Select Polyphenol-Rich Berry Consumption to Defer or Deter Diabetes and Diabetes-Related Complications

Berries are considered “promising functional fruits” due to their distinct and ubiquitous therapeutic contents of anthocyanins, proanthocyanidins, phenolic acids, flavonoids, flavanols, alkaloids, polysaccharides, hydroxycinnamic, ellagic acid derivatives, and organic acids. These polyphenols are part of berries and the human diet, and evidence suggests that their intake is associated with a reduced risk or the reversal of metabolic pathophysiologies related to diabetes, obesity, oxidative stress, inflammation, and hypertension. This work reviewed and summarized both clinical and non-clinical findings that the consumption of berries, berry extracts, purified compounds, juices, jams, jellies, and other berry byproducts aided in the prevention and or otherwise management of type 2 diabetes mellitus (T2DM) and related complications. The integration of berries and berries-derived byproducts into high-carbohydrate (HCD) and high-fat (HFD) diets, also reversed/reduced the HCD/HFD-induced alterations in glucose metabolism-related pathways, and markers of oxidative stress, inflammation, and lipid oxidation in healthy/obese/diabetic subjects. The berry polyphenols also modulate the intestinal microflora ecology by opposing the diabetic and obesity rendered symbolic reduction of Bacteroidetes/Firmicutes ratio, intestinal mucosal barrier dysfunction-restoring bacteria, short-chain fatty acids, and organic acid producing microflora. All studies proposed a number of potential mechanisms of action of respective berry bioactive compounds, although further mechanistic and molecular studies are warranted. The metabolic profiling of each berry is also included to provide up-to-date information regarding the potential anti-oxidative/antidiabetic constituents of each berry.


Introduction
Diabetes mellitus (DM) is a multifactorial disease with high mortality worldwide. Chronic DM is the eighth-leading cause of deaths globally, responsible for 1.5 million deaths each year [1]. According to the World Health Organization (WHO), in 2013, 381 million adults were diagnosed with DM, which increased to 422 million in 2016 and is expected to double by 2030. Type 1 (T1DM) represents 15% of cases, and the remaining cases are type 2 (T2DM) [1]. T2DM is primarily treated with pharmacotherapeutic drugs, evidence-based alternative approaches, and functional food-based approaches [2]. Pharmacotherapeutic approaches generally consist of monotherapy

Blueberries
Blueberries (BlBs) top the list of five fruits recommended by the Food and Agriculture Organization of the United Nations (FAO) against diabetes, cancer, liver disease, anemia, and cardiovascular disease (CVD). Initially, the in vitro antidiabetic activity of BlBs were reported by Barberis et al. [9] and Martineau et al. [10]. Barberis et al. described the reduced amount of glucose absorption in the Caco-2TC7 monolayer human intestinal cell line in the supplementation of phosphate-buffered-saline (PBS) containing BlB juice (BlBJ) prior to glucose stimulation. Martineau et al. [10] used insulin-dependent/independent 3T3-L1, C2C12, and TC-tet cell lines. The overnight incubation of these cells with BlB extracts (BlBEs) enhanced glucose uptake even in the absence of insulin compared to the vehicle-delivered control cell cultures [10]. The basal secretion of insulin from TC-tet cells increased 2.5 times to 7.5 times with increasing glucose amounts from 6 mM to 10 mM.
In one of the in vivo studies, supplementation with bilberry extract (BBE) reduced fasting blood sugars (FBS), total glyceraldehyde (TG), TC, and LDL-C levels. BB ingestion increased islet of Langerhans size and minimized retinopathy prognosis. BBE ingestion improved insulin sensitivity and hypoglycemia by upregulating AMPK, which upregulated GLUT4, PPAR-α, ACOX, and carnitine palmitoyltransferase-1 and ACPT-1A, which is synonymous to the suppression of glucose production and increased insulin sensitivity [15]. In another crossover study, the lyophilized BBE showed an 18% decrease in (incremental rise of) plasma glucose levels in overweight/obese diabetic humans, accompanied by decreased plasma insulin levels [48]. Recently, Alnajjar et al. [49] also reported that BBE anthocyanins reduced plasma glucose, oral glucose tolerance test (OGTT), TC, high-density lipoprotein cholesterol (HDL-C), LDL-C, TG, and inflammatory adipokine [leptin, TNF-α, and high-sensitivity CRP (hs-CRP)] levels, without affecting the plasma Trolox equivalent antioxidant capacity (TEAC). The anti-inflammatory role of BB was also witnessed when BB juice (BBJ) consumption in healthy adults also reduced NF-κB-regulated inflammatory mediator expression (CRP, IL-6, IL-15, and monokine induced by gamma-interferon) and increased plasma levels of quercetin (by 32-51%) and p-coumaric acid [51]. Later on, Kolehmainen et al. [53] examined the anti-inflammatory mechanism associated with BB consumption and reported the regulation of cytoplasmic ribosomal protein expression and the toll-like receptor (TLR) signaling and β-cell receptor signaling pathways, with decreased proinflammatory macrophage and monocyte functional gene expression including C-C chemokine receptor 2 and monocyte-to-macrophage differentiation. Kim et al. [127] also reported that daily BBE consumption reduced vascular permeability by reducing vascular endothelial growth factor levels in diabetic rats, in addition to restoring tight junction protein expression including claudin-5, zonula occludens-1, and occludin [127].
An accumulated number of evidence has also suggested that BB(E) intake is also helpful in relieving the oxidative stress and oxidative stress-related complications in obese and (pre)-diabetic subjects (Table 1). BBE administration alleviated stress-induced liver damage by decreasing plasma alanine aminotransferase (ALT), malondialdehyde (MDA), and nitric oxide (NO) levels and increasing glutathione (GSH) and vitamin C levels [45]. Capillary albumin filtration (CAF) is an early diabetic complication, associated with neuropathy and hypertension. BB anthocyanins prevented experimentally-induced-CAF, improving vision and retinopathy, and remarkable CAF reductions were observed among diabetic patients [46,48,256]. The suggested mechanism for inhibiting CAF involves BB anthocyanosides, which reduced aldose reductase activity and acted as strong antioxidants or pro-reductants, inhibiting AMP and guanosine monophosphate phosphodiesterase by scavenging superoxide anions [256]. Albumin retention (AR) was assessed by the isotopic CAF test in STZ-induced diabetic rats after anthocyanoside-rich BBE administration [46], and BBE treatment was found to reduce and maintain reduced AR (14% to 1.3%) and low-frequency/high-frequency (LF/HF) ratio values in diabetic rats, without toxic effects [47]. BB-derived phenols increased the population of beneficial SCOA-producing gut bacteria (Lactobacillus spp. and Bifidobacterium spp.) and reduced bacterial metabolic syndrome biomarker genera including Enterobacteria. The dysbiosis symbolic Firmicutes/Bacteroidetes ratio, IR, and obesity-led-dysbiosis also decreased following BB consumption [49]. BB added to a fermented oatmeal drink caused a high glucose response, with a significantly reduced insulin index (Table 1) [50].

Cranberries
Cranberries (CrBs, Vaccinium macrocarpon) have also been intensively investigated for their proclaimed favorable cardiometabolic and dysmetabolic syndrome effects, likely due to phytochemicals such as oligosaccharides, procyanidins, and anthocyanins. A comprehensive list of potential well-known antioxidative, antidiabetic, and anti-inflammatory compounds found in CrB (products) or CrB extracts (CrBE) used in clinical or non-clinical interventional studies are listed in Table 2 [226][227][228]. The purified fractions of procyanidins were more antidiabetic potent than the anthocyanin and oligosaccharide fractions [257]. With respect to individual compounds, quercetin-3-galactoside, 5-caffeoylquinic acid, and quercetin-3-rhamnoside were the major compounds comprising 75-77% of total flavonols of cranberry whilst 4-caffeoylquinic acid, 3-caffeoylquinic acid, quercetin-3-arabinopyranoside, myricetin3-galactoside, quercetin, quercetin-3-arabinofuranoside, and quercetin-3-benzoylgalactoside were found in the least amounts. Many authors have initially described the in vitro antidiabetic/antiglycation activities of cranberry extracts or its products [226,257]. Barrett et al. [227] isolated ellagitannins and proanthocyanidins and demonstrated their dose-dependent inhibition of α-amylase and glucoamylase activities. CrB powder from stress-adapted portions of cranberry juice (CrB-JSB) showed increased α-amylase and glucoamylase activities compared with CrB powder, and CrB-JSB (200 mg/mL) also showed anti-hypertensive properties by inhibiting the angiotensin I-converting enzyme (ACE-1) activity [228]. Podsedek et al. [258] found that CrB extracts inhibited pancreatic lipase activities more potently than other berries, but digestive enzyme inhibitory activities were less potent. Purified CrB proanthocyanidins and oligosaccharides also reduced the levels of HbAC1 levels from 7.05% to 5.75, 5.55, and 5.45% in the hemoglobin-glucose assay, whereas the recommended HbAC1 value should be below 7%, according to the American Diabetes Association. Reduced glucose-induced AGE formation during middle glycation stages was also observed during the human serum albumin (HSA)-methylglyoxal and HSA-glucose assays [257]. CrB-derived phenolic-rich extracts decreased fluorescent AGE generation by almost 60%, which was more effective than the other berry anti-AGE activities of raspberries, apples, grapes, and strawberries. The CrB anthocyanin and procyanidin fractions also decreased fluorescent AGE generation in an arginine-methylglyoxal model by 53.3 to 56.8% [226]. The CrB oligosaccharide-rich fraction showed concentration-dependent anti-glycation activity, which reduced AGE formations by 53.3 to 56.8%, respectively, almost as strongly as the reference compound [259].
