GLP-1. By preserving endogenous incretins, Ericaceae phenolics help sustain insulinotropic signaling, improve meal-time insulin release, and attenuate postprandial hyperglycemia [96].

4.3. Aldose Reductase Inhibition and Polyol Pathway Protection

Chronic hyperglycemia in diabetes drives the polyol pathway, where excess glucose is reduced to sorbitol by the enzyme aldose reductase. Sorbitol accumulation causes osmotic and oxidative stress, contributing to complications like neuropathy, retinopathy, and cataracts. Phenolic compounds from Ericaceae can mitigate this by inhibiting aldose reductase (AR). Flavonols are particularly potent AR inhibitors: quercetin and its glycosides (quercitrin and myricitrin) were shown to be significantly more potent than classic AR inhibitor drugs in lens assays. These flavonols exhibited noncompetitive inhibition kinetics against AR, implying they bind to a site distinct from the glucose/NADPH active site (possibly an enzyme-cofactor or enzyme-product complex), thereby modulating enzyme activity without directly competing with the substrate. In functional terms, quercitrin was able to block sorbitol accumulation in isolated rat lenses exposed to high glucose, confirming that flavonoid AR inhibitors work in intact tissues [97]. Anthocyanins and catechins in Ericaceae likely contribute to AR inhibition as well, as many polyphenols share a structural capacity to bind AR’s active pocket or adjacent sites. By reducing flux through the polyol pathway, these compounds help prevent the intracellular sorbitol buildup that underlies diabetic cataract formation and nerve damage. This protective mechanism has been borne out in vivo: quercetin supplementation in diabetic rats lowered retinal sorbitol levels and improved oxidative stress markers, highlighting the relevance of AR inhibition in complication prevention. Thus, Ericaceae phenolics not only control blood sugar levels but also directly guard tissues against hyperglycemic injury by targeting aldose reductase [98].

4.4. PTP1B Inhibition and Insulin Signaling Enhancement

Beyond effects on digestive enzymes and hormones, Ericaceae phenolics improve insulin sensitivity at the cellular level by inhibiting protein tyrosine phosphatase 1B (PTP1B). PTP1B is a negative regulator of insulin signaling—it dephosphorylates the insulin receptor (IR) and insulin receptor substrates, attenuating the PI3K/Akt pathway. In obesity and type 2 diabetes, PTP1B is often overexpressed, contributing to insulin resistance. Remarkably, anthocyanin-rich berry extracts have demonstrated potent PTP1B inhibition. For example, blueberries and bilberries (Vaccinium spp.) yielded anthocyanin fractions with IC50 ~3 μg/mL against PTP1B. Among individual compounds, cyanidin-3-O-glucoside stands out: docking studies show it can occupy both the active site and an adjacent allosteric site of PTP1B, with a binding energy of around –7.8 kcal/mol [99]. By engaging the enzyme in this bidentate manner, cyanidin-3-glucoside effectively blocks PTP1B activity. Flavonols present in Ericaceae (quercetin and myricetin) and even flavan-3-ols (catechins) may also contribute to PTP1B inhibition [100], as these classes have reported PTP1B-inhibitory activity in other plant systems. The downstream consequence of PTP1B inhibition is an enhancement of insulin signaling. With PTP1B activity restrained, the insulin receptor stays phosphorylated for longer upon insulin binding, leading to the amplified recruitment of PI3K and activation of Akt. This has been observed as increased Akt phosphorylation and GLUT4 translocation in muscle and adipose tissues treated with berry polyphenols. In one study, myricetin administration to insulin-resistant rats elevated the phosphorylation of IR, IRS-1, and Akt in skeletal muscle, thereby promoting GLUT4 mobilization to the membrane. Notably, that study linked myricetin’s action to an upstream rise in β-endorphin (acting on opioid receptors) revealing a complementary mechanism by which a flavonol can alleviate insulin resistance. Overall, by inhibiting PTP1B, Ericaceae phenolics release a brake on the insulin signaling cascade, restoring insulin sensitivity and improving glucose uptake in peripheral tissues [101].

4.5. Activation of AMPK and Modulation of Glucose Metabolism

In addition to direct enzyme inhibition, Ericaceae-derived phenolics influence cellular energy-sensing pathways, most importantly the AMP-activated protein kinase (AMPK). AMPK is a central metabolic regulator that, when activated, stimulates glucose uptake and fatty acid oxidation while suppressing gluconeogenesis. Polyphenols like quercetin and anthocyanins are known to activate AMPK in liver and muscle cells. Quercetin has been shown to increase the Thr172-phosphorylation of AMPK in insulin-resistant hepatocytes and myotubes, in turn downregulating gluconeogenic enzymes including glucose-6-phosphatase and PEPCK. This leads to reduced hepatic glucose output and lower fasting glycemia. Concordantly, quercetin-treated diabetic animals exhibit decreased blood glucose along with suppressed hepatic G6Pase activity and gene expression [102]. Anthocyanins can likewise engage AMPK-dependent pathways: black rice anthocyanin extracts, as a model, stimulated AMPK (and p38 MAPK) in skeletal muscle cells, increasing GLUT4 translocation and glucose uptake independently of insulin. Interestingly, the same extracts also enhanced insulin-dependent signaling (IRS-1 and PI3K/Akt), indicating that anthocyanins act on multiple nodes to facilitate glucose disposal. In the muscle and adipose tissue of diabetic models, anthocyanin-rich diets have been found to elevate GLUT4 abundance and incorporation into the plasma membrane, an effect attributed to the upregulation of AMPK activity and restoration of insulin sensitivity in those tissues [103]. Besides improving glycemic control, AMPK activation by these compounds has favorable effects on lipid metabolism (e.g., inhibition of lipogenesis and stimulation of fatty-acid oxidation) and on GLUT4 gene expression in muscle. It is postulated that polyphenols may activate AMPK by causing mild cellular stress or mitochondrial inhibition (somewhat analogous to metformin’s mechanism), thereby increasing the AMP/ATP ratio. For example, catechin-type polyphenols can depolarize mitochondria and activate AMPK in the liver, contributing to decreased gluconeogenic output. Through AMPK, Ericaceae phenolics orchestrate a shift from glucose production to glucose utilization. The net result is improved whole-body glucose homeostasis: enhanced muscle glucose uptake (via more GLUT4 on cell surfaces) and diminished liver glucose release. This synergizes with their insulin-sensitizing effects (via PTP1B inhibition) to overcome insulin resistance [104].

5. In Vitro and In Vivo Antidiabetic Studies for Vaccinium Species

Belonging to the Ericaceae family (notably the Rhododendron genus), the Vaccinium genus consists of a morphologically diverse group of approximately 4250 species (33 types), divided into nine subfamilies and 125 genera, with prevalence mostly across Europe, Southeast and Central Africa, Asia, and North and Central America [90,91]. The wild species of this genus that are prevalent in Europe include V. myrtillus L. (bilberry), V. vitis-idaea L. (lingonberry), V. oxycoccus L. (cranberry), and V. uliginosum L. (bog bilberry) [105]. The most widely cultivated species within the Ericaceae family are found in the subfamily Vaccinioideae, which includes economically and nutritionally important fruits such as cranberry, blueberry, huckleberry, and bilberry [106]. According to multiple studies, the principal health benefits associated with these fruits are largely attributed to their potent antioxidant, antimicrobial, and detoxifying effects on the human body [reference]. These biological activities underpin their growing recognition as functional foods with the potential to support overall health and prevent various chronic diseases [107]. Moreover, it is widely recognized that these plants, especially those rich in polyphenolic compounds such as anthocyanins, possess the ability to inhibit cancer cell proliferation and promote apoptosis within malignant cells [reference]. This dual action highlights their promising role as natural agents in cancer prevention and adjunctive therapy [108,109,110]. Given their benefits and the widespread presence of this genus, it is predictable that numerous studies have explored their potential in diabetes mellitus (Table 5).

5.1. Bilberry

Bilberry (Vaccinium myrtillus) is a perennial, low-growing shrub that can reach a height of 35–60 cm. It grows in acidic soils [121], organic forest soils, mountainous mineral heaths, and old peat bogs in central and northern parts of Europe [122]. Bilberry is commonly known as the European blueberry or whortleberry [121]. An uncommon albino form is characterized by greenish-white fruits, an appearance caused by the suppression of genes involved in anthocyanin synthesis [123]. The fruits are used, often in combination with other ingredients, to produce syrups, pies, tarts, and beverages. The leaves are generally used to prepare decoctions [121,124]. The growing demand for a berry-rich diet has led to the increased consumption and cultivation of two Vaccinium species: V. myrtillus (wild bilberries) and V. corymbosum (cultivated blueberries) [125]. Numerous studies [126] have shown that the consumption of bilberry fruit improves cellular function and glycemic control in diabetic patients. It has been shown that bilberry consumption increases hippuric acid levels in fasting serum, and over time, this can enhance glucose and insulin metabolism. Bilberry extracts also appear to improve eye microcirculation and reduce intraocular pressure [127]. Bilberry is used as an adjuvant therapy (alongside a proper diet) in the early stages of type 2 diabetes [128]. In vitro studies have demonstrated that V. myrtillus leaf extracts inhibit the activity of α-glucosidase and α-amylase [129], helping to prevent hyperglycemia by enhancing pancreatic beta cell function. A reduction in body weight was also observed [130]. Given these health benefits, several studies have explored the antidiabetic potential of bilberry fruits and leaves in T2DM (Figure 2). Two clinical studies from China tested bilberry extract in patients with T2DM, measuring HbA1c as a primary outcome. One study reported a significant 8.5% reduction in fasting blood glucose levels [131], while the other showed a 4.7% decrease in HbA1c in subjects with prediabetes and T2DM [85]. However, a recent study reported the negligible effects of bilberry and grape seed extract on glucose and cholesterol metabolism, although a significant reduction in blood pressure was observed. The limited outcome may be attributed to the small sample size (14 participants) [132]. Another study found a correlation between myricetin content and the degree of α-amylase inhibition, further confirming that bilberry polyphenols play a role in this enzymatic suppression [133]. In vivo experiments investigating non-acylated anthocyanin extracts from bilberries in diabetic rats revealed modulatory or even restorative effects on abnormal urinary metabolite profiles [134]. Additionally, a study developed fast-dissolving films using β-glucan and bilberry juice, capitalizing on the bioactive properties of both components for use in packaging dry powdered antidiabetic medications [135].
The breadth of research on bilberry’s applications in diabetes supports its promising potential as a complementary strategy in diabetes management.

5.2. Cranberry (V. sect. Oxycoccus)

Cranberry is a diploid fruit [136], classified as a woody perennial plant characterized by the production of vertical stems [137]. It is taxonomically divided into four main species: Vaccinium erythrocarpum (southern mountain cranberry), V. macrocarpon (large cranberry, American cranberry, or bearberry), V. microcarpum (small cranberry), and V. oxycoccos (common or northern cranberry) [138]. Among these, V. macrocarpon (American cranberry) and V. oxycoccos (European cranberry) are the most widely cultivated and studied species. Cranberries are particularly valued for their rich content of bioactive compounds, including anthocyanins; flavonols; flavan-3-ols (catechins); proanthocyanidins (PACs); benzoic and phenolic acids; nonflavonoid polyphenols such as phloridzin; and terpenes and sterols [139]. V. macrocarpon stands out both as a traditional medicinal agent and a nutritional food source, largely due to its complex phytochemical profile. Among the more than 150 identified compounds, flavonoids represent the dominant class, encompassing 13 anthocyanins, 16 flavonols, and 26 phenolic acids and benzoates. This rich composition underpins the diverse therapeutic properties attributed to American cranberries [140]. For cranberry fruit, Cermak et al. [141] showed that quercetin glucosides inhibit glucose uptake into the vesicles of the brush membrane of the pig intestine. Strobel et al. [142] demonstrated that the myricetin present in fruit can inhibit glucose assimilation via the type 4 glucose transporter by rat adipocytes. Schell et al. [119] found that a diet enriched with low-calorie cranberries had a significant effect on improving postprandial glucose levels, and Rocha et al. [143], that the daily consumption (240 mL) of cranberry juice improved glucose control in patients with type 2 diabetes. As for the application of cranberry in T2DM, studies included both glucose-lowering (Figure 2) and complication-beneficial effects research. In several studies investigating the glucose-lowering effects of cranberry supplementation, the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was employed as a practical tool to evaluate insulin resistance, a key factor associated with the risk of CVD and T2DM [144]. HOMA-IR is a calculated index based on fasting insulin and fasting blood glucose (FBG) levels [144]. Three clinical trials reported a significant reduction in HOMA-IR values among participants receiving cranberry interventions compared to those in placebo groups, although other metabolic parameters did not show notable differences [121,145,146]. Two studies conducted in Iran further demonstrated that cranberry supplementation could positively influence insulin levels [145,146]. The mechanisms underlying glycemic regulation were hypothesized to be largely attributed to the polyphenolic content of cranberries, a hypothesis supported by numerous animal studies [147,148,149]. Additionally, an acute clinical study on obese individuals with T2DM revealed that postprandial blood glucose levels were significantly lower in participants consuming cranberries compared to controls [150]. The form of cranberry used in interventions appeared to be an important determinant of metabolic outcomes. Studies administering dried cranberry preparations—such as capsules, powders, or tablets—reported more significant improvements in insulin levels compared to those using cranberry juice. Five studies utilized dried forms, with Hormoznejad et al. and Shirazi et al. both noting substantial reductions in insulin concentrations and HOMA-IR scores within the intervention groups [145,146]. Furthermore, Flanagan et al. identified a beneficial effect of cranberry consumption on lipid profiles, suggesting broader cardiometabolic advantages [151]. Arginine-loaded extracts from American cranberry leaves have also been investigated for their potential to improve insulin resistance (IR). The experimental results in rats demonstrated a reduction in body weight, accompanied by decreased triglyceride (TG) accumulation in the liver. Additionally, the serum levels of high-density lipoprotein cholesterol (Ch-HDL) were found to be negatively correlated with HOMA-IR values, suggesting an improvement in insulin sensitivity [152]. Other studies researched the efficacy of cranberry in the complications of T2DM. For wound-healing potential among individuals with diabetes, hydrogel containing cranberry extract and graphene-oxide was used, where animals receiving electroactive and photothermal treatment showed a notably higher percentage of wound healing than the other groups [153]. Another double-blind, placebo-controlled clinical study showed a statistically significant reduction in urinary tract infection (UTI) episodes in the supplemented group compared to placebo administration in T2DM patients [154], where the occurrence is higher. As cranberry consumption lowers the risk of type 2 diabetes [119], the potential for cranberries in the treatment and in the prevention of complications is shown in a high number of studies.

5.3. Blueberry

Blueberries (Vaccinium spp.) are small, spherical fruits native to North America [155]. Notably, the consumption of blueberry juice has been associated with improvements in memory function among older adults experiencing early signs of cognitive decline. Given their versatile phytochemical composition, blueberries have garnered considerable research interest in the context of T2DM.
With respect to glycemic control, 21 studies have evaluated the effects of blueberry consumption on fasting blood glucose and/or HbA1c levels [156,157,158,159]. The majority of these investigations found no significant differences between intervention and control groups. However, several animal studies reported a reduction in blood glucose levels following dietary supplementation with blueberries [158,160], and one study documented a significant decrease in HbA1c levels in rats treated with blueberries compared to controls [161]. Regarding insulin dynamics, four studies demonstrated that blueberry supplementation led to lower insulin levels in mice and rats relative to control groups, suggesting a potential role for blueberries in improving insulin sensitivity [157,162,163,164]. In contrast, other studies observed similar insulin levels between experimental groups [156,158,161]. Moreover, six studies reported a decrease in IR in animals from the fruit group [152,153,154,156,157,158], while two other studies did not observe any reduction in IR in the treated group (vs. controls) [160,161]. Interestingly, Brader et al. [155] reported that rats fed with a blueberry-enriched diet exhibited decreased hepatic expression of glucose transporter 2 (Glut2) and insulin receptor substrate 1 (Irs1), alongside increased expression of Glut4 in adipose tissue compared to controls. Similarly, Seymour et al. [162] observed the upregulation of both Glut4 and Irs1 in adipose tissue and skeletal muscle, as well as elevated expression of uncoupling protein 3 (Ucp3) in the skeletal muscle of blueberry-fed rats. In another study. Liu et al. [156] suggested that blueberries may improve glucose tolerance by enhancing pancreatic β-cell survival and reducing the expression of pro-inflammatory cytokines and oxidative stress markers. Additional mechanisms proposed for the blueberry-induced improvements in glucose metabolism include the upregulation of Glut2 and Glut4 expression [162,165], activation of peroxisome proliferator-activated receptor (PPAR) pathways and AMP-activated protein kinases (AMPKs), and downregulation of retinol-binding protein 4 (RBP4) expression [166]. Furthermore, the modulation of the gut microbiota following blueberry consumption may also contribute to enhanced glucose tolerance [167]. The potential of blueberries in diabetes prevention has been investigated in epidemiological studies, where a higher habitual intake of blueberries was associated with a lower risk of developing type 2 diabetes [167,168,169]. In particular, a prospective longitudinal cohort study reported that consuming two or more servings of blueberries per week was linked to a significantly reduced risk of T2DM compared to infrequent consumption (less than one serving per month) [147]. Clinical trials have provided mixed results regarding the impact of blueberries on insulin sensitivity. In a randomized controlled trial (RCT) involving adults with obesity and prediabetes, daily blueberry intake (equivalent to 300 g fresh blueberries, providing 668 mg of anthocyanins) over six weeks significantly improved insulin sensitivity [170]. However, other studies found no significant improvements in insulin sensitivity after intervention periods of 6 and 24 weeks among individuals with prediabetes [171,172]. Moreover, a 12-week blueberry supplementation study in individuals with prediabetes and subjective cognitive decline reported lower fasting insulin levels, although no significant changes were observed in fasting blood glucose or HOMA-IR scores [173]. An acute clinical trial also demonstrated that consuming blueberries (equivalent to 1 cup or 150 g fresh blueberries, providing 364 mg of anthocyanins) significantly reduced postprandial blood glucose and insulin concentrations over a 24 h period following an energy-dense, high-fat/high-sugar meal [174].

