Exploring the Anti‐Diabetic Potential of Anthocyanins: From Biochemical Pathways to Human Trials

ABSTRACT

Diabetes mellitus (DM) is a global health challenge with increasing prevalence rates, particularly in low‐ and middle‐income countries. Anthocyanins (ACs) are potential bioactive compounds found in various fruits and vegetables, attracting the attention of researchers due to their possible role in managing diabetes and its complications. Studies have demonstrated the beneficial effects of ACs on blood sugar levels, insulin sensitivity, and glucose tolerance. These effects may be associated with multiple mechanisms, including increased glucose transporter type 4 (GLUT4) expression, enhanced glucose uptake, AMP‐activated protein kinase (AMPK) and protein kinase C (PKC) phosphorylation, improved insulin sensitivity, activation of phosphoinositide 3‐kinase/protein kinase B (PI3K/AKT) signaling, increased glutathione (GSH) synthesis, production of short‐chain fatty acids (SCFAs), glucagon‐like peptide‐1 (GLP‐1) secretion, induction of antioxidant enzymes, improved beta‐cell functioning, and activation of insulin signaling pathways. The activity of enzymes (alpha amylase, glucosidase, and dipeptidyl peptidase‐IV [DPP‐IV]) and the expression of inflammatory biomarkers (tumor necrosis factor [TNF], IL6, and MCP1) are reduced. These findings suggest the potential of ACs as adjunctive therapies. However, further studies, including well‐structured clinical trials, are needed to explore the optimal dosage and long‐term efficacy of ACs in diabetes management.

 

Summary

• ACs enhance insulin sensitivity by modulating key signaling pathways, including PI3K/AKT and AMPK.

• ACs reduce the postprandial glucose response by inhibiting the activity of α‐amylase and α‐glucosidase enzymes.

• They can suppress pro‐inflammatory cytokines and reduce oxidative stress.

• They influence gut microbiota composition by increasing the abundance of beneficial bacteria.

1. Introduction

Diabetes mellitus (DM) is a chronic condition characterized by elevated blood sugar levels due to reduced numbers or defects in islet β‐cells [1]. According to the World Health Organization, over the past few years (1980–2014), the prevalence of diabetes increased from 108 million to 422 million. Particularly low‐ and middle‐income countries are more prevalent for DM [2]. It is estimated that by the year 2030, the number of people suffering from diabetes may reach 643 million [3].

DM is categorized into various types, and the most common are type 1 diabetes mellitus (T1DM) (autoimmune disorder), type 2 diabetes mellitus (T2DM) (metabolic disease), and gestational diabetes [4]. The treatments for T1DM are exogenous insulin replacement, xenotransplantation of islets, artificial pancreas, immune modulation, and transplantation of the whole pancreas and islets [5], whereas T2DM therapies include hypoglycemic oral drugs and insulin therapy [6].

However, both types of diabetes may cause several complications, such as diabetic ketoacidosis, hyperosmolar hyperglycemia, nonketotic coma, diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy [7, 8, 9]. DM and related complications have generated enormous global burdens and become global health problems. The increasing prevalence of DM and its complications impacts millions of lives and places an immense burden on healthcare systems [10].

Approximately 5%–10% of diabetic patients experience secondary failure due to deterioration of beta‐cell activity, weight gain, poor medication, dietary modifications, reduced exercise, or illness [11]. In rural areas, the accessibility and affordability of hypoglycemic medications and insulin are poor and have side effects. For example, metformin is the most common drug used for the management of T2DM [12]; however, this drug has side effects, including stomachache, diarrhea, vomiting, nausea, and loss of appetite [13]. On the other hand, COVID‐19‐infected diabetic patients are less sensitive to antidiabetic drugs [14]. DM, along with COVID‐19, highlights the urgent need for novel, nontoxic, more effective, safer, and less expensive antidiabetic therapies [15, 16].

In this context, bioactive compounds with antidiabetic properties have attracted the attention of researchers for the development of novel and effective solutions for managing diabetes. Anthocyanins (ACs), which are plant pigments, offer diverse health benefits that are associated with anticancer [17], anti‐inflammatory [18], antioxidant [19], antidiabetic [20], and gut microbiota‐modulating properties [21]. Studies have shown that ACs may help treat or prevent chronic diseases, including neurodegenerative diseases, eye disorders, diabetes, cardiovascular disease, and certain types of cancer [22, 23, 24, 25]. Increasing the intake of AC‐rich fruits and vegetables may help mitigate several DM markers, including insulin resistance (IR), insulin deficiency, and hyperglycemia [26]. This narrative review addresses the growing interest in ACs as complementary strategies for diabetes management. Therefore, in this article, we explored the mechanistic pathways involved, the therapeutic potential, and highlighted research gaps.

