The Role of FoxM1 in Pancreatic Beta Cell Mass Regeneration and Expansion

Abstract

MOLECULAR PHYSIOLOGY AND BIOPHYSICS

THE ROLE OF FOXM1 IN PANCREATIC BETA CELL MASS REGENERATION AND EXPANSION

AMANDA ACKERMANN MISFELDT

Dissertation under the direction of Maureen Gannon, Ph.D.

The size of an organism’s â cell population, or â cell mass, and its functional capacity are important determinants of glucose homeostasis. In normal individuals, â cell mass increases in response to obesity, pregnancy, and pancreatic injury by increasing â cell proliferation, â cell neogenesis, and/or â cell size. However, one or more of these processes does not occur properly or sufficiently in diabetic patients. Thus, identifying factors that regulate these processes could lend insight into the pathogenesis and potential treatment of diabetes. The forkhead box transcription factor FoxM1 activates expression of multiple genes that control cell cycle progression. Accordingly, FoxM1 is necessary for proper proliferation of postnatal â cells, and loss of FoxM1 in the pancreas results in reduced â cell mass and progressive diabetes. This dissertation examined â cell mass regeneration and expansion in response to pancreatic injury and diet-induced obesity in wild-type mice and littermates with pancreas-wide deletion of Foxm1. Regeneration of â cell mass after surgical removal of 60% of the pancreas was impaired in mice with pancreas-wide deletion of Foxm1 due to reduced â cell proliferation. Importantly, no defects in â cell neogenesis were observed. These studies highlight the similarities between â cell mass regeneration after injury and embryonic â cell mass development, as FoxM1 was not required for â cell proliferation during embryogenesis or in small (neogenic) â cell clusters during regeneration, but was required for proliferation of â cells within large (pre-existing) islets.

When mice with pancreas-wide deletion of Foxm1 were fed a high-fat/high-carbohydrate diet, they were more susceptible to developing glucose intolerance and diabetes than were wild-type littermates, associated with impaired glucose-stimulated insulin secretion. These findings suggested that FoxM1 may play a role in â cell secretory function in addition to â cell mass compensation in response to diet-induced obesity. Together, these studies provide evidence that â cell proliferation is regulated differently during development versus adulthood, that regeneration after pancreatic injury mimics to some extent pancreas development, and that FoxM1 function may not be restricted to cell cycle regulation.