Hesperetin (HST) is a typical flavonoid from the Citrus L. plant in the Rutaceae family, such as sweet orange and lemon, with the chemical name of 3′,5,7-trihydroxy-4′-methoxy flavanone¹. As a benzene-γ-pyrone derivative, Hst consists of two benzene rings (A and B ring) connected through a “bridge” formed by three carbon atoms with the basic skeleton of the C6?C3?C6structure. The 2D and 3D structures of Hst are shown in Figure 1².

Hesperetin is an active compound for antioxidants, neuroprotectives, anti-inflammatories, antivirals, and antibacterials. Increasing evidence has shown that Hst could ameliorate diabetes mellitus and related complications through multiple signaling pathways and is a promising natural product for the prevention and nutritional therapy of these diseases3-4. Possible mechanisms are as follows.

1.Improvement of Insulin Resistance (IR).

IR is a pathological condition during which the biological response to insulin is reduced due to a variety of reasons⁵. The body’s or organs’reduced uptake and utilization of glucose allow excess glucose to remain and accumulate in the blood, eventually leading to hyperglycemia. Therefore, the improvement of IR is important for the prevention of the development of type 2 diabetes mellitus (T2DM). Flavonoids have been found to have potential antidiabetic effects due to their IR improving properties⁶. The preventive effect of hesperetin on IR has been demonstrated in vivo and in vitro models. Hyperglycemia upregulates chronic inflammatory markers and increasing the production of reactive oxygen species (ROS), while prolonged oxidative stress and chronic inflammation can lead to the development of IR. Dhanya et al.⁷ demonstrated that hesperetin exerts a direct antioxidant effect by scavenging intracellular ROS and upregulating natural antioxidant defense systems.The Wistar albino rats were induced DM by being fed with high-fat diet for 2 weeks and streptozotocin (STZ) administration. Oral intake of hesperetin (50 mg/kg/day) daily for 4 weeks considerably improved serum glucose, insulin, glucagon, liver function enzymes, hepatic glycogen, antioxidant enzymes, and oxidative stress indicators in diabetic rats2. Furthermore, Hst treatments extract remedied IR by altering insulin receptors, phosphatidylinositol 3-kinase (PI3K), and AMP activated protein kinase (AMPK) signaling pathways⁸.

2.Preservation of Islet β-Cells and Release of Insulin from β-Cells.

In STZ induced diabetic rats, oral administration of 40 mg/kg/day hesperetin for 45 days positively altered the deranged carbohydrate metabolic enzymes and decreased the levels of liver and kidney damage markers. It also stimulated pancreatic insulin secretion, resulting in a significant increase in plasma insulin levels and control of blood glucose⁹. Further studies showed that hesperetin treatment showed significant potential to improve islet function by attenuating hyperglycemia-mediated pancreatic oxidative stress and protecting against STZ-induced toxicity.

However, some scholars concluded that the protective effect of hesperetin on pancreatic β-cells was not dependent on their direct antioxidant activity, which contradicts the previously described findings. Therefore, the mechanism underlying hesperetin in preventing diabetes-related β-cell dysfunction needs further investigation².

3.Suppression of α-Glucosidase to Reduce Intestinal Glucose Absorption.

Carbohydrates have long been thought to be associated with the risk of developing DM. This is because carbohydrates are decomposed into the corresponding monosaccharides by enzymes in the intestine prior to absorption, predisposing diabetics patients to elevated postprandial blood glucose. Among them, α-amylase and α-glucosidase are essential for the decomposition and absorption of carbohydrates. Therefore, the inhibition of α-amylase and α-glucosidase is one of the main therapeutic strategies to reduce postprandial hyperglycemia in diabetic patients. Rasouli et al.¹⁰ investigated the inhibitory effects of 26 polyphenolic compounds (including  hesperetin) on α-amylase and α-glucosidase activities by molecular docking and virtual prediction methods. The results speculated that  hesperetin significantly inhibited the activities of α-amylase and α-glucosidase, suggesting that hesperetin may have a therapeutic effect on DM. On the basis of computational molecular dynamics and docking simulations, it was found that the interaction of hesperetin with multiple residues (Lys155, Asn241, Glu304, Pro309, Phe311, and Arg312) near the α-glucosidase active site is the main reason for the anti-α-glucosidase activity of  hesperetin. At present, many research conclusions are based on computer simulations, and more in vivo and in vitro experiments are needed to further validate the inhibitory effect of  hesperetin on intestinal glucose absorption.