2. ACs Overview

ACs are water‐soluble glycosides of anthocyanidins, chemically known as flavylium salts or (2‐phenylchromenylium) ion compounds with a molecular weight of 207.25, and they have a distinctive carbon skeleton with two benzene rings that are connected by three carbon atoms to form a C6–C3–C6 skeleton [27, 28]. Sugars such as glucose, galactose, rutinose, rhamnose, arabinose, and xylose are bound mainly to the 3‐hydroxyl, 5‐ or 7‐position of anthocyanidins [28, 29]. ACs can be differentiated based on their number, location, and degree of hydroxyl group (methylation), with the connection of sugar molecules to the aglycone portion and the acylation (nature and number of aliphatic and aromatic acids) of the sugar molecules [28, 29, 30]. Almost 600 ACs have been identified, but only six ACs are present in fruits and vegetables, as shown in Table 1 [31, 32].

Table 1.

Different forms of anthocyanidins [31, 32].

Anthocyanidin	R1	R2	Distribution in plants (%)	Source	Pigment color
Cyanidin	OH	H	50	Berries and red vegetables	Red‐purple/magenta
Pelargonidin	H	H	12	Orange flowers and red fruits	Red
Delphinidin	OH	OH	12	Flowers	Blue‐reddish/purple
Peonidin	OCH3	H	12	Berries, grapes, and red wine	Dark red or purple
Malvidin	OCH3	OCH3	7	Red wine and flowers	Blue/Purple
Petunidin	OH	OCH3	7	Black currant and purple flowers	Magenta

Owing to their reactive ─OH groups, delphinidin and cyanidin are considered more stable than peonidin, malvidin (MV), and petunidin. At low pH values (1–3), ACs are red because of the formation of flavium cations; at neutral pH values, they are colorless because of the formation of carbinol pseudobases; and at high pH values (7–8), they are blue‐purple because of quinoidal base formation or because colorless hemikals that produce pale yellow chalcones [32, 33] further give rise to phenolic acids. These compounds are highly unstable and are affected by various conditions, including pH, temperature, light, oxygen, enzymes, other phenolic acids, proteins, ascorbic acid, hydrogen peroxide (H₂O₂), water, sulfite, and metal ions [29, 30].

Hydrophilic solvents are commonly used for AC extraction, while organic solvents are more suitable for total anthocyanidin extraction. Acidification of the solvent with inorganic or organic acids helps in maintaining the flavylium form of the compounds. Ethanol/methanol, water mixture acidified with HCL, formic acid, or citric acid is commonly used for extraction [34, 35]. Aqueous acetone (70%) is another common solvent used for AC extraction [36]. However, to extract the AC from plant seeds, ultrasonication and temperature can be used with strong and more lipophilic organic solvents [36, 37].

ACs are color pigments responsible for the red, blue, and purple colors of many fruits and vegetables [31]. Commonly consumed foods with relatively high ACs contents include grapes, blueberries, blackberries, black goji berries, mulberries, purple cabbage, raspberries, bilberries, chokeberries, elderberries, red grapes, pomegranates, purple sweet potato, purple potato, purple corn, black rice, and wild rice [38, 39], as shown in Table 2. Due to their high AC content (10–772.4 mg/100 g FW), berries are considered the primary source of ACs, accounting for 39% and 43% of the total AC content in the United States and Europe, respectively [40]. Individuals following the Mediterranean diet consume greater amounts of ACs than those who do not [41]. The average daily intake of AC is estimated to be 12.5, 19.8, 24.2, and 64.9 mg per day per person in the United States [42], the Netherlands [43], Australia [44], and Italy [43], respectively. However, AC intake depends on individual dietary choices.

Table 2.

Anthocyanin sources and their concentrations.

Source	Major compound of ACs	Concentration (C3G mg/100 g)	References
Blueberry	Peonidin‐3‐glucoside, malvidin galactoside, Cyanidin‐3‐glucoside, Pt‐3‐galactoside, Cyanidin 3‐O‐arabinoside	406.90	[32, 40, 45]
Raspberry	Cyanidin‐3‐glucoside, Cyanidin‐3‐glucosyl‐rutinoside	23.17–68.00	[33, 40]
Blackberry	Cyanidin‐3‐glucoside, Cyanidin‐3‐rutinoside	12.5–107.0	[40, 46]
Strawberry	Cyanidin‐3‐glucoside, Pelargodin‐3‐glucoside	20–60	[38, 40, 46]
Black goji berry	Petunidin	1.60–6.25	[38]
Grapes	Malvidin‐3‐glucoside	38.70–186.02	[38, 40]
Mulberry	Cyanidin‐3‐O‐glucoside, Cyanidin‐3‐rutinoside	170.5	[32, 46]
Elderberry	Delphinidin 3‐O‐glucoside, Delphinidin 3‐O‐rutinoside, Cyanidin 3‐O‐glucoside, Cyanidin 3‐O‐rutinoside	664–1816	[29, 40]
Chokeberry	Cyanidin 3‐O‐galactoside, Cyanidin 3‐arabinoside, Cyanidin 3‐O‐glucoside	410–1480	[29, 40]
Black currant	Delphinidin 3‐O‐glucoside, Delphinidin 3‐O‐rutinoside, Cyanidin 3‐O‐glucoside, Cyanidin 3‐O‐rutinoside	130–476	[29, 40]
Apple	Cyanidin‐3‐galactoside	30	[46]
Apricot	Cyanidin‐3‐rutinoside	3	[46]
Black rice	Cyanidin‐3‐O‐glucoside, Peonidin‐3‐O‐glucoside	1.2–110.6	[32]
Açai	Cyanidin 3‐O‐glucoside, Cyanidin 3‐O‐rutinoside, Peonidin 3‐O‐glucoside, Peonidin 3‐O‐rutinoside	45–63	[47]
Mangosteen	Cyanidin‐3‐O‐sophoroside, Cyanidin 3‐O‐glucoside	872.20–1765.25	[48, 49]
Pitaya	Cyanidin 3‐glucoside, Delphinidin 3‐glucoside, Pelargonidin 3‐glucoside	1516–1921	[50, 51]