5.4. Lingonberry (Vaccinium vitis-idaea L.)

Lingonberry (Vaccinium vitis-idaea L.) is a small red berry that grows wild across the forests of Northern countries, Central Europe, Russia, and Canada [175]. Although the majority of lingonberries are harvested from wild populations, limited cultivation efforts exist, and plant breeding programs for this species remain in their early stages [176]. Closely related to the cranberry (Vaccinium oxycoccos), lingonberries are comparatively less well known and less commercially popular. The fruits of V. vitis-idaea are rich in essential nutrients, including a variety of vitamins, polysaccharides, dietary fiber, and minerals. They also contain an array of bioactive compounds such as anthocyanins, proanthocyanidins, flavonols, phenolic acids, simple phenolics, phytosterols [177], hydroxycinnamic acids, triterpenoids, and flavonoids, which collectively contribute to their recognized health benefits [178]. Lingonberries exhibit strong anti-inflammatory, antioxidant, antithrombotic, hypoglycemic, antiseptic, and antibacterial properties [179,180]. Supplementation with lingonberry has been shown to prevent weight gain induced by a high-fat diet in animal models [181,182] and has demonstrated favorable effects on blood glucose, insulin levels, lipid profiles, and inflammatory markers. Mechanistically, lingonberry extract acts as a potent inhibitor of α-glucosidase and α-amylase activities, with reported IC50 values ranging between 12 and 17 μg/mL [183]. Clinical studies further support these findings; one trial revealed that the consumption of a sucrose-sweetened meal containing lingonberries significantly improved postprandial glycemic profiles compared to a similar meal without lingonberries [184]. In vitro studies have also shown that lingonberry extract can stimulate both basal and insulin-stimulated glucose uptake in skeletal muscle cells [185]. Bioactive compounds identified in lingonberries that may contribute to these metabolic effects include proanthocyanidins [186], quercetin [187], and resveratrol [188]. Additionally, the use of lingonberry press residue for extract production has shown promise. Purified polyphenol–polysaccharide conjugates derived from the press residue prevented weight gain in high-cholesterol-fed hamsters [189], while lingonberry pomace extracts demonstrated hypoglycemic effects in vitro through the inhibition of α-amylase and α-glucosidase activities [190]. Furthermore, supplementation with lingonberry skin extract was found to prevent increases in fasting blood glucose, body weight, and visceral fat accumulation in a mouse model of high-fat diet-induced obesity [191].

5.5. Bearberry (Arctostaphylos uva-ursi L.)

Bearberry (Arctostaphylos uva-ursi L.) is a perennial plant belonging to the Ericaceae (heather) family. Its leaves are particularly rich in arbutin, the primary bioactive compound, alongside other phytochemicals such as phenolic acids, flavonoids, and saponins [192]. Traditionally, aqueous infusions of bearberry leaves have been used for the treatment of various ailments. Due to its ecological vulnerability, bearberry is considered an endangered and protected species in several European countries [193]. Bearberry leaves (BLs) have long held a prominent place in folk medicine, valued for their abundance of secondary metabolites with important medicinal and pharmacological properties. The chemical composition of BL includes a diverse array of bioactive compounds such as gallic acid, ursolic acid, tannic acid, p-coumaric acid, galloylarbutin, gallotannins, quercetin, kaempferol, penta-O-galloyl-α-D-glucose, corilagin, picein, and hyperoside, among others [194]. Extracts from Uvae ursi folium have been employed as natural remedies for various conditions, including diuresis [195], and more recently as antioxidant agents in food packaging and skin-whitening agents in dermatological formulations [196]. Arbutin, the principal active compound (Figure 2), is particularly noted for its skin-depigmenting effects, exerting potent antimelanogenic and antioxidant activities [197].
Dried leaves of bearberry showed the potential to lower the risk of diabetic complications with the chemical composition found being the following: hydroquinone derivatives, arbutin, methylarbutica, and gallic acid in studies even older than 50 years [198,199]. Recent in vivo experimental studies have investigated the antidiabetic potential of extracts derived from bearberry leaves under conditions of experimentally induced insulin resistance (IR). Following two weeks of administration, the extracts demonstrated a significant capacity to lower blood glucose levels in rats, attenuate the progression of IR, and improve glucose tolerance. The observed hypoglycemic effect was comparable to that of metformin and was notably superior to the activity of Arphazetin [200]. Additional experimental evidence supports these findings, showing that bearberry leaf extracts effectively reduced blood glucose levels both in animals with induced pathology and in healthy animals subjected to glucose overload [201,202]. Furthermore, another study revealed that a dry alcoholic extract of bearberry leaves enriched with cysteine (PE50_cys) exerted notable hypoglycemic and pancreatic protective effects in a dexamethasone-induced IR model. Treatment with PE50_cys improved hyperglycemia and insulin resistance, and preserved β-cell mass which was otherwise reduced by dexamethasone exposure [203]. Moreover, a dry extract of bearberry leaves enriched with arginine exhibited hepatoprotective effects in diabetic rats. This extract enhanced the parameters of carbohydrate metabolism, including increased glycogen content in the liver and reduced blood lactate levels. The hepatoprotective effect is believed to be mediated primarily by the antioxidant properties of the plant-derived polyphenols within the PE50_arg composition, while the addition of arginine further amplified these beneficial outcomes [204].

5.6. Arbutus unedo, (The Strawberry Tree)

Arbutus unedo (A. unedo), commonly known as the strawberry tree, is a member of the Ericaceae family and is widely distributed throughout the Mediterranean region. It is also found in the Canary Islands and parts of western Asia, where the climatic conditions are favorable for its growth [205]. Traditionally, various parts of A. unedo, including its fruits, leaves, and roots, have been extensively utilized in folk medicine for their diuretic, astringent, antidiarrheal, antiasthmatic, anti-inflammatory, antidiabetic, antihypertensive, and anti-rheumatic properties, as well as for the treatment of gastrointestinal and renal disorders [206,207,208]. A wide range of pharmacological activities has been attributed to A. unedo, including astringent, depurative, anti-inflammatory, hemostatic, antitumor, antioxidant, antimicrobial, spasmolytic, and neuroprotective effects [209,210]. Experimental studies further confirm that extracts from A. unedo exhibit significant biological activities, demonstrating antioxidant, platelet antiaggregant, vasorelaxant, antihypertensive, and antidiabetic properties [211,212]. These diverse therapeutic effects are largely attributed to the plant’s rich phytochemical composition, which includes flavonoids, tannins, phenolic acids, organic acids, α-tocopherol, carotenoids, anthocyanins, triterpenoids, fatty acids, sterols, vitamin C, dietary fibers, and essential minerals such as calcium (Ca), potassium (K), magnesium (Mg), and phosphorus (P) [213,214,215]. Collectively, these bioactive compounds contribute to the remarkable pharmacological and nutritional profile of A. unedo.
In in vivo studies (Table 6), extracts of Arbutus unedo demonstrated a significant reduction in intestinal glucose absorption, which may partially explain the observed decrease in glycemia in the oral glucose tolerance test (OGTT) model [216]. The chronic oral administration of A. unedo extract over a four-week period in streptozotocin–nicotinamide (STZ–NA)-induced diabetic mice resulted in a marked decrease in blood glucose levels, comparable to the effects achieved with metformin, the positive control [217]. Furthermore, treatment with A. unedo extract was associated with the restoration of the histological architecture of the islets of Langerhans, suggesting a protective effect on pancreatic tissue in diabetic mice [217]. The hypoglycemic action of A. unedo is thought to involve the stimulation of insulin secretion from existing pancreatic β-cells or the mobilization of insulin from its bound forms [185,217]. Additionally, the chronic administration of the extract for four weeks significantly improved oral glucose tolerance and promoted weight reduction in rat models [218]. Beyond the roots, several studies have investigated other products derived from A. unedo in the context of T2DM management, as illustrated in Figure 3.

5.7. Crowberry

Crowberry (Empetrum nigrum L.) is a small genus of dwarf evergreen shrubs, recognized as a wild berry with significant potential for use in herbal medicine, largely due to its rich and diverse phenolic content [221]. Among its phytoconstituents, flavonols and benzoic acid derivatives are the most abundant soluble phenolic compounds identified in crowberry leaves [222]. In the context of diabetes management, several studies have explored the inhibitory effects of crowberry extracts on carbohydrate-digesting enzymes. Notably, extracts from the aerial parts of crowberry demonstrated potent α-glucosidase inhibitory activity, suggesting their potential to attenuate postprandial hyperglycemia by delaying carbohydrate digestion [223]. The antidiabetic activities of crude 70% ethyl alcohol extract and its fractions were analyzed to understand the biological activity of crowberry [224]. It was indicated that the significant inhibition of α-glucosidase and α-amylase activities by the ethyl acetate fraction (versus the other fractions) is due to the presence of polyphenolic compounds. Another study of solid phase extraction (SPE) on crowberry tried to enhance glucose uptake in liver cells. Among others, crowberries showed high stimulation of glucose uptake, which can lower blood glucose levels [225]. In a human study, Torronen et al. [226] investigated the fortification of blackcurrant juice with black crowberry powdered fruit extract and assessed its effects on polyphenol composition, urinary and plasma phenolic metabolites, and postprandial glycemic response in healthy subjects. Fortification doubled the TPC of the juice, increasing from 159 to 293 mg/100 mL. Following consumption, the urinary levels of metabolites such as dihydroxybenzoic acid sulfate and dihydroxyphenylacetic acid sulfate were significantly elevated, particularly after the intake of the fortified juice. Importantly, the combination of crowberry and blackcurrant improved the postprandial glycemic response following a 36 g sugar load, likely due to enhanced polyphenol bioavailability [133]. The ethanolic extract of the aerial parts of black crowberry demonstrated strong α-glucosidase inhibitory activity, reinforcing the potential of crowberry as a natural therapeutic agent to manage postprandial hyperglycemia and suggesting its possible use as an alternative antidiabetic treatment (Table 7) [203].

6. Toxicity and Safety Considerations

Ericaceae-derived phytochemicals, while promising for antidiabetic therapy, can exhibit notable toxicity at higher doses due to certain secondary metabolites. Grayanane diterpenoids (grayanoids) from genera like Rhododendron are a prime example—these diterpenes are notorious neurotoxins that hyperactivate voltage-gated sodium channels, leading to continuous nerve and muscle excitation [229]. Even slight overexposure can trigger acute neurocardiac symptoms: human “mad honey” poisoning cases from rhododendron nectar report hypotension, bradyarrhythmia, confusion, convulsions, and even atrioventricular block. Such effects reflect a narrow therapeutic index; beneficial doses can rapidly turn harmful as the concentration rises. Indeed, an EFSA risk assessment in 2023 found measurable cardiac toxicity in rats at ~15 µg/kg of grayanotoxin and warned that only very low levels (<0.05 mg/kg in honey) are considered safe to avoid acute intoxication. This dose-dependent hazard underscores the need for careful control of graminoid-containing preparations [230].
Phenolic glycosides like arbutin (abundant in Arctostaphylos uva-ursi and other Ericaceae) also present safety considerations. Arbutin itself is relatively benign, but it can hydrolyze to release hydroquinone—a compound with known genotoxic, carcinogenic, and organ-toxic effects upon prolonged exposure. High or chronic intake of arbutin-rich extracts could, thus, pose risks of liver and kidney damage if sufficient hydroquinone accumulates over time. In vitro studies support this mechanism: bearberry (uva ursi) extracts showed little cytotoxicity in bladder cell cultures until arbutin was fully converted to free hydroquinone, at which point marked cell toxicity was observed. Conversely, in vivo evidence indicates that toxicity is minimal at proper doses (a recent 90-day study in mice found that Arbutus unedo leaf extract (rich in arbutin and phenolics) caused no adverse effects up to 5000 mg/kg, aside from its desired hypoglycemic action). Notably, the estimated hydroquinone release at standard human doses of bearberry is about 11 µg/kg/day, far below the 100 µg/kg threshold for negligible risk. These findings highlight that appropriate dosing can keep arbutin’s metabolite well within safe margins [231].
Tannins, another common constituent in Ericaceae remedies, exemplify how dose determines remedy versus toxin. At moderate levels, tannins contribute antioxidant and antidiabetic benefits (e.g., slowing glucose absorption), but excessive intake can irritate the gastrointestinal tract and reduce nutrient bioavailability. Users of tannin-rich leaf teas occasionally report nausea or vomiting, an effect attributed to tannins’ astringent action on the gut mucosa. Prolonged high consumption may lead to liver stress—for instance, the chronic dosing of tannic acid in animals has produced hepatic injury. Such observations align with historical reports that sustained exposure to high tannin levels causes organ damage, although typical dietary or medicinal use is far lower. Therefore, proper preparation (e.g., decoction techniques that limit tannin concentration) and adherence to recommended dosages are crucial to mitigate these adverse effects [232].
Overall, the safety profile of Ericaceae-derived compounds is favorable when traditional usage guidelines are followed, but toxicological vigilance is warranted. Many potentially harmful constituents are present in only trace amounts in consumed preparations, and traditional processing often aims to reduce toxin content. Modern studies reinforce the importance of these practices: for example, carefully prepared Rhododendron extracts can exclude dangerous grayanoids, and refining uva ursi formulations can minimize free hydroquinone release. Future research should prioritize comprehensive toxicity assessments and risk evaluations for Ericaceae phenolics. Key gaps include the lack of chronic toxicity data (noted by regulators for compounds like grayanotoxin) and incomplete understanding of toxicological mechanisms (such as the molecular basis of grayanotoxin-induced genotoxicity). Addressing these gaps through long-term in vivo studies and mechanistic assays will help define clear safety margins. In addition, developing standardized extraction and dosing protocols can ensure that antidiabetic efficacy is achieved without accompanying harm. Such proactive safety profiling and dose optimization will be essential as Ericaceae phenolics move from traditional use to evidence-based clinical applications.

7. Perspective

Ericaceae family plants—including berry-bearing shrubs like Vaccinium (blueberries, cranberries, lingonberries) and Gaultheria (salal, wintergreen), as well as medicinal species of Rhododendron and Arbutus (strawberry tree)—have attracted interest for their antidiabetic potential. These plants are rich in polyphenolic compounds, especially flavonoids and pigmented anthocyanins, which confer potent antioxidant activity and contribute to hypoglycemic effects. The high antioxidant capacity of Ericaceous berries and leaves can mitigate diabetes-associated oxidative stress, while their bioactive constituents directly modulate carbohydrate metabolism. For instance, anthocyanin-rich Vaccinium extracts and related polyphenols can inhibit carbohydrate-digesting enzymes like α-glucosidase, slowing glucose absorption. Concurrently, flavonoids such as quercetin (abundant in Vaccinium spp.) have been shown to activate AMP-activated protein kinase and enhance glucose uptake in peripheral tissues, thereby improving insulin sensitivity. Similarly, Arbutus unedo yields catechin and other flavanols that act as strong α-glucosidase inhibitors, and Rhododendron flower extracts have demonstrated antihyperglycemic activity in diabetic models by promoting insulin-mediated glucose utilization. Collectively, the polyphenol-rich Ericaceae plants exhibit multifaceted antidiabetic mechanisms—from antioxidant protection to enzyme inhibition and improved glucose handling—underscoring their promise as functional foods or phytotherapeutic adjuvants for diabetes prevention and management.

