Plant-Derived Strategies for Glycemic Management in Diabetes: A Narrative Review

Abstract

Diabetes mellitus remains a major global health burden, and many patients do not achieve durable glycemic control despite modern pharmacotherapy. This narrative review synthesizes evidence on plant-derived strategies that may complement standard care, focusing on two clinically aligned domains: glucose-lowering medicinal plants and plant-based sugar substitutes that reduce dietary glycemic load. We summarize key mechanistic pathways, including inhibition of α-amylase/α-glucosidase, reduced intestinal glucose entry and absorption kinetics, glucose-dependent insulinotropic effects, improved insulin signaling, suppression of hepatic gluconeogenesis, and microbiota-linked effects. We critically appraise human evidence for selected botanicals (cinnamon, fenugreek, mulberry, gymnema, gynura, rosehip, and Jerusalem artichoke) and plant sweeteners (stevia and monk fruit). Overall, clinical effects are modest and heterogeneous; the most reproducible signals are observed for mulberry leaf in blunting postprandial glucose excursions, and for cinnamon, fenugreek, and gymnema, where meta-analyses suggest modest improvements in glycemic markers. Stevia and monk fruit are best supported as glycemically neutral sucrose substitutes, while inulin-type fructans show small-to-moderate benefits with sustained intake, limited by gastrointestinal tolerability at higher doses. Key gaps include a shortage of long-term randomized trials using standardized preparations and durable endpoints such as glycated hemoglobin. Plant-derived interventions are therefore best positioned as adjuncts within individualized, evidence-based glycemic management.

1. Introduction

Diabetes mellitus is a significant public health challenge. Its global prevalence continues to increase. Extensive pooled epidemiological analyses show a sustained rise in adult diabetes prevalence since 1980, with a growing absolute number of affected individuals due to demographic change and increasing rates [1]. Type 2 diabetes mellitus (T2DM) accounts for most cases. It is strongly linked to excess adiposity, sedentary behavior, and dietary patterns rich in refined carbohydrates and added sugars [2]. Diabetes is also associated with chronic microvascular and macrovascular complications. These include cardiovascular disease, chronic kidney disease, neuropathy, and retinopathy. These outcomes reduce quality of life and increase disability and premature mortality [2].

Dietary modification remains foundational for prevention and management. Prospective evidence associates sugar-sweetened beverage intake with increased T2DM risk [3], and randomized prevention trials confirm that lifestyle interventions can delay or prevent diabetes in high-risk adults [4]. At the same time, pharmacotherapy has expanded and improved outcomes, yet durable glycemic control is still difficult for many patients in routine care. Barriers include adverse effects, weight effects, cost, and adherence challenges. Contemporary guidance therefore emphasizes individualized, combination strategies that address glycemia and cardiometabolic risk across disease stages [5]. This clinical context has stimulated interest in adjunctive, food- and plant-derived options that could support glycemic management alongside evidence-based medical care.

Medicinal plants have long been used in traditional systems and are increasingly studied as sources of phytochemicals that can influence glucose homeostasis. Reported mechanisms include partial inhibition of carbohydrate-digestive enzymes, reduced intestinal glucose entry, glucose-dependent modulation of insulin secretion, improvements in insulin signaling through phosphoinositol-3-kinase–serine/threonine protein kinase (PI3K–AKT) and AMP-activated protein kinase (AMPK)-related pathways, suppression of hepatic gluconeogenesis, and attenuation of oxidative stress and inflammation [6]. However, translation to clinical practice is constrained by heterogeneity in plant species and chemotypes, extraction and processing methods, product standardization, dosing, trial duration, and outcome selection. Many studies emphasize short-term fasting or acute postprandial responses rather than durable endpoints such as glycated hemoglobin (HbA1c), and safety considerations (including interactions with glucose-lowering medications) are not uniformly reported.

In parallel, increasing awareness of the metabolic harms of excess sugar intake has intensified interest in plant-based sugar substitutes as practical tools to reduce dietary glycemic load. Unlike glucose-lowering botanicals intended to exert direct metabolic effects, plant-derived sweeteners primarily act by replacing digestible sugars and thereby reducing postprandial glucose excursions. Steviol glycosides from Stevia rebaudiana provide high sweetness with minimal glycemic impact and have been linked in experimental work to glucose-dependent insulinotropic signaling [7]. Monk fruit sweeteners derived from mogrosides have also demonstrated glycemic neutrality in acute human testing when used as sucrose substitutes [8]. For clinical counseling, these products are relevant because they can help reduce added sugar intake while preserving palatability, although sustained benefit depends on the overall dietary pattern and adherence.

Several reviews and meta-analyses have evaluated plant-derived interventions, but they commonly address either broad categories of medicinal plants or single, high-profile agents rather than integrating complementary plant-based strategies across diet and supplementation. For example, prior syntheses have reviewed medicinal food plants in dysglycemia or traditional herbal options for T2DM [9,10,11], and multiple meta-analyses have focused on individual botanicals such as cinnamon [12,13,14], fenugreek [15], or gymnema [16,17]. Similarly, evidence syntheses on steviol glycosides largely examine cardiometabolic or diabetes biomarkers within the sweetener literature [18,19]. What is less commonly provided is a single clinically oriented narrative that (i) distinguishes and then deliberately links two patient-relevant domains, glucose-lowering botanicals and plant-based sugar substitutes, (ii) maps proposed mechanisms across shared physiological pathways, and (iii) discusses efficacy alongside the practical issues that determine real-world usefulness, including product quality, standardization, tolerability, and interaction potential.

This narrative review synthesizes evidence on plant-derived strategies that may complement standard diabetes care by focusing on two clinically aligned domains: (1) glucose-lowering botanicals with direct metabolic actions, and (2) plant-based sugar substitutes that reduce dietary glycemic load. We summarize key bioactive constituents and mechanistic pathways relevant to glycemic regulation, critically appraise the human evidence for selected interventions, and integrate safety, interaction, and product-quality considerations to support clinically realistic counseling and to highlight evidence gaps for future research.

2. Methodology

This article was prepared as a narrative review based on a structured literature search and qualitative synthesis. The approach aimed to identify and integrate human evidence for clinically relevant plant-derived strategies for glycemic management, while using mechanistic and phytochemical literature to contextualize plausibility and safety.

2.1. Data Sources and Search Strategy

Peer-reviewed literature was identified through searches of major biomedical and multidisciplinary databases, including PubMed, Scopus, Web of Science Core Collection, and ScienceDirect. Google Scholar was used as a supplementary source to capture recently published items, early online articles, and relevant citations not consistently indexed across databases.

Searches combined (i) glycemic/diabetes terms with (ii) plant-derived intervention terms and (iii) specific plant names and key bioactive constituents emphasized in this review. Core concept blocks included:

• Condition/outcomes: “diabetes”, “type 2 diabetes”, “prediabetes”, “hyperglycemia”, “glycemic control”, “fasting glucose”, “postprandial glucose”, “HbA1c”, and “insulin sensitivity”.
• Intervention type: “medicinal plant”, “botanical”, “herbal”, “phytochemical”, “plant extract”, “nutraceutical”, “functional food”, “sweetener”, “sugar substitute”, “non-nutritive sweetener”, and “low-calorie sweetener”.
• Targeted plants/compounds featured in the manuscript: combinations using terms such as cinnamon/Cinnamomum spp., fenugreek/Trigonella foenum-graecum, mulberry/Morus (including “1-deoxynojirimycin”/”DNJ”), Gymnema sylvestre (including “gymnemic acids”), Gynura procumbens, Rosa canina, Stevia rebaudiana (including “steviol glycosides”), Siraitia grosvenorii/monk fruit (including “mogrosides”), and Helianthus tuberosus/Jerusalem artichoke (including “inulin”).

Boolean operators and phrase searching were used as support (e.g., (diabetes OR hyperglycemia) AND (cinnamon OR Cinnamomum) AND (trial OR randomized OR HbA1c OR postprandial)). Reference lists of key papers, meta-analyses, and relevant reviews were also screened to identify additional eligible studies.

2.2. Time Window and Eligibility Criteria

The review prioritized literature from 2000–2025 to align with the contemporary expansion of plant-based metabolic research and the bibliometric mapping presented in the manuscript, while allowing inclusion of earlier foundational studies when needed for mechanistic context.

Studies were considered eligible if they:

• Examined plant-derived glucose-lowering botanicals or plant-based sugar substitutes/sweeteners relevant to glycemic management;
• Reported glycemic outcomes (e.g., fasting glucose, postprandial glucose excursions, HbA1c, insulin/insulin resistance indices) and/or clinically interpretable cardiometabolic endpoints closely linked to glycemic regulation.

Priority was given to human evidence (randomized trials, controlled interventions, meta-analyses, and well-described observational studies) for efficacy-oriented statements. Preclinical and mechanistic studies were included to support interpretation of biological pathways and to connect bioactive constituents with plausible mechanisms but were not used alone to infer clinical effectiveness.

Exclusions included: non-plant sweeteners not central to the manuscript’s scope, studies without relevant glycemic endpoints, and reports where plant interventions were part of complex multi-ingredient mixtures without sufficient description or without a plausible way to attribute effects.

2.3. Screening and Study Selection

Titles and abstracts were screened first to remove clearly irrelevant records. Full texts were then assessed for eligibility based on intervention relevance (botanical glucose-lowering agents or plant-based sugar substitutes) and presence of glycemic outcomes or mechanism–outcome linkage relevant to diabetes management. Duplicate records were removed using citation metadata and manual checking. When multiple publications reported overlapping datasets, the most complete or most clinically informative report was prioritized, while companion papers were consulted for clarification of protocols, formulations, and safety reporting.

2.4. Data Extraction and Narrative Synthesis

From each included study, key information was extracted qualitatively to support structured comparison across interventions, including population characteristics, plant material/formulation (whole plant, extract, standardized constituent where available), dose and duration, comparator/control, and reported glycemic outcomes (fasting, postprandial, HbA1c) alongside adverse events and interaction-relevant details when described.

