Role of ROCK1 in Pancreatic ß Cells

Abstract

Insulin signaling in pancreatic β-cell is critical for normal insulin secretion. ROCK1 plays an important role in the regulation of insulin and leptin signaling in the context of glucose and energy metabolism. However, the role of ROCK1 in pancreatic β-cell remains unknown. The current study was to determine whether deleting ROCK1 from β-cell affects insulin secretion and glucose metabolism in mice and cultured cell lines. Here we show that β-cell-specific deletion of ROCK1 results in a significant decrease insulin secretion in mice fed a normal chow diet, leading to hyperglycemia. These effects were independent of changes in adiposity. Consistent with this, in vitro studies with INS-1 and MIN6 cells indicated that inhibition of ROCK1 decreased insulin secretion in response to glucose without changes in β-cell proliferation and apoptosis. In addition, β-cell-ROCK1 deficient mice displayed glucose intolerance, as evidenced by the fact that the area under the glucose curve was increased 53% in β-cell-ROCK1 deficient mice compared with control mice. However, neither body weight, food intake nor insulin sensitivity was changed in theses mice. Upon insulin stimulation, proximal insulin signaling components, including p-IRS2, p-PI3K and p-Akt were impaired when ROCK1 expression was inhibited in INS-1 cells, suggesting a role for ROCK1 in insulin signaling. These data indicate that activation of ROCK1 in pancreatic β-cell is required for the maintenance of normal insulin secretion. Thus, pancreatic ROCK1 might be a key regulator of glucose homeostasis. Disclosure B. Sung: None. K. Hur: None. J. Kim: None. Y. Kim: None.M. Lee: None.