In addition to mechanisms for regulating blood glucose described previously, hesperetin may also counteract diabetic complications through anti-inflammatory, antioxidant, or other pathways, such as diabetic nephropathy, diabetic retinopathy, diabetic cardiovascular disease, diabetic hepatopathy, diabetic encephalopathy and diabetic reproductive damages.

In summary, the mechanisms of protective effects of hesperetin on DM include improving IR, protecting islet β-cells, and reducing intestinal glucose absorption. hesperetin holds promise as a natural compound for a promising treatment option for diabetes and related complications. However,the current studies on the pharmacological effects of Hst for the treatment of diabetes and its complications are mostly based on animal models and in vitro studies, and further clinical trials are still required to explore the real efficacy, including its side effects.

References

1.Ferreira de Oliveira, J. M. P.; Santos, C.; Fernandes, E. Therapeutic potential of hesperidin and its aglycone hesperetin: Cell cycle regulation and apoptosis induction in cancer models. Phytomedicine. 2020, 73, 152887.

2.Yang H, Wang Y, Xu S, et al. Hesperetin, a Promising Treatment Option for Diabetes and Related Complications: A Literature Review. J Agric Food Chem. 2022;70(28):8582-8592. 

3.Sharma, M.; Akhtar, N.; Sambhav, K.; Shete, G.; Bansal, A. K.;Sharma, S. S. Emerging potential of citrus flavanones as an antioxidant in diabetes and its complications. Curr. Top Med. Chem. 2015, 15,187-195.

4.Dhuique-Mayer, C.; Gence, L.; Portet, K.; Tousch, D.;Poucheret, P. Preventive action of retinoids in metabolic syndrome/type 2 diabetic rats fed with citrus functional food enriched in β-cryptoxanthin. Food Funct. 2020, 11, 9263-9271.

5.Matulewicz, N.; Karczewska-Kupczewska, M. Insulin resistance and chronic inflammation. Postepy. Hig. Med. Dosw. (Online). 2016,70, 1245-1258.

6.Ren, N.; Kim, E.; Li, B.; Pan, H.; Tong, T.; Yang, C. S.; Tu, Y. Flavonoids Alleviating Insulin Resistance through Inhibition of Inflammatory Signaling. J. Agric. Food Chem. 2019, 67, 5361-5373.

7.Dhanya, R.; Jayamurthy, P. In vitro evaluation of antidiabetic potential of hesperidin and its aglycone hesperetin under oxidative stress in skeletal muscle cell line. Cell. Biochem. Funct. 2020, 38, 419-427.

8.Abdou, H. M.; Hamaad, F. A.; Ali, E. Y.; Ghoneum, M. H.Antidiabetic efficacy of Trifolium alexandrinum extracts hesperetin and quercetin in ameliorating carbohydrate metabolism and activating IR and AMPK signaling in the pancreatic tissues of diabetic rats. Biomed. Pharmacother. 2022, 149, 112838.

9.Jayaraman, R.; Subramani, S.; Sheik Abdullah, S. H.; Udaiyar,M. Antihyperglycemic effect of hesperetin, a citrus flavonoid,extenuates hyperglycemia and exploring the potential role in antioxidant and antihyperlipidemic in streptozotocin-induced diabetic rats. Biomed. Pharmacother. 2018, 97, 98-106.

10.Rasouli, H.; Hosseini-Ghazvini, S. M.; Adibi, H.; Khodarahmi,R. Differential α-amylase/α-glucosidase inhibitory activities of plantderived phenolic compounds: a virtual screening perspective for the treatment of obesity and diabetes. Food Funct. 2017, 8, 1942-1954.