Bioenergetics and Type 2 Diabetes

Abstract

Hyperglycemia of type 2 diabetes mellitus (T2DM) develops when pancreatic β-cells damaged by chronic exposure to elevated blood glucose and lipids (glucolipotoxicity) fail to synthesize and secrete sufficient quantities of insulin for maintaining plasma glucose level. Despite intensive studies in this field, the molecular mechanism by which fatty acids (FA) cause β-cell impairment is not well understood. It still remains unknown what are the lipid-or glucose-derived molecules directly responsible for the impairment of β-cell function? Our studies showed that in addition to impaired insulin secretion and loss of biphasicity, T2D islets exhibited altered cell bioenergetics as evidenced by decreased oxygen consumption rate as compared to those of the control islets. We also discovered that fuel overload (high level of FA and glucose leads to incomplete FA oxidation and results in accumulation of "toxic" long-chain 3-OH-fatty acids that could induce oxidative stress and disrupt mitochondrial function. Timedependent impairments of bioenergetics due to chronic exposure to elevated blood glucose and lipids would be the consequence leading to pancreatic β-cell failure.Keywords: Bioenergetics; Pancreatic islets; Fatty acids; Glucolipotoxicity; Type 2 diabetes; Insulin secretion Glucolipotoxicity and DiabetesOverconsumption of calorie rich diets increases the incidence of type 2 diabetes mellitus (T2DM) in genetically predisposed individuals, which has resulted in the worldwide epidemic of T2DM now afflicting about 350 million people. Hyperglycemia of T2DM develops when pancreatic β-cells damaged by chronic exposure to elevated blood glucose and lipids fail to synthesize and secrete sufficient quantities of insulin for maintaining plasma glucose level at a critical level of 5 mM. "Glucolipotoxicity", the operationally defined condition resulting from caloric overload, is proposed to worsen or cause β-cell damage which eventually leads to T2D. The term "glucolipotoxicity" implies that repeated or continued exposure to high blood glucose and lipid levels are required for β-cell damage and functional dysfunction to occur. However, a compelling mechanistic molecular explanation of "glucolipotoxicity" affecting pancreatic β-cells is still lacking. In an attempt to model "glucolipotoxicity" in vitro, pancreatic islets are usually cultured for several days in high glucose and fatty acids (FA) concentrations. Studies have described multiple cellular processes involved in the pathogenesis of β-cell dysfunction, including changes in gene expression [1,2] intermediary metabolism [3], mitochondrial function [4], ion channel activity [5][6][7], insulin synthesis and exocytosis [8]. Different molecular mechanisms of FAinduced β-cell dysfunction have been proposed including accumulation of ceramide [9], apoptosis of β-cells due to oxidative [10][11] and endoplasmic reticulum (ER) stress [12,13] as well as others mechanisms [14,15]. Many of these mechanisms remain controversial. For example, the exposure of human islets for 24 ho...

Early (5-Day) Onset of Diabetes Mellitus Causes Degeneration of Photoreceptor Cells, Overexpression of Incretins, and Increased Cellular Bioenergetics in Rat Retina

“…Diabetes mellitus (DM) is associated with impaired cellular bioenergetics, and its metabolic derangements are known to contribute to the development of retinopathy [1][2][3]. The degeneration of mitochondria in diabetic retina is evident in several studies, but measurements of retinal cellular bioenergetics have been limited [4,5].…”