Insulin secretory defects and impaired islet architecture in pancreatic beta-cell-specific STAT3 knockout mice.

Normal islet formation and function depends on the action of various growth factors operating in pre- and postnatal development; however, the specific physiological function of each factor is largely unknown. Loss-of-function analyses in mice have provided little information so far, perhaps due to functional redundancies of the growth factors acting on the pancreas. The present study focuses on the role of the transcription factor STAT3 in insulin-producing cells. STAT3 is one of the potential downstream mediators for multiple growth factors acting on the pancreatic beta-cells, including betacellulin, hepatocyte growth factor, growth hormone, and heparin-binding EGF-like growth factor. To elucidate its role in the beta-cells, the STAT3 gene was disrupted in insulin-producing cells in mice (STAT3-insKO), using a cre-mediated gene recombination approach. Unexpectedly, STAT3-insKO mice exhibited an increase in appetite and obesity at 8 weeks of age or older. The mice showed partial leptin resistance, suggesting that expression of the RIP (rat insulin promoter)-cre transgene in hypothalamus partially inhibited the appetite-regulating system. Intraperitoneal glucose tolerance tests, performed in non-obese 5-week-old mice, showed that the STAT3-insKO mice were glucose intolerant. Islet perifusion experiments further revealed a deficiency in early-phase insulin secretion. Whereas islet insulin content or islet mass was not affected, expression levels of GLUT2, SUR1, and VEGF-A were significantly reduced in STAT3-insKO islets. Interestingly, STAT3-insKO mice displayed impaired islet morphology: alpha-cells were frequently seen in central regions of islets. Our present observations demonstrate a unique role of STAT3 in maintaining glucose-mediated early-phase insulin secretion and normal islet morphology.