Increasing ?-cell mass requires additional stimulation for adaptation to secretory demand.

ABSTRACT: Type 2 diabetes mellitus (T2DM) is caused by relative insulin deficiency, subsequent to both reduced ?-cell mass and insufficient insulin secretion, and both augmenting ?-cell mass and ?-cell function are therapeutic strategies for treating T2DM. However, the relative significance of increasing ?-cell mass vs improving ?-cell stimulus secretion coupling remains unclear. We have developed a mouse model that allows proliferation of ?-cells in adult mice without affecting ?-cell function by inducible expression of the positive cell cycle regulator cyclin A2 specifically in ?-cells. In these mice, when kept on a standard diet, doubling of ?-cell mass does not result in altered glucose tolerance or glucose-stimulated circulating insulin levels. Notably, a doubling of ?-cell mass also does not confer improved glycemic control and ability of ?-cells to respond to diabetogenic high-fat diet-induced glucose intolerance. However, in high-fat diet-exposed mice, an increase in endogenous ?-cell mass confers increased potentiation of in vivo glucose-stimulated rise in circulating insulin in response to acute pharmacologic treatment with the incretin glucagon-like peptide-1 receptor agonist exendin-4. These observations indicate that increasing endogenous ?-cell mass may not be sufficient to improve glycemic control in T2DM without additional strategies to increase ?-cell stimulus secretion coupling.

SUBMITTER: Mondal P 

PROVIDER: S-EPMC4280528 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature