Role of miRs in Regulation of Insulin Secretion by Pancreatic Beta-cells

Chronic hyperglycemia and hyperlipidemia may result from numerous factors, including but not limited to intrinsic defects in the ability of individual pancreatic b-cells to secrete insulin, nutrient oversupply, and insufficient b-cell hyperplasia or increases in insulin secretion to meet the demands of elevated serum glucose. In response to long-term but sub-acute elevations of plasma glucose, major peripheral tissues may exhibit loss of insulin sensitivity. The further lack of glycemic and lipidemic control engendered by the development of peripheral insulin resistance leads to a feed-forward, self-reinforcing circuit; the compensatory increase in b-cell functional mass observed during prediabetic conditions fails to keep pace with the increased demand for insulin, resulting in overt type 2 diabetes (T2D).

These studies will investigate the contribution of microRNAs to changes in b-cell signaling under adverse hyperglycemic and hyperlipidemic conditions and will shed new light on the causes of eventual b-cell dysfunction. We have made significant progress in delineating microRNA-dependent signaling events taking place during acute and chronic hyperglycemia in the cultured rat b-cell line, INS-1. We have collaborated with the laboratory of Romano Regazzi (University of Lausanne, Switzerland) in their investigation of developmental changes occurring as early postnatal islets transition toward the glucose-sensitive phenotype of adult rat islets, using similar microRNA and RISC-seq methods. There have been many obstacles to overcome in adapting our methods to mouse pancreatic islets, but we plan to continue our studies as follows:

Aim 1

Evaluate the contribution of miR-associated mRNA regulation to hyperglycemic and hyperlipidemic responses in cultured pancreatic islets. Cultured murine pancreatic islets will be subjected to high glucose, palmitate, or both, and miR-associated mRNA regulation assessed by integrated sequencing analyses of miRs and mRNAs.

Hypothesis: miR-associated translational reprogramming in cultured islets will be altered differently by glucose or palmitate treatment while the effects of both will be additive, and will exhibit both similarities and differences to responses obtained from clonal b-cells (such as the rat INS-1 model).

Aim 2

Use genetic and diet-induced mouse models of obesity to investigate b-cell miR signaling in vivo under adverse conditions.

Hypothesis: regardless of disease etiology, b-cells obtained from obese, glucose-intolerant, hyperglycemic and hyperinsulinemic mice will manifest similar miR and mRNA expression profiles, and miR-regulated gene expression under such in vivo conditions will resemble, at least in part, the changes induced by high glucose and palmitate during in vitro culture.

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