The hypoglycemic, hypo-insulinemic, and hypolipidemic properties of CrB or its byproducts have also been reported in many clinical interventions (Table 1) [5,[56][57][58][59][60]260]. Low-calorie dried cranberry (LCDC, 40 g) consumption after HFD reduced hyperglycemic and hyperlipidemic conditions, halted increases in IR/HOMA-IR and inflammatory biomarkers (TNF-α IL-6, IL-2, IL-10, IL-18, malondialdehyde-MDA) in adipose tissue, and lowered plasma lipid oxidation and oxidative stress biomarker levels in the treated group [56]. After testing LCDC, sweetened, dried CrBs (SWDC) consumed by non-insulinemic diabetic patients also reduced plasma glucose levels when compared with white bread (WB) and unsweetened dried CrBs (USCB) [260]. The plasma insulin peak following SWDC consumption appeared earlier than the insulin peaks for WB or USCB consumption and was significantly lower than those for WB and USCB. Bread consumption induced higher insulin and postprandial glucose responses, which could be diminished by incorporating CrBs [58][59][60]260]. CrB extracts (CrBEs) also halted visceral adiposity and weight gain in HFD-fed C57BL/6J mice, and improved HFD-induced hypercholesterolemia, hypertriglyceridemia, antioxidant defense mechanisms, and hepatic oxidative stress and normalized the NF-κB/IκB ratio [54]. Long-term CrBE consumption effects were also investigated [55,63], and the addition of CrBE to normal chow delayed age-related basal plasma insulin concentration declines [63]. CrBE supplementation also improved glucose responsiveness and increased insulin concentrations (7.6%) in rats, without significant HOMA-IR changes. CrBEs also induced duodenal homeobox 1 and insulin expression within islets, which enhanced insulin release, suggesting insulinotropic effect of cranberry intervention [55]. CrBEs showed the anti-obesity effect by inducing the LDL receptor expression, resulting in increased hepatic cholesterol uptake and promoted cholesterol binding to bile acids, causing increased fecal cholesterol excretion [57] CrBJ consumption was also examined in randomized clinical studies (Table 1). Healthy adults who consumed CrB juice (CrBJ) also showed reduced proinflammatory CRP levels [61]. Daily CrBJ supplementation for 60 days increased paraoxonase-1 (PON-1) and apolipoprotein (Apo)A-I expression (dysfunctioning of PON-1 and apoA-I results in glycation in T2DM patients) accompanied by decreased blood glucose and ApoB levels in T2DM patients. CrBJ inhibited GLUT-4-mediated gastric glucose uptake and aldose reductase, α-amylase, and α-glucosidase activities and protected LDL-C against oxidation [60,64,228]. Moreover, both routine-calorie CrBJ (RCCJ) and high-calorie CrBJ (HCCJ) are enriched in hexoses and sugars, which could limit their use by diabetic individuals. Therefore, low-calorie CrBJ (LCCJ) was examined in glycemic and insulinemic T2DM patients by Wilson et al. [58,59] and Novotny et al. [65]. LCCJ consumption did not affect LDL-C, HDL-C, or TC levels; however, ApoA-I, ApoA-II, ApoB, and TG levels were reduced in the treated group. Individuals with higher baseline TG or HOMA-IR values experienced more pronounced drops in TG and HOMA-IR than others [65]. Serum HbA1c levels were reduced by 11.4% and 6.02% following RCCJ and RCCJ enriched with omega-3 fatty acid consumption. Omega-3 fatty acid-enriched RCCJ also increased HDL-C levels by 21.1% compared with the baseline [63]. Additionally, folic acid consumption combined with LCCJ decreased plasma homocysteine levels and increased adiponectin and folic acid levels without any change in inflammatory biomarker levels (IL-6, IL-10, IL-18, and TNF-α) [66].
In summary, CrB consumption exerted antimetabolic syndromic effects by downregulating GLUT2 and GLUT4 expression and increasing hepatic cholesterol uptake. Diet-induced weight gain and low-grade inflammation were counteracted by the prevention of TG accumulation and strengthened antioxidative defense mechanisms. The other proposed possible mechanisms of action of CrB, or its products, consumption include reduction and inhibition of ACE-I activity and oxidative stress, accompanied by improvements in endothelium-dependent vasodilation. Furthermore, CrB-derived bioactive compounds including quercetin, inhibited microsomal TG transfer protein (MTP), preventing ApoB-containing lipoprotein assembly. Quercetin also lowered proinflammatory CRP expression in a transgenic mouse model and decreased cytokine-induced CRP expression in Hep3β cells and Chang liver cells [68,69,261], which was analogous to weight lossand polyunsaturated fatty acid (PUFA)-rich Mediterranean diet-induced CRP suppression [65,261]. Additionally, CrB consumption has beneficial effects on the gut microbiome. HFD reduced Bacteroidetes and increased Firmicutes populations in C57Bl/6J mice, which was reversed by CrBEs intake. CrBEs also increased the Akkermansia gut population, which may prevent HFD-induced increases in circulating pro-inflammatory lipopolysaccharides (LPS) [54].

Raspberries
Raspberries (RBs), especially red RBs (Rubus idaeus L.), are rich in fiber and potent therapeutic phytochemicals that have rendered raspberries as a functional food for metabolic syndrome [199]. The phytochemicals of raspberries provide the healthy and protective affects to its consumers by influencing the cell signaling pathways that affect transporters, receptors, cellular events, and gene expression. These health promoting RB phytochemicals belong to ellagitannins and anthocyanins ( Table 2) [262]. Among these two classes, RB anthocyanins are major contributors to health promoting bioactivities. The anthocyanins of RB are cyanidin-based, but with dissimilar glycosidic units. The pelargonidin-based anthocyanins are only found in RB and strawberries with a sophoroside unit attachment unique to raspberries. Ellagitannins are hydrolyzable tannins that represent another major RB phytochemical group, which are hexahydroxydiphenoyl esters with quinic acid or glucose cores. Glucose cores can attach to galloyl groups, and further arrangements within hexahydroxydiphenoyl molecules yield the ellagic acids. Numerous in vitro studies have described that RB extracts (RBE) reduced lipid oxidation, LDL-oxidation, ROS generation, and DNA damage, associated with upregulated CAT and SOD enzymatic antioxidant activities [73]. Hypoglycemic studies revealed that RBEs inhibited α-amylase, with mixed effects on α-glucosidase, and aglycones and anthocyanin promoted GSIS from pancreatic cells [263,264] Fresh RB extracts (RBEs) and freeze-dried RB powder have also been employed for in vivo evaluation (Table 1), in which oxidative stress was found to be relieved as decreased protein and lipid oxidation and damage was seen [74,75]. RB freeze-dried powder fed to obese and diabetic mice reduced ROS levels in erythrocytes by 0.87% when compared to the controls, indicating the ROS-neutralizing role of RB powder bioactive constituents during homeostasis. The RB intervention reduced ROS levels by increasing the glutathione peroxidase (GPx)/SOD ratio (2%) and GPx activity (2.13%) when compared to the placebo controls. Upregulated GPx activity also inhibited lipid peroxidation and protected against diabetes by delaying perturbed metabolism development [76]. RB juice (RBJ) given to hypercholesterolemic golden Syrian hamsters reduced plasma LDL-C levels and increased hepatic GSHPx and SOD activities by 30% and 25%, respectively [72]. Polyphenol-rich black RBs have also been combined with HCD foods for sustainable postprandial glycemic control, reducing plasma free fatty acid (FFA) and oxidative stress marker levels. RBs, combined with HCD, blunted postprandial insulinemia and ex vivo LDL-oxidation during the postprandial state, hindering glucose uptake (Table 1) [91]. Purified hydrolyzable RB tannin supplementation in rat gastritis models also demonstrated increased endogenous antioxidant defense system components and decreased inflammatory biomarkers and conditions. RB ellagic acid suppressed the specific immunoglobulin antibody response in cytotoxic cells without affecting other immunoglobulin parameters. Reduced lipid peroxidation, neutrophil infiltration, and iNOS overexpression were observed in ex vivo gastritis and Crohn's disease models [85,86]. A recent study showed that RBE consumption mitigated carcinogenic acrylamide-induced liver toxicity in male Wistar rats. RB treatment increased plasma antioxidants enzyme levels and reduced acrylamide-induced hepatic ALT, aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and gamma-glutamyltransferase (γ-GT) activities [265].
Limited human clinical trials have been performed with RBs, but the antidiabetic effects of RBEs and purified compounds have been examined in diabetic rat models (Table 1) [87,88]. Numerous anthocyanin and polyphenolic components have been hypothesized to affect starch digestion, altering postprandial glucose levels [263]. RB anthocyanin also enhanced insulin sensitivity, upregulated adiponectin expression, downregulated inflammatory cytokines, and altered AMPK phosphorylation, which is a T2DM therapeutic target [264]. A clinical trial examined RB intake with a HCD and reported no postprandial insulin and glucose response alterations [92,93]. In another study following HC-bar consumption, RB intake increased postprandial glucose levels, without changing peak glucose concentrations, and diminished postprandial insulinemia [91]. RB effects on IR and the underlying mechanisms in skeletal muscles were studied by Zhao et al. [87]. AMPK inactivation led to skin lipid accumulation and insulin sensitivity loss. This study found that AMPK-α1 is important for AMPK activation, and dietary RB powder inclusion increased insulin sensitivity by upregulating cytochrome C protein in AMPK-α1 +/+ rats [87]. The supplementation of 5% RB with HFD improved insulin sensitivity by increasing IRS-1 phosphorylation at Tyr 612 and increasing the p-Akt/Akt ratio. RB intake also attenuated nod-like receptor pyrin containing 3 (NLRP3) inflammasome activation, which is a major contributor to metabolic syndrome. NLPR3 activation, combined with caspase 1, forms caspase 1p20 and caspase 1p10. Caspase 1p20 activation releases IL-1β and IL-18. RB consumption downregulated NLPR3, caspase 1p20, IL-1β, and IL-18 expression in HFD-fed mice [88]. Recently, Zou et al. [266] also reported that 5% RB powder supplementation with HFD suppressed TNF-α, L-6, IL-1β, and NF-κB p65 expression and increased GLUT4 expression and IRS-1 and Akt phosphorylation. RB powder also increased mitochondrial biogenesis genes (PGC-1α and Nrf1) and mitochondrial abundance markers (cytochrome c, citrate synthase, and cytochrome c oxidase subunit IV) [266].