3. Metabolism of ACs

The digestion and absorption process of AC and its metabolites is complex; however, it is important to understand as it directly impacts the health‐promoting properties. Approximately, an individual from the USA consumes 12.5 mg of AC per day. The bioavailability of AC is very low due to its hydrophilic nature, large size, and susceptibility to gastric pH [52]. AC may have lower bioavailability compared to its metabolites [53]. Studies have shown that the bioavailability of AC is influenced by the physicochemical properties of its molecular structure [54]. However, the exact mechanism of intestinal absorption remains an area of ongoing investigation. In this context, in situ intestinal matrix‐assisted laser desorption/ionization mass spectrometry imaging is an emerging technique that helps us understand the bioavailability and metabolism of AC within real animal intestinal tissue. A study demonstrated that acylated cyanidins were absorbed in the rat jejunum membranes with the OATP 2B1 pathway. Additionally, glucose transporter type 2 (GLUT2) and OATP 2B1 pathways were associated with the transport of aglycon forms of cyanidins. This study provides evidence that acylated AC is absorbed in the intestines [55]. Similarly, studies have suggested that acylated forms of AC may have a significant impact on inflammation, energy metabolism, and gut microbiota in individuals with T2DM [56, 57].

The digestion of AC (shown in Figure 1) starts from the mouth, where physical forces and enzymes break down the food. Thousands of microbes thrive in the oral cavity and release various enzymes, including β‐glucosidase, which play a crucial role in the degradation of cyanidin‐3‐O‐galactoside and cyanidin‐3‐O‐glucoside [58]. After this, the AC reaches the stomach and is highly stable due to the low pH. In the stomach, they can be either absorbed or transferred to the small intestine and further metabolized [59]. Studies have shown that glucose transporter type 1 (GLUT1) and glucose transporter type 3 (GLUT3) aid in the absorption of AC [60, 61]. AC are primarily absorbed in the intestine through active and passive transport by intestinal epithelial cells [62]. These cells express multiple transporters that facilitate active transport of AC across the intestinal epithelium. Additionally, passive diffusion helps in the absorption of AC through the intestinal lumen [63]. The intestinal enzymes, high pH of the intestine, and gut microbiota degrade AC, improving the bioavailability and producing various metabolites [64, 65]. These metabolites are then absorbed into enterocytes, where they are metabolized through phase I and phase II enzymes. Phase 1 enzymes introduce the hydroxyl group into the AC structure, while Phase II enzymes add methyl, sulfuric, or glycoside groups, resulting in the production of conjugated products [39, 56]. The resulting metabolites may offer various health benefits.

Figure 1.

Digestion and absorption of anthocyanins.

4. Potential Mechanism of Action of ACs in DM

The use of ACs has emerged as a promising approach for managing DM. However, ACs have low systemic bioavailability. Current evidence indicates that their biological activity is mediated by a diverse set of gut microbiota‐derived phenolic metabolites, including protocatechuic acid, gallic acid, syringic acid, vanillic acid, and phloroglucinol aldehyde. These metabolites result in multiple nutrient‐sensing pathways central to metabolic regulation [66, 67]. For example, AMP‐activated protein kinase (AMPK) activation by metabolites such as protocatechuic and vanillic acids occurs through shifts in the cellular AMP/ATP ratio and through stimulation of upstream kinases such as LKB1 [68, 69]. AMPK activation inhibits acetyl‐CoA carboxylase and SREBP‐1c, enhances mitochondrial biogenesis via SIRT1–PGC‐1α signaling, and suppresses hepatic gluconeogenesis through downregulation of PEPCK and G6Pase [70]. Additionally, ACs restore impaired insulin signaling by augmenting IRS‐1 and protein kinase B (AKT) phosphorylation, thereby promoting glucose transporter Type 4 (GLUT4) translocation in skeletal muscle and adipose tissue [71]. Protocatechuic acid enhances glucagon‐like peptide‐1 (GLP‐1) secretion and signaling [72], and delphinidin and its metabolites serve as ligands for ERβ and GPER, thus promoting nitric oxide production and endothelial protection [73]. Thus, there are multiple mechanisms by which these ACs exhibit hypoglycemic properties, including antioxidant and anti‐inflammatory effects, improved insulin sensitivity, regulation of enzymes, and modulation of the gut microbiota (as shown in Figure 2). The well‐detailed pathways are discussed below.

Figure 2.