Evidence was synthesized narratively and organized around two clinically oriented domains presented in the manuscript:

• Glucose-lowering botanicals;
• Plant-based sugar substitutes and related low-glycemic carbohydrate replacements.

Mechanistic interpretation was mapped across recurring pathways relevant to glycemic regulation (e.g., carbohydrate digestion/absorption, incretin signaling, insulin secretion and sensitivity, hepatic glucose output, inflammation/oxidative stress) and integrated with the human evidence base to highlight convergence, uncertainty, and evidence gaps. Safety, interaction potential, and product-quality considerations were summarized as cross-cutting themes for translation into clinical counseling.

3. Results and Discussion

3.1. Study Characteristics

The evidence included in this narrative review was identified through a structured search and screening process (described in Section 2). The final set of sources comprised a combination of human clinical studies (including randomized or controlled interventions and shorter postprandial/substitution trials), systematic reviews/meta-analyses where available, and mechanistic/preclinical studies used to support interpretation of biological plausibility. Overall, the human literature varied widely in population characteristics (e.g., type 2 diabetes, prediabetes, overweight/obesity), intervention format (whole plant preparations vs. extracts vs. purified constituents; sweetener substitution vs. fiber-based carbohydrate replacement), dose, and duration. Most clinical studies assessed outcomes such as fasting glucose, postprandial glucose excursions, HbA1c (in longer interventions), and selected markers related to insulin action or cardiometabolic risk.

To align the synthesis with a clinically practical framing, the included evidence was organized into two complementary domains: (i) glucose-lowering botanicals intended to exert direct metabolic effects, and (ii) plant-based sugar substitutes and related replacements intended primarily to reduce dietary glycemic load. Because the literature is heterogeneous in design, product characterization, and outcome reporting, the findings are summarized qualitatively with attention to consistency of effects, mechanistic coherence, and real-world considerations such as tolerability, potential interactions, and product quality.

In this context, Figure 1 is presented here to provide an overview of the research landscape and its evolution over time, while

Table 1. Mechanistic mapping of plants discussed in Section 3 and Section 4.

Plant	Digestion & Absorption	β-Cell Function	Insulin Sensitivity	Hepatic Glucose Output	Gastric Emptying/Hormones	Anti-Inflammatory/Antioxidant	Gut Microbiota
Cinnamomum spp.	✔✔ α-amylase/α-glucosidase inhibition	◐ indirect	✔✔ PI3K-AKT	✔ AMPK-mediated	◐ ghrelin modulation	✔✔ strong	◐ emerging
Trigonella foenum-graecum	✔✔ viscous fiber	✔ 4-hydroxyisoleucine	✔✔ improved sensitivity	◐ indirect	✔ delayed absorption	✔	✔✔ fiber-driven
Morus alba (DNJ)	✔✔✔ α-glucosidase inhibition	✖	◐ secondary	✖	✖	◐ minor	✖
Gymnema sylvestre	✔ intestinal glucose blockade	◐ insulin support	✔ improved sensitivity	◐ indirect	✖	✔	✖
Momordica charantia	✔ enzyme inhibition	✔✔ insulin-like peptides	✔✔ AMPK	✔✔ reduced gluconeogenesis	◐	✔	◐
Salacia spp.	✔✔✔ benchmark α-glucosidase inhibition	✖	✖	✖	✖	◐	✖
Gynura procumbens	◐	◐	✔✔ strong (preclinical)	✔✔	✖	✔✔	◐
Rosa canina	✔ enzyme inhibition	◐ β-cell protection	✔ indirect	◐	✖	✔✔✔ dominant	✔✔ fiber-mediated
Stevia rebaudiana	✖	◐ glucose-dependent	◐	◐	✔ sweet-taste receptors	✔	◐
Siraitia grosvenorii	✖	✖	✖	✖	✔ sensory/incretin neutrality	✔	✖
Helianthus tuberosus	✔ delayed absorption	✖	✔ AMPK (indirect)	✔ reduced	✖	◐	✔✔✔ strong

Legend: ✔✔✔ = strong evidence that the mechanism contributes to glycemic modulation; ✔✔ = consistent mechanism or moderate evidence; ✔ = contributory mechanism; ◐ = limited or indirect evidence; ✖ = not reported or insufficient evidence.

summarizes the principal mechanistic pathways attributed to the plants and plant-derived substitutes discussed in Section 3.2, Section 3.3 and Section 3.4, serving as a roadmap for the evidence synthesis that follows.

The rapid expansion of this research area is illustrated in Figure 1. Publication counts associated with the terms “Glucose AND Plant” and “Antidiabetic AND Plant” increase strongly over the 2000–2025 period. The country’s distribution also shows broad global engagement, with high output from Asia and substantial contributions from Europe and North America. The subject-area profile indicates a strong interdisciplinary structure that spans molecular biosciences, pharmacology, medicine, and food-related disciplines. The keyword landscape highlights frequent emphasis on extracts, bioactive classes, and mechanistic interpretation, alongside a strong presence of preclinical model terminology. This pattern supports the need for synthesis that connects mechanistic claims with human evidence and product-level considerations.

The mechanistic mapping across the plants discussed in Section 3 and Section 4 is consolidated in Table 1 for rapid comparison.

3.2. Mechanistic Pathways of Plant-Derived Glycemic Modulation

Plant-derived interventions can influence glycemic regulation through several physiological targets. These targets include the gastrointestinal tract, pancreas, liver, peripheral tissues, and gut microbiota. Botanicals contain multiple bioactive constituents. Their actions are usually modest and pleiotropic. Their effects often depend on dose, matrix, and metabolic status. For this reason, plant-derived strategies are best viewed as adjunctive modulators of glucose homeostasis. The dominant pathways and their alignment with the individual plants discussed in this article are summarized in Table 1.

To strengthen the structure–bioactivity link, Figure 2 highlights representative constituents. DNJ exemplifies an iminosugar scaffold that mimics carbohydrate transition states and is consistent with α-glucosidase inhibition and reduced postprandial excursions. Steviol glycosides (e.g., rebaudioside A) and mogrosides (e.g., mogroside V) illustrate high-potency sweet triterpene glycosides that enable sucrose replacement without increasing glycemic exposure. Inulin-type fructans are β(2→1)-linked carbohydrates resistant to human digestion, supporting fermentation to short-chain fatty acids and downstream metabolic signaling. For complex triterpene glycosides (e.g., gymnemic acids and mogrosides), stereochemistry is shown according to the predominant naturally occurring isomer reported in reference sources; where multiple congeners exist, the structure is presented as a representative example to illustrate key scaffold features.

A key pathway is the modulation of carbohydrate digestion and intestinal glucose entry. Many plants contain polyphenols, flavonoids, saponins, and iminosugars that inhibit α-amylase and α-glucosidase. These enzymes control starch and disaccharide hydrolysis at the intestinal brush border. Partial enzyme inhibition slows glucose release from complex carbohydrates. It reduces postprandial glucose excursions and lowers insulin demand. This mechanism is central for mulberry leaf extracts rich in 1-deoxynojirimycin and for Salacia spp.—preparations with potent α-glucosidase inhibition [6,20]. This pattern is reflected in the “Digestion and absorption” column in Table 1. Plant-derived inhibition is often weaker than pharmacological inhibitors. This can explain milder gastrointestinal symptoms in many trials.

Some botanicals also modulate intestinal glucose transport—enterocytes transport glucose mainly via sodium–glucose linked transporter 1 (SGLT1) and glucose transporter type 2 (GLUT2). Intestinal sugar sensing involves taste-receptor signaling in the gut epithelium. Type 1 taste receptor member 3 (T1R3) and gustducin regulate SGLT1 (sodium–glucose linked transporter 1) expression in response to luminal sugars [21]. In addition, several flavonoids can inhibit GLUT2-mediated glucose transport in experimental systems [22]. Direct confirmation of transporter modulation in humans remains limited. This mechanism should be interpreted as supportive and is represented mainly as indirect or emerging evidence in Table 1.

Another pathway involves pancreatic β-cell function and insulin secretion. Several plant constituents increase insulin secretion in a glucose-dependent manner. This feature can theoretically reduce the risk of hypoglycemia. Fenugreek-derived 4-hydroxyisoleucine is a representative example. It potentiates insulin secretion when glucose levels are elevated and exhibits insulinotropic activity in vivo models [23]. Some botanicals may also indirectly support β-cell function. Antioxidant and anti-inflammatory effects can reduce glucotoxic stress. The β-cell-related mechanisms and their relative strength across plants are summarized in the “β-cell function” column in Table 1.

Improvement of peripheral insulin sensitivity is another contributory mechanism. Many phytochemicals influence insulin signaling cascades linked to GLUT4 (glucose transporter type 4) translocation. PI3K (phosphoinositol-3-kinase) and AKT (serine/threonine protein kinase) signaling are frequent targets in preclinical work on polyphenol-rich plants. AMPK activation is also common across mechanistic studies. AMPK activation increases glucose uptake and fatty acid oxidation and reduces lipogenesis. These effects are most relevant in insulin-resistant states. They are less appropriate in advanced insulin-deficient diabetes. AMPK also relates to hepatic metabolism and gluconeogenesis [24]. The prominence of PI3K–AKT and AMPK across the reviewed plants is captured in the “Insulin sensitivity” and “Hepatic glucose output” columns in Table 1.

Regulation of hepatic glucose production is vital for fasting glycemia in type 2 diabetes. Excess gluconeogenesis contributes to fasting hyperglycemia. Several plant-derived compounds suppress hepatic glucose output via improved insulin signaling and AMPK activation. This leads to downregulation of gluconeogenic programs and improved glycogen storage. Direct human evidence with quantified hepatic glucose production endpoints is scarce. Most human support is indirect and based on changes in fasting glucose. The extent to which each plant is linked to hepatic mechanisms is summarized in the “Hepatic glucose output” column in Table 1.