In in vivo studies, LB consumption also improved hyperinsulinemic, hyperglycemic, and dyslipidemic conditions (Table 1) [111]. LBE consumption reduced blood glucose levels (17-25%), obesity-induced hepatic steatosis (50-60%), and plasma TG, TC, and LDL-C levels (12-18%) associated with increased GLUT4 expression and AMPK and Akt phosphorylation, increasing glucose metabolism and hepatic fatty acid oxidation [111]. LB juice (LBJ) improved low-grade inflammation and endothelial function by increasing NO availability, which is necessary for the inhibition of adhesion molecules, MCP-1, ACE-1, COX-2, and other pro-inflammatory markers [112]. The LB-rich Okinawan-based Nordic diet improved anthropometric (BW, body mass index (BMI), and waist circumference) and metabolic (HOMA-IR, IR, FBS, TG, CRP, TC, and HDL-C) parameters [119]. Linderborg et al. [120] demonstrated that LB powder consumption compensated for additional glucose and lipid consumption. LBJ intake prevented HFD-induced BW gains in C57BL/6JBomTac mice. LB supplementation reduced FBS, fasting insulin, and HOMA-IR levels (Table 1) [113,114]. Hepatic lipid accumulation and liver function parameters (ALT, TG, and cholesterol) decreased after LB supplementation, more strongly than other berries [113,114]. In a recent hyperlipidic and hypercaloric meals challenge study, the LB supplementation halted increased cholesterolemia and decreased the glycemic response, CRP, and postprandial endotoxemia [121]. In an atherosclerosis ApoE −/− mouse model, whole LB consumption upregulated bile acid synthesis gene Cyp7a1, increased the cecal propionic-acid-producing bacteria proportions, and decreased triglyceridemia and atherosclerosis [115]. The insulinemic and glycemic response following oat bread consumption was also checked. The LB polysaccharide and fiber consumption, following bread consumption, reduced glucose and CRP responses [122]. Whole LB and LB nectar intake reduced postprandial glucose and insulin levels after 35 g sucrose intake, and insulin levels increased more rapidly following LB than after glucose intake. Postprandial glucose levels were also reduced following LBJ consumption. Insulin and FFA changes after LBJ consumption were similar to those observed after whole fruit consumption (Table 1) [113,114,123].
Urinary metabolomics revealed that a LBJ-containing diet increased 4-hydroxyhippuric acid and hippuric acid excretion, whereas 4-deoxythreonic acid, 3-hydroxybutanoic acid, dimethylamine, creatinine, and citric acid excretion reduced, likely due to high polyphenolic compound and benzoic acid contents in LBJ (Table 2)  Quinate levels also increased, and plasma alanine and glucose levels decreased significantly [116]. LBE and powder supplementation of HFD downregulated the expression levels of macrophage marker endothelial growth factor-like module containing mucin-like, hormone receptor-like 1 (EMR1), and LPS-sensing TLR4 (member of the toll-like receptor family activation of which results in signaling the NF-κB pathway and inflammatory cytokine production) and upregulated tight junction-associated occluding (an integral membrane protein whose modulation is associated with cellular proliferation, differentiation, signal transduction, and migration) and proglucagon (a precursor of glucagon from α-pancreatic cells). The HFD-fed control microbiome showed the upregulation of the ATP-binding cassette (ABC) transporter, cell motility, membrane transporter, bacterial chemotaxis, bacterial motility, the two-component system, flagellar assembly, transcription, and signal transduction genes, compared with the LB-treated group [283]. LB consumption enriched genes associated with lipid metabolism, nutrient transport, energy, nucleotides, and amino acids (Table 1) [113,114,117]. At the phyla level, LB supplementation affected the diversity and population of Firmicutes, Bacteroidetes, Proteobacteria, and Verrucomicrobia. The relative abundance of Bacteroidetes increased, and the relative abundance of Firmicutes decreased significantly, reducing the obesity and diabetes symbolic Firmicutes/Bacteroidetes ratio [113,114,117]. At the genus level, HFD increased Firmicutes genera populations including Lachnospiraceae, Oscillospira, and Ruminococcus. The abundance of Bacteroidetes increased following LB supplementation, due to unknown members of the S24-7 family. LB supplementation increased Parabacteriodes, Odoribacter, and Akkermansia populations. The principal component analysis confirmed LB extract-induced gut microbial profile variations. HFD increased the population density of the genera Oscillospira and Ruminococcus and the Lachnospiraceae family, microbes associated with diabetes pathogenesis progression [284], which was prevented by LB fruit/powder/extract consumption [285]. Akkermansia population increases were associated with the abundance of Akkermansia muciniphila species, which are known beneficial gut microbacteria that counteract HFD-induced adipose tissue inflammation, endotoxemia, BW gain, and IR in C57BL/6 mice [286]. Liquid chromatography (LC)-tandem mass spectrometry (MS/MS)-based LB fingerprinting identified several bioactive compounds responsible for antioxidative, antidiabetic, and anti-inflammatory properties. These bioactive compounds primarily belong to anthocyanidins, flavonols, glycosides, catechins, and different conjugates of ferulic and caffeoyl acid ( Table 2). Depending on aglycon weight, cyaniding-containing compounds were the major bioactive compounds followed by proanthocyanidins, which represent phenolic compounds in LB [236,237].

Blackberries
Blackberries (Rubus grandifolius L and Rubus fruticosus L.) are consumed fresh or as juices, jams, and liquors. Blackberries are enriched in health-promoting compounds ( Table 2) belonging to flavanals, flavanones, flavonols (kaempferol and quercetin glycosides), anthocyanins, hydroxycinnamic acids, and caffeic acid conjugates. The high-performance liquid chromatography (HPLC)-electrospray ionization (ESI)-mass spectrometry (MS)-based Rubus grandifolius L. metabolic profiling revealed 50 phytochemicals including anthocyanins, hydroxycinnamic acids, flavonols, flavanones, and ellagitannins (Table 2) [131,238,239]. These blackberry-derived compounds offered an antidiabetic and anti-obesity role by inhibiting digestive enzymes (α-and β-glucosidase, aldose reductase, lipase, and α-amylase) and exhibiting anti-glycation abilities. The blackberry α-glucosidase and α-amylase inhibitory activity was superior to the reference compounds, Acarbose and 1-Deoxynojirimycin (1-DNJ) [287]. Anthocyanins are considered to be the primary mediator of blackberry extract anti-digestive activities, and glycosides are the primary inhibitors of α-glucosidase activity. The interaction between glycosides and enzymes is considered to be competitive, suggesting that glycosides bind to enzymatic active sites [288]. Cytidine glycosides from leaf and fruit R. grandifolius extracts reduced aldose reductase activity, which is responsible for AGE accumulation in diabetic patients via dicarbonyl activity [289]. The recorded anti-glycation activity of BB fruit extracts was IC 50 = 1.87 mg/mL, and ellagitannins and flavonols were the most prominent anti-glycation agents [131,238,239]. HepG2 cells incubated with gut microbial-fermented blackberry metabolites (GMBB) and gastrointestinal-digested BB slurry (GIDBB) showed improved glucose uptake. Increased HepG2 uptake also increased glycogen synthesis. GIDBB and GMBB also maintained the desired cellular redox status by neutralizing ROS and restoring the mitochondrial membrane potential. GIDBB and GMBB supplementation restored glutathione levels, strengthening the oxidative defense system [290].
In in vivo studies, blackberry-derived purified anthocyanin-enriched and ellagitannin-enriched fractions decreased lipid peroxidation markers (TBARS and MDA) and increased hepatic and brain antioxidant enzyme activities (CAT, GSH, SOD, and GPx) [125]. Similarly, blackberry extract consumption attenuated the HFD-induced effects in an obesity-prone mouse model and prevented the increase in metabolic and lipidemic parameters, while reinforcing endogenous and exogenous antioxidant enzyme systems (Table 1) [126]. LPL activity, plasma glucose, insulin, and acyl-carnitines were also upregulated after blackberry consumption. Antioxidative enzyme system reinforcement correlated with the anti-inflammatory and anti-dyslipidemia potential of blackberry extracts [127]. The glycemic and lipidemic-controlling mechanisms of blackberry extracts were mediated through the downregulation of lipogenesis factors (FAS, SCD-1, microsomal triglyceride transfer protein, diglycerides acyltransferase, and adipose triglyceride lipase), energy coupling/uncoupling proteins (UCP-1, UCP-2, and UCP-3), pro-inflammatory cytokines (PPAR-α, Nrf2, IL-6, and TNF-α), and fatty acid β-oxidation genes (CPT-1a and ACOX-1) ( Table 1) [127], which were maintained by long-term and chronic blackberry extract consumption. Additionally, the increases in total monounsaturated fatty acid contents of adipocytes, plasma brain-derived neurotrophic factor levels, and pro-inflammatory leptin levels in HFD-fed controls were counteracted by blackberry extract consumption [128]. Human clinical trials were also run, in which healthy human subjects were given BB fruits in addition to HFD, resulting in reduced fat accumulation and increased fat oxidation. Blackberry consumption lowered postprandial glucose and lipid levels by activating AMPK and BAdTs. [291]. Pulpy blackberry juice consumption by dyslipidemic patients decreased ApoB and hs-CRP, increased ApoA-1 and HDL-C, and left other lipid parameters unaffected [134]. In healthy subjects, blackberry juice increased exogenous and endogenous antioxidant enzymes. Cyanidin, ascorbate, total ellagic acid, urate, and R-tocopherol contributed to increased plasma and urine antioxidant capacities [125,133]. Daily blackberry consumption reduced dyslipidemia and insulinemic parameters in diabetic and obese adults [132]. Blackberry polyphenolic compounds inhibit digestive enzyme activities, physically interacting with hexose absorption transporters and modulating transporter expression at the genomic level [292]. Blackberry compounds may also modulate peripheral glucose use, damaged pancreatic cell regeneration, and enhance blood glucose withdrawal by increasing insulin sensitivity (Table 1) [109,129].
