Minireview: Secondary β-Cell Failure in Type 2 Diabetes—A Convergence of Glucotoxicity and Lipotoxicity

Abstract

Chronic hyperglycemia and hyperlipidemia can exert deleterious effects on beta-cell function, respectively referred to as glucotoxicity and lipotoxicity. Over time, both contribute to the progressive deterioration of glucose homeostasis characteristic of type 2 diabetes. The mechanisms of glucotoxicity involve several transcription factors and are, at least in part, mediated by generation of chronic oxidative stress. Lipotoxicity is probably mediated by accumulation of a cytosolic signal derived from the fatty acid esterification pathway. Our view that hyperglycemia is a prerequisite for lipotoxicity is supported by several recent studies performed in our laboratories. First, prolonged in vitro exposure of isolated islets to fatty acids decreases insulin gene expression in the presence of high glucose concentrations only, and glucose is rate-limiting for the incorporation of fatty acids into neutral lipids. Second, normalization of blood glucose in Zucker diabetic fatty rats prevents accumulation of triglycerides and impairment of insulin gene expression in islets, whereas normalization of plasma lipid levels is without effect. Third, high-fat feeding in Goto-Kakizaki rats significantly impairs glucose-induced insulin secretion in vitro, whereas a similar diet has no effect in normoglycemic animals. We propose that chronic hyperglycemia, independent of hyperlipidemia, is toxic for beta-cell function, whereas chronic hyperlipidemia is deleterious only in the context of concomitant hyperglycemia.

Insulin counteracts glucotoxic effects by suppressing thioredoxin-interacting protein production in INS-1E beta cells and in Psammomys obesus pancreatic islets

“…Palmitate is toxic to beta cells through multiple, incompletely understood mechanisms [3,4]. Intriguingly, palmitate decreased TXNIP production, rather than increasing it.…”

“…The mechanisms underlying the deleterious effects of glucose on beta cell function and survival are not entirely clear but are thought to involve oxidative stress induced by increased nutrient flux, leading to excessive generation of free radicals [3,4]. The balance between free radical generation and the capacity of antioxidants to scavenge them determines the degree of oxidative stress exerted on the beta cells.…”

Metabolic adaptations to chronic glucose infusion in rats

“…Several authors have suggested that diabetes is characterised by insufficient beta cell adaptation to insulin resistance [15,21,22] followed by beta cell failure. While there is increasing evidence suggesting that glucose plays a critical role in beta cell failure [23,24,25,26,27], the role of glucose during the early phase of insufficient adaptation has been the subject of much debate. Some authors have proposed that glucose is the primary regulator of beta cell mass and function in vivo, whereas others have noted beta cell adaptation in the absence of hyperglycaemia [5,6,8,10,15,28,29,30,31,32].…”

High glucose and hydrogen peroxide increase c-Myc and haeme-oxygenase 1 mRNA levels in rat pancreatic islets without activating NF?B

“…Chronic hyperglycaemia induces phenotypic alterations of rodent beta cells, including GSIS abnormalities, reduced expression of specific genes (loss of beta cell differentiation), hypertrophy, slight increase in apoptosis, and increased expression of genes normally repressed in fully differentiated beta cells [6,[8][9][10][11][12][13][14]. These phenotypic alterations may contribute to the progressive worsening of GSIS in type 2 diabetes [15,16].…”