| Insulin is normally secreted in an oscillatory manner from pancreatic β-cells. Insulin oscillations are impaired in patients with type 2 diabetes and their near relatives, suggesting the importance of the secretory pattern and the mechanisms that regulate the oscillations. Glucose stimulation of insulin secretion via KATP-channel closure, causing [Ca2+] increase is well established; however, the idea that glucose also signals via modulation of lipid metabolism is gaining acceptance. These studies investigated the importance of the Misoform of phosphofructokinase (PFK-M) in the generation of insulin oscillations. Studies also investigated the role of long chain acyl CoA (LC-CoA), modulated by glucose metabolism or the provision of exogenous or endogenous free fatty acids (FFA), in regulating insulin release.; Mice obtained from Lexicon Genetics with a disrupting tag inserted in the PFK-M gene upstream from the coding region (OST#56064) showed variable, tissue-dependent loss of PFK-M: nearly 99% loss in brain, 50–75% loss in skeletal muscle, little if any loss in heart, and about 95–98% loss in islets. These animals displayed impaired glucose tolerance with elevated fasting and nonfasting blood glucose levels; they were not insulin resistant but had impaired secretion in response to glucose. Isolated perifused islets from PFK-M deficient mice exhibited a 50% reduction in average insulin secretion as well as pulse amplitude, and less regularity according to Approximate Entropy measurements, compared to wild type islets. Pulse frequencies remained unchanged. These results indicate that PFK-M may indeed be important in oscillatory insulin secretion.; LC-CoA is formed from exogenous or endogenous FFA and its levels are modulated by glucose metabolism. The acyl CoA synthetase inhibitor triacsin C (TC) at 48 μM decreased LC-CoA and insulin secretion in a clonal β-cell line (HIT) by 40% to 50%, and 96 μM TC inhibited secretion by 60%. The incretin glucagon-like peptide 1 (GLP-1) enhanced glucose-stimulated oscillatory insulin secretion in perifused rat islets and this effect was greatly attenuated by the lipase inhibitor orlistat. Exogenous FFA caused a similar enhancement, suggesting that GLP-1 may act via increasing lipolysis and hence LC-CoA. These data support the hypothesis that LC-CoA is an important effector molecule in the insulin secretory pathway. |