The intestinal bioavailability of blackberry polyphenols and resulting impact on gut microflora have also been recently investigated. The low-absorption and cecal accumulation of BB polyphenols were the main reasons for positive health effects. The cecal microbial fermentation of blackberry polyphenols generates antidiabetic and antioxidative blackberry metabolites including C3G, 2,4,6-trihydroxybenzoic acid, coumarin, and caffeic acid. The increased cecal glycoside concentration and secondary metabolites improved glucose consumption (Table 1) [290]. The increased cecal SCFA concentration suggested an increase in SCFA-producing bacteria; however, the relative abundance of different bacterial groups was not reported [130]. Blackberry treatment altered the gut microfloral composition by increasing cecal Bacteriodetes over Firmicutes. Lactobacillus johnsonii was abundant in both blackberry-treated and control groups, whereas Lachnospiraceae dominated the blackberry group, promoting glycoside metabolism. However, Clostridiales, Enterococcus faecalis, and Bifidobacterium pseudolongum were more dominant in the control groups [131].

Strawberries
Strawberry (Fragaria × ananassa) consumption has been associated with decreased risk and occurrence of metabolic syndrome, cancer, diabetes, chronic inflammation, and hypertension. The credit of these health-promoting activities goes to its rich phytochemical contents (Table 2). Many studies analytically analyzed the crude and fractionated phytochemical contents of strawberry and found strawberry rich in antioxidative, anti-obesity, antiglycation, anti-inflammatory, and antidiabetic compounds from flavanols, flavonols, anthocyanins, hydroxycinnamic acid derivatives, hydroxybenzoic acid derivatives, ellagic acid and ellagic acid glycosides, and ellagitannins ( Table 2). The most surplus glucose-lowering acid moieties were malonic and p-coumaric acid and the most identified flavonols of strawberry were derivatives of kaempferol and quercetin glycosides. The red-coloration-granting and anti-oxidative anthocyanins of strawberries were mostly the derivatives of pelargonidin and cyanidin [240]. The hydrolysis of ellagitannins gave rise to the most important antidiabetic phytochemical called ellagic acid, which comprised more than 50% of the total polyphemolic components of strawberry. The level of ellagic acid is about 3-10 times higher in the strawberry than other berries, fruits, and nuts. It is one of the constituents due to which strawberry can regarded as a functional food [293]. In in vitro studies, strawberry ethanolic extracts inhibited pancreatic lipase activity more strongly than reference orlistat. Aqueous and ethanolic strawberry extracts inhibited adipocyte cell division and inhibited inflammatory mediator (β-hexosaminidase and histamine) release by 61.8 to 80% [294]. Strawberry polyphenolic compounds interact with glucose transporters such as SGLTI and GLUT2 and attenuate glucose uptake due to polyphenol compound competition for transporter active sites [295]. HPLC-diode array detector (DAD)-MS analysis and statistical correlations showed the contribution of pelargonidin-3-O-glucoside to glucose uptake inhibition. Strawberry extracts effectively inhibited uptake and transport of glucose up to 5% in HepG2 cultures [295]. Da Silva Pinto et al. [296] showed that the strawberry extract α-glucosidase inhibitory activity was superior to the α-amylase inhibitory activity. Strawberry-derived ellagitannin consumption (>50 mg/mL) sufficiently inhibited ACE activity [296]. Methanolic strawberry extracts activated p-AMPK/AMPK expression in HepG2 cells, resulting in fatty acid and cholesterol regulatory gene inactivation and phosphorylation including HMG-CoA-R and ACC. Activated p-AMPK/AMPK expression increased LDL receptor expression including PGC-1α and sirtuin 1 (a NAD + -dependent deacetylase that inhibit hepatic lipogenesis, stimulating FA β-oxidation, and maintaining cholesterol and bile acid levels) in HepG2 cells [297].
Numerous in vivo studies have also cited the health promoting activities of strawberry or its byproducts in animal models and human clinical trials. The intake of aqueous, alcoholic, and hydro-alcoholic strawberry extracts improved the serum glucose level, liver function (decreased serum glutamic pyruvic transaminase, serum glutamic oxaloacetic transaminase, alkaline phosphatase), lipid profile (decreased LDL-C, LDL-C/HDL-C, and LDL-C/TC ratio), and lipid oxidation markers (decreased MDA and CAT) [136,137]. Genes associated with glucose, cholesterol, and lipid metabolism [FAS, ACC, CPT-1A, malonyl-CoA, acyltransferase, ACC-α (ACACA), and acyl-CoA synthetase long-chain family member 1] were also downregulated by strawberry treatment [135]. Paquette et al. [143] used the hyperinsulinemic-euglycemic clamp methodology to examine improved insulin sensitivity and secretion after strawberry extract consumption, but did not detect improvements in fasting insulin and glucose concentrations. In animal studies, HFD supplementation with strawberry prevented weight gain without influencing food and water intake. Strawberry beverage consumption protected against postprandial lipemia by reducing TG (14%), TC (5%), and LDL-C levels (5%) in hyperlipidemic patients following HFD [144]. Sugar-rich strawberry jam consumption also attenuated glycemic index and postprandial glucose level increases in diabetic human subjects [145,298]. Strawberry jam consumption showed favorable lipid and sugar metabolism results, even compared with low-sugar strawberry jam [146]. Strawberry consumption with HCD also controlled postprandial glucose levels, affected glucose and insulin responses, and GLP-1 expression. Regular strawberry beverage and juice consumption decreased blood pressure, TC, and the TC/HDL-C ratio in diabetic patients. T2DM and CVD risk factors were also ameliorated (Table 1) [66,114,123,147]. Strawberry extracts reduced IL-6 and plasminogen activator inhibitor 1 (PAI-1) (a risk factor for atherosclerosis) levels in obese individuals after HFD/HCD, without influencing TNF-α, CRP, platelet aggregation, or fasting insulin and glucose levels [148]. In another similar study, the postprandial insulin level and inflammatory response (hs-CRP and IL-6) were reduced with increased plasma pelargonidin sulfate and pelargonidin-3-O-glucosidein levels after strawberry powder consumption with high-carbohydrate, moderate-fat meals [149]. In another recent study, strawberry-blueberry powder, consumed with a HFD/HCD, reduced BW gains (12.7%), visceral fat mass (18%), retroperitoneal and subcutaneous white adipose tissues (up to 10.45-16.5%), postprandial insulin and glucose levels, IR, and inflammatory markers (MCP-1, TNF-α, IL6, CRP, and PPAR-α), in male Wistar rats and C57BBL/6J mice (Table 1) [19,138]. Strawberry-blueberry powder exerted anti-adipogenic effects by regulating lipid metabolizing genes including PPAR-α and C/EBPα. Inflammatory and lipogenesis-related gene expression were reduced including TNF-α, IL6, and C/EBPα, adipogenesis-driver transcription factors (PPAR-γ), adiponectin, adipocyte fatty acid-binding protein, SREBF1, leptin, SCD-1, and FAS [138]. In another dose-response checking study, the intake of strawberry against the Western-type-meal reduced the oxidized low-density lipoproteins and post-meal insulin demand in insulin resistant patients [150].
Oxidative stress is a leading cause of metabolic syndrome and diabetes. Strawberry powder supplementation in an isoenergetic diet containing the oxidative-inducing antibiotic drug doxorubicin reversed doxorubicin-induced decreases in the antioxidants retinol and α-tocopherol and upregulated liver antioxidant enzymes including GPx, CAT, GSH, SOD, and GST (Table 1). Plasma hepatic stress biomarker levels including protein carbonyls and hydroperoxide were reduced by strawberry intake [139,152]. Strawberry-based foods containing carbohydrate, fat, and lipids increased total antioxidant levels (1.26 to 1.45 mmol/l) of the subjects while decreasing HbA1C (from 7.00 to 6.72%) levels. The plasma hs-CRP and MDA levels also decreased from 3.36 to 2.76 nmol/mL and 3.36 to 2.76 nmol/mL, respectively [153]. Strawberry powder intake prevented HFD-and stress-induced decreases in γ-aminobutyric acid levels and reduced oxidative stress and lipid oxidation markers, in male Wistar rats [140]. Fresh strawberry consumption reduced linseed oil-induced DNA damage and plasma oxidative marker levels and increased the plasma antioxidant status of pigs [299].
Strawberry intake effects on gut microbial ecology in diabetic subjects increased phylogenetic species richness (α-diversity) and global microbial composition (β-diversity) variations at the genus and operational taxonomic unit levels. Proteobacteria, Actinobacteria, and Verrucomicrobia were significantly altered after the strawberry intervention. Strawberry intake significantly increased the abundance of beneficial Bacteroides and Actinobacteria and decreased Akkermansia, Verrucomicrobia, Dehalobacterium, and Dorea (Firmicutes). At the genus level, the abundance of SCOA-producing Lactobacillus and "prebiotic-effect-giving" Bifidobacterium increased, whereas Dehalobacterium, Dorea, SMB53, and Turicibacter remained unaltered [141]. Additionally, a specific relationship between ingested flavonoids and microbial community patterns was identified [151]. Dietary flavanol and flavanone intake were positively associated with Eggerthela lenta. Flavonols and flavanol monomer intake was positively associated with Adlercreutzia equolifaciens (involved in phytochemical degradation) and inversely associated with Flavonifractor plauti (Gram-negative poorly understood) populations [151].

