FoxM1 and Cholecystokinin control beta-cell Mass Regulation during Obesity and Diabetes

Obesity and insulin resistance contribute to type 2 diabetes pathogenesis. The beta-cell adaptively compensates by increasing insulin secretion and expanding beta-cell mass. beta-cell mass adaptation occurs via beta-cell proliferation. In type 2 diabetes, beta-cell mass fails to expand because of reduced beta-cell replication and increased apoptosis.;We model obesity and diabetes by comparing the obese non-diabetic C57BL/6- Leptinob/ob mouse (B6-ob/ob) to the diabetic BTBR-Leptinob/ob mouse (BTBR- ob/ob). From islet transcriptional profiling, we detected increased expression of Foxm1 and its target genes in the B6- ob/ob but not the BTBR-ob/ob mouse. FoxM1 is a transcription factor that regulates cell cycle transcripts and is necessary for beta-cell replication. We hypothesized that obesity-dependent FoxM1 upregulation stimulates beta-cell replication and prevents diabetes. We found that FOXM1b overexpression stimulated mouse and human beta-cell proliferation by activating many cell cycle phases. Additionally, FOXM1 and its target genes are positively correlated with obesity in human islets. These data suggest that the FoxM1 transcriptional program increases during rodent and human obesity and stimulates beta-cell mass replication, preventing diabetes.;By transcriptional profiling, we additionally identified islet Cholecystokinin (Cck) as the most upregulated gene by obesity. CCK is a gastrointestinal hormone and neuropeptide that regulates digestion, behavior, and insulin secretion. We hypothesized that upregulation of islet CCK expression expands beta-cell mass. We bred a null Cck allele into the B6-ob/ob mouse and investigated its beta-cell mass and metabolic parameters. Cck-deficiency decreased islet size, reduced beta-cell mass, increased beta-cell death, exacerbated hyperglycemia, and reduced hyperinsulinemia. CCK directly reduced cell death in beta-cell lines and isolated islets. These data suggest that CCK is upregulated by islets during obesity, increases beta-cell survival, and expands beta-cell mass.;Although CCK does not affect mouse beta-cell proliferation, CCK stimulates rat beta-cell replication. We determined the mechanisms of CCK-triggered rat beta-cell mitogenesis. CCK-8 treatment stimulated rat beta-cell proliferation through the CCK-A receptor. Inhibition of protein kinase A reduced CCK-8-triggered beta-cell replication. In the nucleus, CCK-8 treatment enhanced cyclins E and A expression and activated Cdk2, triggering mitosis. In summary, CCK binds the CCK-A receptor, increases PICA signaling, activates cdk2, and stimulates rat beta-cell proliferation.