Cholesterol in Pancreatic β-Cell Death and Dysfunction

Abstract

The mechanisms or causes of pancreatic β-cell death as well as impaired insulin secretion, which are the principal events of diabetic etiopathology, are largely unknown. Diabetic complications are known to be associated with abnormal plasma lipid profile, mainly elevated level of cholesterol and free fatty acids. However, in recent years, elevated plasma cholesterol has been implicated as a primary modulator of pancreatic β-cell functions as well as death. High-cholesterol diet in animal models or excess cholesterol in pancreatic β-cell causes transporter desensitization and results in morphometric changes in insulin granules. Moreover, cholesterol is also held responsible to cause oxidative stress, mitochondrial dysfunction, and activation of proapoptotic markers leading to β-cell death. The present review focuses on the pathways and molecularevents that occur in the β-cell under the influence of excess cholesterol that hampers the basal physiology of the cell leading to the progression of diabetes.

Mice Fed a High‐Cholesterol Diet Supplemented with Quercetin‐3‐Glucoside Show Attenuated Hyperlipidemia and Hyperinsulinemia Associated with Differential Regulation of PCSK9 and LDLR in their Liver and Pancreas

“…Excessive intracellular cholesterol renders in pancreatic beta cells dysfunctional . In this study, mice under HCD remained euglycemic but became hyperinsulinemic, an indication that they were insulin resistant, as translated by their decreased GIR values.…”

“…We previously reported that PCSK9 knockout (PCSK9KO) mice had more LDLR and cholesterol in their islets . Intracellular accumulation of cholesterol is known to deleteriously affect the endocrine function of β cells . It is presumably a cause of the insulin‐insufficiency and the prediabetes exhibited by PCSK9KO mice .…”

Effect of LDL cholesterol, statins and presence of mutations on the prevalence of type 2 diabetes in heterozygous familial hypercholesterolemia

“…The lower risk of T2DM appeared in a large LDL cholesterol range, and the LDL cholesterol concentration did not significantly affect T2DM risk. Although there is in-vivo and ex-vivo evidence showing that LDL concentration modulates insulin secretion and pancreatic β-cell survival 13 , large prospective studies showed no significant effect of LDL cholesterol on T2DM risk, in contrast to the association with high triglycerides or low HDL cholesterol that has been repeatedly demonstrated 14, 15 . In human β cell islets, LDL overload lowered insulin secretion 16 and diet-induced hypercholesterolemia also reduced insulin secretion in mice 17 ; however, this diabetogenic effect of hypercholesterolemic diets has also been associated with saturated fatty acid accumulation rather than with cholesterol 16, 18 .…”

The Role of Vegan Diets in Lipotoxicity-Induced Beta-Cell Dysfunction in Type-2-Diabetes

“…6,16 Moreover, excessive accumulation of cholesterol appears to play an important role in beta-cell function. 17,18 The increased uptake of low-density lipoprotein cholesterol by islet beta-cells and subsequent oxidative reactions were shown to be detrimental for these cells. 17,19 Unsaturated fatty acids, on the other hand, were associated with a variety of beta-cell protective effects, including prevention of beta-cell apoptosis and enhanced insulin sensitivity.…”