Goji Berries
Goji berry (GB, Lycium Barbarum) is a functional food and alternative therapeutic tool for T2DM treatment [155]. The major GB therapeutic phytochemicals include polysaccharides (5-8%), carotenoids (0.03-0.5%), and phenolic compounds (traces). The compounds belonging to these classes have been listed in Table 2 [123,242]. The GB is considered the best source of dipalmitin zeaxanthin carotenoids. These carotenoids showed effective protection against diabetic-induced-retinopathy [300]. The in vitro hypoglycemic tests showed the inhibitory capability of GB carotenoids was 9.6 to 82.6% and 5.7 to 15.3% for α-glucosidase and α-amylase enzymes, respectively [242]. In GB polyphenolic compounds, phenolic acids (24.7%) and flavonoids (75.3%) are major phytochemical classes. The major therapeutic flavonoids in GB are squercetin-3-O-rutinoside (from 7.1 to 232.7 mg/kg) and quercetin-3-O-hexoside (from 169.1 to 1107.7 mg/kg) whereas phenolic compounds include caffeoylquinic acid (0.34 µg/g), caffeic acid (3.73 µg/g), p-coumaric acid (6.06 µg/g), chlorogenic acid (12.4 µg/g), kaempferol-3-O-rutinoside (11.3 µg/g), quercetin-diglucoside (66.0 µg/g), and rutin (42.0 µg/g) [242]. As GB polysaccharides (GBPS) are major contributors of health-endowing activities and have been vastly investigated, this section will primarily focus on GBPS. GBPS are considered to be therapeutic in alternative medicine with immunomodulation, antioxidant, neuroprotection, anti-tumor, antidiabetic, radioprotection, anti-osteoporosis, hepatoprotection, and anti-fatigue activities. The GBPS biological activities depend on their molecular weight, chemical structure, and chain conformation [154,301]. The GBPS are among a few plant-based bioactive compounds that have shown simultaneous hypoglycemic and hypolipidemic properties. Due to hypoglycemic and anti-hyperlipidemic properties, GBPS may be a potent T2DM inhibitor, delaying disease prognosis, even after disease development. Antidiabetic assays showed impressive lipid and glucose reducing effects [155,302]. Acidic GBPS treatment in rat insulinoma cells decreased oxidative stress biomarkers and increased antioxidant enzyme systems. GBPS treatment of IR alloxan-treated-HepG2 cells protected against oxidative stress and improved cell survival and proliferation [302]. Similarly, the GBPS was further checked for possibly hampering glucose uptake in the gut and intestine. The GBPS intensively reduced glucose absorption in a dose-dependent manner by competing for intestinal absorption [303]. Rat insulinoma cells incubated with GBPS rescued damaged pancreatic cells, improved the survival rate, and encouraged insulin secretion. The IR cell model was supplemented with purified GBPS, which upregulated glucose consumption. GBPS was easily translocated and transported across the Caco-2 intestinal cell membrane through the SGLT-1 transporter, producing a hypoglycemic effect. Therefore, GBPS is a plant-based bioactive compound that shows simultaneous hypoglycemic and hypolipidemic properties [303]. Purified GBPS fractions showed dose-dependent hypoglycemic activities, resulting in increased glucose uptake [156,303]. Besides GBPS, GB carotenoids have also shown antidiabetic and α-glucosidase and α-amylase enzyme inhibitory activities [242].
The hypolipidemic effects of GB intake have been studied by in vivo approaches (Table 1), but human clinical trials for GB have been limited, with most studies performed using small sample sizes in China. GB consumption effectively reduced serum lipid peroxide species in diabetic patients. Reductions in waist circumference, TG, transaminase, and TC levels were reported in metabolic syndrome patients following routine GB intake. Lipid profile improvements were accompanied by increased GSH and CAT enzymatic activities [167]. GB anthocyanins reduced BW gain (17.4 to 38.7%) by increasing fecal fatty acid contents and downregulating IL-6, TNF-α, IFN-γ, NF-κB, and iNOS gene expression [157]. GBPS decoction treatment of alloxan-induced, diabetic, obese rabbits effectively reduced blood glucose levels. GBPS substantially decreased serum TG (−4.27%), TC (−3.5%), LDL-C levels, and increased HDL-C serum levels (0.78) [154]. The hypoglycemic and hypolipidemic effects of GBPS were later confirmed by the works of Zhao et al. [158]. Supplementation of HFD with GBPS decreased HOMA-IR, fasting and postprandial insulin and glucose levels, serum TG, TC, and LDL-C levels, and weight gain [158].
The oxidative stress relieving effect of GBPS was also checked ( Table 1). The effect of GBPS treatment on the kidneys of STZ-induced diabetic rats increased kidney antioxidant enzymes including CAT, SOD, GBPx, GST, and GSH [170]. The supplementation of GB in the form of GB milkshakes increased plasma zeaxanthin and antioxidant levels by 57 and 26%, respectively. GB juice (GBJ) also increased GSH peroxidase (GSH-Px) and SOD by 9.87% and 8.7%, respectively and decreased MDA levels by 5.95% [166]. GBPS intake also protected against glaucoma, which was confirmed in retinal ganglion cells, and disrupted intraocular pressure [159]. GBPS administration to C57BL/6 mice reversed oxidative stress, dyslipidemia, and diabetic changes. GBPS administration downregulated nitrotyrosine and MDA expression and increased antioxidant enzymes such as CAT, GPx, and Cu/Zn SOD. GBPS intake also diminished pro-inflammatory biomarkers including TNF-α, IL-1β, iNOS, and COX-2. Following pro-inflammatory marker reduction, liver injury biomarkers, called chemokines, were also reduced. The liver regeneration process was also observed following GB intake, enhancing liver regeneration biomarkers [168,304].
With respect to hypoglycemic effect specifically (Table 1), Zhao et al. [160] confirmed the antidiabetic characteristics of GBPS, which increased GLUT-4 expression in the skeletal muscle plasma membrane. Purified GBPS in pancreatic cells increased glucose uptake and metabolism, insulin secretion, and proliferation. The enhanced glucose metabolism mechanism was associated with increased hepatic hexokinase and pyruvate kinase expression/activity (Table 1) [26,161]. GBPS may block the ATP-sensitive K + channel, activate glycogen synthetase and insulin-like growth factor, enhance peripheral glucose utilization, or inhibit glucagon releasing factors in pancreatic α-cells [197]. In a recent single meal challenge study, increased glucose and lipid consumption were observed in GB-treated patients, associated with increased respiratory quotients, oxygen usage, and carbon dioxide release. However, no single-dose effects on substrate oxidation and postprandial-energy-expenditure were reported [169]. Du et al. [162] compared GBPS with metformin and reported similar normalization effects on blood glucose and insulin levels. This study also reported reduced IL-2, IL-6, TNF-α, intercellular adhesion molecule-1 (ICAM-1), MCP-1, and blood urea/nitrogen levels, inhibited albuminuria, and reversed histopathological alterations. GBPS treatment in HFD/HCD-fed rats also demonstrated hypoglycemic and hypolipidemic effects [115]. Ni et al. [163] examined the potential neuroprotective effects of aqueous GB extracts. Retinal apoptosis causes photoreceptor degradation and diabetic retinopathy (DN), and GB carotenoid supplementation in rats hampered caspase-2-induced apoptosis, protecting photoreceptors [163]. Prolonged or chronic hyperglycemia downregulates luteolin and zeaxanthin-metabolizing gene expression, causing retinopathy. GB carotenoids protected against diabetes-induced retinopathy. GB supplementation upregulated carotenoid metabolism genes and retina biogenesis in STZ-induced diabetic rats [300]. GB also contains taurine, a non-essential amino acid, and GB-derived taurine enhanced PPAR-γ activity and elevated cAMP levels, hampering the prognosis of DN with reversal of epithelial barrier impairments [300].
