Mechanisms of Fuel Surfeit Detoxification in Pancreatic β-cells

Abstract

Elevated glucose and free fatty acids (FFA) cause pancreatic β-cell dysfunction, depletion of insulin stores and apoptosis (glucolipotoxicity). If much knowledge has been gained on the biochemical basis of glucolipotoxicity, little is known as to how the β-cell detoxifies fuel excess. We tested the hypothesis that β-cells averts metabolic stress caused by fuel surfeit through glucose metabolism via the glycerolipid/FFA cycle and the subsequent release of lipolysis-derived glycerol and long-chain FFA. Isolated rat islets exposed for 1 h to elevated glucose concentrations showed enhanced glycerolipid/FFA cycling and converted significant amount of glucose carbon to FFA and exported a large fraction of them out of the cell. The stearic and palmitic acids were the predominant FFA species released into the medium. Glycerol release, an index of lipolysis, and glucose utilization did not show saturation even at 16 mmol/L glucose, unlike glucose oxidation, ATP production and insulin secretion. Incorporation of glucose carbons to "inert" triglycerides and cholesterol esters were also elevated with increasing glucose concentration. The results suggest that in islets external glucose concentration is increased, the pathways involved in signalling for secretion and energy production reach saturation earlier than detoxification processes and that at high glucose islets convert a significant portion of the sugar into glycerol and FFA, which are exported outside the β-cell. The identification of fuel surfeit detoxification mechanisms by a targeted metabolomic approach should reveal additional pathways of β-cell fuel detoxification. Targeting fuel detoxification processes may provide a novel approach to preserve β-cell mass and function.