8. Methodology

The search for information was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, using Google Scholar, PubMed, and ScienceDirect. Articles published within the last 5 years were prioritized; however, older studies were included when more recent data were unavailable, provided they reflected the current state of research. The keywords used in the search included “Ericaceae”, in combination with “diabetes”, “diabetes mellitus”, “type 1 diabetes mellitus”, and “type 2 diabetes mellitus.” These terms were used primarily to gather general information on disease classification, complications, and pathophysiology. Additionally, “Vaccinium” (both generally and for each species individually) was combined with “diabetes”, and for each plant species discussed, both the Latin and common English names (e.g., “bilberry” and “crowberry”) were used to ensure comprehensive coverage. The inclusion/exclusion criteria emphasized studies addressing the core elements of diabetes mellitus, including its definition, classification, risk factors, complications, and pathophysiology, as well as those evaluating antidiabetic or hypoglycemic effects, specifically through α-amylase and α-glucosidase inhibition. After an initial search using Google Scholar, relevant data were verified and supplemented with full-text articles from PubMed and ScienceDirect, based on relevance to the review objectives.

9. Conclusions

The evidence gathered in this review highlights the significant antidiabetic potential of Ericaceae plants, primarily attributed to their rich content of phenolic compounds such as anthocyanins, flavonoids, and proanthocyanidins. These bioactive molecules exhibit multiple beneficial effects, including antioxidant, anti-inflammatory, and enzyme-inhibitory actions, contributing to improved glycemic control and insulin sensitivity. Both in vitro and in vivo studies confirm their capacity to modulate key metabolic pathways involved in diabetes pathophysiology. Given their efficacy, accessibility, and natural origin, the Ericaceae species represent a promising complementary strategy for diabetes prevention and management, warranting further clinical validation.

Author Contributions

Conceptualization, M.P., A.O., R.M.V. and I.E.; methodology, D.-M.T. and I.E.; software, K.R. and M.P.; validation, A.O., R.M.V. and K.R.; formal analysis, D.-M.T. and M.P.; investigation, K.R. and A.O.; resources, R.M.V.; data curation, D.-M.T. and M.P., writing—original draft preparation, A.O. and K.R.; writing—review and editing, R.M.V. and I.E.; visualization, M.P. and D.-M.T.; supervision, K.R. and R.M.V.; project administration, D.-M.T.; funding acquisition, R.M.V. and M.P. All authors have read and agreed to the published version of the manuscript.

Funding

The Article Processing Charges were funded by the University of Medicine and Pharmacy of Craiova, Romania.

Data Availability Statement

Data are contained within the article.