The mechanism by which anthocyanins improve glucose metabolism and insulin sensitivity. AKT, protein kinase B; AMPK, AMP‐activated protein kinase; DPP‐IV, dipeptidyl peptidase‐IV; GLP‐1, glucagon‐like peptide‐1; GLUT4, glucose transporter type 4; GSH, glutathione; IL‐6, interleukin‐6; MCP‐1, monocyte chemoattractant protein‐1; PI3K, phosphoinositide 3‐kinase; PKC, protein kinase C; SCFAs, short‐chain fatty acids; TNF, tumor necrosis factor.

4.1. Antioxidant Activity

Oxidative stress is associated with lipid peroxidation, non‐enzymatic glycation of proteins, and oxidation of glucose, all of which contribute to the development of DM and its complications. Therefore, inhibiting or reducing oxidative processes can prevent or delay the onset of complications associated with diabetes. Studies have shown that antioxidants can neutralize free radicals, thus reducing oxidative stress, which is crucial for the treatment and management of diabetes [74]. The antioxidant activity of ACs was measured via various methods, such as DPPH (diphenyl‐1‐picrylhydrazyl), ORAC (oxygen radical absorbance capacity), TRAP (total peroxyl radical‐trapping antioxidant parameter), ferric thiocyanate, FRAP (ferric reducing antioxidant power), and CUPRAC (cupric ion‐reducing antioxidant capacity) assays [75].

In a previous study, blueberry ACs were administered to STZ‐induced diabetic mice at varying dosages (20, 40, and 80 mg/kg) for 12 weeks. The study demonstrated that administration of blueberry ACs resulted in increased glutathione (GSH) and glutathione peroxidase (GPx) activity and reduced malondialdehyde (MDA) and reactive oxygen species (ROS) levels [76]. These changes play a crucial role in ameliorating diabetes. The elevated ROS in insulin‐responsive tissues impairs insulin receptor signaling by promoting serine phosphorylation of IRS‐1; thus, lowering ROS restores insulin sensitivity. Similarly, enhanced GSH–GPx activity improves cellular redox balance, protecting pancreatic β‐cells from oxidative damage and apoptosis [77, 78, 79]. All these studies have revealed that AC supplementation improves blood sugar levels and protects against diabetic complications such as retinopathy and nephropathy.

4.2. Anti‐Inflammatory

Inflammation is also a major factor in the onset of IR and promotes the progression of its complications. Tumor necrosis factor‐alpha (TNF‐α), interleukin‐6 (IL‐6), and interleukin‐1 (IL‐1) are inflammatory cytokines that play a crucial role in the inflammatory response. Similarly, monocyte chemoattractant protein 1 (MCP‐1) controls leukocyte migration and infiltration and contributes to the pathophysiology of DM [80]. Numerous studies have demonstrated that ACs may regulate the IKK/nuclear factor kappa B (NF‐κB) pathway, thus reducing the expression of inflammatory cytokines [81, 82] and expression of MCP‐1 [83]. ACs increase the secretion of adiponectin, reduce the expression of TNF‐α and IFN‐γ, and stimulate interleukin‐10 (IL‐10) production [83, 84]. The AC metabolites stabilize IκBα and prevent nuclear accumulation of the p65/p50 complex, thereby reducing the expression of TNF‐α, IL‐6, COX‐2, and iNOS. ACs also activate the Nrf2 antioxidant program by facilitating Nrf2 release from Keap1, thereby inducing robust expression of HO‐1, NQO1, and related cytoprotective enzymes [85, 86, 87, 88].

4.3. Improvements in Insulin Secretion and Sensitivity

Increased expression of inflammatory markers, including TNF‐α, MCP‐1, and IL‐6, may contribute to IR. Studies have demonstrated that ACs may downregulate the expression of these inflammatory markers and play a crucial role in reducing the risk of T2DM [89, 90]. A study showed that sour cherry AC‐rich extract downregulated the expression of proinflammatory cytokines, including TNF‐α, IL‐6, interleukin‐8 (IL‐8), and interleukin‐1α (IL‐1α) [91].

The chronic supplementation of ACs at a dosage of 60 mg/kg body weight to high‐fat diet (HFD)‐fed mice resulted in increased levels of insulin, C‐peptide, and leptin. Additionally, supplementation increased MCP‐1 levels, water‐soluble antioxidant capacity, SOD levels, and adiponectin levels and reduced IL‐6 levels [83]. Similarly, chronic consumption of a diet enriched with 1% freeze‐dried whole‐tart cherry reduced the expression of IL‐6, TNF‐α, NF‐κB, peroxisome proliferator‐activated receptor alpha (PPAR‐α), and peroxisome proliferator‐activated receptor gamma (PPAR‐γ) in the retroperitoneal fat [92]. A diet supplemented with 1% freeze‐dried whole‐tart cherries significantly reduced fasting blood glucose, hyperlipidemia, and hyperinsulinemia by increasing the expression and activity of hepatic PPAR‐α in Dahl salt‐sensitive rats [93].