Gastric emptying and gastrointestinal hormone dynamics also influence postprandial glycemia. Slower gastric emptying delays the appearance of glucose in the circulation. Cinnamon is often discussed in this context. An acute crossover trial reported delayed gastric emptying and reduced postprandial glycemia with a high cinnamon dose added to a meal [25]. Dose-dependence is likely. Reproducibility varies across studies. Plant-derived modulation of incretin pathways is also plausible. Sweet-taste receptors are expressed in enteroendocrine cells. These receptors participate in nutrient sensing. This creates a mechanistic basis for subtle incretin effects of some sweet-tasting plant compounds [21].

Antioxidant and anti-inflammatory modulation support insulin signaling and β-cell resilience. Chronic oxidative stress activates stress-sensitive kinases. These kinases impair insulin receptor signaling and contribute to insulin resistance. Oxidative stress also promotes inflammatory signaling and cytokine production. Many plants are rich in polyphenols, carotenoids, and vitamin C. These compounds can reduce oxidative burden and inflammatory tone. These actions are permissive rather than primary glucose-lowering drivers in most human contexts [26]. The relative prominence of this pathway for each plant is summarized in the “Anti-inflammatory and antioxidant” column in Table 1.

Gut microbiota-mediated metabolic effects are central for fiber-rich interventions. Non-digestible polysaccharides and resistant carbohydrates reach the colon and undergo fermentation. This process generates short-chain fatty acids such as acetate, propionate, and butyrate. Short-chain fatty acids (SCFAs) stimulate glucagon-like peptide-1 (GLP-1) secretion via free fatty acid receptors and improve glucose tolerance in mechanistic models [27,28]. SCFAs also relate to AMPK activation and systemic insulin sensitivity in integrative models [29]. This pathway is most relevant for inulin-type fructans from Jerusalem artichoke and for viscous and fermentable fibers from fenugreek. The strength of microbiota-related mechanisms across plants is summarized in the “Gut microbiota” column in Table 1 [30].

Some plant-derived sweeteners have a distinct mechanism of action. Steviol glycosides can modulate nutrient sensing and β-cell electrophysiology in experimental models by potentiating TRPM5 (transient receptor potential cation channel, subfamily M (melastatin) member 5) [7]. Gymnema provides a different entry point. Gymnemic acids inhibit sweet taste receptor signaling at TR2 (type 1 taste receptor member 2) and TR3. This can reduce perceived sweetness and may lower sugar intake behaviorally. It can also reduce intestinal sugar uptake through receptor-level interference in the absorptive layer [31]. For monk fruit, the best-supported contributions are glycemic neutrality and sugar displacement, rather than direct glucose lowering.

Taken together, plant-derived strategies converge on several dominant pathways. The most reproducible effects involve delayed carbohydrate digestion and reduced postprandial glucose exposure. Improvements in insulin sensitivity and supportive anti-inflammatory actions also contribute, especially with longer-term dietary use. The overall clinical role is to provide adjunctive support and reduce glycemic load. It is not a replacement for established pharmacotherapy.

3.3. Glucose-Lowering Medicinal Plants

3.3.1. Cinnamomum spp. (Cinnamon)

Cinnamon (Cinnamomum spp.) belongs to the genus Cinnamomum of the Lauraceae family. This plant group includes about 250 species and is widely used in cooking [32]. Cinnamon contains various active substances (phenolic acids, flavonoids, volatile oils, and polysaccharides) that can help lower glucose levels and have anti-diabetic properties [32,33]. Moreover, cinnamaldehyde (a key ingredient in cinnamon essential oil) exhibits anti-inflammatory and antioxidant activities [34]. The formulation containing cinnamon essential oil has been reported to counteract insulin deficiency and improve insulin resistance in diabetic and hypertensive rats [35]. The results of several recent meta-analyses indicate that cinnamon can reduce fasting plasma glucose, HOMA-IR, and HbA1c levels in patients with type 2 diabetes mellitus [12,13,14]. The reduction in HbA1c levels is dose-dependent. A more pronounced effect was observed when consuming more than 2 g/day of cinnamon [13].

One mechanism of action of cinnamon is the inhibition of digestive enzymes (α-amylase and α-glucosidase), which are involved in carbohydrate metabolism and help regulate blood glucose [36,37,38]. Comparing different cinnamon species, Hayward and colleagues found that they exhibit varying degrees of inhibitory activity against α-amylase and α-glucosidase, and the correlation between the concentration of polyphenols in the cinnamon extract and its inhibitory effect [36]. The more substantial inhibitory impact of cinnamon on α-glucosidase indicates that it may be more influential in limiting sugar hydrolysis at the intestinal brush border, including intermediate products generated by α-amylase [36]. Because β-glucosidases are key players in cleaving 1–6 glycosidic bonds, their suppression would diminish the digestion of amylopectins, the starch fraction most strongly linked to elevated glycemic responses [36]. α-Amylase inhibition can slow carbohydrate digestion, leading to reduced glucose absorption and a delayed postprandial rise in blood sugar levels [39]. Hyperglycemia is also closely linked to oxidative stress and lipid peroxidation [40].

Cinnamon has been extensively investigated for its potential to modulate insulin signaling, with both preclinical and clinical studies indicating beneficial effects on glucose homeostasis and insulin sensitivity. One of the central mechanisms by which cinnamon exerts its antidiabetic effects is through the PI3K-AKT signaling cascade, which was confirmed by changes in gene expression levels [41]. Once activated, AKT (serine/threonine protein kinase) enhances glycogen synthesis and glycolysis by modulating multiple targets [42]. Under hyperglycemic conditions, insulin induces phosphorylation of PI3K and AKT, which in turn regulate GSK3β and glycogen synthase (GS), the principal enzymes controlling glycogen metabolism (Figure 3) [43]. Experimental studies in diabetic mice have demonstrated that cinnamon powder supplementation significantly increased AKT phosphorylation by activating PI3K, thereby inhibiting GS signaling, leading to improved liver glycogen synthesis, accompanied by a reduction in fasting blood glucose and enhanced insulin sensitivity [41].

Cinnamon also modulates the expression and activity of glucose transporters. In models of diet-induced insulin resistance, cinnamon restored the expression of GLUT1 and GLUT2 in hepatic tissue and GLUT4 in skeletal muscle, thereby promoting glucose uptake and improving glycemic control [44]. Phosphorylation of AKT promotes the inactivation of TBC1D1 and TBC1D4, which, in turn, increases GLUT4 translocation to the membrane, thereby improving glucose transport [45].

Compounds present in cinnamon have been reported to increase AMPK phosphorylation [41]. AMPK activation supports cellular energy homeostasis by increasing glucose uptake and oxidation and by reducing lipid synthesis [24]. In the liver, AMPK activation is most often linked to acute repression of gluconeogenic transcription (e.g., by dampening cAMP response element-binding protein/CREB-regulated transcription coactivator 2 (CREB/CRTC2)-driven programs), thereby lowering hepatic gluconeogenic output. However, during fasting-like conditions, sirtuin 1 (SIRT1) deacetylates and activates peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), which promotes gluconeogenic gene expression and increases hepatic glucose production; AMPK can intersect with this SIRT1/PGC-1α axis in a context- and dose-dependent manner (e.g., via NAD/SIRT1 regulation), so SIRT1/PGC-1α should be discussed explicitly in relation to the physiological state and experimental conditions [46]. Liu and colleagues reported decreased pyruvate levels and downregulation of gluconeogenesis-related genes under cinnamon consumption, consistent with suppression of hepatic gluconeogenesis [41].

Regulation of postprandial blood glucose level depends on the gastric emptying rate. Slowing gastric emptying reduces postprandial blood glucose levels [47]. A study by Hlebowicz and colleagues suggests that cinnamon may also slow gastric emptying during carbohydrate-rich meals. In a crossover trial in healthy volunteers, 6 g of cinnamon added to a meal significantly delayed gastric emptying and reduced postprandial glycemia [25]. However, consuming 1 g and 3 g of cinnamon had no significant effect on gastric emptying rate [48,49]. It has been proven that in healthy people, gastric emptying is stimulated by the gastrointestinal hormone ghrelin. It is also responsible for feelings of hunger [50]. Cinnamon likely reduces ghrelin secretion, leading to decreased gastric emptying. Camacho et al. found that cinnamaldehyde (one of the active ingredients in cinnamon) reduces ghrelin levels in MGN3-1 cell culture. The authors also observed a reduction in total food intake and gastric emptying rate in mice given cinnamaldehyde [51]. The results of cinnamon’s effect on gastric emptying rate are ambiguous. Cinnamon probably has a dose-dependent effect. Therefore, the impact of cinnamon on this function requires further study.

Overall, cinnamon emerges as a promising complementary strategy for improving glycemic control. Still, the lack of knowledge of specific molecular mechanisms and variability of study designs underscores the need for further mechanistic studies and well-controlled clinical trials to confirm its efficacy and define optimal therapeutic use.

3.3.2. Trigonella foenum-graecum (Fenugreek)

Trigonella foenum-graecum L. is an annual plant of the Fabaceae family. It is used in the pharmaceutical, nutraceutical, and food industries. Fenugreek has a long history of use in Ayurvedic medicine in India, as well as in traditional Tibetan and Chinese medical systems [52,53,54]. The scope of reported biological actions is vast and includes anti-inflammatory, antitumor, hypoglycemic, antihypertensive, immunomodulatory, hypocholesterolemic, neuroprotective, antioxidant, reproductive, gastroprotective, galactagogue, and hepatoprotective effects [55]. The plant contains many bioactive compounds. Major constituents include galactomannan [56], saponins, diosgenin, and 4-hydroxyisoleucine (4-OH-Ile) [57] (Figure 4).