Acknowledgments

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Bennici, G.; Almahasheer, H.; Alghrably, M.; Valensin, D.; Kola, A.; Kokotidou, C.; Lachowicz, J.; Jaremko, M. Mitigating Diabetes Associated with Reactive Oxygen Species (ROS) and Protein Aggregation through Pharmacological Interventions. RSC Adv. 2024, 14, 17448–17460. [Google Scholar] [CrossRef] [PubMed]
  2. American Diabetes Association Professional Practice Committee. Standards of Care in Diabetes-2024. Diabetes Care 2024, 47 (Suppl. 1), S20–S42. [Google Scholar] [CrossRef] [PubMed]
  3. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in diabetes prevalence and treatment from 1990 to 2022: A pooled analysis of 1108 population-representative studies with 141 million participants. Lancet 2024, 404, 2077–2093. [Google Scholar] [CrossRef] [PubMed]
  4. Lu, X.; Xie, Q.; Pan, X.; Zhang, R.; Zhang, X.; Peng, G.; Zhang, Y.; Shen, S.; Tong, N. Type 2 diabetes mellitus in adults: Pathogenesis, prevention and therapy. Signal Transduct. Target. Ther. 2024, 9, 262. [Google Scholar]
  5. Strati, M.; Moustaki, M.; Psaltopoulou, T.; Vryonidou, A.; Paschou, S.A. Early onset type 2 diabetes mellitus: An update. Endocrine 2024, 85, 965–978. [Google Scholar] [CrossRef] [PubMed]
  6. Kaul, N.; Ali, S. Genes, Genetics, and Environment in Type 2 Diabetes: Implication in Personalized Medicine. DNA Cell Biol. 2016, 35, 1–12. [Google Scholar] [CrossRef] [PubMed]
  7. GBD 2021 Diabetes Collaborators. Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: A systematic analysis for the Global Burden of Disease Study 2021. Lancet 2023, 402, 203–234. [Google Scholar] [CrossRef]
  8. Alicic, R.Z.; Rooney, M.T.; Tuttle, K.R. Diabetic Kidney Disease: Challenges, Progress, and Possibilities. Clin. J. Am. Soc. Nephrol. 2017, 12, 2032–2045. [Google Scholar] [CrossRef]
  9. Bryl, A.; Mrugacz, M.; Falkowski, M.; Zorena, K. The Effect of Diet and Lifestyle on the Course of Diabetic Retinopathy—A Review of the Literature. Nutrients 2022, 14, 1252. [Google Scholar] [CrossRef]
  10. Jensen, T.S.; Karlsson, P.; Gylfadottir, S.S.; Andersen, S.T.; Bennett, D.L.; Tankisi, H.; Finnerup, N.B.; Terkelsen, A.J.; Khan, K.; Themistocleous, A.C.; et al. Painful and non-painful diabetic neuropathy, diagnostic challenges and implications for future management. Brain 2021, 144, 1632–1645. [Google Scholar] [CrossRef]
  11. Perumpail, B.J.; Khan, M.A.; Yoo, E.R.; Cholankeril, G.; Kim, D.; Ahmed, A. Clinical epidemiology and disease burden of nonalcoholic fatty liver disease. World J. Gastroenterol. 2017, 23, 8263–8276. [Google Scholar] [CrossRef] [PubMed]
  12. American Diabetes Association. 8. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2018. Diabetes Care 2018, 41 (Suppl. S1), S73–S85. [Google Scholar] [CrossRef] [PubMed]
  13. Gattringer, T.; Posekany, A.; Niederkorn, K.; Knoflach, M.; Poltrum, B.; Mutzenbach, S.; Haring, H.P.; Ferrari, J.; Lang, W.; Willeit, J.; et al. Predicting Early Mortality of Acute Ischemic Stroke. Stroke 2019, 50, 349–356. [Google Scholar] [CrossRef]
  14. Lee, M.; Saver, J.L.; Hong, K.S.; Song, S.; Chang, K.H.; Ovbiagele, B. Effect of pre-diabetes on future risk of stroke: Meta-analysis. BMJ 2012, 344, e3564. [Google Scholar] [CrossRef] [PubMed]
  15. Rahman, M.S.; Hossain, K.S.; Das, S.; Kundu, S.; Adegoke, E.O.; Rahman, M.A.; Hannan, M.A.; Uddin, M.J.; Pang, M.G. Role of Insulin in Health and Disease: An Update. Int. J. Mol. Sci. 2021, 22, 6403. [Google Scholar] [CrossRef]
  16. Sun, W.; Shahrajabian, M.H. Therapeutic Potential of Phenolic Compounds in Medicinal Plants—Natural Health Products for Human Health. Molecules 2023, 28, 1845. [Google Scholar] [CrossRef] [PubMed]
  17. Kang, B.B.; Chiang, B.H. A Novel Phenolic Formulation for Treating Hepatic and Peripheral Insulin Resistance by Regulating GLUT4-Mediated Glucose Uptake. J. Tradit. Complement. Med. 2022, 12, 195–205. [Google Scholar] [CrossRef]
  18. Weinberg Sibony, R.; Segev, O.; Dor, S.; Raz, I. Drug Therapies for Diabetes. Int. J. Mol. Sci. 2023, 24, 17147. [Google Scholar] [CrossRef] [PubMed]
  19. Sarkar, D.; Christopher, A.; Shetty, K. Phenolic Bioactives from Plant-Based Foods for Glycemic Control. Front. Endocrinol. 2022, 12, 727503. [Google Scholar] [CrossRef]
  20. Chhabria, S.; Mathur, S.; Vadakan, S.; Sahoo, D.K.; Mishra, P.; Paital, B. A Review on Phytochemical and Pharmacological Facets of Tropical Ethnomedicinal Plants as Reformed DPP-IV Inhibitors to Regulate Incretin Activity. Front. Endocrinol. 2022, 13, 1027237. [Google Scholar] [CrossRef] [PubMed]
  21. Thomas, J. Elpel’s WebWorld Pages, Wildflowers-and-Weeds.com, November 2021. Available online: https://www.wildflowers-and-weeds.com/ (accessed on 25 March 2025).
  22. Sater, H.M.; Bizzio, L.N.; Tieman, D.M.; Muñoz, P.D. A Review of the Fruit Volatiles Found in Blueberry and Other Vaccinium Species. J. Agric. Food Chem. 2020, 68, 5777–5786. [Google Scholar] [CrossRef] [PubMed]
  23. Sharma, A.; Lee, H.J. Anti-Inflammatory Activity of Bilberry (Vaccinium myrtillus L.). Curr. Issues Mol. Biol. 2022, 44, 4570–4583. [Google Scholar] [CrossRef] [PubMed]
  24. Hasanloo, T.; Jafarkhani Kermani, M.; Dalvand, Y.A.; Rezazadeh, S. A Complete Review on the Genus Vaccinium and Iranian Ghareghat. J. Med. Plants 2019, 18, 46–65. [Google Scholar] [CrossRef]
  25. Niu, C.S.; Li, Y.; Liu, Y.B.; Ma, S.G.; Liu, F.; Li, L.; Xu, S.; Wang, X.J.; Wang, R.B.; Qu, J.; et al. Pierisketolide A and Pierisketones B and C, Three Diterpenes with an Unusual Carbon Skeleton from the Roots of Pieris formosa. Org. Lett. 2017, 19, 906–909. [Google Scholar] [CrossRef]
  26. Niu, C.-S.; Li, Y.; Liu, Y.-B.; Ma, S.-G.; Li, L.; Qu, J.; Yu, S.-S. Analgesic diterpenoids from the twigs of Pieris formosa. Tetrahedron 2016, 72, 44–49. [Google Scholar] [CrossRef]
  27. Niu, C.-S.; Li, Y.; Liu, Y.-B.; Ma, S.-G.; Liu, F.; Li, L.; Xu, S.; Wang, X.-J.; Liu, S.; Wang, R.-B.; et al. Biological and chemical guided isolation of 3,4-secograyanane diterpenoids from the roots of Pieris formosa. RSC Adv. 2017, 7, 43921–43932. [Google Scholar] [CrossRef]
  28. Zhou, J.; Liu, T.; Zhang, H.; Zheng, G.; Qiu, Y.; Deng, M.; Zhang, C.; Yao, G. Anti-inflammatory Grayanane Diterpenoids from the Leaves of Rhododendron molle. J. Nat. Prod. 2018, 81, 151–161. [Google Scholar] [CrossRef] [PubMed]
  29. Niu, C.-S.; Li, Y.; Liu, Y.-B.; Ma, S.-G.; Liu, F.; Cui, L.; Yu, H.-B.; Wang, X.-J.; Qu, J.; Yu, S.-S. Grayanane diterpenoids with diverse bioactivities from the roots of Pieris formosa. Tetrahedron 2018, 74, 375–382. [Google Scholar] [CrossRef]
  30. Sun, N.; Zhu, Y.; Zhou, H.; Zhou, J.; Zhang, H.; Zhang, M.; Zeng, H.; Yao, G. Grayanane Diterpenoid Glucosides from the Leaves of Rhododendron micranthum and Their Bioactivities Evaluation. J. Nat. Prod. 2018, 81, 2673–2681. [Google Scholar] [CrossRef]
  31. Rabia, R.; Zaitoon, I.; Sajid, A.; Muhammad, N.; Muhammad, Y.K.; Jamshed, I. Identification of Highly Potent and Selective α-Glucosidase Inhibitors with Antiglycation Potential, Isolated from Rhododendron arboreum. Rec. Nat. Prod. 2015, 9, 262–266. [Google Scholar]
  32. Moyer, R.A.; Hummer, K.E.; Finn, C.E.; Frei, B.; Wrolstad, R.E. Anthocyanins, Phenolics, and Antioxidant Capacity in Diverse Small Fruits: Vaccinium, Rubus, and Ribes. J. Agric. Food Chem. 2002, 50, 519–525. [Google Scholar] [CrossRef] [PubMed]
  33. Edger, P.P.; Iorizzo, M.; Bassil, N.V.; Benevenuto, J.; Ferrão, L.F.V.; Giongo, L.; Hummer, K.; Lawas, L.M.F.; Leisner, C.P.; Li, C.; et al. There and Back Again: Historical Perspective and Future Directions for Vaccinium Breeding and Research Studies. Hortic. Res. 2022, 9, uhac083. [Google Scholar] [CrossRef] [PubMed]
  34. Helmstädter, A.; Schuster, N. Vaccinium myrtillus as an Antidiabetic Medicinal Plant—Research through the Ages. Pharmazie 2010, 65, 315–321. [Google Scholar]
  35. Bujor, O.C.; Tanase, C.; Popa, M.E. Phenolic Antioxidants in Aerial Parts of Wild Vaccinium Species: Towards Pharmaceutical and Biological Properties. Antioxidants 2019, 8, 649. [Google Scholar] [CrossRef] [PubMed]
  36. Katsarou, A.; Gudbjörnsdottir, S.; Rawshani, A.; Dabelea, D.; Bonifacio, E.; Anderson, B.J.; Jacobsen, L.M.; Schatz, D.A.; Lernmark, Å. Type 1 diabetes mellitus. Nat. Rev. Dis. Prim. 2017, 3, 1–17. [Google Scholar] [CrossRef]
  37. Fliegerová, K.O.; Mahayri, T.M.; Sechovcová, H.; Mekadim, C.; Mrázek, J.; Jarošíková, R.; Dubský, M.; Fejfarová, V. Diabetes and gut microbiome. Front. Microbiol. 2025, 15, 1451054. [Google Scholar] [CrossRef]
  38. Eiselein, L.; Schwartz, H.J.; Rutledge, J.C. The challenge of type 1 diabetes mellitus. ILAR J. 2004, 45, 231–236. [Google Scholar] [CrossRef]
  39. Bloem, S.J.; Roep, B.O. The elusive role of B lymphocytes and islet autoantibodies in (human) type 1 diabetes. Diabetologia 2017, 60, 1185–1189. [Google Scholar] [CrossRef]
  40. Campbell-Thompson, M.; Fu, A.; Kaddis, J.S.; Wasserfall, C.; Schatz, D.A.; Pugliese, A.; Atkinson, M.A. Insulitis and β-cell mass in the natural history of type 1 diabetes. Diabetes 2015, 65, 719–731. [Google Scholar] [CrossRef]
  41. Thingholm, L.B.; Rühlemann, M.C.; Koch, M.; Fuqua, B.; Laucke, G.; Boehm, R.; Bang, C.; Franzosa, E.A.; Hübenthal, M.; Rahnavard, G.; et al. Obese individuals with and without type 2 diabetes show different gut microbial functional capacity and composition. Cell Host Microbe 2019, 26, 252–264.e10. [Google Scholar] [CrossRef]
  42. Halban, P.A.; Polonsky, K.S.; Bowden, D.W.; Hawkins, M.A.; Ling, C.; Mather, K.J.; Powers, A.C.; Rhodes, C.J.; Sussel, L.; Weir, G.C. Beta-cell failure in type 2 diabetes: Postulated mechanisms and prospects for prevention and treatment. Diabetes Care 2014, 37, 1751–1758. [Google Scholar] [CrossRef] [PubMed]
  43. Christensen, A.A.; Gannon, M. The Beta Cell in Type 2 Diabetes. Curr. Diabetes Rep. 2019, 19, 81. [Google Scholar] [CrossRef] [PubMed]
  44. Yamamoto, W.R.; Bone, R.N.; Sohn, P.; Syed, F.; Reissaus, C.A.; Mosley, A.L.; Wijeratne, A.B.; True, J.D.; Tong, X.; Kono, T.; et al. Endoplasmic reticulum stress alters ryanodine receptor function in the murine pancreatic beta cell. J. Biol. Chem. 2019, 294, 168–181. [Google Scholar] [CrossRef]
  45. Galicia-Garcia, U.; Benito-Vicente, A.; Jebari, S.; Larrea-Sebal, A.; Siddiqi, H.; Uribe, K.B.; Ostolaza, H.; Martín, C. Pathophysiology of Type 2 Diabetes Mellitus. Int. J. Mol. Sci. 2020, 21, 6275. [Google Scholar] [CrossRef]
  46. Hussein, R.A.; El-Anssary, A.A. Plants secondary metabolites: The key drivers of the pharmacological actions of medicinal plants. In Herbal Medicine; Builders, P.F., Ed.; IntechOpen: London, UK, 2019; p. 76139. [Google Scholar]
  47. Wang, L.; Lan, W.; Chen, D. Blueberry (Vaccinium spp.) Anthocyanins and Their Functions, Stability, Bioavailability, and Applications. Foods 2024, 13, 2851. [Google Scholar] [CrossRef]
  48. Patanè, G.T.; Putaggio, S.; Tellone, E.; Barreca, D.; Ficarra, S.; Maffei, C.; Calderaro, A.; Laganà, G. Catechins and Proanthocyanidins Involvement in Metabolic Syndrome. Int. J. Mol. Sci. 2023, 24, 9228. [Google Scholar] [CrossRef] [PubMed]
  49. Boaru, D.L.; Fraile-Martinez, O.; De Leon-Oliva, D.; Garcia-Montero, C.; De Castro-Martinez, P.; Miranda-Gonzalez, A.; Saez, M.A.; Muñon-Zamarron, L.; Castillo-Ruiz, E.; Barrena-Blázquez, S.; et al. Harnessing the Anti-Inflammatory Properties of Polyphenols in the Treatment of Inflammatory Bowel Disease. Int. J. Biol. Sci. 2024, 20, 5608–5672. [Google Scholar] [CrossRef] [PubMed]
  50. Karunakaran, U.; Park, K.G. A Systematic Review of Oxidative Stress and Safety of Antioxidants in Diabetes: Focus on Islets and Their Defense. Diabetes Metab. J. 2013, 37, 106–112. [Google Scholar] [CrossRef]
  51. Amin, M.M.; Arbid, M.S. Estimation of ellagic acid and/or repaglinide effects on insulin signaling, oxidative stress, and inflammatory mediators of liver, pancreas, adipose tissue, and brain in insulin resistant/type 2 diabetic rats. Appl. Physiol. Nutr. Metab. 2017, 42, 181–192. [Google Scholar] [CrossRef]
  52. Ghorbani, A. Mechanisms of antidiabetic effects of flavonoid rutin. Biomed. Pharmacother. 2017, 96, 305–312. [Google Scholar] [CrossRef]
  53. Eid, H.M.; Nachar, A.; Thong, F.; Sweeney, G.; Haddad, P.S. The molecular basis of the antidiabetic action of quercetin in cultured skeletal muscle cells and hepatocytes. Pharmacogn. Mag. 2015, 11, 74–81. [Google Scholar] [PubMed]
  54. Stefanescu, R.; Laczkó-Zöld, E.; O˝sz, B.E.; Vari, C.E. An Updated Systematic Review of Vaccinium myrtillus Leaves: Phytochemistry and Pharmacology. Pharmaceutics 2022, 15, 16. [Google Scholar] [CrossRef] [PubMed]
  55. Martau, G.A.; Bernadette-Emoke, T.; Odocheanu, R.; Soporan, D.A.; Bochis, M.; Simon, E.; Vodnar, D.C. Vaccinium Species (Ericaceae): Phytochemistry and Biological Properties of Medicinal Plants. Molecules 2023, 28, 1533. [Google Scholar] [CrossRef]
  56. Huang, H.; Luo, Y.; Wang, Q.; Zhang, Y.; Li, Z.; He, R.; Chen, X.; Dong, Z. Vaccinium as Potential Therapy for Diabetes and Microvascular Complications. Nutrients 2023, 15, 2031. [Google Scholar] [CrossRef]
  57. Shamilova, A.A.; Bubenchikova, V.N.; Chernikov, M.V.; Pozdnyakov, D.I.; Garsiya, E.R.; Larsky, M.V. Bearberry (Arctostaphylos uva-ursi (L.) Spreng.): Chemical Content and Pharmacological Activity. J. Excip. Food Chem. 2021, 12, 3. [Google Scholar]
  58. Ockun, M.A.; Baranauskaite, J.; Uner, B.; Kan, Y.; Kırmızıbekmez, H. Preparation, characterization and evaluation of liposomal-freeze dried anthocyanin-enriched Vaccinium arctostaphylos L. fruit extract incorporated into fast dissolving oral films. J. Drug Deliv. Sci. Technol. 2022, 72, 103428. [Google Scholar] [CrossRef]
  59. Alam, F.; Saqib, Q.N.; Ashraf, M. Gaultheria trichophylla (Royle): A Source of Minerals and Biologically Active Molecules, Its Antioxidant and Anti-Lipoxygenase Activities. BMC Complement. Altern. Med. 2017, 17, 3. [Google Scholar] [CrossRef]
  60. Sharma, M.; Gargi, A.; Borah, A. Rhododendron arboreum and Its Potential Health Benefit: A Review. Pharma Innov. J. 2022, SP-11, 926–933. [Google Scholar]
  61. Eid, H.M.; Ouchfoun, M.; Saleem, A.; Guerrero-Analco, J.A.; Walshe-Roussel, B.; Musallam, L.; Rapinski, M.; Cuerrier, A.; Martineau, L.C.; Arnason, J.T.; et al. A Combination of (+)-Catechin and (−)-Epicatechin Underlies the In vitro Adipogenic Action of Labrador Tea (Rhododendron groenlandicum), an Antidiabetic Medicinal Plant of the Eastern James Bay Cree Pharmacopeia. J. Ethnopharmacol. 2016, 178, 251–257. [Google Scholar] [CrossRef]
  62. Bebek Markovinović, A.; Brčić Karačonji, I.; Jurica, K.; Lasić, D.; Skendrović Babojelić, M.; Duralija, B.; Šic Žlabur, J.; Putnik, P.; Bursać Kovačević, D. Strawberry Tree Fruits and Leaves (Arbutus unedo L.) as Raw Material for Sustainable Functional Food Processing: A Review. Horticulturae 2022, 8, 881. [Google Scholar] [CrossRef]
  63. Jurikova, T.; Mlcek, J.; Skrovankova, S.; Balla, S.; Sochor, J.; Baron, M.; Sumczynski, D. Black Crowberry (Empetrum nigrum L.) Flavonoids and Their Health Promoting Activity. Molecules 2016, 21, 1685. [Google Scholar] [CrossRef] [PubMed]
  64. National Center for Biotechnology Information. PubChem Compound Summary for CID 5280343, Quercetin. 2025. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/Quercetin (accessed on 25 March 2025).