AMPK plays a crucial role in hepatic and systemic glucose–lipid metabolism, by promoting glucose uptake and inhibiting gluconeogenesis. Exposure to high glucose concentrations resulted in the hypo‐phosphorylation of AMPK in HepG2 cells. A study revealed that malvidin (Mv), malvidin‐3‐glucoside (Mv‐3‐glc), malvidin‐3‐galactoside (Mv‐3‐gal), or blueberry ACs upregulated the expression of p‐AMPK/AMPK [94]. The upregulated AMPK may improve insulin sensitivity and reduce hepatic glucose production. In a study, Vaccinium arctostaphylos extract was administered to alloxan‐induced diabetic Wistar rats. The results showed upregulation of insulin expression in both cardiac and pancreatic cells. The possible mechanism may involve the stimulation of β‐cells and/or enhanced insulin release from these cells [95]. A study investigated the ability of ACs and anthocyanidins to stimulate insulin secretion and found that delphinidin‐3‐glucoside and cyanidin‐3‐galactoside were the most effective in stimulating insulin secretion at glucose concentrations of 4 and 10 mmol/L [96]. In another study, a pelargonidin‐supplemented diet resulted in improved blood glucose levels, serum insulin levels, and reduced oxidative stress in diabetic rats.

Several studies have demonstrated that ACs improve glycemic control by increasing the expression of the glucose transporter GLUT4. In this context, cyanidin‐3‐glucoside (C3G)‐supplemented diet significantly reduces blood sugar levels and improves insulin sensitivity by increasing the expression of GLUT4 and reducing retinol‐binding protein 4 (RBP4) levels in T2DM mice [97, 98]. The administration of Vaccinium arctostaphylos extract activated AMPK [95], which resulted in increased expression of GLUT4, reduced gluconeogenesis, and improved insulin sensitivity [99].

4.4. Regulation of Enzymes

Several enzymes have been identified as potential therapeutic targets for T2DM. Inhibition of the activity of digestive enzymes (α‐amylase and α‐glucosidase) results in slow carbohydrate absorption. Similarly, inhibition of dipeptidyl peptidase‐IV (DPP‐IV) resulted in prolonged incretin levels, which led to increased insulin secretion and improved glucose control. Studies have demonstrated that polyphenols can modulate the activity of these enzymes [100]. The study revealed that AC‐rich bilberry extract presented IC₅₀ values of 0.31 ± 0.02 and 4.06 ± 0.12 mg/mL for α‐glucosidase and α‐amylase, respectively [101]. Similarly, in another study, different solvents were used for bilberry extract, in which the minimum IC₅₀ value was for the ethanolic extract (20.8 μg GAE/mL), whereas the highest IC50 value was for the aqueous extract (194.8 μg GAE/mL) for α‐amylase inhibition [102]. A study demonstrated that Vaccinium myrtillus L. extracts exhibited α‐amylase inhibition comparable to that of standard acarbose, with IC₅₀ values ranging from 61.38 to 281.53 μg/mL, whereas that of acarbose was 87.55 μg/mL [103]. Methanolic extracts of Rubus grandifolius inhibited the activity of α‐amylase, α‐glucosidase, and other enzymes associated with metabolic syndrome [104]. Real‐Hernandez et al. reported that ACs significantly upregulated hepatic nuclear factor 1α (HNF1α) gene expression and inhibited DPP‐IV, thus regulating T2DM [105]. A previous study investigated the impact of chronic ACs supplementation on glucose metabolism in C57BL/6 J mice. They demonstrated that a diet supplemented with either 40 mg ACs or 20 mg epigallocatechin gallate per kg body weight significantly increased plasma GLP‐1 levels, which was associated with upregulated expression of the glucagon gene and decreased expression of the DPP‐IV gene [106].

4.5. Modification of the Gut Microbiota

The gut microbiota plays a crucial role in host health. They can influence various functions, including mucus production, digestion, metabolic regulation, intestinal permeability, epithelial morphology, and immune responses. Dysbiosis is associated with the pathogenesis of various diseases, including diabetes. Studies have shown that ACs can modulate the composition of the gut microbiota, resulting in improved glucose metabolism and reduced inflammation. In a study, the diet of diabetic rats was supplemented with AC extracts derived from black rice and black bean husks for 4 weeks. The study found a significant increase in the abundance of Coprococcus spp., Bacteroides spp., Phascolarctobacterium spp., and Akkermansia spp., resulting in increased production of SCFAs. Additionally, the intervention led to improved insulin sensitivity, reduced levels of inflammatory cytokines, and lower blood glucose concentrations [107]. Similarly, in another study, diabetic mice were supplemented with black bean peel ACs extract in their diet, which resulted in increased abundances of Turicibacterium spp., Phascolarctobacterium spp., Bacteroidetes spp., and Akkermansia spp. The administration of the extract also reduced oxidative stress and inflammatory responses. Additionally, ACs extracts regulate the expression of LXR, LKB1, and SREBP‐1c [108]. In a previous study, the diet of diabetic Zucker fatty rats supplemented with acylated ACs from purple potatoes and nonacylated ACs from bilberries resulted in a reduced abundance of Lachnospiraceae bacterium 4_1_37FAA, Ruminococcus torques, and Parabacteroides spp. while increasing the abundance of Peptostreptococcaceae spp [109]. A study revealed that the administration of Euterpe oleracea Mart. Fruit extract alleviated HFD‐induced obesity, IR, and hepatic steatosis and increased the abundance of Akkermansia muciniphila [110].