In in vivo studies, AB fruit proved to be a very useful therapeutic agent for circumventing oxidative stress, and controlling dyslipidemic and metabolic syndrome conditions ( Table 1). The supplementation of AB fruit effectively prevented protein oxidation as increased protein sulfhydryl groups were observed, with decreased protein oxidation biomarker carbonyl proteins. A single AB pulp dose enhanced plasma antioxidant capacity 7-fold 3 h after its consumption. Plasma anthocyanins reached maximum levels 2.2 h after AB pulp consumption [179,180]. In another in vivo study, AB pulp supplementation in oxidatively damaged mutant Drosophila melanogaster, in combination with HFD, reversed HFD-induced oxidative stress damage and prolonged the lifespan expectancy by 22% [172,308]. AB supplementation with exercise improved hepatic oxidation status by reducing inflammatory MCP-1 expression, SOD activity, redox-sensitive signaling pathway activation, ROS generation, and ROS stress [173]. To elucidate the antidiabetic and antioxidative molecular mechanism of AB, AB-mediated transcript-level changes were examined in 12 genes associated with JNK, nutrient sensing, and insulin-like signaling pathways [309]. PEPCK genes, involved in glyceroneogenesis and gluconeogenesis, were reduced in the AB pulp group. Cholesterolemic diet consumption decreased lethal/essential or life gene (lefl2) expression, which was reversed by AB fruit consumption. Two JNK targets, metallothionein A, and glutathione S transferase D1, which have antioxidant activities, were upregulated after AB consumption without affecting the remaining JNK downstream target genes (Ferritin 1 heavy chain homolog, Ice, Heat shock protein 68, and Puckered). Moreover, AB ingestion promoted longevity by intensifying stress response pathway activity and suppressing PEPCK genes [172,309]. Treatment with AB seed extracts also reduced blood pressure, the hypertension biomarker renin, and DN biomarker levels (creatinine, urea, creatin, and albumin). Diabetes onset leads to oxidative stress and hypertension, decreasing the number of glomeruli per area per kidney, a major DN marker. AB seed extracts reduced kidney volume expansion and prevented a decrease in the number of glomeruli per area per kidney [174]. AB seed extracts substantially reduced renal injury (resulting in reduced urea and creatine excretion), hampering renal fibrosis progression. The diabetes-induced glomerular filtration barrier injury markers, podocin and nephrin, decreased in diabetic male Wistar rats, whereas AB seed extract treatment restored these levels. AB seed extract treatment also reduced renal proinflammatory cytokines and oxidative stress biomarkers, reinforcing the anti-oxidative defense system [174]. The effects of exercise and AB seed-rendered extract consumption in STZ and HFD-induced diabetic rats reduced HbA1C, glycemia, serum insulin, HOMA-IR, serum TG, TC, LDL-C, and HDL-C levels [176]. Insulin signaling components (insulin receptors, pAKT, and AKT) in skeletal muscles were upregulated following AB seed extract consumption and exercise [176]. Reduced adiponectin levels are observed in T2DM, associated with deregulated sugar and lipid metabolism, and AB seed extracts reversed this effect. AB seeds induced increased GLUT-4 expression and glucose uptake due to AMPK activation [176] and increased GLP-1 and incretin levels with reduced leptin and inflammatory cytokine expression, which were not observed in HFD-fed rats treated with exercise alone. Increased GLP-1 and incretin expression promotes insulin secretion, suppressing gastric emptying, and glucagon synthase [176,310]. The same research group then used the AB seed extracts to check the anti-obesity features in the C57BL/6 mice strain fed on HFD. HFD supplemented with the AB seed extract prevented weight gain in mice [311]. Adiponectin levels, which are responsible for lipid metabolism, decreased in HFD-fed mice and were restored by AB seed extract supplementation. AB seed extracts increased glucose and lipid metabolizing protein expression including pAMPK/AMPK, pACC/ACC, HMG-CoA, and various transporters including ATP-binding cassette sub-family G member 5-ABCG5 and ATP-binding cassette sub-family G member 8-ABCG8, while reducing SREBP-1c expression. Similarly, protein and lipid oxidation products including carbonyl proteins and MDA were reduced by strengthening the anti-oxidative enzyme system [311].
Regarding glucose-lowering effect, recently, the human AB fruit consumption with normal meals decreased FBS and mean plasma insulin levels after one month. Plasma TG, TC, and LDL-C levels, and the LDL-C/HDL-C ratio also decreased, with increased plasma HDL-C levels [181]. The AB consumption with HFD enhanced fecal cholesterol contents, with no influence on low-grade-inflammation biomarkers [113]. Freeze-dried AB fruit pulp reversed the HFD-induced alterations in PEPCK expression [312]. Aqueous ethanolic AB extracts restored mitochondrial complex I function by modulating NADH:ubiquinone oxidoreductase core unit 7 and 8 expression. NLRP3 (a component of inflammasome) and caspase 1/caspase 3/caspase 8 (Interleukin-1 converting enzyme family, which initiates inflammatory response) were downregulated in oxidative-agent-treated macrophages [313]. AB supplementation also interfered with hepatic cholesterolemic metabolism. AB attenuated the high-cholesterol diet effects by reducing weight gain, TC and LDL-C levels, and key regulatory gene expression associated with the cholesterol biosynthesis pathway including HMG CoA-R, EBP-2, ApoB100, LDL-R, ABCG8, and CYP7A1 [175]. Intensive feeding with freeze-dried AB pulp attenuated HFD-induced hepatic steatosis by improving IR, adiponectin expression, adiponectin receptor 2, SREBP-1c, PPAR-α, and its target gene, CPT. Fat accumulating gene expression including UCP-2 and fatty acid translocase were reduced by AB treatment [179]. Both lipid accumulation and oxidation were reduced in zebrafish fed with a high-cholesterol diet, and reduced serum TC, LDL-C, and MDA levels were observed in AB-treated zebrafish [171]. Aside from lipid oxidation inhibition, the AB intake also prevented amino acid oxidation after HCD, reducing protein carbonyls and sulfhydryl groups, which are important protein damage biomarkers. Reduced arylesterase and PON activities and reduced hepatic ALT, AST, and ALP levels demonstrated improved hepatic operation [175]. AB powder also improved anti-inflammatory mechanisms after HFD by improving glucose intolerance and reducing IL-6 and TNF-α concentrations in epididymal adipose tissue [312].
A comprehensive study examining AB intake on the gut microflora is currently lacking. Simulated digestion studies examining AB polyphenols inhibited the growth of symbiotic and saccharolytic Bacteroides, Prevotella, and Clostridium histolyticum. AB polyphenols showed favorable effects on the intestinal SCFA bacteria population including LAB [178]. Guergoletto et al. [177] noted increased intestinal populations of obesity-protecting bacteria (i.e., Bifidobacterium spp., Eubacterium rectale-Clostridium coccoides group, Bacteroides spp-Prevotella group, and FOS-Raftilose P95). However, AB polyphenols showed no considerable effects on Enterococcus spp and C. histolyticum [177].
Addressing the anti-inflammatory potential of CB, in in vivo clinical studies, Kardum et al. [195,196] administered CBJ to patients with pharmacologically incurable grade I hypertension and high blood pressure, resulting in decreased systolic/diastolic blood pressure, with a stronger effect associated with long-term consumption. CBEs also reduced systolic/diastolic blood pressure [197], particularly in congenital heart disease patients [198]. Following hypertension, inflammation is another diabetes complication and numerous studies have cited the anti-inflammatory potential of BCB or its juice consumption. Increased PPAR-γ2 expression was attenuated by BCBEs, reducing downstream lipid metabolizing PPAR-γ2 target expression such as PGE receptor and LPL, decreasing intracellular lipid droplet accumulation [184]. Regular BCBJ consumption improved chronic inflammatory conditions, lowering IFN-γ and TNF-α levels [195,196,198]. The immunomodulatory effects of BCB intake have also been discussed in the literature in STZ-induced male Wistar rats. DM causes immune imbalances because damaged pancreatic cells trigger macrophage and T lymphocyte infiltration, which lesion β-cells. BCB consumption by STZ-induced male Wistar rats reduced fibrinogen, TNF-α, and IFN-γ levels, which returned to their normal values 72 h post-administration of BCB [199].
decreased oxidative stress production [183]. BCBE pretreatment (0.001, 0.01, 0.1, or 1 mg/mL) of diabetic hepatic cells line RINm5F) reduced cytokine-induced-oxidative stress from 19.3-0.39 µM to 14.9-0.35 µM [183]. Similarly, BCBE pretreatment of HAECs nullified the TNF-α-induced ICAM-1 and VCAM-1 expression by 35 and 45%, respectively, in a dose-dependent manner. BCBEs also prevented NF-κB p65 phosphorylation, which activates the pro-inflammatory transcription factor NF-κB [317,318]. Glucose is transported across the cell membrane via glucose transporter (i.e., GLUT-2), followed by glycolysis and pyruvate production. Afterward, pyruvate is used for the generation of ATP in mitochondria. Here, in connection with the electron transport chain, radicals, like superoxide anion (O2 •-), are also produced and simultaneously neutralized by the enzymatic antioxidant SOD. SOD converts the O2 •into harmless O2 and another radical H2O2. In addition to H2O2 diffusion through the cell membrane, H2O2 is also scavenged by CAT and GPx resulting in water and oxygen production. Chokeberry-derived anthocyanins strengthen this inherent enzymatic antioxidant system (i.e., SOD, CAT, and GPx), which can more actively neutralize the radicals generated during glucose metabolism. H2O2-stimulated reduction of GSH is also ameliorated by chokeberry anthocyanins. Chokeberry-derived anthocyanins strengthen this inherent enzymatic antioxidant system (i.e., SOD, CAT, and GPx), which can more actively neutralize the radicals generated during glucose metabolism. H 2 O 2 -stimulated reduction of GSH is also ameliorated by chokeberry anthocyanins. Chokeberry anthocyanins also replenish the pool of insulin by increasing the insulin gene expression. Proinsulin, a precursor of insulin, folded in the endoplasmic reticulum, is transported to the Golgi apparatus. Chokeberry anthocyanins can also influence the opening of the voltage-gated Ca 2+ channels, leading to an increased fusion of insulin granules with the cell membrane (Source: Rugina et al. [316]).
Regarding hypoglycemic response, BCBJ consumption also modulated circulating lipid levels including TG, TC, and LDL-C in mild hypertensive patients (Table 1) [185,198]. BCBJ consumption also reduced serum TG, TC, and LDL-C levels in hypercholesterolemic healthy subjects [128]. Long-term BCB consumption was recommended for desirable hypoglycemic and hypolipidemic effects [128,185,198]. Valcheva-Kuzmanova et al. [186] demonstrated up to 39% reduced postprandial serum TG levels in STZ-induced diabetic rats after BCBJ consumption and reported encouraging results for both diabetic and healthy rats. However, Lipińska and Jóźwik [187] showed pronounced hypolipidemic effects only in diabetic Polish Merino lambs including significantly decreased serum LDL-C and increased HDL-C levels, without significant effects on serum TC levels. In addition to preventing increased plasma glucose, homocysteine, and fibrinogen levels, reduced serum lipid levels (TG, TC, and LDL-C) were observed in STZ-induced diabetic rats [201]. Hepatic steatosis and NAFLD were prevented by BCB treatment in HFD-fed diabetic C57BL/6N mice. Daily BCBE administration prevented increased body, liver, and epididymis weights [188]. Several possible mechanisms have been proposed in the literature referring to the lipid-lowering property of BCB consumption. The BCB hypoglycemic effect may be associated with increased cynidine-induced lipid metabolism, reduced catechin-induced cholesterol absorption, and the flavonoid-influenced downregulation of cholesterol synthesis enzymes including HMG-CA-R, cholesterol acyltransferase, and acyl-CoA [185,188].