The rising global prevalence of diabetes in recent years has increased interest in fenugreek as a therapeutic option. Studies are ongoing in Asia [9], India [10], the Middle East [58], and North America [59]. Experiments in humans and animals support fenugreek’s ability to reduce blood glucose and cholesterol levels [60,61]. The therapeutic potential is most substantial in the plant’s seeds and leaves [62]. Fenugreek seeds contain 58% carbohydrates, 23–26% proteins, 0.9% fats, and 25% fiber. The leaves contain 6% carbohydrates, 4.4% proteins, and 1.1% fiber [63].

Clinical trials of T. foenum-graecum seeds in early dysglycemia and established type 2 diabetes mellitus (T2DM) support their use as a dietary component [64,65,66]. Benefits were reported with both ground seeds diluted in water [67,68,69] and seed extracts [70,71,72,73]. A clinical study reported that daily intake of 10 g of T. foenum-graecum powder may suppress progression from prediabetes to T2DM during long-term use [74,75]. A systematic review of medicinal interventions for improved glucose tolerance reported that fenugreek produced a more substantial reduction in fasting blood glucose (FBG) and the HOMA-IR (homeostatic model assessment of insulin resistance) index than other plant-based preparations used in impaired glucose tolerance [11].

Safety has been evaluated in patients with T2DM for both raw seeds [76] and seed extracts [77]. Overall, the interventions were considered safe. Severe adverse events were not reported. Safety in people with prediabetes still requires further confirmation.

Pickering et al. reported that T. foenum-graecum seed extract may improve elevated fasting glucose and impaired glucose tolerance in prediabetes [75]. The authors also reported a cardioprotective effect. The effect was linked to stabilization of triglyceride levels.

Kim et al. reported improvements in glycemic control and lipid parameters after fenugreek supplementation [15]. Significant reductions were observed in FBG, postprandial glucose, and HbA1c. Improvements were also reported for total cholesterol and high-density lipoprotein cholesterol. No significant changes were found in HOMA-IR or body mass index. Adverse events were mainly mild gastrointestinal symptoms. Severe complications and hepatic or renal toxicity were not reported. Fenugreek is an effective and generally safe option for patients with T2DM.

3.3.3. Morus alba (Mulberry Leaf; DNJ-Enriched Extracts)

Morus alba L. (white mulberry) is recognized as a medicinal plant widely utilized in both food applications and traditional medicine [78]. It is a fast-growing shrub or medium-sized tree native to Central Asia, and it is now also cultivated in Europe [79]. Leaves of M. alba are highly valued for their nutritional and bioactive composition. They contain significant amounts of proteins, carbohydrates, dietary fiber, and a broad spectrum of vitamins. In addition, mulberry leaves are rich in phytochemicals, including flavonoids, triterpenes, phenolic acids, and the iminosugar 1-deoxynojirimycin (DNJ), which collectively contribute to their health-promoting properties (Figure 5) [80].

Among the various biologically active compounds, DNJ stands out for its distinct role in regulating carbohydrate metabolism. This iminosugar has been reported in multiple tissues of M. alba, including leaves, seeds, and root bark [81,82]. Dietary carbohydrates undergo enzymatic digestion within the small intestine, where α-glucosidases cleave glycosidic bonds in polysaccharides and disaccharides, yielding simple sugars such as glucose and fructose that can be rapidly absorbed into the bloodstream [83]. DNJ functions as a potent competitive inhibitor of α-glucosidase enzymes located on the brush border membrane of intestinal enterocytes [84]. By binding to the enzyme’s active site, DNJ prevents substrate attachment, thereby delaying carbohydrate hydrolysis and reducing glucose release and absorption. Therefore, DNJ mitigates postprandial hyperglycemia and lowers insulin secretion [85].

A series of clinical studies has shown that mulberry leaf extract, whose main active component is DNJ, exerts a glucose-lowering effect in humans. Both single and long-term intake of DNJ-enriched products have been found to reduce postprandial glucose and insulin fluctuations and not cause clinically significant side effects [85,86,87,88,89,90].

In the study by Kimura et al., healthy participants were administered 0, 0.4, 0.8, or 1.2 g of DNJ-enriched powder (corresponding to 0, 6, 12, and 18 mg of DNJ), followed by 50 g of sucrose. Plasma glucose and insulin were monitored before and at intervals of 30 to 180 min after ingestion. Consuming 0.8 or 1.2 g of the DNJ-enriched powder effectively reduced postprandial elevations in blood glucose and insulin, demonstrating the physiological activity of mulberry-derived DNJ and establishing an effective dose in humans [87].

In the study by Kojima et al., mulberry leaves were used to produce DNJ-enriched powder (1.5%) through hot-air drying, a process that minimizes DNJ degradation. A single intake of the resulting powder significantly suppressed the postprandial rise in blood glucose and insulin secretion. At the same time, long-term administration did not induce hypoglycemia in healthy volunteers with a mean age of 25 years [88].

Wang et al. reported that mulberry leaf extract (MLE) significantly reduced the glycemic index of various carbohydrates. In healthy adult men and women aged 18–40 years receiving 7.5 mg of DNJ, co-consumption of MLE with sucrose, maltose, or maltodextrin markedly attenuated postprandial glucose excursions compared with glucose alone or glucose combined with MLE [85].

Asai et al. conducted two studies on the effects of mulberry leaf extract enriched with DNJ. In a short-term study, the impact of a single dose of MLE (3, 6, or 9 mg DNJ) was evaluated in 12 volunteers with elevated fasting plasma glucose (100–140 mg/dL). Following a 200 g load of boiled white rice, MLE reduced the postprandial rise in blood glucose in a dose-dependent manner over 2 h, accompanied by a less pronounced increase in insulin levels. In a long-term study, the efficacy of regular MLE intake (6 mg DNJ, three times daily) was assessed over 12 weeks in 76 participants with fasting glucose levels of 110–140 mg/dL. The main finding was a significant increase in 1,5-anhydroglucitol (1,5-AG) concentrations in the MLE group compared with controls. As 1,5-AG is a sensitive marker of postprandial glycemic control, these results indicate an improvement in short-term glucose regulation [86].

In the study by Shinkawa et al., 31 healthy adults consumed Kanzaki tea, containing 2.85 g of mulberry leaves and 0.15 g of water chestnut husks for two weeks. The tea consumption significantly reduced postprandial glucose fluctuations and increased 1,5-AG levels; the product was well tolerated and safe for short-term use [89].

Takahashi et al. investigated the role of mulberry leaf extract intake timing on postprandial glucose levels, addressing a critical yet previously unexplored aspect of chrononutrition. Twelve healthy young adult males and females aged 21–39 years participated in a randomized crossover trial. A dose of 6.0 mg of DNJ was administered with a test meal, based on prior evidence, corresponding to levels naturally present in common foods and beverages such as green tea. The findings showed that acute MLE intake in the evening, but not in the morning, significantly reduced postprandial glucose levels [90].

Overall, findings from the reviewed research suggest that mulberry leaf extract effectively stabilizes postprandial glucose responses and enhances short-term glycemic regulation by the presence of the bioactive iminosugar DNJ, which inhibits α-glucosidase enzymes. Consequently, this extract may serve as a potential natural therapeutic agent for managing postprandial glycemia and decreasing overall glycemic load, while exhibiting minimal or no undesirable effects.

3.3.4. Gymnema sylvestre (Gymnema)

Gymnema sylvestre (Retz.) R.Br. ex Sm. is a perennial, woody climbing herb that grows slowly and occurs naturally in regions of India, Africa, Australia, and China [91,92]. The glucose-lowering effect of G. sylvestre is attributed to its bioactive compounds, including gurmarin, gymnemic acids, and gymnemasaponins [91]. In addition, this plant exhibits multiple pharmacological properties, such as antioxidant, antimicrobial, anti-inflammatory, antiviral, gastroprotective, hepatoprotective, anticancer, and lipid-lowering activities. The stems, leaves, and roots of this plant are particularly valuable for research [92].

The key players in the glucose-lowering effect of G. sylvestre are the gymnemic acids, which can slow glucose absorption into the bloodstream. They are triterpenoid glucosides consisting of a glucose-like moiety linked to a bulky triterpenoid group (Figure 6). This allows them to occupy taste-bud receptors and temporarily block activation of these receptors by dietary sugars, thereby reducing sugar cravings (Figure 6). Similarly, in the intestine, gymnemic acids bind to receptors in the absorptive layer, inhibiting glucose uptake and ultimately lowering blood sugar levels [91,92].

Experimental studies by Tiwari et al. in animal models of diabetes mellitus induced by beryllium nitrate and streptozotocin have demonstrated that G. sylvestre administration reduces fasting blood glucose levels. In rats treated with extracts of G. sylvestre, as well as Cassia auriculata, Eugenia jambolanum, and Salacia reticulata, a slight increase in body weight and total protein was observed, along with a marked decrease in glycemia [92].

Patients aged 30–60 years who received capsules containing 1 g G. sylvestre powder per day for 30 days showed a 37% reduction in glucose, a 5% reduction in triglycerides, a 13% reduction in cholesterol, and a 19% decrease in low-density lipoproteins [93].

Gaytán Martínez and co-workers studied how G. sylvestre supplementation influences glycemic regulation, insulin output, and insulin responsiveness in individuals with impaired glucose tolerance. They performed a clinical trial involving 30 participants diagnosed with impaired glucose tolerance. Of these, 15 subjects received G. sylvestre capsules at a dose of 300 mg twice daily, while the remaining 15 received a matching placebo. Treatment with G. sylvestre led to notable decreases in 2-h glucose levels during the oral glucose tolerance test, as well as reductions in glycated hemoglobin A1c, body weight, body mass index, and low-density lipoprotein cholesterol compared with the placebo group [94].

The meta-analysis by Devangan et al., which included 10 studies with a total of 419 participants with T2DM, demonstrated that G. sylvestre supplementation significantly reduced fasting blood glucose, postprandial glucose, and glycated hemoglobin levels compared to baseline. Additionally, the study found that G. sylvestre significantly decreased triglyceride and total cholesterol levels [16]. These results were confirmed by Zamani et al. Adults who used G. sylvestre supplements for more than one week had significantly reduced triglyceride, total cholesterol, low-density lipoprotein cholesterol, fasting blood glucose, and diastolic blood pressure. These findings suggest that G. sylvestre supplementation may improve cardiovascular risk factors [17].