5. ACs and DM

5.1. Animal Studies (Table 3)

Table 3.

Animal studies on the effects of ACs on different biomarkers of diabetes.

ACs source	Subject	Dosage and duration	Mechanism	Outcome	References
Tart cherries	Male Wistar rats	0.1 mg/g/day and 17 weeks	Reduced inflammatory cytokines	Reduced blood pressure and hyperglycemia	[111]
Hibiscus rosa sinensis	Male Sprague–Dawley rats	50 mg/kg body weight and 30 days	Protected the hepatocytes and increased the antioxidant enzymes.	Reduced serum glucose and HbA1c levels	[112]
Rosa damascene extract	Male Wistar rats	250–1000 mg/kg/day and 28 days	Suppressed NF‐κB expression	Reduced FBS	[113]
Pelargonidin‐3‐O‐glucoside	db/db mice	50–150 mg/kg/day and 8 weeks	Regulated glucose and lipid metabolism	Alleviated glucose intolerance and insulin resistance	[114]
Morus nigra and Bauhinia variegata	Streptozotocin‐induced diabetic rats	250 and 500 mg/kg and 4 weeks	Inhibited α‐glucosidase enzyme	Reduced FBS and prevented liver and kidney damage	[115]
Red‐cabbage extract	Wistar male rats	800 mg/kg and 4 weeks	Improved pancreatic islet morphology and increased the abundance of pancreatic β‐cells	Reduced FBG and glycated, and improved glucose tolerance	[116]
Black rice ACs	Sprague Dawley Rat	200–400 mg/kg and 4 weeks	Regulated the PI3K/AKT signaling pathway and modulated gut microbiota	Reduced FBG, improved glucose tolerance	[117]
Clitoria ternatea flower extracts	Wistar rats	300 mg/kg and 28 days	Suppressed the activity of α‐glucosidase	Reduced FBG and HbA1c	[118]
Mulberry fruit extract	Male Wistar rats	10–250 mg/kg and 8 weeks	Increased PPAR‐γ expression	Reduced cholesterol, TG, LDL, FBG, glucose AUC, and increased HDL	[119]
Dietary raspberry	Mice	5% dry weight and 10 weeks	Activated AMPK α1	Improved insulin sensitivity	[120]
Pelargonidin‐3‐O‐glucoside derived from wild Raspberry	db/db diabetic mice	150 mg/kg and 8 weeks	Induced autophagy and modulated gut microbiota	Improved glucose tolerance, insulin sensitivity, elevated Bacteroidetes/Firmicutes ratio, and increased abundance of Prevotella	[121]

Abbreviations: ACs, anthocyanins; AKT, protein kinase B; AMPK, AMP‐activated protein kinase; AUC, area under the curve; FBG, fasting blood glucose; FBS, fasting blood sugar; HbA1c, glycated hemoglobin; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; NF‐κB, nuclear factor kappa B; PI3K, phosphoinositide 3‐kinase; PPAR‐γ, peroxisome proliferator‐activated receptor gamma; TG, triglycerides.

5.1.1.

5.1.1.1.

Tian et al. reported that C3G improved glucose tolerance by 26% in 6‐week‐old male C57BL‐6J mice fed an HFD, while no impact was observed in low‐fat diet (LFD). C3G increased hepatic fibroblast growth factor 21 (FGF21) expression by fourfold in LFD‐fed mice and attenuated FGF21 overexpression in HFD mice. These observations suggest that C3G intervention acts in a context‐dependent manner rather than functioning as a simple stimulant or suppressor of FGF21. Mice on an LFD diet, with C3G‐preserved metabolic homeostasis and elevated FGF21 levels [122], are consistent with physiological activation of hepatic nutrient‐sensing pathways, particularly those regulated by PPAR‐α [123]. Such activation may enhance fatty‐acid oxidation and maintain metabolic flexibility, serving as a normal adaptive response that supports energy expenditure under low‐fat dietary conditions. In contrast, diet‐induced obesity is characterized by chronically elevated circulating FGF21 levels due to impaired adipose tissue signaling. Reduced hepatic FGF21 expression in HFD‐fed mice demonstrated that the intervention improved peripheral FGF21 responsiveness. This interpretation is supported by reductions in inflammation, lipotoxicity, and ER stress, which can restore expression of key components of the FGF21 receptor complex [122]. Mechanistic studies further indicate that C3G enhances glycogen synthesis and reduces fasting blood glucose by upregulating GLUT1 and modulating the Wnt/β‐catenin/WISP‐1 axis. This highlights its potential role as a pleiotropic metabolic modulator rather than a unidirectional hypoglycaemic compound [124].