  65. National Center for Biotechnology Information. PubChem Compound Summary for CID 5280863, Kaempferol. 2025. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/Kaempferol (accessed on 25 March 2025).
  66. National Center for Biotechnology Information. PubChem Compound Summary for CID 5281672, Myricetin. 2025. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/Myricetin (accessed on 25 March 2025).
  67. National Center for Biotechnology Information. PubChem Compound Summary for CID 128861, Cyanidin. 2025. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/Cyanidin (accessed on 25 March 2025).
  68. National Center for Biotechnology Information. PubChem Compound Summary for CID 68245, Delphinidin. 2025. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/Delphinidin (accessed on 25 March 2025).
  69. National Center for Biotechnology Information. PubChem Compound Summary for CID 159287, CID 159287. 2025. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/Malvidin (accessed on 25 March 2025).
  70. National Center for Biotechnology Information. PubChem Compound Summary for CID 73386, Petunidin. 2025. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/Petunidin (accessed on 25 March 2025).
  71. National Center for Biotechnology Information. PubChem Compound Summary for CID 67249, Pelargonidin Chloride. 2025. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/Pelargonidin-Chloride (accessed on 25 March 2025).
  72. Celik, F.; Bozhuyuk, M.R.; Ercisli, S.; Gundogdu, M. Physicochemical and Bioactive Characteristics of Wild Grown Bilberry (Vaccinium myrtillus L.) Genotypes from Northeastern Turkey. Not. Bot. Horti Agrobot. 2018, 46, 128–133. [Google Scholar] [CrossRef]
  73. Jurikova, T.; Skrovankova, S.; Mlcek, J.; Balla, S.; Snopek, L. Bioactive Compounds, Antioxidant Activity, and Biological Effects of European Cranberry (Vaccinium oxycoccos). Molecules 2019, 24, 24. [Google Scholar] [CrossRef]
  74. Urbonaviciene, D.; Bobinaite, R.; Viskelis, P.; Viskelis, J.; Petruskevicius, A.; Puzeryte, V.; Cesoniene, L.; Daubaras, R.; Klavins, L.; Bobinas, C. Nutritional and Physicochemical Properties of Wild Lingonberry (Vaccinium vitis-idaea L.)—Effects of Geographic Origin. Molecules 2023, 28, 4589. [Google Scholar] [CrossRef] [PubMed]
  75. Sugier, P.; Sęczyk, Ł.; Sugier, D.; Krawczyk, R.; Wójcik, M.; Czarnecka, J.; Okoń, S.; Plak, A. Chemical Characteristics and Antioxidant Activity of Arctostaphylos uva-ursi L. Spreng. at the Southern Border of the Geographical Range of the Species in Europe. Molecules 2021, 26, 7692. [Google Scholar] [CrossRef]
  76. Özgen, M.; Çelik, H.; Saraçoğlu, O. Less known Vaccinium: Antioxidant and chemical properties of selected Caucasian whortleberry (Vaccinium arctostaphylos L.) fruits native to Black Sea region of Turkey. Acta Sci. Pol. Hortorum Cultus 2014, 13, 59–68. [Google Scholar]
  77. Bahukhandi, A.; Pandey, A.; Sekar, K.C.; Bhatt, I.D. Polyphenolics, nutrients and antioxidant activity of Gaultheria trichophylla Royle: A high value wild edible plant of Trans Himalaya. Horticult. Int. J. 2017, 1, 39–43. [Google Scholar]
  78. Barola, A.; Tewari, A.; Kabdwal, N.C. Effect of pre-treatments and drying methods on nutritional quality of Rhododendron arboreum, West Himalaya. J. Adv. Sci. Res. 2022, 13, 121–128. [Google Scholar] [CrossRef]
  79. Dampc, A.; Luczkiewicz, M. Labrador tea—The aromatic beverage and spice: A review of origin, processing and safety. J. Sci. Food Agric. 2015, 95, 1577–1583. [Google Scholar] [CrossRef]
  80. Brčić Karačonji, I.; Jurica, K.; Gašić, U.; Dramićanin, A.; Tešić, Ž.; Milojković Opsenica, D. Comparative Study on the Phenolic Fingerprint and Antioxidant Activity of Strawberry Tree (Arbutus unedo L.) Leaves and Fruits. Plants 2021, 11, 25. [Google Scholar] [CrossRef]
  81. Urbonaviciene, D.; Bobinaite, R.; Viskelis, P.; Bobinas, C.; Petruskevicius, A.; Klavins, L.; Viskelis, J. Geographic Variability of Biologically Active Compounds, Antioxidant Activity and Physico-Chemical Properties in Wild Bilberries (Vaccinium myrtillus L.). Antioxidants 2022, 11, 588. [Google Scholar] [CrossRef] [PubMed]
  82. Karcheva-Bahchevanska, D.; Nikolova, M.; Iliev, I. Inhibitory Potential of Different Bilberry (Vaccinium myrtillus L.) Extracts on Human Salivary α-Amylase. Molecules 2023, 28, 5820. [Google Scholar] [CrossRef]
  83. Nemzer, B.V.; Al-Taher, F.; Yashin, A.; Revelsky, I.; Yashin, Y. Cranberry: Chemical Composition, Antioxidant Activity and Impact on Human Health: Overview. Molecules 2022, 27, 1503. [Google Scholar] [CrossRef] [PubMed]
  84. Mannino, G.; Di Stefano, V.; Lauria, A.; Pitonzo, R.; Gentile, C. Vaccinium macrocarpon (Cranberry)-Based Dietary Supplements: Variation in Mass Uniformity, Proanthocyanidin Dosage and Anthocyanin Profile Demonstrates Quality Control Standard Needed. Nutrients 2020, 12, 992. [Google Scholar] [CrossRef]
  85. Bernal-Gallardo, J.O.; Mena-Violante, H.G.; Luna-Suárez, S. Study of the Phenolic Compounds and Biological Activities of the Wild Fruits of Vaccinium leucanthum Schltdl. Horticulturae 2024, 10, 1091. [Google Scholar] [CrossRef]
  86. Wang, S.; Penhallegon, R. Antioxidant Activity in Lingonberries (Vaccinium vitis-idaea L.). HortScience 2005, 40, 1090C. [Google Scholar] [CrossRef]
  87. Sugier, P.; Sęczyk, Ł.; Sugier, D. Variation in Population and Solvents as Factors Determining the Chemical Composition and Antioxidant Potential of Arctostaphylos uva-ursi (L.) Spreng. Leaf Extracts. Molecules 2022, 27, 2247. [Google Scholar] [CrossRef]
  88. Barut, B.; Barut, E.N.; Engin, S.; Özel, A.; Sezen, F.S. Investigation of the antioxidant, α-glucosidase inhibitory, anti-inflammatory, and DNA protective properties of Vaccinium arctostaphylos L. Turk. J. Pharm. Sci. 2019, 16, 175–183. [Google Scholar] [CrossRef]
  89. Grace, M.H.; Esposito, D.; Dunlap, K.L.; Lila, M.A. Comparative Analysis of Phenolic Content and Profile, Antioxidant Capacity, and Anti-inflammatory Bioactivity in Wild Alaskan and Commercial Vaccinium Berries. J. Agric. Food Chem. 2014, 62, 4007–4017. [Google Scholar] [CrossRef]
  90. Dufour, D.; Pichette, A.; Mshvildadze, V.; Bradette-Hébert, M.E.; Lavoie, S.; Longtin, A.; Laprise, C.; Legault, J. Antioxidant, anti-inflammatory and anticancer activities of methanolic extracts from Ledum groenlandicum Retzius. J. Ethnopharmacol. 2007, 111, 22–28. [Google Scholar] [CrossRef]
  91. Ogawa, K.; Sakakibara, H.; Iwata, R.; Ishii, T.; Sato, T.; Goda, T.; Shimoi, K.; Kumazawa, S. Anthocyanin Composition and Antioxidant Activity of the Crowberry (Empetrum nigrum) and Other Berries. J. Agric. Food Chem. 2008, 56, 4457–4462. [Google Scholar] [CrossRef] [PubMed]
  92. Moein, S.; Moein, M.; Javid, H. Inhibition of α-Amylase and α-Glucosidase of Anthocyanin Isolated from Berberis integerrima Bunge Fruits: A Model of Antidiabetic Compounds. Evid. Based Complement. Alternat. Med. 2022, 2022, 6529590. [Google Scholar] [CrossRef] [PubMed]
  93. Niisato, N.; Marunaka, Y. Therapeutic Potential of Multifunctional Myricetin for Treatment of Type 2 Diabetes Mellitus. Front. Nutr. 2023, 10, 1175660. [Google Scholar] [CrossRef] [PubMed]
  94. Yousefi, F.; Mahjoub, S.; Pouramir, M.; Khadir, F. Hypoglycemic Activity of Pyrus biossieriana Buhse Leaf Extract and Arbutin: Inhibitory Effects on Alpha-Amylase and Alpha-Glucosidase. Casp. J. Intern. Med. 2013, 4, 763–767. [Google Scholar]
  95. Fan, J.; Johnson, M.H.; Lila, M.A.; Yousef, G.; de Mejia, E.G. Berry and Citrus Phenolic Compounds Inhibit Dipeptidyl Peptidase IV: Implications in Diabetes Management. Evid. Based Complement. Alternat. Med. 2013, 2013, 479505. [Google Scholar] [CrossRef] [PubMed]
  96. Wang, Y.; Alkhalidy, H.; Liu, D. The Emerging Role of Polyphenols in the Management of Type 2 Diabetes. Molecules 2021, 26, 703. [Google Scholar] [CrossRef]
  97. Varma, S.D.; Mikuni, I.; Kinoshita, J.H. Flavonoids as Inhibitors of Lens Aldose Reductase. Science 1975, 188, 1215–1216. [Google Scholar] [CrossRef]
  98. Al Mamun, M.A.; Rakib, A.; Mandal, M.; Kumar, S.; Singla, B.; Singh, U.P. Polyphenols: Role in Modulating Immune Function and Obesity. Biomolecules 2024, 14, 221. [Google Scholar] [CrossRef]
  99. Kopystecka, A.; Kozioł, I.; Radomska, D.; Bielawski, K.; Bielawska, A.; Wujec, M. Vaccinium uliginosum and Vaccinium myrtillus—Two Species, One Used as a Functional Food. Nutrients 2023, 15, 4119. [Google Scholar] [CrossRef]
  100. Ansari, P.; Khan, J.T.; Chowdhury, S.; Reberio, A.D.; Kumar, S.; Seidel, V.; Abdel-Wahab, Y.H.A.; Flatt, P.R. Plant-Based Diets and Phytochemicals in the Management of Diabetes Mellitus and Prevention of Its Complications: A Review. Nutrients 2024, 16, 3709. [Google Scholar] [CrossRef]
  101. Tzeng, T.F.; Liou, S.S.; Liu, I.M. Myricetin Ameliorates Defective Post-Receptor Insulin Signaling via β-Endorphin Signaling in the Skeletal Muscles of Fructose-Fed Rats. Evid. Based Complement. Alternat. Med. 2011, 2011, 150752. [Google Scholar] [CrossRef]
  102. Li, M.; Ding, L.; Cao, L.; Zhang, Z.; Li, X.; Li, Z.; Xia, Q.; Yin, K.; Song, S.; Wang, Z.; et al. Natural Products Targeting AMPK Signaling Pathway Therapy, Diabetes Mellitus and Its Complications. Front. Pharmacol. 2025, 16, 1534634. [Google Scholar]
  103. Feng, S.Y.; Wu, S.J.; Chang, Y.C.; Ng, L.T.; Chang, S.J. Stimulation of GLUT4 Glucose Uptake by Anthocyanin-Rich Extract from Black Rice (Oryza sativa L.) via PI3K/Akt and AMPK/p38 MAPK Signaling in C2C12 Cells. Metabolites 2022, 12, 856. [Google Scholar] [CrossRef] [PubMed]
  104. Hu, R.; Yan, H.; Fei, X.; Liu, H.; Wu, J. Modulation of Glucose Metabolism by a Natural Compound from Chloranthus japonicus via Activation of AMP-Activated Protein Kinase. Sci. Rep. 2017, 7, 778. [Google Scholar] [CrossRef] [PubMed]
  105. Tundis, R.; Tenuta, M.C.; Loizzo, M.R.; Bonesi, M.; Finetti, F.; Trabalzini, L.; Deguin, B. Vaccinium species (Ericaceae): From chemical composition to bio-functional activities. Appl. Sci. 2021, 11, 5655. [Google Scholar] [CrossRef]
  106. Wronska-Pilarek, D.; Szkudlarz, P.; Bocianowski, J. Systematic importance of morphological features of pollen grains of species from Erica (Ericaceae) genus. PLoS ONE 2018, 13, e0204557. [Google Scholar] [CrossRef] [PubMed]
  107. Gailīte, A.; Gaile, A.; Rungis, D.E. Genetic diversity and structure of wild Vaccinium populations—V. myrtillus, V. vitis-idaea and V. uliginosum in the Baltic states. Silva Fenn. 2020, 54, 10396. [Google Scholar] [CrossRef]
  108. Kulkarni, K.P.; Vorsa, N.; Natarajan, P.; Elavarthi, S.; Iorizzo, M.; Reddy, U.K.; Melmaiee, K. Admixture analysis using genotyping-by-sequencing reveals genetic relatedness and parental lineage distribution in highbush blueberry genotypes and cross derivatives. Int. J. Mol. Sci. 2021, 22, 163. [Google Scholar] [CrossRef]
  109. Mitrea, L.; Nemes, S.-A.; Szabo, K.; Teleky, B.-E.; Vodnar, D.-C. Guts Imbalance Imbalances the Brain: A Review of Gut Microbiota Association With Neurological and Psychiatric Disorders. Front. Med. 2022, 9, 813204. [Google Scholar] [CrossRef]
  110. Aaby, K.; Grimmer, S.; Holtung, L. Extraction of phenolic compounds from bilberry (Vaccinium myrtillus L.) press residue: Effects on phenolic composition and cell proliferation. LWT 2013, 54, 257–264. [Google Scholar] [CrossRef]
  111. Basu, A.; Feng, D.; Planinic, P.; Ebersole, J.L.; Lyons, T.J.; Alexander, J.M. Dietary Blueberry and Soluble Fiber Supplementation Reduces Risk of Gestational Diabetes in Women with Obesity in a Randomized Controlled Trial. J. Nutr. 2021, 151, 1128–1138. [Google Scholar] [CrossRef] [PubMed]
  112. Stote, K.; Corkum, A.; Sweeney, M.; Shakerley, N.; Kean, T.; Gottschall-Pass, K. Postprandial Effects of Blueberry (Vaccinium angustifolium) Consumption on Glucose Metabolism, Gastrointestinal Hormone Response, and Perceived Appetite in Healthy Adults: A Randomized, Placebo-Controlled Crossover Trial. Nutrients 2019, 11, 202. [Google Scholar] [CrossRef]
  113. Stote, K.S.; Wilson, M.M.; Hallenbeck, D.; Thomas, K.; Rourke, J.M.; Sweeney, M.I.; Gottschall-Pass, K.T.; Gosmanov, A.R. Effect of Blueberry Consumption on Cardiometabolic Health Parameters in Men with Type 2 Diabetes: An 8-Week, Double-Blind, Randomized, Placebo-Controlled Trial. Curr. Dev. Nutr. 2020, 4, nzaa030. [Google Scholar] [CrossRef] [PubMed]
  114. Mirfeizi, M.; Mehdizadeh Tourzani, Z.; Mirfeizi, S.Z.; Asghari Jafarabadi, M.; Rezvani, H.R.; Afzali, M. Controlling type 2 diabetes mellitus with herbal medicines: A triple-blind randomized clinical trial of efficacy and safety. J. Diabetes 2016, 8, 647–656. [Google Scholar] [CrossRef]
  115. de Mello, V.D.; Lankinen, M.A.; Lindström, J.; Puupponen-Pimiä, R.; Laaksonen, D.E.; Pihlajamäki, J.; Lehtonen, M.; Uusitupa, M.; Tuomilehto, J.; Kolehmainen, M.; et al. Fasting serum hippuric acid is elevated after bilberry (Vaccinium myrtillus) consumption and associates with improvement of fasting glucose levels and insulin secretion in persons at high risk of developing type 2 diabetes. Mol. Nutr. Food Res. 2017, 61, 1700019. [Google Scholar] [CrossRef]
  116. Chan, S.W.; Chu, T.T.W.; Choi, S.W.; Benzie, I.F.F.; Tomlinson, B. Impact of short-term bilberry supplementation on glycemic control, cardiovascular disease risk factors, and antioxidant status in Chinese patients with type 2 diabetes. Phytother. Res. 2021, 35, 3236–3245. [Google Scholar] [CrossRef] [PubMed]
  117. Yang, L.; Ling, W.; Yang, Y.; Chen, Y.; Tian, Z.; Du, Z.; Chen, J.; Xie, Y.; Liu, Z.; Yang, L. Role of Purified Anthocyanins in Improving Cardiometabolic Risk Factors in Chinese Men and Women with Prediabetes or Early Untreated Diabetes—A Randomized Controlled Trial. Nutrients 2017, 9, 1104. [Google Scholar] [CrossRef]
  118. Li, D.; Zhang, Y.; Liu, Y.; Sun, R.; Xia, M. Purified anthocyanin supplementation reduces dyslipidemia, enhances antioxidant capacity, and prevents insulin resistance in diabetic patients. J. Nutr. 2015, 145, 742–748. [Google Scholar] [CrossRef]
  119. Schell, J.; Betts, N.M.; Foster, M.; Scofield, R.H.; Basu, A. Cranberries improve postprandial glucose excursions in type 2 diabetes. Food Funct. 2017, 8, 3083–3090. [Google Scholar] [CrossRef] [PubMed]
  120. Novotny, J.A.; Baer, D.J.; Khoo, C.; Gebauer, S.K.; Charron, C.S. Cranberry juice consumption lowers markers of cardiometabolic risk, including blood pressure and circulating C-reactive protein, triglyceride, and glucose concentrations in adults. J. Nutr. 2015, 145, 1185–1193. [Google Scholar] [CrossRef] [PubMed]
  121. Antonella, S.; Barreca, D.; Giuseppina, L.; Ersilia, B.; Domenico, T. Bilberry (Vaccinium myrtyllus L.); Elsevier Inc.: Amsterdam, The Netherlands, 2018; ISBN 9780128124918. [Google Scholar]
  122. Carvalho, M.; Matos, M.; Carnide, V. Identification of cultivated and wild Vaccinium species grown in Portugal. Span. J. Agric. Res. 2018, 16, e07SC01-01. [Google Scholar] [CrossRef]
  123. Vaneková, Z.; Rollinger, J.M. Bilberries: Curative and Miraculous—A Review on Bioactive Constituents and Clinical Research. Front. Pharmacol. 2022, 13, 2343. [Google Scholar] [CrossRef] [PubMed]
  124. Stanoeva, J.P.; Stefova, M.; Andonovska, K.B.; Vankova, A.; Stafilov, T. Phenolics and mineral content in bilberry and bog bilberry from Macedonia. Int. J. Food Prop. 2017, 20, S863–S883. [Google Scholar] [CrossRef]