In summary, clinical trials and animal experiments indicate that Gymnema sylvestre helps regulate blood sugar levels and supports overall metabolic balance. Its use may help lower glucose and cholesterol levels, making the plant a promising natural aid for managing metabolic disorders.

3.3.5. Gynura procumbens (Gynura)

Gynura procumbens (Lour.) Merr. is a medicinal and food plant from Southeast Asia that is rich in phenolic acids and flavonoids, together with other polar constituents enriched in aqueous and hydroalcoholic extracts. These compound classes are repeatedly associated with glucose control in experimental diabetes models [95,96].

Fractionation studies support the contribution of polyphenol-rich extracts to glycemic outcomes. In streptozotocin-induced diabetic rats, graded ethanol extraction identified hydroalcoholic fractions that produced rapid and marked reductions in fasting blood glucose, and the activity correlated with higher total phenolic and flavonoid content and with the presence of marker compounds such as chlorogenic acid and rutin. The authors described a metformin-like profile, consistent with improved glucose handling and reduced glycemic peaks rather than an isolated insulin secretagogue effect [96].

Mechanistic evidence indicates that G. procumbens lowers glycemia mainly through non-secretagogue pathways that involve gastrointestinal carbohydrate handling and peripheral glucose utilization. In streptozotocin-induced diabetic mice, G. procumbens extract inhibited α-glucosidase and α-amylase in vitro and attenuated postprandial glucose excursions in vivo, including a reduced area under the glucose curve after a starch challenge, which supports delayed carbohydrate hydrolysis and absorption as a driver of postprandial glycemic control (Figure 3) [97]. In streptozotocin-induced rats, repeated dosing with a water extract lowered fasting blood glucose and improved intraperitoneal glucose tolerance, while producing minimal changes in plasma insulin and limited effects on in vitro RIN-5F cell culture, supporting enhanced peripheral glucose disposal and reduced intestinal glucose uptake as the principal contributors [95].

The glucose-lowering activity of G. procumbens has also been linked to astragalin (kaempferol-3-O-β-D-glucopyranoside), a flavonol glycoside reported in the leaves. Astragalin reduced glycemia during an oral glucose tolerance test in rats and increased plasma insulin, while isolated rat pancreatic islets showed increased basal calcium influx and stimulation of insulin secretion. The reported targets included ATP-sensitive potassium channels, L-type voltage-dependent calcium channels, sarcoendoplasmic reticulum calcium transport ATPase, and signaling involving protein kinase A and protein kinase C, which supports an insulinotropic component that may contribute to the activity of flavonoid-rich preparations [98].

Translational studies further implicate insulin sensitivity pathways. Network pharmacology with validation in mice and cell models identified PI3K–AKT-related signaling as a key pathway underlying the anti-hyperglycemic effect of G. procumbens, with improved insulin resistance and glucose metabolism in vitro and lower blood glucose with improved insulin sensitivity in vivo. An integrative analysis combining clinical plasma profiles with C57BL/KsJ db/db mouse data reported metabolic pathway shifts and validated changes in proteins within PI3K–AKT-related signaling and concluded that G. procumbens could alleviate insulin resistance through regulation of PI3K, AKT, and related stress response pathways, including AGE–RAGE signaling [99,100].

Beyond glycemic endpoints, astragalin has been reported to modulate pathways relevant to diabetic complications. In streptozotocin-induced diabetic mice, astragalin improved renal injury markers and reduced renal oxidative stress without lowering blood glucose. The authors also reported inhibition of aldose reductase activity, with activation of AMPK and downstream PGC-1α-related mitochondrial quality control. These findings suggest pleiotropic actions that may be relevant to complication-oriented endpoints in diabetes [101].

Clinical evidence for G. procumbens in humans remains limited, and most mechanistic insights derive from animal studies, cell systems, and pathway analyses. Current translational work supports three routes that plausibly contribute to glucose lowering: attenuation of postprandial glycemia via inhibition of α-glucosidase and α-amylase, improvement of insulin sensitivity via PI3K–AKT-related signaling, and improved glucose tolerance through enhanced peripheral glucose disposal, with extract-dependent effects on insulin secretion. Future human trials should use standardized extracts with quantified marker compounds and report fasting and postprandial endpoints, along with safety outcomes [99].

In summary, Gynura procumbens appear to reduce glycemia primarily through inhibition of gastrointestinal enzymes and improved insulin sensitivity, with supporting evidence for enhanced peripheral glucose utilization in relevant models [95,97,100]. Astragalin may contribute as a bioactive flavonoid through insulinotropic effects in targeted experimental systems and by modulating pathways relevant to diabetic complications, although its contribution to the net glycemic phenotype of whole extracts remains to be defined in humans. Claims regarding suppression of hepatic gluconeogenesis warrant caution, given the retraction of a commonly cited study, and the limited human evidence underscores the need for well-designed clinical trials with standardized preparations and robust metabolic endpoints.

3.3.6. Rosa canina (Rosehip)

Rosehip (Rosa canina) belongs to the genus Rosa of the Rosaceae family [102] and is traditionally used in cooking and medicine. It is most often used to treat gastrointestinal disorders, infections, and fever [103]. Rosehip is rich in bioactive compounds, including dietary fiber, a range of polyphenols, vitamin C, and other antioxidants [102]. The most significant polyphenols in rosehip are phenolic acids (gallic acid, ellagic acid, caffeic acid, p-coumaric acid), carotenoids (lycopene, β-carotene, zeaxanthin), anthocyanins, tocopherols (α- and β-tocopherols), tannins, and flavonoids (flavan-3-ols) [104,105]. Several recent reviews highlight its antioxidant and anti-inflammatory potential, which allows rosehip to be used to suppress diabetes, cancer, and other diseases [102,106,107]. Rosehip fruits were reported also to be capable of preventing obesity by reducing the expression of mRNA encoding adipogenic transcription factors and genes involved in lipid biosynthesis [108].

The protective properties of rosehip may be attributed to several mechanisms. Studies using extracts from seeds and fruits of rosehip have found that R. canina inhibits α-amylase and α-glucosidase activity [109,110,111]. That can reduce glucose absorption from the gut lumen, helping to lower blood glucose levels [112]. This produces lower early postprandial glucose peaks and reduces glycemic load. However, the effect of rosehip on the activity of these enzymes in humans and mice has not been sufficiently studied.

The normal functioning of pancreatic cells also plays a vital role in maintaining glucose metabolism. Chronic hyperglycemia exacerbates β-cell dysfunction [113]. A study by Javid et al. showed that the application of rosehip extracts to diabetic rats regulates the methylation of the Pdx-1, Pax-4, and Ins-1 genes, which are responsible for the activity and regeneration of pancreatic β-cells [114]. This contributed to the reduction of blood glucose levels in the experimental animals. Bahrami et al. found that administration of purified rosehip oligosaccharide increased the expression of the insulin-producing genes Ins-1 and Pdx-1, which in turn increased the expression of insulin-responsive genes such as Gck and Ptp1b. Increased insulin levels decreased the expression of the gene Slc2a2, which encodes glucose transporter 2 [115]. Research data from Fattahi et al. confirmed that R. canina extract can act as a growth factor for pancreatic β-cells [113].

Chronically elevated levels of reactive oxygen species (ROS) disrupt insulin signaling and contribute to pancreatic β-cell dysfunction through oxidative damage and inflammatory cytokine activation [116]. Oxidative stress activates redox-sensitive kinases, including JNK (c-Jun N-terminal kinase), IKKβ (IκB kinase beta), and p38 MAPK (p38 mitogen-activated protein kinase) (Figure 7). These kinases phosphorylate insulin receptor substrates (IRS-1/2) on serine residues, thereby impairing their normal tyrosine phosphorylation and downstream PI3K–AKT signaling [26]. As a result, glucose is reduced, and gluconeogenesis becomes dysregulated. Polyphenols and vitamin C from rosehip can directly neutralize ROS and reduce lipid peroxidation. In addition, R. canina components can increase the activity of first-line defense antioxidant enzymes by transcriptionally activating protective pathways [108,117]. Lowering ROS and cytokine levels leads to reduced serine phosphorylation of IRS-1/2, allowing restoration of tyrosine phosphorylation of insulin receptor substrates and activation of PI3K, AKT, and GLUT4, as well as AMPK activation. This enhances glucose uptake and fatty acid oxidation [118].

Lowering ROS levels also prevents inflammation by reducing NF-κB activation. Activation of NF-κB enhances the expression of proinflammatory cytokines (IL-6, IL-1β, TNF-α, MCP-1) in adipocytes [119]. Chronic low-grade inflammation of adipose tissue is one of the main mechanisms of insulin resistance. Proinflammatory cytokines produced during this process contribute to the hyperactivation of kinases (JNK, IKKβ, p38 MAPK), which disrupt insulin signaling [120]. Rosehip may reduce inflammation due to its antioxidant effects. This reduces NF-κB activation, which in turn reduces the expression of inflammatory markers [108].

Rosehip is rich in fiber, which can prevent insulin resistance. Dietary fiber from R. canina consists primarily of complex pectic polysaccharides, which are resistant to digestion in the upper gastrointestinal tract and therefore serve as fermentable substrates for gut microbiota [121]. It is known that such polysaccharides undergo microbial fermentation to form SCFAs—mainly acetate, propionate, and butyrate [122]. SCFAs (especially propionate and butyrate) can increase AMPK phosphorylation by elevating the AMP/ATP ratio in the liver and muscle, leading to increased GLUT4-dependent glucose uptake, decreased gluconeogenesis, and increased fatty acid oxidation (Figure 7). This indirectly improves insulin sensitivity [123]. However, no studies directly confirm the antiglycemic effect of rosehip fiber. Andersson et al. suggested that the high fiber content in rosehip may lower cholesterol levels in the liver by increasing bile acid synthesis from cholesterol [124]. Excess of bile acids in the liver activates hepatic farnesol X receptor (FXR), which induces the excretion of bile acids by increasing the expression of the bile salt efflux pump [125]. It is known that metabolic diseases are associated with increased bile acid levels, and activation of the FXR receptor can mitigate this effect [126].

