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.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/38590 |
| Date | 07 October 2019 |
| Creators | Rumala, Courtney |
| Contributors | Rameh, Lucia E., Deeney, Jude T. |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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