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- Title
Novel insights into pancreatic β-cell glucolipotoxicity from real-time functional analysis of mitochondrial energy metabolism in INS-1E insulinoma cells.
- Authors
BARLOW, Jonathan; AFFOURTIT, Charles
- Abstract
High circulating glucose and non-esterified (free) fatty acid levels can cause pancreatic ß-cell failure. The molecular mechanisms of this ß-cell glucolipotoxicity are yet to be established conclusively. In the present paper we report on the involvement of mitochondrial dysfunction in fatty-acid-induced ß-cell failure. We have used state-of-the-art extracellular flux technology to functionally probe mitochondrial energy metabolism in intact INS-1E insulinoma cells in real-time. We show that 24-h palmitate exposure at high glucose attenuates the glucosesensitivity of mitochondrial respiration and lowers coupling efficiency of glucose-stimulated oxidative phosphorylation. These mitochondrial defects coincide with an increased level of ROS (reactive oxygen species), impaired GSIS (glucose-stimulated insulin secretion) and decreased cell viability. Palmitate lowers absolute glucose-stimulated respiration coupled to ATP synthesis, but does not affect mitochondrial proton leak. Palmitate is not toxic when administered at low glucose unless fatty acid ß- oxidation is inhibited. Palmitoleate, on the other hand, does not affect mitochondrial respiration, ROS levels, GSIS or cell viability. Although palmitoleate protects against the palmitateinduced ROS increase and cell viability loss, it does not protect against respiratory and insulin secretory defects. We conclude that mitochondrial dysfunction contributes to fatty-acid-induced GSIS impairment, and that glucolipotoxic cell viability and GSIS phenotypes are mechanistically distinct.
- Subjects
PANCREATIC beta cells; ENERGY metabolism; INSULINOMA; PHYSIOLOGICAL effects of glucose; PHYSIOLOGICAL effects of fatty acids; MITOCHONDRIAL pathology; OXIDATIVE phosphorylation; TYPE 2 diabetes
- Publication
Biochemical Journal, 2013, Vol 456, Issue 3, p417
- ISSN
0264-6021
- Publication type
Academic Journal
- DOI
10.1042/BJ20131002