Minireview: Secondary  -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.

Glucagon-like peptide-1 prevents beta cell glucolipotoxicity

“…Recent studies have investigated the effect of chronic elevated glucose and NEFA concentrations on beta cell function [4]. Long-term exposure of the beta cell to high glucose induces glucose desensitisation, depletion of the readily releasable pool of insulin and may cause apoptosis [55].…”

“…Calorigenic nutrients, in particular glucose and NEFA, are the principal regulators of pancreatic beta cell function [1,2,3,4]. Short-term exposure of the beta cell to elevated concentrations of glucose promotes insulin release and enhances insulin biosynthesis [1,5].…”

“…We initially developed the concept of glucolipotoxicity, proposing that elevated glucose and NEFA could have synergistic deleterious effects on the beta cell [2,3,19,20]. Glucolipotoxicity might play an important role in the beta cell decompensation phase during the development of obesity-associated Type 2 diabetes, since the effect of post-prandial and subsequently persistent hyperglycaemia, added to the high levels of NEFA and triglycerides, could lead to beta cell apoptosis and impaired beta cell function [3,4,20].…”

Laminitis and the Equine Metabolic Syndrome

“…Glucose dysregulation may contribute to risk for laminitis in an insulin resistant state because hyperglycemia may directly influence vascular endothelial cells (glucotoxic endotheliopathy). 19,41 Mild elevations in the plasma glucose concentration over time are sufficient to affect endothelial regulation of vasomotor tone (vasoconstrictive influence) and promote a prothrombotic endothelial phenotype. 41 Vascular endothelial cells are also directly influenced by insulin in such a manner that interference with the action of insulin (IR) would likely promote vasoconstriction and platelet/leukocyte adhesion to endothelial surfaces.…”

“…19,41 Mild elevations in the plasma glucose concentration over time are sufficient to affect endothelial regulation of vasomotor tone (vasoconstrictive influence) and promote a prothrombotic endothelial phenotype. 41 Vascular endothelial cells are also directly influenced by insulin in such a manner that interference with the action of insulin (IR) would likely promote vasoconstriction and platelet/leukocyte adhesion to endothelial surfaces. 6,42 Therefore, perturbations in the regulation and action of insulin and glucose could theoretically lead to a microvascular dysregulation basis for the risk of laminitis that attends IR.…”