A study demonstrated that dietary blackcurrant extracts, particularly delphinidin 3‐rutinoside (D3R), significantly improved glucose tolerance and reduced blood glucose levels in diabetic mice (KK‐A^y). These results were associated with upregulation of PC1/3 gene expression, which plays an essential role in proglucagon processing, thereby enhancing the production and release of biologically active GLP‐1. This is accompanied by activation of AMPK, which leads to an increase in movement of the GLUT4 from intracellular stores to the cell surface, enabling more efficient glucose uptake by peripheral tissues [125]. Similar activation of AMPK by blueberry ACs in streptozotocin‐induced diabetes supports AMPK as a convergent mechanistic pathway across multiple ACs sources [94]. The AMPK activation promotes GLUT4 expression and modest increases in GLUT4 translocation in skeletal muscles, thereby enhancing insulin‐independent glucose uptake. Similarly, its activation suppresses gluconeogenic gene expression, including PEPCK and G6Pase, thereby reducing hepatic glucose output. In adipose tissue, AMPK activation attenuates lipogenesis by promoting fatty acid oxidation through inhibition of acetyl‐CoA carboxylase and a reduction in malonyl‐CoA levels. Additionally, ACs‐mediated AMPK signaling intersects with anti‐inflammatory and antioxidant pathways, helping to reduce NF‐κB activity and mitigate oxidative stress, both of which contribute to improved insulin sensitivity [126, 127].

The molecular form of ACs also appears to influence metabolic outcomes. For example, both protein‐bound and free ACs from purple sweet potato significantly improved lipid metabolism and glucose tolerance (p < 0.05), suggesting that food–matrix interactions do not eradicate bioactivity but may modify absorption and tissue distribution, an essential consideration for functional‐food development, which is associated with increased protein levels of glucokinase, glucose transporter type 2, AMPK, and insulin receptor α. Additionally, it reduced oxidative stress and liver damage and upregulated pyruvate kinase and phosphofructokinase, while reducing the expression of phosphoenolpyruvate carboxykinase and glucose‐6‐phosphatase [128].

According to Chen et al., black soybean seed coat extract can be utilized as a functional food for the treatment of T2DM. They found that C3G, D3G, and peonidin‐3‐O‐glucoside are the anthocyanidins present in the seed coat of black soybean. The extract exhibited α‐amylase‐inhibitory activity, enhanced the activities of catalase, GPx, and superoxide dismutase, and reduced oxidative stress damage. Additionally, the administration of extract resulted in reduced fasting blood glucose level and insulin level by 47.97% and 46.49%, respectively [129]. These antioxidant and enzyme‐modulating effects are responsible for glycaemic improvements; however, there is a mechanistic gap.

Combining ACs with conventional antidiabetic agents such as metformin results in improvement in glycaemia, insulin sensitivity, and lipid metabolism. ACs with metformin are more effective in downregulated SREBP‐1c, ACC, FAS, IL‐6, IL‐8, NF‐κB, and upregulated PPARα, CPT1, LPL. Additionally, it suppressed protein tyrosine phosphatase 1B and modulated the phosphoinositide 3‐kinase (PI3K/AKT/GSK3β) signaling pathway [130, 131]. These diverse findings highlight the mechanistic pathways such as AMPK activation, modulation of glucose transporters, suppression of hepatic gluconeogenesis, and anti‐inflammatory signaling. A more standardized methodological framework and mechanistic validation in human studies are essential to translate these promising preclinical effects into practical interventions.

5.2. Clinical Studies

In a clinical trial, individuals with diabetes consumed 320 mg of AC per day for 4 weeks. The study revealed significant reductions in uric acid, fasting blood glucose (FBG), low‐density lipoprotein cholesterol (LDL‐C), IL‐6, interleukin‐18 (IL‐18), and TNF‐α [89]. A similar magnitude of benefit was observed in a randomized controlled trial (RCT) revealed the potential of AC supplementation (320 mg) for managing prediabetes and early‐stage diabetes. After 12 weeks of intervention, an improvement was observed in apolipoprotein A‐1 (apo A‐1) (0.12 g/L [0.03, 0.21], p = 0.01), apolipoprotein B (apo B) (−0.07 g/L [−0.14, −0.01], p = 0.03), HbA1c (−0.11% [−0.22, −0.11], p = 0.03), adiponectin, and visfatin levels decreased (−3.5 ng/mL [−6.69, −0.31], p = 0.03) [132]. Consistent results were reported in an RCT conducted on local communities in Guangzhou, China. The study has shown that administration of AC resulted in a reduction of LDL‐C (−0.2 mmol/L, [−0.38, −0.01], p = 0.04) and HbA1c (−0.14%, [−0.23, −0.04], p = 0.01) [133]. Interestingly, whole‐food interventions, such as short‐term blackberry supplementation (600 g/day) during an HFD, also enhanced insulin sensitivity, HbA1c, and HOMA‐IR in overweight or obese men, suggesting that the metabolic benefits of ACs extend beyond purified extracts and may function within complex food matrices [134].

