Under physiological conditions, glucose-stimulated insulin secretion requires the metabolism of glucose and thereby the generation of ATP. The resulting increase in the ATP/ADP ratio triggers the closure of the ATP-sensitive potassium (KATP) channel, depolarization of the cell membrane and influx of calcium through voltage-dependent calcium channels, resulting in insulin granule exocytosis . The p-cell's adaptive response to changes in insulin sensitivity is probably mediated by increased cellular glucose metabolism, NEFA signaling and sensitivity to incretins. Data from animal studies suggest that the increase in p-cell glucose metabolism involves an increase in the activity of glucokinase, the rate-limiting enzyme responsible for glucose phosphorylation after its entry into the cell . Glucose utilization rises as both oxidation and flux of glucose are increased, the latter through pyruvate carboxylase and the replenishment of tricarboxylic acid cycle intermediates in the mitochondria. Increased citrate levels generated by glucose metabolism may lead to generation of malonyl-CoA and increased long-chain acyl-CoA and diacylglycerol levels through inhibition of carnitine palmitoyl transferase 1 . This leads to PKC activation and stimulation of insulin release. In humans, however, the role of increased glucose levels for the adaptive increase in insulin release in response to decreased insulin sensitivity is still debated .
NEFAs are important for normal P-cell function and may mediate increased P-cell output in response to decreased insulin sensitivity. NEFAs potentiate insulin release in response to glucose and non-glucose secretagogues by binding to the G-protein-coupled receptor GPR40 on the cell membrane, resulting in the activation of phos-pholipase C signaling and a subsequent increase in intracellular calcium and secretory granule exocytosis . Additionally, fatty acyl-CoA may also be generated, which increases insulin release both by directly stimulating secretory granule exocy-tosis and by PKC activation . A third possible mechanism is increased sensitivity to incretin hormones, such as glucagon-like peptide-1 (GLP-1), that are produced in the intestinal mucosa and are responsible for the enhancement of the insulin response observed after oral - compared with intravenous - glucose administration . The P-cell might become more responsive to the effects of GLP-1 to modulate insulin secretion by G-protein-coupled receptor activation involving stimulation of protein kinase A (PKA) and the guanine nucleotide exchange factor EPAC2. The extensive innervation of the islet by both parasympathetic and sympathetic neurons, and the intimate involvement of the central nervous system (CNS) in the regulation of metabolism suggest that the CNS may also have an important role in the functional adaptation to changes in insulin sensitivity [for review, see 30].
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