Flavonoids help regulate gut hormones and show promise in managing type 2 diabetes

By Dr. Priyom Bose, Ph.D.Reviewed by Benedette Cuffari, M.Sc.Mar 26 2025

New research reveals how plant-based flavonoids can regulate gut hormones like GLP-1 and ghrelin, offering a natural strategy to manage insulin resistance and slow the progression of type 2 diabetes.

Study: The Emerging Role of Flavonoids in the Treatment of Type 2 Diabetes Mellitus: Regulating the Enteroendocrine System. Image Credit: Shutterstock AI Generator / Shutterstock.com 

A recent review published in the journal Exploratory Research and Hypothesis in Medicine discusses flavonoids' role in regulating the enteroendocrine system and their potential efficacy in treating type 2 diabetes mellitus (T2DM).

What are flavonoids?

Flavonoids are plant-based substances found throughout nature associated with numerous health benefits. Over 10,000 different flavonoid compounds have been identified, most of which can be categorized as flavonols, anthocyanidins, flavonones, flavonols, isoflavones, flavones, and chalcones.

Several studies have described the antioxidant, anti-inflammatory, lipid-regulating, cytotoxic, antibacterial, and anticancer properties associated with flavonoid compounds. More recently, researchers have reported that flavonoids may also exhibit anti-diabetic effects through various mechanisms.

The impact of flavonoids on insulin sensitivity and oxidative stress

Insulin resistance (IR) arises when muscle, fat, and liver cells become less sensitive to the activity of insulin, which can prevent efficient uptake and storage of glucose. Several studies have reported that certain flavonoids may improve insulin sensitivity through different mechanisms.

For example, cyanidin-3-O-glucoside has been shown to suppress protein tyrosine phosphatase 1B levels, thereby increasing phosphorylation of insulin receptor substate 2 (IRS-2). Cyanidin-3-O-glucoside also appears to inhibit IRS-1 phosphorylation, which reduces tumor necrosis factor α (TNF- α),-induced insulin resistance in adipocytes.

Oxidative stress occurs when an imbalance exists between the production of reactive oxygen species (ROS) and antioxidant intracellular activities. During T2DM, mitochondrial dysfunction can increase ROS generation, thereby leading to IR, vascular complications, and β-cell damage in the pancreas to prevent sufficient insulin production.

Flavonoids such as naringin and fucoidan can reduce ROS levels by increasing mitochondrial membrane protection and protecting β-cells against inflammation, respectively.

Flavonoids, the enteroendocrine system, and T2DM management

T2DM has a wide range of adverse effects on various enteroendocrine cells (EECs), crucial for maintaining metabolic homeostasis. For example, several studies have reported that T2DM reduces the effectiveness of the incretin hormone and density of cells responsible for secreting glucagon-like peptide 1 (GLP-1).

The effects of flavonoids on the enteroendocrine system have been widely reported. Chlorogenic acid and curcumin, both phenol compounds, have been shown to increase GLP-1 levels in humans and mice, respectively.

Multiple studies confirm that flavonoids regulate GLP-1, auxin-releasing peptide, peptide YY (PYY), and cholecystokinin (CCK).”

Grape seed proanthocyanidin extract (GSPE) can also reverse the decline of GLP-1 messenger ribonucleic acid (mRNA) levels in the colon. Hispidulin, a flavonoid isolated from medicinal plants, also facilitates GLP-1 release by stimulating L cells, further enhancing blood glucose control.

Glucose-dependent insulinotropic polypeptide (GIP) stimulates the secretion of glucagon under lower plasma glucose concentrations, thereby aiding glycemic management. Although research suggests that flavonoids may promote insulin secretion by inhibiting glucagon secretion in T2DM, thereby preserving GIP levels, these observations have not been confirmed by larger studies.

CCK is produced by I cells in the duodenum. Flavonoids, such as quercetin, kaempferol, apigenin, rutin, and baicalein, may regulate blood sugar levels and food intake by influencing CCK secretion.

Flavonoids may influence blood glucose levels in T2DM patients by altering somatostatin secretion, which can subsequently impact the secretion of CCK. Catechins may inhibit somatostatin release by decreasing gastrin secretion in G cells; however, the mechanisms involved in this activity remain unclear.

Serotonin suppresses appetite in mammals, regulates fluid secretion, intestinal motility, and vasodilation, in addition to promoting insulin secretion in the pancreas. Supplementation with quercetin has been shown to improve serotonergic function impaired by diabetes. Likewise, an extract of the Viscum album plant was reported to increase elevated serotonin levels, whereas luteolin decreased fat degradation in Caenorhabditis elegans, more commonly referred to as roundworm.

Plasma levels of ghrelin, a hormone that stimulates appetite and enhances food intake, rise during fasting and decrease after meals. In T2DM patients, reduced plasma ghrelin activity has been significantly associated with IR and hyperinsulinism.

In rat anterior pituitary cells, quercetin 3-O-malonylglucoside (Q3MG), obtained from mulberry leaves, has been shown to augment ghrelin secretion. Phloretin supplementation also led to a significant rise in ghrelin in C57BL/6J mice.

Conclusions

Flavonoids have the potential to control T2DM by regulating gut hormones; therefore, supplementation with beneficial flavonoids may delay T2DM progression and/or assist in the management of this disease. However, the precise molecular pathways by which flavonoids influence intestinal hormones remain unclear, thus highlighting the need for larger, long-term studies to translate these findings into clinical practice.