The anti-oxidative, anti-obesity, and anti-diabetic potential of BCB was checked in the various diabetic model mice (Table 1), where BCB increased serum insulin secretion with reduced pro-inflammatory cytokine expression (MAPKs, NF-κB, COX-2, and iNOS) in a dose-dependent manner [183]. Jurgoński et al. [189] fed BCBE to high-fructose-diet-fed STZ-induced diabetic rats and showed increased maltase and sucrase activity, and decreased lactase production in the small intestinal mucosal membrane. Daily BCBJ consumption lowered postprandial glucose levels after OGTT, regardless of gender, and reduced ACE, α-glucosidase, and DPP IV activities in a dose-dependent manner [182]. Valcheva-Kuzmanova et al. [186] showed lower postprandial glucose levels (up to 44%) in STZ-induced diabetic rats after BCB consumption, and Lipińska and Jóźwik [187] demonstrated a pronounced FBS decrease in BCB-treated Polish merino lambs. Postprandial OGTT results for BCB-treated mice decreased, with improved intraperitoneal ITT results [185]. Similarly, consumption by STZ-induced diabetic mice reduced serum TBARS levels and mitigated lipid peroxidation (by 29-50%) and kidney hypertrophy [190]. Following CCl 4 administration, the decreased concentration of CAT, GPx, and GR were increased by 117%, 56% and 44%, respectively, after the intake of BCBJ. Protein carbonyls, protein oxidation biomarkers, decreased by 22% after BCBJ consumption in male Wistar rats [190]. BCBJ consumption by the KK-Ay and C57BL/6JmsSlc mice reduced BW, white adipose tissue weight, α-glucosidase and DPP IV activity, and blood TG levels. Mesenteric, epididymal, subcutaneous, and retroperitoneal white adipose tissue weights were reduced by 26%, 27%, 48%, and 38% compared with those in control animals [39]. Bhaswant et al. [191] administered BCBJ to male Wister HFD-and HCD-fed rats and observed reduced BW gain and feed conversion efficiency. Total body fat mass, BMI, abdominal fat (epididymal, omental fat pads, and retroperitoneal), and visceral adiposity index reductions were more pronounced in Wistar rats fed with BCBJ than in those fed with biofunctional purple maize flour. BCBJ consumption also reduced liver injury biomarkers (ALP, AST, and ALT), although these levels remained within the normal range [191]. In another study, male Wistar rats were fed high-fructose diets containing BCBE, resulting in increased plasma HDL-C and adiponectin levels [192]. IRS-1/2 and PI3K regulatory subunit protein expression increased by 2.3-, 1.8-, and 1.5-times, respectively, along with inhibiting the phosphatase and tensin homolog (Pten) (−0.61%) expression. The expression level of glucose uptake, transportation (GLUT1 and GLUT4) and gluconeogenesis (GYS) was uplifted by 1.5 times compared to high-fructose fed control rats. BCB consumption inhibited lipogenesis and lipid accumulation by reducing fatty acid-binding protein, FAS, and LPL (lipogenesis protein) by 0.6-0.7%. Improved glucose and lipid metabolism and increased glucose and lipid regulatory metabolizing protein expression (adiponectin and PPAR-γ) were also observed [192]. Cynidine 3, 5-diglucoide was identified as a DPP IV inhibitor. DPP IV cleaves incertins including GLP-I and glucose-dependent-insulinotropic polypeptide at their N-terminal regions, resulting in decreased insulin secretion [182,186]. Cyanidin glycosides including 3-galactoside, 3-glucoside, cyanidin 3-O-β-glucoside3-arabinoside, and 3-xyloside enhance glucose uptake and GLUT4 translocation. Diabetes-associated hyperlipidemic complications were improved by regulating the FOXO1-mediated adipose TG lipase transcription [185].
Cynidine-3-O-glucoside, cynidine-3-O-galactoside, cynidine-3-O-xyloside, and cynidine-3-O-arabinoside are the primary antidiabetic and anti-oxidative anthocyanin compounds in BCBJ (Table 2). No studies have examined the CB consumption effects on gut microflora in diabetic/obese individuals, although CB consumption has been examined in healthy individuals [202]. Chronic BC capsule treatment influenced the intestinal diversity of health promoting and SCOA-producing Anaerostipes, Bifidobacterium, Faecalibacterium, and Clostridium genera. CBE capsules increased the relative abundance of Anaerostipes, whereas whole CB capsules increased Bacteroides and Clostridium XiV populations. Correlation analysis between gut microbial genera and plasma polyphenolic contents revealed that Prevotella, Dialister, Desulfovibrio, and Bifidobacteria were responsible for the increased levels of nine, eight, seven, and six health promoting plasma CB metabolites, respectively, including derivatives of benzoic acid, hippuric acid, phenylacetic acid, cinnamic acid, caffeic acid, flavonols, (iso)ferulic acid, benzaldehydes, and pyrogallol [202].

Black Currants
Black currant (BCT, Ribes nigrum L.) is cultivated primarily in Europe, New Zealand, and Australia. BCT is a rich source of anthocyanins that represent 95% of polyphenolic compounds, with the remaining 5% including other minor polyphenol classes. Delphinidin-3-rutinoside (D3R) is the major BCT antidiabetic anthocyanin compound that improves glucose tolerance. In BCT nectar, cynidine and delphinidin rutinosides are the dominating anthocyanins, followed by glucoside compounds [93,319]. A full list of other therapeutic BCT compounds are presented in Table 2. GLP-1 and AMPK are the primary BCT polyphenolic compound targets. BCT extract (BCTE) consumption increased GLP-1 secretion. GLP-1, an incretin, promotes pancreatic β-cell division and glucose-dependent insulin release [212,213,289]. BCTEs contain approximately 70% anthocyanins (especially rutinosides and glucosides of delphinidin and cyanidin) and are considered to be effective α-glucosidase inhibitors [289]. Apple and BCT juice (BCTJ) treatment in human Caco-2 cells reduced sodium-independent and total glucose uptake by 46 and 51%, respectively. In oocytes, apple and BCTJ-derived phloretin and phlorizin effectively reduced glucose uptake by 58 and 85%, respectively [213]. The BCT polysaccharide BCP-I also showed remarkable antiglycation activities due to its inhibitory effects on Amadori products [320]. BCT powder incorporation into high-glycemic-indexed food decreased glucose release and increased antioxidant capacities [321].
In addition to in vitro studies, glucose and lipid lowering effect of BC extracts or its screened anthocyanins have also been investigated enormously in various in vivo studies ( Table 1). The intake of major BCT anthocyanin consumption, in combination with intraperitoneal glucose administration, prevented increased serum glucose concentrations with the simultaneous increase in serum insulin levels [203]. Improved hyperglycemia and hypoinsulinemia are caused by the GLP-activation-induced increase in insulin secretion. BCT powder, administered for six days before OGTT, improved postprandial plasma insulin and glucose levels in healthy human subjects [214]. BCTE consumed with a normal diet by KK-Ay mice induced hypoglycemia and modulated basal GLP-1 concentrations without affecting plasma insulin levels, food intake, or BW [204]. Proglucagon cleaving agent proprotein convertase subtilisin/Kexin type 1, which processes proglucagon into GLP-1, increased. BCTE treatments also increased AMPK phosphorylation in skeletal muscles, upregulating insulin-independent glucose uptake pathways by increasing downstream target expression including GLUT-4 and the translocating plasma membrane [204]. Previously, Esposito et al. [205] also conducted an anti-diabetic study using 1% BCT powder, which decreased rat BWs, irrespective of dietary fat contents. Microbiological fecal analyses showed increased fecal anthocyanin contents, especially in lean animals. These results suggested that gut microflora more actively transform polyphenolic metabolites in lean animals rather than in obese animals. BCT supplementation reversed the postprandial glucose levels associated with HFD; however, the postprandial glucose level continued to rise due to gut microbiota disruption. Similarly, BCT improved HFD-induced insulin, but the gut microflora disruption increased IR. These results signified the importance of gut microflora during the BCT polyphenol metabolization and biotransformation [205]. The supplementation of 0.1% BCTE in HFD reduced retroperitoneal and epididymal adipose fat. BCTE hypolipidemic characteristics were verified by upregulated lipogenic/lipid metabolizing genes in adipocytes including UCP-2, UCP-3, mitochondrial transcription factor A (TFAM), PPAR-α, SREBP-1c, FAS, and SCD-1, and fatty acid oxidation genes including CPT-1α and 1β [206]. Repressed inflammatory marker expression in macrophages has also been reported. Reduced IKKε (an enzyme complex that is involved in propagating the cellular response to inflammation) and TANK-binding kinase 1 (a member of IKK subfamily, which activates in response to lipopolysaccharides) expression was observed in the BCT-treated group, compared with upregulation in the HFD group [206,212]. BCTJ/nectar waste extract (pomace) was much richer in anthocyanins than in BCT pulp. Phytochemically, BCT pomace extracts are rich in D3G, D3R, cyanidin-3-rutinoside, glycosides, and flavonol aglycones. HFD supplemented with BCT pomace extracts did not affect food intake or BW. Fat in the diet increases small intestinal digesta viscosity, whereas BCT pomace polyphenolic extracts made this digesta more acidic [207]. The polyphenolic-rich Nutrients 2020, 12, 2538 48 of 69 BCTE also reduced cecal tissue mass and increased ammonia contents. HFD reduced bacterial glycolytic enzyme activities such as αand β-galactosidases and αand β-glucosidases, which were restored by BCT pomace extract. BCT supplementation reduced β-glucuronidase activity, which is associated with reduced pressure on the intestinal detoxification mechanism [208]. BCT supplementation reduced the cecal putrefactive SFCA concentration, regardless of diet [207,208]. BCTE consumption increased mean fat oxidation during prolonged cycling exercise by endurance-trained females with reduced mean carbohydrate oxidation [215]. However, the opposite outcome was observed when BCTJ was consumed before exercise, without significant effects on blood lactate, glucose, and MDA levels [216].