Two meta‐analyses demonstrated a dose‐dependent association between AC intake and the risk reduction of T2DM. The dose‐response found a significant curvilinear association between total flavonoid intake and the incidence of T2DM (p for nonlinearity = 0.04). Studies indicate that the optimal dosage of flavonoid intake for managing blood sugar levels is ≥ 550 mg/day. The 300 mg/day increase in total flavonoid intake was associated with a 5% reduction in T2DM risk (relative risk [RR]: 0.95; 95% confidence interval [CI]: 0.93–0.97) [135, 136]. A 20‐year follow‐up study of 60,586 women with T2DM demonstrated that the intake of AC, stilbenes, lignans, flavonols, hydroxybenzoic acids, dihydroflavonols, and catechins can reduce the risk of T2DM (logHR = −0.004; 95% CI: −0.002, −0.007) [137]. Together, these clinical findings and large‐scale epidemiological analyses reveal a coherent pattern. ACs intake is associated with modest yet physiologically relevant improvements in glycemic control, lipid profiles, inflammatory biomarkers, and long‐term diabetes risk. However, variability in dosing, ACs composition, and intervention duration across studies highlights the need for standardized clinical protocols and mechanistic exploration to elucidate dose thresholds, bioactive forms, and population‐specific responses. Table 4 presents clinical studies on the effects of ACs on different biomarkers of diabetes.

Table 4.

Clinical studies on the effects of ACs on different biomarkers of diabetes.

ACs source	Subject	Dosage and duration	Mechanism	Outcome	References
Bilberry extract	T2DM patients	1.4 g/day and 4 weeks	The study is short term	No significant reduction in HbA1c and FBG	[138]
ACs	Patients with hyperglycemic conditions	320 mg/day and 12 weeks	Increased serum IGFBP‐4 fragments	Reduces FBG and postload C‐peptide	[139]
Berry‐rich AC supplements	Metabolic syndrome and healthy subjects	320 mg/day and 4 weeks	Downregulated the expression of NF‐κB	Reduced FBG, TG, cholesterol, and LDL	[140]
Dietary raspberries	T2DM obese adults	250,000 mg/day and 10 weeks	Reduced IL‐6 and TNF‐α	Reduced postprandial serum glucose levels	[141]
Bilberry extract	Overweight volunteers	0.47 g of Mirtoselect per day and 3 weeks	Decreased carbohydrate digestion and/or absorption	Reduced the OGTT AUC	[142]
Freeze‐dried blueberries	T2DM patients	22 g and 8 weeks	Delayed carbohydrate breakdown and glucose absorption	Reduced HbA1c and fructosamine	[143]

Abbreviations: ACs, anthocyanins; AUC, area under the curve; FBG, fasting blood glucose; HbA1c, glycated hemoglobin; IGFBP‐4, insulin‐like growth factor binding protein‐4; IL‐6, interleukin‐6; LDL, low‐density lipoprotein; NF‐κB, nuclear factor kappa B; OGTT, oral glucose tolerance test; T2DM, type 2 diabetes mellitus; TG, triglycerides; TNF‐α, tumor necrosis factor‐alpha.

6. Conclusion and Future Perspective

Various natural sources of ACs offer a positive impact on DM management. Both preclinical and clinical studies have demonstrated that ACs may improve lipid metabolism, blood sugar levels, glucose metabolism, Hb1Ac levels, anti‐inflammatory and antioxidative markers, insulin sensitivity, and gut bacterial composition through various mechanisms. However, few studies have shown that ACs had no significant impact on DM management. This may be due to the variation in dosage and duration. The systematic review studies have demonstrated that the anti‐diabetic potential of ACs is associated with the risk of DM in a dose‐dependent manner. In the mentioned studies, the intake of ACs varied significantly; however, the population is restricted to specific regions, so the results cannot be generalized. In this context, cohort studies with a diversified population are needed to optimize the optimal daily intake of ACs. Further studies are also needed to elucidate the exact anti‐diabetic mechanism of ACs.

Knowledge about AC's absorption and metabolism is limited; therefore, well‐structured in vitro and in vivo studies should be carried out. Furthermore, techniques for controlling the release of ACs should be developed to enhance biological activity. ACs are less stable, but they can be stabilized by methylating, glycosylating, and acylating glycosyl ligands. However, to further improve the stability of ACs, additional studies are needed to assess their impact in clinical settings. Generally, anti‐diabetic medications exhibit adverse responses as the dosage increases, while there is no adverse effect of ACs. Therefore, a combination of ACs with anti‐diabetic medications may be more effective with reduced adverse effects as observed in animal studies. Currently, there are limited studies on the synergistic effects of ACs with antidiabetic medications. Further studies in this direction may pave the way for the utilization of ACs in hospitals as an adjunctive therapy for anti‐diabetic medications.

Author Contributions

Conceptualization: Sarvesh Rustagi, Rahul Mehra, and Akash Kumar. Supervision: Sarvesh Rustagi and Akash Kumar. Writing – original draft: Lakshay Panchal, Sangeeta Yadav, Yashna Bawa, and Tanbeer Kaur. Visualization: Akash Kumar. Writing – review and editing, Sarvesh Rustagi, Rahul Mehra, and Akash Kumar.

Ethics Statement

This study is a narrative review based exclusively on previously published literature. It did not involve any experiments on human participants or animals. Therefore, ethical approval and informed consent were not required.

Funding

The authors received no specific funding for this work.

Conflicts of Interest

The authors declare no conflicts of interest.

Use of Large Language Models, AI, and Machine Learning Tools

The authors declare that no large language models, artificial intelligence, or machine learning tools were used in the preparation, analysis, or writing of this narrative review.

Data Availability Statement

Data sharing is not applicable to this article, as no datasets were generated or analyzed during the current study.