Metabolic regulation of insulin secretion: the link between excess glucose, mechanistic target of rapamycin complex 1 & hyperinsulinemia
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Obesity, a major risk factor in the development of Type 2 Diabetes (T2D), is commonly associated with insulin resistance and hyperinsulinemia. The long accepted view has been that insulin resistance drives hyperinsulinemia; however, there are multiple lines of evidence that hyperinsulinemia can precede and drive insulin resistance. The signals and mechanisms by which chronic excess nutrients promote pancreatic β-cell dysfunction remain poorly understood. This prompted us to define the signaling events that contribute to basal insulin hypersecretion induced by excess glucose. Of particular interest is signaling through mechanistic target of rapamycin complex 1 (mTORC1), a nutrient sensitive kinase complex whose hyperactivation has been shown to promote hyperinsulinemia. Clonal ß-cells (INS-1 cells) with and without mTORC1 inhibition were pre-exposed to physiological (5mM) or excess (11mM) glucose for 4 to 24 hrs. Basal insulin secretion, respiration and metabolites were measured. Pre-exposure to excess glucose resulted in sustained mTORC1 hyperactivation, basal insulin secretion, higher basal respiration and increased maximal respiratory capacity, due to accelerated mitochondrial pyruvate metabolism. Inhibition of mTORC1 reduced basal insulin secretion, basal respiration and maximal respiratory capacity. Moreover, cells challenged with excess glucose had increased levels of glycolysis and TCA cycle intermediates. Our results suggest that hyperactivation of mTORC1 induced by excess glucose results in increased energy demand and in the generation of metabolic factors that can lead to basal insulin hypersecretion. Therefore, targeting mitochondrial pyruvate metabolism and /or mTORC1 signaling could potentially lead to specific therapies to control hyperinsulinemia and diabetes progression.