3.4. Plant-Based Sugar Substitutes and Glycemic Control

Excessive intake of added sugars and refined carbohydrates is a major contributor to postprandial hyperglycemia, weight gain, and cardiometabolic risk in individuals with and without diabetes. In this context, plant-based sugar substitutes have gained increasing attention as tools to reduce dietary glycemic load while preserving palatability and dietary adherence. Unlike glucose-lowering medicinal plants, which exert direct metabolic effects, plant-based sweeteners primarily influence glycemic control by replacing digestible sugars, thereby limiting glucose excursions after consumption. Importantly, not all plant-based sugar substitutes are metabolically inert. Some interact with intestinal sweet-taste receptors, incretin signaling, gut microbiota, or glucose transport pathways, suggesting potential physiological effects beyond sweetness alone. The following sections focus on three widely studied plant-derived sweeteners with relevance to glycemic management.

3.4.1. Stevia rebaudiana

Stevia rebaudiana Bertoni is a perennial shrub native to South America. Its leaves contain diterpene steviol glycosides. Stevioside and rebaudioside A are the major constituents used in food products. These compounds provide high sweetness intensity and do not supply digestible carbohydrates. They therefore add minimal energy and do not increase dietary glycemic load. The primary mechanism by which stevia supports glycemic control is by replacing sugar. Steviol glycosides can substitute sucrose in foods and beverages. This reduces intake of rapidly absorbable carbohydrates. Human studies commonly show no increase in fasting or postprandial glucose when stevia replaces sugar. A pilot study in people with type 1 and type 2 diabetes reported good tolerance and no clinically relevant changes in glucose or HbA1c after repeated exposures to steviol glycosides [127]. A controlled preload study also showed lower postprandial glucose levels after a stevia preload than after a sucrose preload. The effect was reflected in lower carbohydrate exposure following sucrose removal [128]. A crossover trial in adults found that stevia did not increase postprandial glucose compared with water. The trial also reported lower subjective hunger after Stevia [129]. These findings support a practical “glycemic neutrality” profile in real meals.

Stevia may influence postprandial glycemia through intestinal nutrient handling. The dominant and best-supported pathway remains reduced carbohydrate intake due to sugar replacement. Additional mechanisms are under investigation. One candidate pathway involves sweet taste receptors in the gut. These receptors participate in nutrient sensing and incretin-related signaling. Their modulation could alter postprandial glucose dynamics in a context-dependent way. Evidence for receptor-mediated effects is still heterogeneous (Figure 8). A recent mechanistic study discussed interactions of rebaudioside A with metabolic signaling relevant to glycemic regulation [130]. Current human trials do not show a significant or consistent glucose-lowering effect that is independent of carbohydrate reduction.

Preclinical research suggests a direct effect of steviol glycosides on insulin secretion. A key proposed mechanism involves TRPM5 channels. TRPM5 contributes to stimulus–secretion coupling in pancreatic β-cells (Figure 8). Steviol glycosides can potentiate TRPM5 activity in experimental systems. This can enhance insulin release in a glucose-dependent manner. This mechanism is attractive because it implies a lower risk of hypoglycemia during fasting states [7]. Another translational concept involves steviol metabolites. Steviol glucuronide has been studied as a circulating metabolite with potential insulinotropic activity in experimental settings [131]. These data support biological plausibility. They have not yet established a robust clinical effect size in humans.

Stevioside has shown effects on insulin signaling and antioxidant defense in animal models. These effects include improvements in insulin sensitivity markers and reductions in oxidative stress indices in insulin-resistant settings. An obesity model study reported improved insulin signaling and antioxidant defense with stevioside exposure [132]. A pharmacology review also summarized mechanisms that may involve modulation of insulin secretion, changes in insulin sensitivity, and hepatic glucose metabolism pathways [133]. These findings support potential indirect glycemic benefits through improved metabolic milieu. Direct confirmation in well-controlled long-term human trials remains limited.

Steviol glycosides are not absorbed intact in the upper gastrointestinal tract. Colonic microbiota hydrolyzes them to steviol. Steviol is then absorbed and converted to conjugated metabolites for excretion. In vitro work with human microflora demonstrated complete hydrolysis of stevioside and rebaudioside A to steviol, with no further degradation of steviol by the same cultures [134]. This metabolism explains low direct exposure to intact glycosides in plasma. It also supports a low likelihood of classical “fiber-like” fermentation effects at typical intakes. It does not exclude microbiota-mediated signaling effects. Human evidence of clinically meaningful microbiome-driven glycemic improvement remains insufficient.

Systematic reviews and meta-analyses generally report small and variable effects on fasting glucose and related markers. Heterogeneity is common across trials. Differences include product composition, dose, background diet, and baseline metabolic status. A systematic review and meta-analysis focused on T2DM biomarkers emphasized variability in trial quality and modest average effects [18]. Another meta-analysis reported small reductions in fasting blood glucose with stevioside but noted notable heterogeneity and limited robustness of the conclusions [19]. Clinical data on rebaudioside A in adults with type 2 diabetes also suggest neutral effects on glycemic endpoints during supplementation, which supports safety for glycemic control rather than strong glucose-lowering [135].

Overall, the most consistent human benefit is indirect. It occurs when stevia replaces caloric sugars and reduces carbohydrate load. Evidence for additional glucose-lowering actions exists at the mechanistic and preclinical level. Translation into consistent improvements in FPG, HbA1c, or insulin resistance indices in humans remains limited.

Steviol glycosides have undergone extensive safety evaluation for food use. The European Food Safety Authority (EFSA) assessments support an acceptable daily intake expressed as steviol equivalents. EFSA concluded that available data does not justify increasing the current acceptable daily intake and maintained the established safety framework [136,137]. From a glycemic perspective, this supports use as a long-term sugar substitute within recommended exposure levels.

Stevia rebaudiana supports glycemic management primarily through glycemic neutrality and sugar displacement. This lowers dietary glycemic load and can reduce postprandial glucose excursions when sucrose is replaced [127,128]. Preclinical studies propose additional mechanisms. These include TRPM5-mediated glucose-dependent insulin secretion and improvements in insulin signaling under insulin-resistant conditions [7,132]. Human trials and meta-analyses indicate that direct glucose-lowering effects independent of substitution are small and inconsistent [18,19]. Stevia therefore functions best as a dietary tool to reduce added sugar intake, with potential supportive metabolic actions that require further confirmation in long-term clinical studies.

3.4.2. Siraitia grosvenorii (Monk Fruit)

Siraitia grosvenorii (Swingle) C. Jeffrey (monk fruit, luo han guo) is a perennial vine native to southern China. It is used as a sweetener and as a traditional food plant. Its sweetness is mainly provided by cucurbitane-type triterpene glycosides called mogrosides. Mogroside V is typically the dominant compound in standardized extracts and is responsible for intense sweetness at low doses [138]. Monk fruit sweeteners provide sweetness with negligible digestible carbohydrate and minimal caloric contribution. This feature is the primary reason for interest in glycemic control.

The most reliable glucose-related mechanism in humans is dietary substitution. Monk fruit replaces sucrose or other nutritive sugars, so it reduces the carbohydrate load of foods and beverages. This reduces the size of postprandial glycemic excursions by displacing sugars into otherwise comparable products. Randomized crossover studies in healthy adults reported that beverages sweetened with monk fruit did not increase postprandial glucose or insulin when compared with sucrose, and overall glycemic exposure did not differ materially when monk fruit replaced caloric sugar in the tested settings [8]. A related randomized crossover study using continuous glucose monitoring found no significant differences in 24-h glucose profiles when beverages sweetened with monk fruit were compared with sucrose and other non-nutritive sweeteners in healthy men [139]. These data support glycemic neutrality under acute conditions in healthy participants. They also indicate that the primary benefit is reduced sugar intake, not a consistent pharmacological lowering of glucose.

A second mechanism is the possible inhibition of intestinal carbohydrate digestion. In rats, triterpene glycosides from S. grosvenorii inhibited intestinal disaccharidase activity, including maltase, and produced anti-hyperglycemic effects after carbohydrate exposure [140]. This mechanism is conceptually similar to enzyme inhibition strategies used to blunt postprandial glycemia. Evidence for this effect in humans remains limited, and dose equivalence between animal experiments and typical food-use levels are uncertain. Still, the enzyme inhibition pathway is biologically plausible and may contribute under specific conditions, especially with higher-dose extracts.

Preclinical studies also suggest that mogrosides and related aglycones have intracellular metabolic effects. Mogroside V and mogrol activated AMPK in experimental studies, supporting a mechanistic link to reduced hepatic glucose output and improved metabolic efficiency in animal models [141]. Other experimental data indicate improved insulin resistance and enhanced glycogen synthesis via PI3K–AKT-related signaling in diabetic models, with mogroside V showing the most pronounced activity among the tested mogrosides [142]. These findings are mechanistically relevant because AMPK activation can suppress gluconeogenesis and increase glucose uptake, while PI3K–AKT signaling supports insulin action and glycogen storage. However, these effects have not yet been established as clinically meaningful in human trials of monk fruit sweeteners at culinary doses.

The gastrointestinal fate of mogrosides is essential for interpreting both efficacy and tolerability. Mogroside V undergoes biotransformation and deglycosylation by intestinal bacteria, and multiple metabolites can be detected in experimental systems and in vivo models [143]. In vitro incubation with the human gut microbiota also showed that mogroside V can modulate microbial composition and short-chain fatty acid profiles under controlled conditions, suggesting potential indirect metabolic interactions [144]. These observations justify research interest in gut-mediated mechanisms. They do not yet prove a consistent glucose-lowering effect in humans, and they do not indicate that monk fruit behaves like fermentable fiber.