  125. Klavins, L.; Maaga, I.; Bertins, M.; Hykkerud, A.L.; Karppinen, K.; Bobinas, C.; Salo, H.M.; Nguyen, N.; Salminen, H.; Stankevica, K.; et al. Trace element concentration and stable isotope ratio analysis in blueberries and bilberries: A tool for quality and authenticity control. Foods 2021, 10, 567. [Google Scholar] [CrossRef] [PubMed]
  126. Asgary, S.; Rafieian-Kopaei, M.; Sahebkar, A.; Shamsi, F.; Goli-Malekabadi, N. Anti-Hyperglycemic and Anti-Hyperlipidemic Effects of Vaccinium myrtillus Fruit in Experimentally Induced Diabetes (Antidiabetic Effect of Vaccinium myrtillus Fruit). J. Sci. Food Agric. 2016, 96, 764–768. [Google Scholar] [CrossRef]
  127. Wojdyło, A.; Nowicka, P.; Laskowski, P.; Oszmiański, J. Evaluation of Sour Cherry (Prunus cerasus L.) Fruits for Their Polyphenol Content, Antioxidant Properties, and Nutritional Components. J. Agric. Food Chem. 2014, 62, 12332–12345. [Google Scholar] [CrossRef] [PubMed]
  128. Bljajic, K.; Petlevski, R.; Vujic, L.; Cacic, A.; Šoštarić, N.; Jablan, J.; Saraiva De Carvalho, I.; Zovko Končić, M. Chemical Composition, Antioxidant and α-Glucosidase-Inhibiting Activities of the Aqueous and Hydroethanolic Extracts of Vaccinium myrtillus Leaves. Molecules 2017, 22, 703. [Google Scholar] [CrossRef]
  129. Stefanescu (Braic), R.; Vari, C.; Imre, S.; Huţanu, A.; Fogarasi, E.; Todea, T.; Groşan, A.; Eşianu, S.; Laczkó-Zöld, E.; Dogaru, M. Vaccinium Extracts as Modulators in Experimental Type 1 Diabetes. J. Med. Food 2018, 21, 1106–1112. [Google Scholar] [CrossRef]
  130. Varut, R.M.; Gîrd, C.E.; Rotaru, L.T.; Varut, M.C.; Pisoschi, C.G. Evaluation of Polyphenol and Flavonoid Profiles and the Antioxidant Effect of Carduus Acanthoides Hydroalcoholic Extract Compared with Vaccinium myrtillus in an Animal Model of Diabetes Mellitus. Pharm. Chem. J. 2018, 51, 1088–1095. [Google Scholar] [CrossRef]
  131. do Rosario, V.A.; Chang, C.; Spencer, J.; Alahakone, T.; Roodenrys, S.; Francois, M.; Weston-Green, K.; Hölzel, N.; Nichols, D.S.; Kent, K.; et al. Anthocyanins Attenuate Vascular and Inflammatory Responses to a High Fat High Energy Meal Challenge in Overweight Older Adults: A Cross-Over, Randomized, Double-Blind Clinical Trial. Clin. Nutr. 2021, 40, 879–889. [Google Scholar] [CrossRef]
  132. Grohmann, T.; Walker, A.W.; Russell, W.R.; Hoggard, N.; Zhang, X.; Horgan, G.; de Roos, B. A grape seed and bilberry extract reduces blood pressure in individuals at risk of developing type 2 diabetes: The PRECISE study, a double-blind placebo-controlled cross-over intervention study. Front. Nutr. 2023, 10, 1139880. [Google Scholar] [CrossRef] [PubMed]
  133. Grussu, D.; Stewart, D.; McDougall, G.J. Berry Polyphenols Inhibit α-Amylase in Vitro: Identifying Active Components in Rowanberry and Raspberry. J. Agric. Food Chem. 2011, 59, 2324–2331. [Google Scholar] [CrossRef]
  134. Chen, K.; Wei, X.; Zhang, J.; Kortesniemi, M.; Zhang, Y.; Yang, B. Effect of Acylated and Nonacylated Anthocyanins on Urine Metabolic Profile during the Development of Type 2 Diabetes in Zucker Diabetic Fatty Rats. J. Agric. Food Chem. 2022, 70, 15143–15156. [Google Scholar] [CrossRef] [PubMed]
  135. Avramia, I.; Amariei, S. Formulation of Fast Dissolving β-Glucan/Bilberry Juice Films for Packaging Dry Powdered Pharmaceuticals for Diabetes. Plants 2022, 11, 2040. [Google Scholar] [CrossRef]
  136. Diaz-Garcia, L.; Schlautman, B.; Covarrubias-Pazaran, G.; Maule, A.; Johnson-Cicalese, J.; Grygleski, E.; Vorsa, N.; Zalapa, J. Massive phenotyping of multiple cranberry populations reveals novel QTLs for fruit anthocyanin content and other important chemical traits. Mol. Genet. Genom. 2018, 293, 1379–1392. [Google Scholar] [CrossRef]
  137. Bolivar-Medina, J.L.; Villouta, C.; Workmaster, B.A.; Atucha, A. Floral meristem development in cranberry apical buds during winter rest and its implication on yield prediction. J. Am. Soc. Hortic. Sci. 2019, 144, 314–320. [Google Scholar] [CrossRef]
  138. Feghali, K.; Feldman, M.; La, V.D.; Santos, J.; Grenier, D. Cranberry proanthocyanidins: Natural weapons against periodontal diseases. J. Agric. Food Chem. 2012, 60, 5728–5735. [Google Scholar] [CrossRef] [PubMed]
  139. Rodriguez-Bonilla, L.; Williams, K.A.; Rodríguez Bonilla, F.; Matusinec, D.; Maule, A.; Coe, K.; Wiesman, E.; Diaz-Garcia, L.; Zalapa, J. The genetic diversity of cranberry crop wild relatives, Vaccinium macrocarpon Aiton and V. oxycoccos L., in the US, with special emphasis on national forests. Plants 2020, 9, 1446. [Google Scholar] [CrossRef] [PubMed]
  140. Cesoniene, L.; Daubaras, R. Phytochemical Composition of the Large Cranberry (Vaccinium macrocarpon) and the Small Cranberry (Vaccinium oxycoccos); Elsevier Inc.: Amsterdam, The Netherlands, 2015; ISBN 9780124081178. [Google Scholar]
  141. Cermak, R.; Landgraf, S.; Wolffram, S. Quercetin Glucosides Inhibit Glucose Uptake into Brush-Border-Membrane Vesicles of Porcine Jejunum. Br. J. Nutr. 2004, 91, 849–855. [Google Scholar] [CrossRef] [PubMed]
  142. Strobel, P.; Allard, C.; Perez-Acle, T.; Calderon, R.; Aldunate, R.; Leighton, F. Myricetin, Quercetin and Catechin-Gallate Inhibit Glucose Uptake in Isolated Rat Adipocytes. Biochem. J. 2005, 386, 471–478. [Google Scholar] [CrossRef]
  143. Rocha, D.M.U.P.; Caldas, A.P.S.; Da Silva, B.P.; Hermsdorff, H.H.M.; Alfenas, R.D.C.G. Effects of Blueberry and Cranberry Consumption on Type 2 Diabetes Glycemic Control: A Systematic Review. Crit. Rev. Food Sci. Nutr. 2019, 59, 1816–1828. [Google Scholar] [CrossRef] [PubMed]
  144. Son, D.H.; Lee, H.S.; Lee, Y.J.; Lee, J.H.; Han, J.H. Comparison of triglyceride-glucose index and HOMA-IR for predicting prevalence and incidence of metabolic syndrome. Nutr. Metab. Cardiovasc. Dis. 2022, 32, 596–604. [Google Scholar] [CrossRef] [PubMed]
  145. Shirazi, K.M.; Shirinpour, E.; Shirazi, A.M.; Nikniaz, Z. Effect of cranberry supplementation on liver enzymes and cardiometabolic risk factors in patients with NAFLD: A randomized clinical trial. BMC Complement. Med. Ther. 2021, 21, 283. [Google Scholar]
  146. Hormoznejad, R.; Mansoori, A.; Hosseini, S.A.; Zilaee, M.; Asadi, M.; Fathi, M.; Kiany, F. Effects of cranberry consumption on features of the metabolic syndrome: A systematic review and meta-analysis of randomized control trials. Nutr. Food Sci. 2020, 51, 1006–1016. [Google Scholar] [CrossRef]
  147. Faheem, S.A.; Saeed, N.M.; El-Naga, R.N.; Ayoub, I.M.; Azab, S.S. Hepatoprotective Effect of Cranberry Nutraceutical Extract in Non-alcoholic Fatty Liver Model in Rats: Impact on Insulin Resistance and Nrf-2 Expression. Front. Pharmacol. 2020, 11, 218. [Google Scholar] [CrossRef]
  148. Anhê, F.F.; Roy, D.; Pilon, G.; Dudonné, S.; Matamoros, S.; Varin, T.V.; Garofalo, C.; Moine, Q.; Desjardins, Y.; Levy, E.; et al. A polyphenol-rich cranberry extract protects from diet-induced obesity, insulin resistance and intestinal inflammation in association with increased Akkermansia spp. population in the gut microbiota of mice. Gut 2015, 64, 872–883. [Google Scholar] [CrossRef] [PubMed]
  149. Khanal, R.C.; Rogers, T.J.; Wilkes, S.E.; Howard, L.R.; Prior, R.L. Effects of dietary consumption of cranberry powder on metabolic parameters in growing rats fed high fructose diets. Food Funct. 2010, 1, 116–123. [Google Scholar] [CrossRef]
  150. Paquette, M.; Medina Larqué, A.S.; Weisnagel, S.J.; Desjardins, Y.; Marois, J.; Pilon, G.; Dudonné, S.; Marette, A.; Jacques, H. Strawberry and Cranberry Polyphenols Improve Insulin Sensitivity in Insulin-Resistant, Non-Diabetic Adults: A Parallel, Double-Blind, Controlled and Randomised Clinical Trial. Br. J. Nutr. 2017, 117, 519–531. [Google Scholar] [CrossRef] [PubMed]
  151. Flanagan, E.; Cameron, D.; Sobhan, R.; Wong, C.; Pontifex, M.G.; Tosi, N.; Mena, P.; Del Rio, D.; Sami, S.; Narbad, A.; et al. Chronic Consumption of Cranberries (Vaccinium macrocarpon) for 12 Weeks Improves Episodic Memory and Regional Brain Perfusion in Healthy Older Adults: A Randomised, Placebo-Controlled, Parallel-Groups Feasibility Study. Front. Nutr. 2022, 9, 849902. [Google Scholar] [CrossRef]
  152. Koshovyi, O.; Vlasova, I.; Laur, H.; Kravchenko, G.; Krasilnikova, O.; Granica, S.; Piwowarski, J.P.; Heinämäki, J.; Raal, A. Chemical Composition and Insulin-Resistance Activity of Arginine-Loaded American Cranberry (Vaccinium macrocarpon Aiton, Ericaceae) Leaf Extracts. Pharmaceutics 2023, 15, 2528. [Google Scholar] [CrossRef] [PubMed]
  153. Elhabal, S.F.; Al-Zuhairy, S.A.S.; El-Nabarawi, M.; Elrefai, M.F.M.; Shoela, M.S.; Hababeh, S.; Nelson, J.; Abdel Khalek, M.A.; Fady, M.; Elzohairy, N.A.; et al. Enhancing Photothermal Therapy for Antibiofilm Wound Healing: Insights from Graphene Oxide-Cranberry Nanosheet Loaded Hydrogel in vitro, in silico, and in vivo Evaluation. Int. J. Nanomed. 2024, 19, 12999–13027. [Google Scholar] [CrossRef] [PubMed]
  154. Rondanelli, M.; Mansueto, F.; Gasparri, C.; Solerte, S.B.; Misiano, P.; Perna, S. Supplementation with Highly Standardized Cranberry Extract Phytosome Achieved the Modulation of Urinary Tract Infection Episodes in Diabetic Postmenopausal Women Taking SGLT-2 Inhibitors: A RCT Study. Nutrients 2024, 16, 2113. [Google Scholar] [CrossRef] [PubMed]
  155. Girard, K.K.; Sinha, N.K. Cranberry, Blueberry, Currant, and Gooseberry. In Handbook of Fruits and Fruit Processing, 2nd ed.; Sinha, N.K., Sidhu, J.S., Barta, J., Wu, J.S.B., Cano, M.P., Eds.; Wiley-Blackwell: Hoboken, NJ, USA, 2012; Chapter 24; pp. 399–417. [Google Scholar]
  156. Liu, W.; Mao, Y.; Schoenborn, J.; Wang, Z.; Tang, G.; Tang, X. Whole blueberry protects pancreatic beta-cells in diet-induced obese mouse. Nutr. Metab. 2019, 16, 34. [Google Scholar] [CrossRef] [PubMed]
  157. Lee, S.; Keirsey, K.I.; Kirkland, R.; Grunewald, Z.I.; Fischer, J.G.; de La Serre, C.B. Blueberry Supplementation Influences the Gut Microbiota, Inflammation, and Insulin Resistance in High-Fat-Diet-Fed Rats. J. Nutr. 2018, 148, 209–219. [Google Scholar] [CrossRef]
  158. Nunes, S.; Viana, S.D.; Preguiça, I. Blueberry Counteracts Prediabetes in a Hypercaloric Diet-Induced Rat Model and Rescues Hepatic Mitochondrial Bioenergetics. Nutrients 2021, 13, 4192. [Google Scholar] [CrossRef]
  159. Morissette, A.; Kropp, C.; Songpadith, J.P.; Junges Moreira, R.; Costa, J.; Mariné Casadó, R.; Pilon, G.; Varin, T.V.; Dudonné, S.; Boutekrabt, L.; et al. Blueberry proanthocyanidins and anthocyanins improve metabolic health through a gut microbiota-dependent mechanism in diet-induced obese mice. Am. J. Physiology. Endocrinol. Metab. 2020, 318, E965–E980. [Google Scholar] [CrossRef]
  160. Mykkänen, O.T.; Huotari, A.; Herzig, K.H.; Dunlop, T.W.; Mykkänen, H.; Kirjavainen, P.V. Wild blueberries (Vaccinium myrtillus) alleviate inflammation and hypertension associated with developing obesity in mice fed with a high-fat diet. PLoS ONE 2014, 9, e114790. [Google Scholar] [CrossRef]
  161. Vendrame, S.; Zhao, A.; Merrow, T.; Klimis-Zacas, D. The effects of wild blueberry consumption on plasma markers and gene expression related to glucose metabolism in the obese Zucker rat. J. Med. Food 2015, 18, 619–624. [Google Scholar] [CrossRef]
  162. Seymour, E.M.; Tanone, I.I.; Urcuyo-Llanes, D.E.; Lewis, S.K.; Kirakosyan, A.; Kondoleon, M.G.; Kaufman, P.B.; Bolling, S.F. Blueberry intake alters skeletal muscle and adipose tissue peroxisome proliferator-activated receptor activity and reduces insulin resistance in obese rats. J. Med. Food 2011, 14, 1511–1518. [Google Scholar] [CrossRef] [PubMed]
  163. Heyman, L.; Axling, U.; Blanco, N.; Sterner, O.; Holm, C.; Berger, K. Evaluation of Beneficial Metabolic Effects of Berries in High-Fat Fed C57BL/6J Mice. J. Nutr. Metab. 2014, 2014, 403041. [Google Scholar] [CrossRef]
  164. Khanal, R.C.; Howard, L.R.; Wilkes, S.E.; Rogers, T.J.; Prior, R.L. Effect of dietary blueberry pomace on selected metabolic factors associated with high fructose feeding in growing Sprague-Dawley rats. J. Med. Food 2012, 15, 802–810. [Google Scholar] [CrossRef]
  165. Brader, L.; Overgaard, A.; Christensen, L.P.; Jeppesen, P.B.; Hermansen, K. Polyphenol-rich bilberry ameliorates total cholesterol and LDL-cholesterol when implemented in the diet of Zucker diabetic fatty rats. Rev. Diabet. Stud. RDS 2013, 10, 270–282. [Google Scholar] [CrossRef] [PubMed]
  166. Rozanska, D.; Regulska-Ilow, B. The significance of anthocyanins in the prevention and treatment of type 2 diabetes. Adv. Clin. Exp. Med. 2018, 27, 135–142. [Google Scholar] [CrossRef]
  167. Wedick, N.M.; Pan, A.; Cassidy, A.; Rimm, E.B.; Sampson, L.; Rosner, B.; Willett, W.; Hu, F.B.; Sun, Q.; van Dam, R.M. Dietary flavonoid intakes and risk of type 2 diabetes in US men and women. Am. J. Clin. Nutr. 2012, 95, 925–933. [Google Scholar] [CrossRef]
  168. Halvorsen, R.E.; Elvestad, M.; Molin, M.; Aune, D. Fruit and vegetable consumption and the risk of type 2 diabetes: A systematic review and dose-response meta-analysis of prospective studies. BMJ Nutr. Prev. Health 2021, 4, 519–531. [Google Scholar] [CrossRef] [PubMed]
  169. Muraki, I.; Imamura, F.; Manson, J.E.; Hu, F.B.; Willett, W.C.; van Dam, R.M.; Sun, Q. Fruit consumption and risk of type 2 diabetes: Results from three prospective longitudinal cohort studies. BMJ 2013, 347, f5001. [Google Scholar] [CrossRef] [PubMed]
  170. Stull, A.J.; Cash, K.C.; Johnson, W.D.; Champagne, C.M.; Cefalu, W.T. Bioactives in blueberries improve insulin sensitivity in obese, insulin-resistant men and women. J. Nutr. 2010, 140, 1764–1768. [Google Scholar] [CrossRef] [PubMed]
  171. Curtis, P.J.; van der Velpen, V.; Berends, L.; Jennings, A.; Feelisch, M.; Umpleby, A.M.; Evans, M.; Fernandez, B.O.; Meiss, M.S.; Minnion, M.; et al. Blueberries improve biomarkers of cardiometabolic function in participants with metabolic syndrome-results from a 6-month, double-blind, randomized controlled trial. Am. J. Clin. Nutr. 2019, 109, 1535–1545. [Google Scholar] [CrossRef] [PubMed]
  172. Stull, A.J.; Cash, K.C.; Champagne, C.M.; Gupta, A.K.; Boston, R.; Beyl, R.A.; Johnson, W.D.; Cefalu, W.T. Blueberries improve endothelial function, but not blood pressure, in adults with metabolic syndrome: A randomized, double-blind, placebo-controlled clinical trial. Nutrients 2015, 7, 4107–4123. [Google Scholar] [CrossRef]
  173. Krikorian, R.; Skelton, M.R.; Summer, S.S.; Shidler, M.D.; Sullivan, P.G. Blueberry supplementation in midlife for dementia risk reduction. Nutrients 2022, 14, 1619. [Google Scholar] [CrossRef]
  174. Curtis, P.J.; Berends, L.; van der Velpen, V.; Jennings, A.; Haag, L.; Chandra, P.; Kay, C.D.; Rimm, E.B.; Cassidy, A. Blueberry anthocyanin intake attenuates the postprandial cardiometabolic effect of an energy-dense food challenge: Results from a double blind, randomized controlled trial in metabolic syndrome participants. Clin. Nutr. 2022, 41, 165–176. [Google Scholar] [CrossRef] [PubMed]
  175. Mane, C.; Loonis, M.; Juhel, C.; Dufour, C.; Malien-Aubert, C. Food Grade Lingonberry Extract: Polyphenolic Composition and In vivo Protective Effect against Oxidative Stress. J. Agric. Food Chem. 2011, 59, 3330–3339. [Google Scholar] [CrossRef] [PubMed]
