Type 2 diabetes is a 'two-hit' disease; one 'hit' is dysfunction of glucose clearance by the skeletal muscle and adipose tissues (GLUT4 vesicle translocation), and another 'hit' is dysfunction of insulin secretion by the pancreatic islet beta cells (insulin granule exocytosis). Remarkably, these seemingly divergent processes require similar molecular machinery termed SNARE proteins, and aberrant quantities and functions of particular SNARE and SNARE-associated proteins are implicated in each 'hit' of diabetes. Specifically, the aberrant function of the Munc18c protein with its binding partner Syntaxin 4 has been reported in diabetic human muscle and islets and therefore carries great potential for development of novel therapeutic strategies that could simultaneously tackle both 'hits' of this disease to improve the livelihood of people with diabetes.
Current treatments of diabetic patients with insulin delivery or other stimulants of insulin release fail to mimic the body's natural and complex pattern of insulin secretion, often resulting in hypoglycemia problems and eventual beta cell failure. Thus, another focus area of the lab is in deciphering the mechanisms used by pancreatic islet beta cells to meter insulin release, and then devise ways to recapitulate this metering mechanism pharmacologically in the patient. Thousands of insulin granules exist behind a filamentous actin (F-actin) barrier in the beta cell and F-actin remodeling is known to mobilize granules to the t-SNARE proteins at the cell surface, yet the mechanisms involved in remodeling and granule mobilization are largely unknown and untested. We and others have made progress in discovering that a key protein in this is Cdc42, a small Rho family GTPase that promotes actin reorganization in response to glucose. In addition, we have discovered that Cdc42 'multi-tasks' and also functions in targeting insulin granules directly to the SNARE proteins at the cell surface. Thus, pharmacologically targeting Cdc42 signaling in an effort to enhance actin-mediated granule mobilization may also impact granule targeting to the SNARE proteins.
