Flavonol kaempferol in the regulation of glucose homeostasis in diabetes
Alkhalidy, Hana Awwad
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Diabetes mellitus is a major public health concern. Although the accessible novel drugs, techniques, and surgical intervention has improved the survival rate of individuals with diabetes, the prevalence of diabetes is still rising. Type 2 diabetes (T2D) is a result of chronic insulin resistance (IR) and loss of �-cell mass and function. Therefore, the search for naturally occurring, low-cost, and safe compounds that could enhance insulin sensitivity and protect functional �-cell mass can be an effective strategy to prevent this disease. Kaempferol, a flavonol present in various medicinal herbs and edible plants, has been shown to elicit various pharmacological activities in preclinical studies. However, studies investigating the effect of kaempferol on diabetes are limited. In this dissertation, I explored the anti-diabetic potential of dietary intake of kaempferol in diet-induced obese mice and insulin-deficient diabetic mice. First, kaempferol was supplemented in the diet to determine whether it can prevent IR and hyperglycemia in high fat (HF) diet-induced obese mice or STZ-induced obese diabetic mice. To evaluate its efficacy for treating diabetes, kaempferol was administrated once daily via oral gavage to diet-induced obese and insulin-resistant mice or lean STZ-induced diabetic mice. The results demonstrated that long-term oral administration of kaempferol prevents HFD-induced metabolic disorders in middle-aged obese mice. Oral administration of kaempferol improved glucose intolerance and insulin sensitivity, and this effect was associated with increased Glut4 and AMPKa expression in muscle and adipose tissues. Consistent with our findings from the in iii vitro study in C2C12 muscle cell line, these findings suggest that kaempferol may reduce IR at the molecular level by improving glucose metabolism in peripheral tissues. In the second study, dietary kaempferol supplementation prevented hyperglycemia and glucose intolerance by protecting �-cell against the induced damage in obese STZ-induced diabetic mice. In the third study, the administration of kaempferol by oral gavage significantly ameliorated hyperglycemia and glucose intolerance and reduced the incidence of diabetes from 100 % to 77.8% in lean STZinduced diabetic mice. This kaempferol effect was associated with reduced hepatic glucose production, the primary contributor to hyperglycemia, and increased glucose oxidation in the muscle of diabetic mice. Kaempferol treatment restored hexokinase activity in the liver and skeletal muscle and reduced pyruvate carboxylase (PC) activity and glycogenolysis in the liver. Unlike its effect on T2D mice, kaempferol effect in lean STZ-induced diabetic mice was not associated with changes in plasma insulin levels. In the last study, we found that administration of kaempferol by oral gavage significantly improved blood glucose control by suppressing hepatic glucose production and improving glucose intolerance in obese insulin-resistant mice. Similar to its effect in old obese mice, kaempferol enhanced whole-body insulin sensitivity. Kaempferol increased Akt and hexokinase activity and decreased PC activity in the liver. However, kaempferol did not exert any changes in glucose metabolism or insulin sensitivity when administered to healthy lean mice. Overall, findings from these studies provide new insight into the role of kaempferol in the regulation of glucose homeostasis and suggest that kaempferol may be a naturally occurring anti-diabetic compound by improving insulin sensitivity, improving glucose regulation and metabolism, and preserving functional �-cell mass.
- Doctoral Dissertations