  176. Drózdz, P.; Šežiene, V.; Wójcik, J.; Pyrzynska, K. Evaluation of Bioactive Compounds, Minerals and Antioxidant Activity of Lingonberry (Vaccinium vitis-idaea L.) Fruits. Molecules 2017, 23, 53. [Google Scholar] [CrossRef]
  177. Kowalska, K. Lingonberry (Vaccinium vitis-idaea L.) fruit as a source of bioactive compounds with health-promoting effects-A review. Int. J. Mol. Sci. 2021, 22, 5126. [Google Scholar] [CrossRef] [PubMed]
  178. Fan, M.; Li, T.; Li, Y.; Qian, H.; Zhang, H.; Rao, Z.; Wang, L. Vaccinium bracteatum Thunb. as a promising resource of bioactive compounds with health benefits: An updated review. Food Chem. 2021, 356, 129738. [Google Scholar] [CrossRef] [PubMed]
  179. Xu, J.; Li, H.; Yang, H.; Wang, T.; Chang, Y.; Nie, C.; Nie, S.; Fu, Y. Lingonberry (Vaccinium vitis-idaea L.) fruits: Potential characterization of flavor and functional profiles during ripening based on UHPLC-QqQ-MS/MS. J. Food Compos. Anal. 2024, 130, 106143. [Google Scholar] [CrossRef]
  180. Esposito, D.; Overall, J.; Grace, M.H.; Komarnytsky, S.; Lila, M.A. Alaskan berry extracts promote dermal wound repair throughmodulation of bioenergetics and integrin signaling. Front. Pharmacol. 2019, 10, 1058. [Google Scholar] [CrossRef] [PubMed]
  181. Ryyti, R.; Hämäläinen, M.; Peltola, R.; Moilanen, E. Beneficial effects of lingonberry (Vaccinium vitis-idaea L.) supplementation on metabolic and inflammatory adverse effects induced by high-fat diet in a mouse model of obesity. PLoS ONE 2020, 15, e0232605.7. [Google Scholar] [CrossRef]
  182. Marungruang, N.; Kovalenko, T.; Osadchenko, I.; Voss, U.; Huang, F.; Burleigh, S.; Ushakova, G.; Skibo, G.; Nyman, M.; Prykhodko, O.; et al. Lingonberries and their two separated fractions differently alter the gut microbiota, improve metabolic functions, reduce gut inflammatory properties, and improve brain function in ApoE−/− mice fed high-fat diet. Nutr. Neurosci. 2020, 23, 600–612. [Google Scholar] [CrossRef]
  183. Ho, G.T.T.; Nguyen, T.K.Y.; Kase, E.T.; Tadesse, M.; Barsett, H.; Wangensteen, H. Enhanced Glucose Uptake in Human Liver Cells and Inhibition of Carbohydrate Hydrolyzing Enzymes by Nordic Berry Extracts. Molecules 2017, 22, 1806. [Google Scholar] [CrossRef]
  184. Torronen, R.; Kolehmainen, M.; Sarkkinen, E.; Mykkanen, H.; Niskanen, L. Postprandial glucose, insulin, and free fatty acid responses to sucrose consumed with blackcurrants and lingonberries in healthy women. Am. J. Clin. Nutr. 2012, 96, 527–533. [Google Scholar] [CrossRef]
  185. Harbilas, D.; Martineau, L.C.; Harris, C.S.; Adeyiwola-Spoor, D.C.; Saleem, A.; Lambert, J.; Caves, D.; Johns, T.; Prentki, M.; Cuerrier, A.; et al. Evaluation of the antidiabetic potential of selected medicinal plant extracts from the Canadian boreal forest used to treat symptoms of diabetes: Part II. Can. J. Physiol. Pharmacol. 2009, 87, 479–492. [Google Scholar] [CrossRef]
  186. Li, X.; Liu, J.; Chang, Q.; Zhou, Z.; Han, R.; Liang, Z. Antioxidant and antidiabetic activity of proanthocyanidins from Fagopyrum dibotrys. Molecules 2021, 26, 2417. [Google Scholar] [CrossRef]
  187. Eraky, S.M.; Ramadan, N.M.; Abo El-Magd, N.F. Antidiabetic effects of quercetin and liraglutide combination through modulation of TXNIP/IRS-1/PI3K pathway. Cell Biochem. Funct. 2022, 40, 90–102. [Google Scholar] [CrossRef] [PubMed]
  188. Oyenihi, O.R.; Oyenihi, A.B.; Adeyanju, A.A.; Oguntibeju, O.O. Antidiabetic Effects of Resveratrol: The Way Forward in Its Clinical Utility. J. Diabetes Res. 2016, 2016, 9737483. [Google Scholar] [CrossRef] [PubMed]
  189. Olennikov, D.N.; Chemposov, V.V.; Chirikova, N.K. Polymeric Compounds of LingonberryWaste: Characterization of Antioxidant and Hypolipidemic Polysaccharides and Polyphenol-Polysaccharide Conjugates from Vaccinium vitis-idaea Press Cake. Foods 2022, 11, 2801. [Google Scholar] [CrossRef] [PubMed]
  190. Muceniece, R.; Klavins, L.; Kviesis, J.; Jekabsons, K.; Rembergs, R.; Saleniece, K.; Dzirkale, Z.; Saulite, L.; Riekstina, U.; Klavins, M. Antioxidative, hypoglycaemic and hepatoprotective properties of five Vaccinium spp. berry pomace extracts. J. Berry Res. 2019, 9, 267–282. [Google Scholar] [CrossRef]
  191. Ryyti, R.; Hamalainen, M.; Tolonen, T.; Maki, M.; Jaakkola, M.; Peltola, R.; Moilanen, E. Lingonberry (Vaccinium vitis-idaea L.) Skin Extract PreventsWeight Gain and Hyperglycemia in High-Fat Diet-Induced Model of Obesity in Mice. Nutrients 2024, 16, 2107. [Google Scholar] [CrossRef] [PubMed]
  192. Bone, K.; Mills, S.C. Principles and Practice of Phytotherapy: Modern Herbal Medicine, 2nd ed.; Churchill Livingstone: Edinburgh, UK, 2013. [Google Scholar]
  193. Allen, D.; Bilz, M.; Leaman, D.J.; Miller, R.M.; Timoshyna, A.; Window, J. European Red List of Medicinal Plants; Publications Office of the European Union: Luxembourg, 2014. [Google Scholar]
  194. Stefanescu, B.E.; Szabo, K.; Mocan, A.; Crisan, G. Phenolic compounds from five Ericaceae species leaves and their related bioavailability and health benefits. Molecules 2019, 24, 2046. [Google Scholar] [CrossRef] [PubMed]
  195. Vranješ, M.; Popovi’c, B.M.; Štajner, D.; Ivetic, V.; Mandic, A.; Vranješ, D. Effects of bearberry, parsley and corn silk extracts on diuresis, electrolytes composition, antioxidant capacity and histopathological features in mice kidneys. J. Funct. Foods 2016, 21, 272–282. [Google Scholar] [CrossRef]
  196. Wrona, M.; Blasco, S.; Becerril, R.; Nerin, C.; Sales, E.; Asensio, E. Antioxidant and antimicrobial markers by UPLC®–ESIQ-TOF-MSE of a new multilayer active packaging based on Arctostaphylos uva-ursi. Talanta 2019, 196, 498–509. [Google Scholar] [CrossRef] [PubMed]
  197. Boo, Y.C. Arbutin as a skin depigmenting agent with antimelanogenic and antioxidant properties. Antioxidants 2021, 10, 1129. [Google Scholar] [CrossRef]
  198. Lin, Y.C. Studies on the hypoglycemic activity of the medicinal herbs. Formos. Med. Assoc. 1964, 63, 400–404. [Google Scholar]
  199. Kokate, C.K. A Text Book of Pharmacognocy, 35th ed.; Nirali Prakashan: New Delhi, India, 2006; pp. 218–219, 252–253, 268–269, 309–310. [Google Scholar]
  200. Kravchenko, G.B.; Krasilnikova, O.A.; Mazen, M. The study of the hypoglycemic action of extracts from bearberry leaves under experimental insulin resistance in rats. Clin. Pharm. 2020, 24, 40–46. [Google Scholar] [CrossRef]
  201. Kravchenko, G.; Matar, M.; Krasilnikova, O. Screening of bearberry leaves extracts hypoglycemic effect and study of acute toxicity. Ukr. Biopharm. J. 2018, 2, 13–16. [Google Scholar] [CrossRef]
  202. Chaika, N.; Mazen, M.; Koshovyi, O.; Kravchenko, G.; Goryacha, O.; Kireyev, I.; Kovalenko, S.; Darmograi, R. Research in phytochemical composition and hypoglycemic activity screening of the dry extracts from bearberry leaves. Sci. Rise Pharm. Sci. 2021, 3, 42–50. [Google Scholar]
  203. Kravchenko, G.; Krasilnikova, O.; Raal, A.; Mazen, M.; Chaika, N.; Kireyev, I.; Grytsyk, A.; Koshovyi, O. Arctostaphylos uva-ursi L. leaves extract and its modified cysteine preparation for the management of insulin resistance: Chemical analysis and bioactivity. Nat. Prod. Bioprospect. 2022, 12, 30. [Google Scholar] [CrossRef] [PubMed]
  204. Mazen, M.; Kravchenko, G.; Krasilnikova, O. Study of hepatoprotective effect of bearberry leaves extract under insulin resistance in rats. EUREKA Health Sci. 2021, 6, 48–53. [Google Scholar] [CrossRef]
  205. Celikel, G.; Demirsoy, L.; Demirsoy, H. The strawberry tree (Arbutus Unedo L.) selection in Turkey. Sci. Hortic. 2008, 118, 115–119. [Google Scholar] [CrossRef]
  206. Bachar, M.; Zidane, L.; Rochdi, A. Ethno-medicinal and traditional phytotherapy of plants used in bouhachem natural regional park “Rif of Morocco”—Case of tazroute district. J. Mater. Environ. Sci. 2018, 7, 4175–4204. [Google Scholar]
  207. Rhattas, M.; Douira, A.; Zidane, L. ‘Etude ethnobotanique des plantes m’edicinales dans le Parc National de Talassemtane (Rif Occidental du Maroc). J. Appl. Biosci. 2016, 97, 9187–9211. [Google Scholar] [CrossRef]
  208. Mrabti, H.N.; Jaradat, N.; Kachmar, M.R. Integrative herbal treatments of diabetes in Beni Mellal region of Morocco. J. Integr. Med. 2019, 17, 93–99. [Google Scholar] [CrossRef]
  209. Zlabur, J.S.; Bogdanovic, S.; Voca, S.; Babojelic, M.S. Biological potential of fruit and leaves of strawberry tree (Arbutus unedo L.) from Croatia. Molecules 2020, 25, 2521. [Google Scholar] [CrossRef]
  210. Erkekoglou, I.; Nenadis, N.; Samara, E.; Mantzouridou, F.T. Functional teas from the leaves of Arbutus unedo: Phenolic content, antioxidant activity, and detection of ePcient radical scavengers. Plant Foods Hum. Nutr. 2017, 72, 176–183. [Google Scholar] [CrossRef] [PubMed]
  211. El Haouari, M.; Mekh, H. Anti-platelet aggregation effects of extracts from Arbutus unedo leaves. Plant Sci. Today 2017, 4, 68–74. [Google Scholar] [CrossRef]
  212. Bnouham, M.; Merhfour, F.Z.; Ziyyat, A.; Aziz, M.; Legssyer, A.; Mekh, H. Antidiabetic effect of some medicinal plants of Oriental Morocco in neonatal non-insulin-dependent diabetes mellitus rats. Hum. Exp. Toxicol. 2010, 29, 865–871. [Google Scholar] [CrossRef]
  213. Mrabti, H.N.; Jaradat, N.; Fichtali, I. Separation, identication, and antidiabetic activity of catechin isolated from Arbutus unedo L. Plant roots. Plants 2018, 72, 31. [Google Scholar] [CrossRef]
  214. Delgado-Pelayo, R.; Gallardo-Guerrero, L.; Hornero-Mendez, D. Carotenoid composition of strawberry tree (Arbutus unedo L.) fruits. Food Chem. 2016, 199, 165–175. [Google Scholar] [CrossRef]
  215. Lopez, C.J.; Caleja, C.; Prieto, M.A.; Barreiro, M.F.; Barros, L.; Ferreira, I. Optimization and comparison of heat and ultrasound assisted extraction techniques to obtain anthocyanin compounds from Arbutus unedo L. Fruits. Food Chem. 2018, 264, 81–91. [Google Scholar] [CrossRef] [PubMed]
  216. Bnouham, M.; Merhfour, F.Z.; Legssyer, A.; Mekh, H.; Maallem, S.; Ziyyat, A. Antihyperglycemic activity of Arbutus unedo, Ammoides pusilla and Thymelaea hirsuta. Die Pharm. 2007, 62, 630–632. [Google Scholar]
  217. Mrabti, H.N.; Sayah, K.; Jaradat, N. Antidiabetic and protective effects of the aqueous extract of Arbutus unedo L. in streptozotocin-nicotinamide-induced diabetic mice. J. Complement. Integr. Med. 2018, 15, 3. [Google Scholar] [CrossRef]
  218. Mrabti, H.N.; El Abbes Faouzi, M.; Mayuk, F.M. Arbutus unedo L., (Ericaceae) inhibits intestinal glucose absorption and improves glucose tolerance in rodents. J. Ethnopharmacol. 2019, 235, 385–391. [Google Scholar] [CrossRef] [PubMed]
  219. Touzani, S.; Al-Waili, N.; Imtara, H.; Aboulghazi, A.; Hamma, N.; Falcão, S.; Vilas-Boas, M.; El Arabi, I.; Al-Waili, W.; Lyoussi, B. Arbutus unedo honey and propolis ameliorate acute kidney injury, acute liver injury, and proteinuria via hypoglycemic and antioxidant activity in streptozotocin-treated rats. Cell Physiol. Biochem. 2022, 56, 66–81. [Google Scholar]
  220. Al-Mijalli, S.H.; Mrabti, H.N.; Ouassou, H.; Flouchi, R.; Abdallah, E.M.; Sheikh, R.A.; Alshahrani, M.M.; Awadh, A.A.A.; Harhar, H.; Omari, N.E.; et al. Chemical Composition, Antioxidant, Anti-Diabetic, Anti-Acetylcholinesterase, Anti-Inflammatory, and Antimicrobial Properties of Arbutus unedo L. and Laurus nobilis L. Essential Oils. Life 2022, 12, 1876. [Google Scholar] [CrossRef] [PubMed]
  221. Koskela, A.K.; Anttonen, M.J.; Soininen, T.H.; Saviranta, N.M.; Auriola, S.; Julkunen-Tiitto, R.; Karjalainen, R.O. Variation in the anthocyanin concentration of wild populations of crowberries (Empetrum nigrum L subsp. hermaphroditum). J. Agric. Food Chem. 2010, 58, 12286–12291. [Google Scholar]
  222. Vaisanen, M.; Martz, F.; Kaarlejarvi, E.; Julkunen-Tiitto, R.; Stark, S. Phenolic responses of mountain crowberry (Empetrum nigrum ssp. hermaphroditum) to global climate change are compound specific and depend on grazing by reindeer (Rangifer tarandus). J. Chem. Ecol. 2013, 39, 1390–1399. [Google Scholar]
  223. Hyun, T.K.; Kim, H.-C.; Ko, Y.-J.; Kim, J.-S. Antioxidant, α-glucosidase inhibitory, and anti-inflammatory effects of aerial parts extract from Korean crowberry (Empetrum nigrum var. japonicum). Saudi J. Biol. Sci. 2016, 23, 181–188. [Google Scholar] [CrossRef] [PubMed]
  224. Hyun, T.K.; Ra, J.H.; Han, S.H.; Kim, J.S. Antioxidant, antimicrobial, and antidiabetic activities of crowberry fruits. Indian J. Pharm. Sci. 2018, 80, 489–495. [Google Scholar] [CrossRef]
  225. Kashtoh, H.; Baek, K.-H. Recent Updates on Phytoconstituent Alpha-Glucosidase Inhibitors: An Approach towards the Treatment of Type Two Diabetes. Plants 2022, 11, 2722. [Google Scholar] [CrossRef]
  226. Törrönen, R.; McDougall, G.J.; Dobson, G.; Stewart, D.; Hellström, J.; Mattila, P.; Pihlava, J.M.; Koskela, A.; Karjalainen, R. Fortification of blackcurrant juice with crowberry: Impact on polyphenol composition, urinary phenolic metabolites, and postprandial glycemic response in healthy subjects. J. Funt. Foods 2012, 4, 746–756. [Google Scholar] [CrossRef]
  227. Vengrytė, M.; Raudonė, L. Phytochemical Profiling and Biological Activities of Rhododendron Subsect. Ledum: Discovering the Medicinal Potential of Labrador Tea Species in the Northern Hemisphere. Plants 2024, 13, 901. [Google Scholar] [CrossRef]
  228. Ni, H.; Hayes, H.E.; Stead, D.; Raikos, V. Incorporating salal berry (Gaultheria shallon) and blackcurrant (Ribes nigrum) pomace in yogurt for the development of a beverage with antidiabetic properties. Heliyon 2018, 4, e00875. [Google Scholar] [CrossRef]
  229. Liu, S.; Sun, L.; Zhang, P.; Niu, C. Recent Advances in Grayanane Diterpenes: Isolation, Structural Diversity, and Bioactivities from Ericaceae Family (2018–2024). Molecules 2024, 29, 1649. [Google Scholar] [CrossRef] [PubMed]
  230. EFSA Panel on Contaminants in the Food Chain (CONTAM); Schrenk, D.; Bignami, M.; Bodin, L.; Chipman, J.K.; del Mazo, J.; Grasl-Kraupp, B.; Hogstrand, C.; Hoogenboom, L.; Leblanc, J.-C.; et al. Scientific Opinion on the Risks for Human Health Related to the Presence of Grayanotoxins in Certain Honey. EFSA J. 2023, 21, 7866. [Google Scholar]
  231. Doudach, L.; Mrabti, H.N.; Al-Mijalli, S.H.; Kachmar, M.R.; Benrahou, K.; Assaggaf, H.; Qasem, A.; Abdallah, E.M.; Rajab, B.S.; Harraqui, K.; et al. Phytochemical, Antidiabetic, Antioxidant, Antibacterial, Acute and Sub-Chronic Toxicity of Moroccan Arbutus unedo Leaves. J. Pharmacopunct. 2023, 26, 27–37. [Google Scholar] [CrossRef] [PubMed]
  232. Cosme, F.; Aires, A.; Pinto, T.; Oliveira, I.; Vilela, A.; Gonçalves, B. A Comprehensive Review of Bioactive Tannins in Foods and Beverages: Functional Properties, Health Benefits, and Sensory Qualities. Molecules 2025, 30, 800. [Google Scholar] [CrossRef]
Pharmaceuticals 18 00682 g001
Figure 1. Graphical summary of Ericaceae-derived phenolic compounds, their molecular targets, and physiological outcomes in diabetes management. Created with BioRender.com: https://app.biorender.com/illustrations/6812a4fbba4c52be0bd59244 (accessed on 14 March 2025).
Figure 1. Graphical summary of Ericaceae-derived phenolic compounds, their molecular targets, and physiological outcomes in diabetes management. Created with BioRender.com: https://app.biorender.com/illustrations/6812a4fbba4c52be0bd59244 (accessed on 14 March 2025).
Pharmaceuticals 18 00682 g001
Pharmaceuticals 18 00682 g002