Another proposed pathway involves sweet taste receptors in the gut and downstream incretin signaling. Sweet taste receptor activation has been discussed as a modulator of GLP-1 and GIP (glucose-dependent insulinotropic polypeptide) secretion. Still, experimental work indicates that activation of the gut sweet taste receptor is of limited importance for glucose-stimulated incretin secretion under several tested conditions [145]. Therefore, it is not currently supported that monk fruit sweeteners reliably improve glycemia by stimulating incretins. The safer interpretation is that monk fruit is neutral, mainly on this axis, at typical exposures, while its long-term endocrine effects in diverse populations remain insufficiently characterized.

Mogrosides also show antioxidant and anti-inflammatory activity in experimental studies, which can be relevant to insulin sensitivity in principle. Oxidative stress and inflammatory signaling can impair insulin action, so compounds that reduce these processes may support metabolic homeostasis. Current evidence for these effects is most substantial in cellular and animal settings, not in clinical glycemic outcomes. For this reason, antioxidant and anti-inflammatory actions should be described as supportive mechanisms with uncertain translation to glucose-lowering in humans.

Safety and regulatory assessment require careful wording. The European Food Safety Authority evaluated monk fruit extract as a proposed food additive. It concluded that the available toxicity database was insufficient to assess the safety of the proposed uses [146]. This assessment does not establish harm, but it indicates that the safety characterization was not adequate for that specific regulatory decision and the intended applications. Product purity and composition also vary, and commercial preparations are often blended with other sweeteners. This can complicate attribution of metabolic effects to monk fruit alone.

Overall, Siraitia grosvenorii is best suited for glycemic management as a non-nutritive sweetener that supports sugar reduction. Human trials in healthy participants support glycemic neutrality in acute settings and over 24-h monitoring [8,139]. Direct glucose-lowering mechanisms are more strongly supported by preclinical evidence, including inhibition of intestinal disaccharidases and AMPK-related pathways [140,141,142]. These mechanisms remain candidates rather than confirmed clinical drivers. The most defensible conclusion is that monk fruit reduces glycemic exposure primarily by replacing added sugars, while mechanistic effects beyond substitution require more substantial evidence from human studies.

3.4.3. Helianthus tuberosus (Jerusalem Artichoke)

Helianthus tuberosus L. (Jerusalem artichoke) is a tuber crop that is relevant to glycemic control mainly because it is a rich dietary source of inulin-type fructans. Inulin is a non-digestible carbohydrate built from fructose units linked predominantly by β-(2→1) bonds. This structure makes inulin resistant to hydrolysis by human digestive enzymes. It therefore does not provide rapidly absorbable glucose in the small intestine and does not directly increase postprandial glycemia, as refined starch or sucrose does [147,148].

The first glycemia-related mechanism of Jerusalem artichoke is dietary substitution. Inulin-rich tubers can replace digestible carbohydrates in the meal. This reduces total carbohydrates and lowers dietary glycemic load. It also reduces the substrate for rapid glucose appearance in the blood after eating. This mechanism is nutritionally driven and depends on the overall diet composition and portion size. It is conceptually different from the pharmacology of enzyme inhibitors. It aligns with the classification of Jerusalem artichoke as a functional food rather than a drug-like glucose-lowering agent [147].

The second mechanism involves fermentation and microbiota-mediated metabolic signaling. Inulin reaches the colon largely intact. There, it serves as a selective substrate for commensal bacteria and supports a prebiotic shift in microbiota composition. Colonic fermentation of inulin produces SCFAs, mainly acetate, propionate, and butyrate that act as metabolic mediators [148,149]. They interact with G-protein-coupled receptors in the gut and peripheral tissues and can influence systemic glucose regulation [149]. SCFAs can also support enteroendocrine signaling. This includes modulation of GLP-1 and peptide YY release, which may affect postprandial glucose handling and appetite regulation [149,150]. These pathways provide a plausible biological link between inulin intake and improved insulin sensitivity over time.

Several lines of evidence support the effects of inulin-type fructans on glycemic markers in humans. A systematic review and dose–response meta-analysis of randomized trials in prediabetes and type 2 diabetes reported improvements in glycemic control with inulin-type fructan supplementation [151]. Another meta-analysis of patients with type 2 diabetes also reported favorable effects on fasting plasma glucose and indices of insulin resistance, with stronger signals for longer interventions and in specific subgroups [152]. Broader evidence for soluble fiber supplementation in type 2 diabetes is consistent with these findings and shows reductions in HbA1c and fasting plasma glucose across randomized trials. However, heterogeneity remains substantial [153]. These data support the interpretation that the metabolic benefit is typically modest, cumulative, and dependent on sustained intake.

Evidence on Jerusalem artichoke-based interventions also exist, but it is less consistent and sometimes involves combined formulations. A randomized controlled trial in adults with prediabetes reported improvements in glycemic and metabolic outcomes after an intervention containing Jerusalem artichoke components, combined with other ingredients, which limits attribution to Jerusalem artichoke alone [154]. Preclinical work provides mechanistic support for Jerusalem artichoke inulin as a driver of microbiota changes and glucose improvement in experimental diabetes models, but translation to humans requires careful interpretation [155].

Tolerability is an essential practical factor for inulin-rich foods. Fermentation can cause bloating, flatulence, abdominal discomfort, and diarrhea. These effects are dose-dependent and more common with rapid dose escalation. Gradual introduction and consumption with meals can improve tolerance and adherence. This limitation is expected for fermentable fibers and does not indicate toxicity [147].

Overall, Helianthus tuberosus supports glycemic management mainly through fiber-driven mechanisms rather than acute glucose-lowering activity. The most credible pathways are reduced glycemic load through carbohydrate displacement and indirect modulation of insulin sensitivity through fermentation-derived SCFA-related signaling and gut hormone responses. Human trials and meta-analyses suggest small-to-moderate improvements in fasting and postprandial glycemia in dysglycemia, but effects on HbA1c can be variable in short interventions. Jerusalem artichoke is therefore best positioned as a supportive functional food within dietary strategies for insulin resistance and early dysglycemia [151,152,153].

3.5. Safety, Interactions, and Quality Considerations

The growing use of plant-derived strategies for glycemic management requires careful assessment of safety, potential for interactions, and product quality. Many plants contain bioactive compounds that affect carbohydrate digestion, intestinal glucose uptake, insulin secretion, insulin sensitivity, and hepatic glucose output. These actions can overlap with conventional antidiabetic therapy. They can change clinical response when plants are used as supplements or concentrated extracts [11].

A key safety issue is additive glucose-lowering during combined use with antidiabetic drugs. This risk is most relevant for plants that target the same pathways as pharmacotherapy. Mulberry leaf products that are enriched in 1-deoxynojirimycin reduce postprandial glycemia via intestinal α-glucosidase inhibition [86,87]. This mechanism resembles pharmacological α-glucosidase inhibition. It can increase the probability of late postprandial hypoglycemia when combined with insulin or insulin secretagogues in patients with tight control. Fenugreek interventions can also shift glycemia and lipids in humans [15,75]. This effect can become clinically relevant when fenugreek is combined with sulfonylureas or insulin in people with variable intake or inconsistent monitoring. Gymnema supplementation has shown reductions in fasting and postprandial glucose and HbA1c in meta-analyses, often as adjunct therapy [16,17]. This pattern supports the possibility of pharmacodynamic additivity when used in combination.

Cinnamon illustrates another interaction pattern. Meta-analyses and umbrella reviews report small but significant improvements in fasting plasma glucose, HOMA-IR, and HbA1c in type 2 diabetes mellitus, with heterogeneity by dose and study design [12,14]. These effects can amplify glucose-lowering in patients who also receive metformin or basal insulin, mainly when cinnamon is used as a high-dose supplement. Clinical trials often report acceptable tolerability, but a cautious approach remains appropriate during initiation and dose escalation. Self-monitoring of glucose is essential when adding any plant extract that can change postprandial handling or insulin action.

Pharmacokinetic interactions represent an additional concern. Many phytochemicals can modulate drug-metabolizing enzymes and transporters in experimental systems. This issue becomes more relevant with standardized extracts, high doses, or long-term use. A focused review of herb–drug interactions in diabetes summarizes cytochrome P450-related concerns for commonly used antidiabetic plants [156]. Gymnema extracts can inhibit major human CYP (Cytochrome P450) isoforms in vitro, including CYP1A2, CYP3A4, and CYP2C9 [157]. Such findings support the plausibility of altered exposure to co-administered drugs, including antidiabetics and cardiovascular agents. Clinical interaction studies remain limited in populations with diabetes and polypharmacy. This gap supports conservative guidance and clinician oversight during supplement use.

Gastrointestinal adverse effects are frequent and mechanistically predictable. Enzyme inhibition in the small intestine can leave more carbohydrates for colonic fermentation. This can lead to gas, bloating, and diarrhea, like effects seen with pharmacological α-glucosidase inhibitors. Mulberry leaf DNJ products can blunt carbohydrate digestion and can cause mild gastrointestinal symptoms in some users, although human trials often report good tolerability [86,87]. Fermentable fibers add a different burden. Inulin-type fructans and other prebiotic fibers can cause dose-dependent bloating and flatulence. Reviews of inulin describe these effects as common and related to fermentation and the production of short-chain fatty acids [158]. Practical management includes gradual dose titration and intake with meals. Gastrointestinal tolerance also affects adherence, which is a key determinant of long-term benefit.

Product standardization is a significant limitation for clinical translation. Bioactive content can vary by species, cultivar, geography, harvest time, and processing. Cinnamon shows notable variation across species and extracts. Enzyme inhibition depends on phytochemical profile and polyphenol concentration [36]. Mulberry efficacy depends strongly on DNJ content and on formulation that preserves DNJ during processing [87]. Gymnema activity depends on the composition of gymnemic acid and the dose, which can vary across products. Fenugreek efficacy depends on the amount of viscous galactomannan and on the extraction method [15]. Without quantified active components and transparent labeling, dose selection becomes uncertain, and extrapolation from trials to commercial products becomes unreliable.

