Glucolipotoxicity of the pancreatic beta cell

Abstract

SummaryThe concept of glucolipotoxicity refers to the combined, deleterious effects of elevated glucose and fatty acid levels on pancreatic beta-cell function and survival. Significant progress has been made in recent years towards a better understanding of the cellular and molecular basis of glucolipotoxicity in the beta cell. The permissive effect of elevated glucose on the detrimental actions of fatty acids stems from the influence of glucose on intracellular fatty-acid metabolism, promoting the synthesis of cellular lipids. The combination of excessive levels of fatty acids and glucose therefore leads to decreased insulin secretion, impaired insulin gene expression, and beta-cell death by apoptosis, all of which probably have distinct underlying mechanisms. Recent studies from our laboratory have identified several pathways implicated in fatty-acid inhibition of insulin gene expression, including the extracellular-regulated kinase (ERK1/2) pathway; the metabolic sensor Per-Arnt-Sim kinase (PASK); and the ATF6 branch of the unfolded protein response. We have also confirmed in vivo in rats that the decrease in insulin gene expression is an early defect which precedes any detectable abnormality in insulin secretion. While the role of glucolipotoxicity in humans is still debated, the inhibitory effects of chronically elevated fatty acid levels has been clearly demonstrated in several studies, at least in individuals genetically predisposed to developing type 2 diabetes. It is therefore likely that glucolipotoxicity contributes to beta-cell failure in type 2 diabetes as well as to the decline in beta-cell function observed after the onset of the disease.

Cellular responses of novel human pancreatic β-cell line, 1.1B4 to hyperglycemia

“…29 This is supported by observations in INS-1E cells exposed to hyperglycemia and isolated human islets. 19,[30][31][32][33][34] Such downregulation could be due to concomitant reduction in PDX1, which is involved in regulation of insulin gene transcription and expression of other important genes involved in β-cell secretory function. 16 Reduced PDX1 levels have been observed also in HIT-T15 cells, INS-1E cells and human islets treated with high glucose.…”

Deoxyhypusine synthase haploinsufficiency attenuates acute cytokine signaling

“…8,9 Similarly, lipotoxicity arising from high fat diets triggers impairments in insulin release and eventual apoptosis. 10 Despite its central importance in metabolic physiology, the β cell in general has a poor capacity to withstand stresses, a feature that is compounded by its limited numbers and low inherent replication rate. 11 From a teleological perspective, the extent to which an individual's β cells adapt to stress may distinguish those insulin resistant individuals who develop diabetes from those who do not.…”

Metabolic crosstalk between fatty pancreas and fatty liver: effects on local inflammation and insulin secretion

“…These factors favour low grade tissue inflammation and insulin resistance [10][11][12][13][14]. The ultimate cause of hyperglycaemia, however, is insufficient insulin secretion as a consequence of impaired glucoseinduced insulin secretion (GIIS), dedifferentiated beta cells or beta cell apoptosis [15][16][17][18][19][20].…”