Figure 2. Therapeutic applications of bearberry (Arctostaphylos uva-ursi) leaf extracts. The diagram illustrates both the traditional and emerging uses of bearberry. Aqueous infusions containing arbutin are used for urinary tract infections, while ethanol extracts rich in flavonoids, formulated with cysteine, have shown hypoglycemic and pancreatic protective effects in experimental settings.
Figure 2. Therapeutic applications of bearberry (Arctostaphylos uva-ursi) leaf extracts. The diagram illustrates both the traditional and emerging uses of bearberry. Aqueous infusions containing arbutin are used for urinary tract infections, while ethanol extracts rich in flavonoids, formulated with cysteine, have shown hypoglycemic and pancreatic protective effects in experimental settings.
Pharmaceuticals 18 00682 g002
Pharmaceuticals 18 00682 g003
Figure 3. Therapeutic potential of Arbutus unedo products and isolates in type 2 diabetes mellitus (T2DM). The table highlights various A. unedo-derived products, including honey, essential oil, and isolated catechins, and their reported antidiabetic effects such as enzyme inhibition, glycemic control, increased insulin levels, and pancreatic protection [217,219,220].
Figure 3. Therapeutic potential of Arbutus unedo products and isolates in type 2 diabetes mellitus (T2DM). The table highlights various A. unedo-derived products, including honey, essential oil, and isolated catechins, and their reported antidiabetic effects such as enzyme inhibition, glycemic control, increased insulin levels, and pancreatic protection [217,219,220].
Pharmaceuticals 18 00682 g003
Table 1. Flavonoids and anthocyanins in Ericaceae plants with antidiabetic effect, F—flavonoids; ANT—anthocyanins.
Table 1. Flavonoids and anthocyanins in Ericaceae plants with antidiabetic effect, F—flavonoids; ANT—anthocyanins.
SpeciesContent TypeIdentified DerivativesClass
V. myrtillus
(bilberry)
Pharmaceuticals 18 00682 i001		Cyanidin
Delphinidin
Malvidin
Petunidin
Myricetin
Quercetin
Others		cyanidin 3-galactoside, cyanidin 3-glucoside, cyanidin 3-arabinoside, peonidin 3-arabinoside, cyanidin 3-xyloside, cyanidin 5-glucoside, cyanidin 3,5-diglucoside
delphinidin 3-galactoside, delphinidin 3-arabinoside, delphinidin 3-glucoside,
malvidin 3-galactoside, malvidin 3-arabinoside, malvidin 3-glucoside
petunidin 3-arabinoside, petunidin 3-acetylglucoside, petunidin 3-glucoside,
myricetin 3-glucoside, myricetin 3-arabinoside, myricetin3-rhamnoside, myricetin-3-xyloside, myricetin 3-galactoside
quercetin 3-arabinoside,
quercetin 3-rhamnoside, quercetin 3-galactoside,
quercetin 3-glucoside, quercetin 3-rutinoside, apigenin, chrysoeriol, isorhamnetin, laricitrin, syringetin, luteolin, kaempferol [54]		ANT
ANT
ANT
ANT
ANT
F
F
V. macrocarpon (cranberry)
Pharmaceuticals 18 00682 i002		Cyanidin
Delphinidin
Malvidin
Peonidin
Pelargonidin
Quercetin
Kaempferol		cyanidin-3-glucoside, cyanidin-3-galactoside, cyanidin-3-arabinoside
delphinidin-3-arabinoside
malvidin-3-galactoside, malvidin-3-arabinoside
peonidin-3-glucoside,
peonidin-3-galactoside, peonidin-3-arabinoside
pelargonidin-3-galactoside, pelargonidin-3-arabinoside
quercetin-3-galactoside,
quercetin-3-arabinoside, quercetin-3-rhamnoside
kaempferol-3-glucoside [44]		ANT
ANT
ANT
ANT
ANT
F
F
Vaccinium spp.
(blueberry)
Pharmaceuticals 18 00682 i003		Cyanidin
Delphinidin
Malvidin
Petunidin
Myricetin
Quercetin		cyanidin 3-galactoside, cyanidin 3-glucoside,
cyanidin 3-arabinoside
delphinidin 3-arabinoside, delphinidin 3-acetylglucoside
malvidin 3-galactoside, malvidin 3-glucoside, malvidin 3-arabinoside, malvidin 3-acetylglucoside
petunidin 3-galactoside, petunidin 3-glucoside, petunidin 3-arabinoside
myricetin 3-galactoside, myricetin 3-glucoside,
myricetin 3-rhamnoside
quercetin 3-galactoside,
quercetin 3-glucoside,
quercetin 3-glucosylxyloside, quercetin 3-rutinoside,
quercetin 3-xyloside [55]		ANT
ANT
ANT
ANT
F
F
V. vitis idaea
(lingonberry)
Pharmaceuticals 18 00682 i004		Cyanidin
Delphinidin
Petunidin
Peonidin
Myricetin
Quercetin
Kaempferol
Isorhamnetin		cyanidin 3-glucoside, cyanidin 3-arabinoside
delphinidin 3-glucoside, delphinidin 3-arabinoside, delphinidin 3-galactoside,
petunidin 3-galactoside, petunidin 2-glucoside, peonidin 3-arabinoside,
peonidin 3-glucoside, peonidin 3-galactoside
myricetin 3-glucoside
quercetin 3-glucoside, quercetin 3-galactoside, quercetin 3-arabinoside, quercetin 3-xyloside
kaempferol 3-rhamnoside, kaempferol
3-glucoside
isorhamnetin 3-galactoside,
isorhamnetin 3-glucoside [56]		ANT
ANT
ANT
ANT
F
F
F
F
Arctostaphylos uva-ursi L. (Bearberry)
Pharmaceuticals 18 00682 i005		Quercetin
Kaempferol
Myricetin		Isoquercetin, quercitin-3-gentiobioside, hyperoside, avicularin, rutin
Kaempferol-pentoside/hexoside,
Myricetin-pentoside/hexoside [57]		F
F
F
Vaccinium arctostaphylos (Caucasian whortleberry)
Pharmaceuticals 18 00682 i006		Delphinidin
Petunidin
Malvidin
Cyanidin 		delphinidin 3-galactoside, delphinidin 3-arabinoside, delphinidin 3-glucoside
petunidin 3-arabinoside, petunidin 3-glucosidemalvidin 3-galactoside, malvidin 3-arabinoside, malvidin 3-glucoside
cyanidin-3-O-xyloside [58]		ANT
ANT
ANT
ANT
Gaultheria trichophylla (Himalayan snowberry)
Pharmaceuticals 18 00682 i007		Quercetin
Kaempferol
Catechin
Epicatechin		Quercetin 3- glycoside, Quercetin 3-O-galactoside, Quercetin 3-rhamnoside,
Kaempferol 7- glucoside, Kaempferol 3-glucoside [59]		F
Rhododendron arboreum (Himalayan rhododendron)
Pharmaceuticals 18 00682 i008		Ursolic acid derivatives
Quercetin 		quercetin-3-O-galactoside [60]F
Rhododendron groenlandicum (Labrador tea)
Pharmaceuticals 18 00682 i009		Catechin
Epicatechin
[61]		 F
Arbutus unedo
Pharmaceuticals 18 00682 i010		Myricetin
Quercetin
Kaempferol		Myricetin 3-glucoside, Myricetin 3-pentosideQuercetin 3- glycoside, Quercetin 3-O-galactoside, Quercetin 3-rhamnoside,
Kaempferol 7- glucoside, Kaempferol 3-glucoside [62]		F
F
F
Empetrum nigrum (Crowberry)
Pharmaceuticals 18 00682 i011		Cyanidin
Delphinidin
Petunidin
Malvidin
Quercetin
Kaempferol		cyanidin 3-galactoside, cyanidin 3-glucoside, cyanidin 3-arabinoside
delphinidin 3-galactoside, delphinidin 3-arabinoside, delphinidin 3-glucoside
petunidin 3-arabinoside, petunidin 3-glucosidemalvidin 3-galactoside, malvidin 3-arabinoside, malvidin 3-glucoside
quercetin-3-glucoside, quercetin-3-arabinose, quercetin-3-xyloside, quercetin-3-galactoside, quercetin-3-rhamnoside
glucoside and galactoside forms [63]		ANT
ANT
ANT
ANT
F
F
Table 2. Chemical structure of the main flavonoids and anthocyanins from Ericaceae.
Table 2. Chemical structure of the main flavonoids and anthocyanins from Ericaceae.
Compound IUPAC NameMolecular Formula2D Structure
Quercetin
[64]		2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-oneC15H10O7 Pharmaceuticals 18 00682 i012
Kaempferol
[65]		3,5,7-trihydroxy-2-(4-hydroxyphenyl)chromen-4-oneC15H10O6Pharmaceuticals 18 00682 i013
Myricetin
[66]		3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)chromen-4-oneC15H10O8Pharmaceuticals 18 00682 i014
Cyanidin
[67]		2-(3,4-dihydroxyphenyl)chromenylium-3,5,7-triolC15H11O6Pharmaceuticals 18 00682 i015
Delphinidin
[68]		2-(3,4,5-trihydroxyphenyl)chromenylium-3,5,7-triol;C15H11O7Pharmaceuticals 18 00682 i016
Malvidin
[69]		(2S,3R,4S,5S,6R)-2-[5,7-dihydroxy-2-(4-hydroxy-3,5-dimethoxyphenyl)chromenylium-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triolC23H25O12Pharmaceuticals 18 00682 i017
Petunidin
[70]		C22H23O12(2S,3R,4S,5S,6R)-2-[2-(3,4-dihydroxy-5-methoxyphenyl)-5,7-dihydroxychromenylium-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triolPharmaceuticals 18 00682 i018
Pelargonidin
[71]		C15H11ClO52-(4-hydroxyphenyl)chromenylium-3,5,7-triol;chloridePharmaceuticals 18 00682 i019
Table 3. Total phenolic content of selected Ericaceae plants (mg GAE/100 g FW or g DW) GAE = Gallic Acid Equivalents; FW—fresh weight; DW—dry weight.
Table 3. Total phenolic content of selected Ericaceae plants (mg GAE/100 g FW or g DW) GAE = Gallic Acid Equivalents; FW—fresh weight; DW—dry weight.
SpeciesVarietyTotal Phenolic ContentReference
V. myrtillusWild bilberry492–563 mg GAE/100 g FW[72]
V. macrocarpon“Early Black” cultivated~441 mg GAE/100 g FW[73]
Vaccinium spp.“Bluecrop” highbush blueberry~327 mg GAE/100 g FW[72]
V. vitis-idaeaWild lingonberry468–661 mg GAE/100 g FW[74]
Arctostaphylos uva-ursi L.Leaf extracts (wild populations)238.85–318.28 mg GAE/g DW[75]
Vaccinium arctostaphylosWild fruit (Caucasian whortleberry)389–578 mg GAE/100 g FW[76]
Gaultheria trichophyllaWild fruit (Himalayan snowberry)~3.71 mg GAE/g FW (≈371 mg/100 g FW)[77]
Rhododendron arboreumFlower petals (Himalayan rhododendron)~4.89 mg GAE/g DW (best processing)[78]
Rhododendron groenlandicumLeaves (Labrador tea)20 g/100 g DW (leaf extract)[79]
Arbutus unedoStrawberry tree fruit16.78–25.86 mg GAE/g DW[80]
Empetrum nigrumWild black crowberry (Canada)~454 mg GAE/100 g FW (fresh fruit)[75]
Table 4. Antioxidant activity of total phenolic compounds from Ericaceae Plants.
Table 4. Antioxidant activity of total phenolic compounds from Ericaceae Plants.
SpeciesMain Compounds Class Responsible for Antioxidant ActivityABTSDPPH
V. myrtillusAnthocyanins (anthocyanidin glycosides)—e.g., delphinidin and cyanidin derivatives60.9–106.0 µmol Trolox/g FW (ABTS radical cation scavenging) [81]216.5–376.8 µmol Trolox/g FW (DPPH radical scavenging [82]
V. macrocarponProanthocyanidins (A-type PAC oligomers)189–264 µmol Trolox/g DW (ABTS, cultivar range) [83]214–320 µmol Trolox/g DW (DPPH, cultivar range) [84]
Vaccinium spp.Anthocyanins (flavonoid pigments)—malvidin, petunidin, and cyanidin glycosides~259.9 µmol Trolox/g DW (ABTS in highbush cv. ‘Biloxi’) [85]~214.1 µmol Trolox/g DW (DPPH in ‘Biloxi’ fruit) [85]
V. vitis idaeaAnthocyanins (cyanidin glycosides)~74.3–104.0 µmol Trolox/g DW (TEAC/ABTS assay) [80]Potent DPPH scavenging capacity (multiple radicals quenched; ORAC/DPPH assays confirm high activity) [86]
Arctostaphylos uva-ursi L.Phenolic glycosides (arbutin)173.5–643.7 mg Trolox/g (ABTS•⁺ scavenging, water vs. EtOH extracts) [87]377.4–821.8 mg Trolox/g (DPPH scavenging, water vs. EtOH) [87]
Vaccinium arctostaphylosAnthocyanins (delphinidin, petunidin, and malvidin glycosides)~19.5 µmol Trolox/g FW [76]SC50 = 0.14 mg/mL (ethanol extract) [88,89]
Gaultheria trichophyllaPolyphenols (flavonoids and tannins)4.35 mM AAE/100 g FW [77]2.56 mM AAE/100 g FW
[77]
Rhododendron arboreumAnthocyanins and flavonoids (quercetin derivatives)21.25–31.87 mM AAE/100 g DW [78]22.59–36.61 mM AAE/100 g DW [78]
Rhododendron groenlandicumFlavonol glycosides, catechins (quercetin, myricetin, and catechin) -Strong radical scavenging activity (ORAC assay confirms high potency) [90]
Arbutus unedoFlavan-3-ols (catechin and gallocatechin tannins)74.3–104.0 µmol Trolox/g DW (antioxidant capacity, TEAC assay) [80]DPPH radical scavenging EC50 in low mg/mL; activity strongly correlates with total phenolics [80]
Empetrum nigrumAnthocyanins107 µmol Trolox/g [91]~90 mg Trolox/g [89,91]
Table 5. Studies on Vaccinium species on diabetes mellitus.
Table 5. Studies on Vaccinium species on diabetes mellitus.
Plant AgeNumber DurationResultsReference
Blueberry27 ± 53418 weeksLower C-reactive protein and blood glucose levels compared to the control group[111]
22–6517/Significant increase in pancreatic polypeptide(PP) concentrations in intervention group[112]
51–75588 weeksLower hemoglobin A1c, fructosamine, and triglycerides[113]
Bilberry30–6510590 daysReduced 2 h blood postprandial glucose and homeostasis model assessment of insulin resistance (HOMA-IR) scores[114]
25–60478 weeksSignificant increase in fasting serum hippuric acid in intervention group[115]
55.8 ± 9.5204 weeksTendency of improved glycemic control in intervention group[116]
Cranberry40–7516012 weeksReduced HbA1c, low-density lipoprotein-c, apolipoprotein A-1, apolipoprotein B in intervention group[117]
56–675824 weeksDecreased serum LDL cholesterol, triglycerides, apolipoprotein B, and apo C-III; increased HDL cholesterol[118]
56 ± 625/Lower postprandial increases in glucose at 2 and 4 h in the cranberry group,[119]
25–65568 weeksReduced circulating TGs, CRP, glucose, insulin resistance, and diastolic BP in intervention group[120]
Llingonberry25–6920/Improved postprandial glycemic profiles[74]
Table 6. In vivo studies on A. unedo roots in T2DM.
Table 6. In vivo studies on A. unedo roots in T2DM.
Plant PartExtract/FractionModel AppliedEffect/Mechanism of ActionReference
RootsWaterOGTT *
IVGTT *		Antihyperglycemic effect
Inhibition of jejunal glucose
absorption		[216]
RootsWaterOGTT
n-str-induced diabetic rats		Hypoglycemic effect
Potentiation of the insulin
Activity
Improved glucose peripheral
consumption		[212]
RootsCatechinα-glucosidase assayAntidiabetic effect through
inhibition of α-glucosidase
enzyme		[213]
RootsWaterα–glucosidase and
α-amylase assays		Regeneration of pancreatic
C-cells		[217]
Roots barkWaterOGTTImproved oral glucose
tolerance		[218]
* OGTT—oral glucose tolerance test; IVGTT—intravenous glucose tolerance test.
Table 7. Ericaceae species with in vitro antidiabetic activity and potential for in vivo efficacy.
Table 7. Ericaceae species with in vitro antidiabetic activity and potential for in vivo efficacy.
SpeciesExperimental ModelObserved ActivityMain Compounds
Gaultheria hispidula (Creeping snowberry) [185]C2C12 myotubes and 3T3-L1 adipocytes (cell assays)Stimulated glucose uptake; promoted adipogenesis (~50% of rosiglitazone); antioxidant and neuroprotective activityPhenolic glycosides (e.g., gaultherin and arbutin) and flavonoids
Rhododendron tomentosum (Marsh Labrador tea) [227]C2C12, 3T3-L1 adipocytes, and antioxidant assaysStrong glucose uptake stimulation; PPARγ-like adipogenic activity; potent antioxidant; no insulin secretionFlavonoids, catechins, and polyphenols
Gaultheria shallon (Salal berry) [228]α-amylase, α-glucosidase, and DPP-IV enzyme assaysInhibited α-glucosidase, α-amylase (>60%), DPP-IV (~56%); high antioxidant potentialAnthocyanins, procyanidins, and flavonoids
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Popescu, M.; Radivojevic, K.; Trasca, D.-M.; Varut, R.M.; Enache, I.; Osman, A. Natural Antidiabetic Agents: Insights into Ericaceae-Derived Phenolics and Their Role in Metabolic and Oxidative Modulation in Diabetes. Pharmaceuticals 2025, 18, 682. https://doi.org/10.3390/ph18050682

AMA Style

Popescu M, Radivojevic K, Trasca D-M, Varut RM, Enache I, Osman A. Natural Antidiabetic Agents: Insights into Ericaceae-Derived Phenolics and Their Role in Metabolic and Oxidative Modulation in Diabetes. Pharmaceuticals. 2025; 18(5):682. https://doi.org/10.3390/ph18050682

Chicago/Turabian Style

Popescu, Mihaela, Kristina Radivojevic, Diana-Maria Trasca, Renata Maria Varut, Irina Enache, and Andrei Osman. 2025. "Natural Antidiabetic Agents: Insights into Ericaceae-Derived Phenolics and Their Role in Metabolic and Oxidative Modulation in Diabetes" Pharmaceuticals 18, no. 5: 682. https://doi.org/10.3390/ph18050682

APA Style

Popescu, M., Radivojevic, K., Trasca, D.-M., Varut, R. M., Enache, I., & Osman, A. (2025). Natural Antidiabetic Agents: Insights into Ericaceae-Derived Phenolics and Their Role in Metabolic and Oxidative Modulation in Diabetes. Pharmaceuticals, 18(5), 682. https://doi.org/10.3390/ph18050682

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop