Citrus compounds show zesty promise in type 2 diabetes management

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In a systematic review published in the journal Diabetes and metabolic syndrome: clinical research and reviewsauthors have described the therapeutic potential of citrus bioflavonoids in controlling blood glucose levels and metabolic complications in patients with type 2 diabetes.

Study: A systematic review examining the mechanisms by which citrus bioflavonoid supplementation benefits blood glucose control and metabolic complications in type 2 diabetes mellitus. Image credits: siam.pukkato / Shutterstock


With an ever-increasing prevalence, type 2 diabetes has become a major public health problem worldwide. The condition is characterized by decreased insulin secretion or sensitivity, impaired glycemic control, and metabolic complications. Type 2 diabetes increases the risk of developing microvascular and macrovascular complications, ultimately leading to organ failure.

Persistently high blood glucose levels (hyperglycemia) and insulin resistance related to diabetes cause the formation of free radicals and inflammatory mediators, which collectively result in the development of several complications, including nerve damage, cardiovascular disease, liver, kidney and eye damage, and skin disorders. hearing disorders and neurodegenerative disorders.

Metformin and sulfonylureas are the first-line treatments against diabetes and its complications. The second line of treatments includes glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors.

Citrus bioflavonoids (flavonols and flavanones) are organic polyphenolic compounds derived mainly from citrus fruits (lemon, orange and grapefruit) and vegetables. These compounds are known to have strong antioxidant properties that help reduce oxidative stress and inflammation.

In this systematic review, the authors searched several scientific databases to select relevant studies conducted between January 2012 and February 2023. The final screen identified 129 studies investigating diabetes management with citrus bioflavonoids.

Therapeutic potential of citrus bioflavonoids in type 2 diabetes

Inflammation and oxidative stress are the key features of type 2 diabetes. Excessive production of reactive oxygen species (ROS) via mitochondrial and endoplasmic reticulum (ER) pathways negatively impacts the body’s antioxidant defense system, leading to oxidative damage to proteins, lipids , enzymes and other cellular components. These factors are collectively associated with insulin resistance and persistent hyperglycemia.

Management of hyperglycemia

Citrus bioflavonoids with potent antioxidant properties are known to control blood sugar levels through several pathways. These compounds, especially naringin and hesperidin, have been shown to inhibit starch hydrolyzing enzymes (alpha-amylase and alpha-glucosidase) and glucose transporters (GLUT2) to reduce the digestion and absorption of carbohydrates in the intestines, which in turn leads to a reduction in the amount of glucose. release into the bloodstream and attenuation of postprandial hyperglycemia.

Among the starch hydrolyzing enzymes, alpha-amylase breaks down ingested starch to generate maltodextrins, which are then converted into glucose by the intestinal brush border enzyme alpha-glucosidase. Thus, the inhibition of these enzymes by citrus bioflavonoids helps prevent hyperglycemia.

Glucose transporters play a crucial role in absorbing glucose and fructose from the small intestine into the bloodstream. There is some evidence that hesperidin 1, hesperetin 8, and whole orange juice can significantly inhibit glucose transporters, including GLUT2, SGLT1, and GLUT5. However, poor solubility of isolated bioflavonoids, such as hesperidin 1, in water and other solvents may limit their bioavailability and bioactivity.

As an important metabolic organ, the liver plays a crucial role in maintaining blood glucose balance by regulating various metabolic pathways including gluconeogenesis, glycogenolysis, and glycolysis.

Evidence suggests that citrus bioflavonoids control hepatic glucose metabolism by increasing glucokinase activity and decreasing phosphoenolpyruvate carboxykinase and glucose-6-phosphatase activities. Specifically, hesperidin 1, neohesperidin 4, naringin 6, and nobiletin 13 have been found to stimulate glycolysis, increase glycogen levels, and reduce gluconeogenesis in liver cells by modulating various liver enzymes. These effects are similar to those caused by metformin, a proven diabetes drug.

Several animal studies have reported a positive effect of hesperidin in lowering total cholesterol, triglycerides and low-density lipoprotein levels in the blood. However, this compound does not show any beneficial effect in human clinical trials. In this context, it should be noted that, despite the significant therapeutic impact on hepatic glucose metabolism, the poor bioavailability of citrus bioflavonoids in the circulation raises concerns about their physiological relevance.

Management of insulin resistance

Insulin, a hormone secreted by beta cells of the pancreas, is primarily responsible for regulating blood sugar levels. A grapefruit-derived flavonoid, naringenin, has been found to increase insulin secretion by pancreatic beta cells in response to glucose. In a mouse model of gestational diabetes, this flavonoid was shown to improve insulin and glucose levels and restore normal body weight.

In diabetic rats, Citrus sinensis (L.) Osbeck peel extract has been shown to reduce insulin resistance by increasing the expression of peroxisome proliferator-activated receptor gamma (PPAR-γ), GLUT4, and insulin receptors. In diabetic patients, hesperidin supplementation has been shown to significantly reduce fasting blood glucose and glycosylated hemoglobin levels and increase blood insulin levels. Studies on the mechanism of action of citrus flavonoids have shown that these compounds increase insulin sensitivity by modulating several signaling pathways, including the PI3K/Akt, PKA, and AMPK pathways.

Inhibition of DPP-4

Recent evidence indicates that citrus bioflavonoids may act as potential DPP-4 inhibitors. In one study, hesperetin 8 and naringenin 9 demonstrated a 15-fold greater ability to inhibit DPP-4 activity than a potent DPP inhibitor diprotin A.

Management of diabetes-related complications

Quercetin, a citrus flavonol, has been shown to prevent the development of diabetic nephropathy (kidney complication) in mice by reducing lipid peroxidation, increasing antioxidant activity, inhibiting GLUT2, and suppressing insulin-dependent activation of PI3K.

In diabetic patients, supplementing with quercetin three times a day for four weeks was found to significantly alleviate symptoms of diabetic neuropathy (nerve damage). In diabetic rats, hesperidin has been shown to reduce diabetic retinopathy (eye damage) by reducing retinal inflammation, preserving the blood-retinal barrier, increasing retinal thickness, and reducing blood glucose levels and aldose reductase activity.

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