Glucolipotoxicity age-dependently impairs beta cell function in rats despite a marked increase in beta cell mass

Abstract

Aims/hypothesis Prolonged exposure of pancreatic beta cells to excessive levels of glucose and fatty acids, referred to as glucolipotoxicity, is postulated to contribute to impaired glucose homeostasis in patients with type 2 diabetes. However, the relative contribution of defective beta cell function vs diminished beta cell mass under glucolipotoxic conditions in vivo remains a subject of debate. We therefore sought to determine whether glucolipotoxicity in rats is due to impaired beta cell function and/ or reduced beta cell mass, and whether older animals are more susceptible to glucolipotoxic condition. Methods Wistar rats (2 and 6 months old) received a 72 h infusion of glucose + intravenous fat emulsion or saline control. In vivo insulin secretion and sensitivity were assessed by hyperglycaemic clamps. Ex vivo insulin secretion, insulin biosynthesis and gene expression were measured in isolated islets. Beta cell mass and proliferation were examined by immunohistochemistry. Results A 72 h infusion of glucose + intravenous fat emulsion in 2-month-old Wistar rats did not affect insulin sensitivity, insulin secretion or beta cell mass. In 6-month-old rats by contrast it led to insulin resistance and reduced insulin secretion in vivo, despite an increase in beta cell mass and proliferation. This was associated with: (1) diminished glucose-stimulated second-phase insulin secretion and proinsulin biosynthesis; (2) lower insulin content; and (3) reduced expression of beta cell genes in isolated islets. Conclusions/interpretation In this in vivo model, glucolipotoxicity is characterised by an age-dependent impairment of glucose-regulated beta cell function despite a marked increase in beta cell mass.

A causal role for hyperinsulinemia in obesity

“…For example, free fatty acids can acutely stimulate insulin secretion in some individuals, either alone or in the context of elevated glucose levels (Paolisso et al 1995, Carpentier et al 1999, Jeffrey et al 2008, Staaf et al 2016. Prolonged exposure to high levels of lipids can also increase the number of beta-cells and induce fasting hyperinsulinemia in some rodent models (Fontes et al 2010). Exposure to free fatty acids at very high concentrations, or for long periods of time, can eventually induce beta-cell death and dysfunction in human islets and in animal models (Jeffrey et al 2008).…”

G protein-coupled receptor (GPR)40-dependent potentiation of insulin secretion in mouse islets is mediated by protein kinase D1

“…Perifusions and static incubations Islet perifusions were performed as described [24] with the following modifications: after a 20-min equilibration period with KRB solution containing 0.1% (wt/vol.) BSA and 2.8 mmol/l glucose, islets were perifused for 40 min with 16.7 mmol/l glucose with or without 0.5 mmol/l oleate.…”

ChREBP Mediates Glucose Repression of Peroxisome Proliferator-activated Receptor α Expression in Pancreatic β-Cells

“…ChREBP Knockdown Blunts Glucose Repression of Fatty Acid Oxidation Capacity Induced by PPAR␣ Activation-Sustained exposure to elevated levels of glucose and fatty acids is detrimental to the function of pancreatic ␤-cells in vitro (52)(53)(54) and in vivo (55). This may in part be due to a compromised fatty acid oxidation capacity as a result of glucose repression of PPAR␣ expression mediated by ChREBP.…”