Quality control is also a direct safety issue. Contamination with heavy metals, pesticides, and microbes can occur due to cultivation conditions or manufacturing practices. Recent analytical work on commercial herbal supplements documented clinically relevant heavy metal contamination in a substantial proportion of tested products [159]. Adulteration with undeclared pharmaceuticals is a separate and serious risk in products marketed for metabolic or weight-related indications. A systematic review documented adulteration of herbal medicines with synthetic drugs and reported cases of harm [160]. A later assessment also emphasized regulatory gaps in traditional medicine markets and the need for surveillance [161]. These risks support preference for products manufactured under good manufacturing practices, with independent testing and clear certificates of analysis.

Evidence remains limited for several vulnerable populations. Safety data in pregnancy, lactation, childhood, and advanced age are sparse for most glucose-modulating botanicals. Risks may also increase in chronic kidney disease, hepatic impairment, or advanced cardiovascular disease due to altered clearance and higher susceptibility to adverse events. Dietary-level exposure is usually safer than concentrated supplementation in these groups. Standardized extracts require additional caution until long-term safety and interaction data become more robust [156].

Overall, plant-based sugar substitutes and glucose-modulating plants appear generally safe at dietary or traditionally used doses, mainly when used as foods or standardized preparations. Their central clinical role is adjunctive support. This includes reduced dietary glycemic load and improved postprandial control. These strategies do not replace evidence-based pharmacotherapy. Safe integration requires individualized selection, attention to formulation, monitoring during initiation, and awareness of interaction and quality risks. Future research should focus on standardized dosing, long-term safety outcomes, and dedicated interaction studies in real-world diabetes populations.

4. Evidence Gaps and Future Directions

Interest in plant-derived approaches to glycemic management continues to increase, but significant evidence gaps limit confidence in clinical translation. The current literature is heterogeneous in study design, participant characteristics, intervention duration, and outcome selection. Product composition also varies widely across trials. These factors reduce comparability and weaken inference, especially when findings are pooled across studies with different plant species, extraction methods, and dosing strategies.

A central limitation is the predominance of short-term interventions that focus on fasting plasma glucose or acute postprandial responses. These measures are helpful for mechanistic inference, but they do not fully represent long-term disease control. HbA1c remains the most clinically meaningful biomarker for chronic glycemia in diabetes care. Yet many trials do not assess HbA1c, or they are too short to detect a stable change. Longer interventions are also needed to evaluate the durability of effect and progression from prediabetes to type 2 diabetes. Future randomized controlled trials should therefore use longer durations, ideally beyond 12–24 weeks. They should include HbA1c as a primary endpoint and should also capture glycemic variability, continuous glucose monitoring metrics, and medication requirements. Patient-reported outcomes should be included because tolerability and adherence often determine real-world value.

Standardization of plant preparations is another significant barrier. Many studies use whole powders or extracts with limited chemical characterization. This problem is particularly relevant for interventions where bioactivity depends on a defined compound class. Mulberry efficacy depends strongly on DNJ content and its stability during processing [87]. Gymnema activity depends on the composition of gymnemic acid and the dose [91]. Cinnamon effects vary by species and polyphenol content, and enzyme inhibition differs across extracts [36]. Monk fruit products can vary in mogroside V and related mogrosides and can be blended with other sweeteners, which complicates attribution of effects to monk fruit alone [146]. Future trials should therefore use standardized products with quantified active constituents and traceable manufacturing methods. This approach is necessary for reproducibility and for meaningful dose–response analysis.

Dose–response evidence is still insufficient for many plants and sweeteners. Many trials use a single dose or a narrow range. This prevents the identification of minimum effective doses and safety margins. Future studies should include multiple dosing arms and report exposure as both the product dose and the active compound dose. Dose–response work is vital for high-intensity sweeteners and their metabolites. Steviol glycosides are metabolized to steviol in the colon and then conjugated to steviol glucuronide. Pharmacokinetic behavior may vary with age, kidney function, and liver function, and may differ under polypharmacy [134]. Mogrosides undergo deglycosylation and metabolic conversion, and the extent of metabolism may vary across populations and microbiota states [143]. Future research should include pharmacokinetic profiling of steviol and mogroside metabolites in special populations, including older adults, individuals with chronic kidney disease, and individuals with hepatic impairment. These studies should also characterize interindividual variability and potential accumulation during long-term use.

Population heterogeneity in existing clinical trials remains a significant gap. Many studies enroll small cohorts with mixed metabolic status, variable medication use, and different disease stages. This limits the identification of responders and non-responders. It also reduces external validity for people receiving intensive therapy. Future trials should include metabolic phenotyping at baseline. This should consist of insulin resistance indices, measures of β-cell function when feasible, and documentation of background therapy. Stratification by prediabetes, early type 2 diabetes, and established type 2 diabetes is essential. Stratification by using insulin secretagogues is also vital for the interpretation of safety. This design will support more precise conclusions and more clinically useful recommendations.

Plant–drug interaction research remains underdeveloped. Many controlled trials exclude individuals receiving complex pharmacotherapy. This practice increases internal validity but reduces applicability to clinical populations. Future studies should explicitly assess both pharmacodynamic and pharmacokinetic interactions under real-world conditions. Pragmatic randomized trials and well-designed observational studies can complement efficacy trials. Herb–drug interaction assessments should include CYP and transporter evaluation where relevant. Gymnema has shown in vitro CYP inhibition, which supports the plausibility of pharmacokinetic interactions, even if clinical significance remains uncertain [157]. Interaction studies should include structured glucose monitoring and adverse event reporting, especially hypoglycemia risk during combination use.

Head-to-head comparisons are also rare. Many trials compare a plant to a placebo, but fewer compare two plant interventions or compare a plant intervention with a standard dietary strategy. Comparative designs are needed to determine relative utility. This issue is relevant to interventions targeting similar pathways, such as α-glucosidase inhibition for mulberry and Salacia-type products, or viscosity-driven absorption delay for fenugreek and other soluble fibers. Head-to-head trials should use matched carbohydrate exposure and standardized co-interventions. They should also include consistent endpoints and harmonized follow-up duration. This will reduce interpretive ambiguity and improve clinical relevance.

Microbiome-mediated mechanisms represent a promising but incomplete area of evidence. Fiber-rich plants and inulin-type fructans can alter the composition of the microbiota and increase short-chain fatty acid production. These processes can influence insulin sensitivity, hepatic glucose output, and enteroendocrine signaling. Yet causal links between specific microbial signatures and reproducible glycemic improvements in humans remain limited. Future trials should integrate microbiome profiling with metabolomics and host metabolic endpoints. This is particularly important for inulin-rich sources such as Jerusalem artichoke and for broader dietary patterns that alter fermentation dynamics. Multi-omics approaches can help explain heterogeneity of response and can identify microbial and metabolic markers that predict benefit.

Regulatory context also affects translation. Many interventions fall between food, supplement, and therapeutic agent categories. This classification differs by region and influences product quality, labeling, and permissible claims. Monk fruit illustrates regulatory uncertainty for specific additive uses due to limitations in the toxicity database for applications [146]. Future research should align intervention definitions with regulatory frameworks and with practical dietary implementation. Trials should specify whether an intervention is intended as a functional food, a dietary supplement, or an adjunctive therapeutic agent. This clarity will improve interpretation and will support integration into nutritional guidelines and clinical counseling.

In summary, current evidence supports an adjunctive role for selected medicinal plants and plant-based sugar substitutes, particularly for reducing postprandial glycemic exposure and lowering dietary glycemic load. The clinical utility of these strategies remains constrained by limited long-term trials, inconsistent standardization, and insufficient integration with medication-based care. Progress requires larger and longer randomized trials with standardized extracts and hard endpoints, including HbA1c and glycemic variability. It also involves dose–response studies, head-to-head comparisons, microbiome-integrated designs for fiber-mediated interventions, and pharmacokinetic profiling of mogroside and steviol glycoside metabolites in special populations.

5. Conclusions

Plant-derived interventions are a diverse and rapidly expanding area in glycemic management. Overall, the evidence supports the concept that selected botanicals and plant-based sugar substitutes can contribute to glucose control through convergent mechanisms—most notably modulation of carbohydrate digestion and intestinal glucose entry, attenuation of postprandial excursions, and support of insulin signaling (including AMPK- and PI3K–AKT-related pathways). Fiber-rich plants may also act via gut microbiota fermentation and short-chain fatty acid production, with downstream effects on enteroendocrine signaling and metabolic flexibility.

Across interventions, clinical effects are generally modest and heterogeneous, and plant-derived approaches are rarely sufficient as stand-alone therapies. The most consistent and clinically actionable signals fall into two categories: (1) dietary glycemic-load reduction, where stevia and monk fruit appear glycemically neutral when replacing sucrose and inulin-type fructans can provide small-to-moderate benefits with sustained intake; and (2) direct glucose modulation, where DNJ-enriched mulberry leaf shows the clearest evidence for reducing postprandial glucose excursions, with additional supportive evidence from meta-analyses for cinnamon, fenugreek, and gymnema indicating modest improvements in glycemic and related cardiometabolic markers.

Safety and implementation are central to translation. While dietary-level use is typically well tolerated, concentrated supplements may cause gastrointestinal intolerance and can potentiate glucose-lowering when combined with antidiabetic drugs. Because efficacy and risk depend strongly on composition, standardization and quality control (including validated manufacturing and transparent labeling) are essential when supplementation is considered.

In practice, plant-derived interventions are best positioned as adjuncts within individualized, evidence-based diabetes prevention and management. Future research should prioritize larger, longer randomized trials using standardized preparations, defined dose–response relationships, rigorous safety/interaction assessment, and durable endpoints such as HbA1c, postprandial metrics, and glycemic variability.