In addition to HFD, the high-fructose-diet or HCD were also involved in the hyperglycemic, hyperlipidemic, and metabolic syndrome conditions. BCTE administration with high-fructose-diet prevented increases in liver weight, BW, and epididymal fat pad weight. OGTT results improved, with decreased p-AMPK and IRS-1 levels in the BCTE-treated group. BCTE supplementation also decreased high-fructose-diet-induced hyperglycemic marker expression and reduced atherosclerosis risk by diminishing ICAM-1, VCAM-1, E-selectin, endothelin, and eNOS expression levels in aortic tissues [209]. Consumption of an anthocyanin-rich sugar-free BCT drink with a normal-carbohydrate diet delayed the glycemic and insulinemic response with reduced incretin and GLP-1 expression [212,213]. The consumption of BB, BCT, CrB, and strawberries restricted post-meal blood insulin and glucose fluctuations induced by HFD/HCD. LB combined with BCT (whole or nectar) ameliorated postprandial insulinemic and glycemic control and response [62,123,267]. The irreversible hydrolysis of sucrose into fructose and glucose under high temperature and low pH conditions produces invertase sugars. BCT nectar, sweetened with invertase sugars, reduced postprandial blood glucose levels and the maximal blood glucose level by 33 and 87%, respectively. The nectar x time interaction also revealed lower insulin secretion at 15 and 30 min of post-nectar-consumption and expulsion of insulin from the baseline was cut by 13% compared to the reference [62,123,267].
Regarding oxidative stress and diabetes-related complications, ample amounts of evidence have suggested that anthocyanins from BC exert anti-hypertensive, anti-inflammatory, anti-fibrotic, and anti-hepatic steatosis effects by limiting lipogenesis and gluconeogenesis (Table 2) [217]. BCT-derived purified extracts administered to hepatic steatosis model C57BL/6J mice did not prevent BW loss, but serum ALT and AST levels increased. BCT anthocyanin supplementation decreased hepatic TG and TC accumulation [304]. Histological analysis showed that microvascular steatosis, inflammatory cell infiltration, and hepatocyte ballooning were reduced by (up to 50%) BCT anthocyanins. Hepatic stellate cells produce collagen during fibrogenesis. Reduced α-smooth muscle actin and upregulated carbamoyl phosphate synthase 1 suggest hepatic stellate cell inhibition, inhibiting fibrosis and non-alcoholic hepatic steatosis. BCTE treatment increased mitochondrial biogenesis and decreased the AMPK/pAMPK ratio and pivotal mitochondrial biogenesis regulators including PGC-1α and β, Nrf-1 and -2, and TFAM. Mitochondrial fatty acid β-oxidation occurs due to mitochondrial oxidative phosphorylation, which was reversed through effects on PPAR-α, CPT-1, and medium-chain acyl CoA dehydrogenase expression [62,93,123,217,304,319].
With respect to in vivo antidiabetic and anti-obesity potential of MqB (Table 1), Rojo et al. [220] fed C57BL/BJ mice anthocyanin-rich MqBEs, which significantly decreased plasma glucose levels following glucose ingestion. Anthocyanin-rich MqBEs also reduced G6Pase and increased insulin sensitivity. Glucose uptake was upregulated in L6 skeletal muscle cells, without toxic effects [220]. Delphinidin 3-sambubioside-5-glucoside, a signature MqB biomarker, showed an equivalent capacity to metformin for normalizing blood glucose levels [326]. Lipid accumulation was inhibited by 4-11% by MqBE treatment in 3T3-L1 mice; however, lipogenesis was inhibited by 6-38% during adipocyte differentiation. The lipogenesis inhibitor protein, preadipocyte factor 1, was upregulated in MqB-treated 3T3-L1 mice. MqB supplementation also exerted an anti-inflammatory response by reducing ROS expression by 9.8 to 61.8%. The expression of COX-2 and production of PGE2 was also evaluated in the RAW 264.7 macrophages to understand the anti-inflammatory mechanism of MqB. MqB inhibited PGE2 expression and reduced COX-2 expression (by 16.2-62%), inhibiting LPS-induced iNOS/NO production and COX-2/PGE2 pathway activation in macrophages [218,326]. MqB delphinidin anthocyanins inhibited glucose uptake and transport from the rat duodenum by inhibiting SGLT-1. The inclusion of MqB-derived 35% anthocyanins and 25% delphinidin glycosides in a rice-chicken diet effectively reduced postprandial glucose levels. Purified delphinidin anthocyanin supplementation with a normal diet reduced fasting glucose and insulin levels [218,326]. MqB anthocyanins, in capsular form (3 × 150 mg per day), decreased oxidized LDL-C and 8-iso-prostaglandin F2α, a urinary excretion oxidative stress marker [221,326]. Furthermore, MqB-derived-delphinidin treatment effectively increased AMPK phosphorylation. Gene expression analysis showed that sodium palmitate exposure upregulated lipid accumulating genes such as SREBF1, CPT1-A, patatin-like phospholipase domain containing 2, and FASN, which were reduced by delphinidin treatment. Delphinidin supplementation limited weight gain in HFD-fed C57BL/6Nhsd mice, but not increased liver weight. Glucose homeostasis variations induced by HFD/HCD were also minimized by delphinidin treatment [222]. Hidalgo et al. [327] showed that delphinidin supplementation in rat jejunum tissues/cells reduced the short circuit current generated by glucose addition to an Ussing chamber. Delphinidin halted 3-O-methyl-glucose incorporation in the mouse intestine, with effects similar to the inhibition of electrogenic glucose transportation by SGLT-1 [328]. In response to delphinidin treatment and FFA1 activation, the Gαq/11 subunit was coupled with inositol trisphosphate, propionyl l-carnitine, and diacylglycerol upregulation, which modulates intracellular Ca 2+ from the endoplasmic reticulum. In previous studies, delphinidin treatment also caused intracellular Ca 2+ release and prevented 3-O-methyl-glucose uptake by FFA1 activation. Therefore, delphinidin may represent a new ligand class that can reduce intestinal glucose uptake through FFA1 activation and increased cAMP expression [327].
MqB juice (MqBJ) consumption limited oxidation in human subjects ( Table 2). The copper-triggered LDL-C oxidation time lag increased with MqBJ consumption because anthocyanins chelate copper. LDL-C oxidation time is proportional to the MqBJ anti-oxidative capacity. H 2 O 2 treatment-induced increased oxidative stress was reduced by MqBJ treatment in human umbilical vein endothelial cells [329]. A pilot study showed that the daily MqBE consumption with folic acid and berberine effectively reduced TC, LDL-C, oxidized cholesterol glycemia, free radical levels, and increased serum antioxidant capacity. Furthermore, the insulinemia, microalbuminuria, HDL, CRP, and TG values increased. MqB treatment counteracted hyperlipidemia, hyperglycemia, and ROS production in metabolic syndrome patients. An MqB polyphenol-based-nutraceutical reversed low-grade-inflammation, oxidative stress, and atherosclerogenesis in pre-diabetic patients [223]. MqBE and purified anthocyanin consumption showed positive outcomes for post-stroke stress and depression in diabetic mice. MqBEs and anthocyanins can mitigate anhedonia in humans. Anhedonic mice consumed less sucrose with increased water intake, which was mitigated by MqBE or purified anthocyanins in a dose-dependent-manner. Stroke and stress biomarkers such as TBARS, SOD, CAT, and GSH levels decreased following MqBE/anthocyanin treatment in stroke model mice [219].

Conclusions
This review aimed to collect and discuss scientific evidence regarding the positive role of berry consumption on the prevention of diabetes and its complications. Available human, animal, and in vitro studies were collected and comprehensively presented. This review demonstrated that berry product consumption represents a reliable and effective method for preventing and managing metabolic hyperglycemic and hyperlipidemic conditions. Variations in postprandial glucose and insulin levels could be reversed and normalized in diabetic subjects following post-meal berry consumption as supplements for HFD/HCD. Berry anthocyanins promoted glucose uptake and metabolism by activating pAMPK/AMPK, GLUT-4, and SGLUT-1, and inhibited weight gain and pro-inflammatory responses, downregulating lipogenesis genes (adipogenic transcription factors and PPAR-γ2) and pro-inflammatory cytokine production. Berry consumption also showed glucose-lowering and insulin sensitivity improvements, which are closely associated with hypoinsulinemia, insulin signaling activation (in adipose and skeletal muscles), the adiponectin-AMPK pathway, and GLP-1 upregulation. Regarding the relation of gut microbial ecosystem and DM, berry intake not only counteracted the deleterious HFD/HCD effects, but also favored the population of health promoting fermentative, SCOA/SCFA-producing, obesity-preventing, glycolytic, proteolytic, and secondary metabolites metabolizing microflora. The primary potential health-promoting classes of bioactive compounds found in berries include glycosides, glucosides, catechins, epicatechins, proanthocyanidins, cynidines, delphinidins, quercetin, myricetin, malvidins, petunidin, flavanols, flavonols, caffeic acids, chlorogenic acids, phenolic acids, ferulic acids, p-coumaric acids, vanillic acids, ellagic acids, hydroxycinnamic acid derivatives, and polysaccharides. Based on the reviewed papers, to obtain these health-endowing effects, the daily recommended dose of whole berry varies from 200 to 400 g of berry intake for a 70 kg BW middle aged person.

Conflicts of Interest:
The authors declare no conflict of interest.