Overexpression of ST5, an activator of Ras, has no effect on ß-cell proliferation in adult mice.

OBJECTIVE: Both Type I and Type II diabetes mellitus result from insufficient functional ß-cell mass. Efforts to increase ß-cell proliferation as a means to restore ß-cell mass have been met with limited success. Suppression of Tumorigenicity 5 (ST5) activates Ras/Erk signaling in the presence of Epidermal Growth Factor (EGF). In the pancreatic islet, Ras/Erk signaling is required for augmented ß-cell proliferation during pregnancy, suggesting that ST5 is an appealing candidate to enhance adult ß-cell proliferation. We aimed to test the hypothesis that overexpression of ST5 drives adult ß-cell proliferation. METHODS: We utilized a doxycycline-inducible bitransgenic mouse model to activate ß-cell-specific expression of human ST5 in adult mice at will. Islet morphology, ß-cell proliferation, and ß-cell mass in control and ST5-overexpressing (ST5 OE) animals were analyzed by immunofluorescent staining, under basal and two stimulated metabolic states: pregnancy and streptozotocin (STZ)-induced ß-cell loss. RESULTS: Doxycycline treatment resulted in robust ST5 overexpression in islets from 12-16 week-old ST5 OE animals compared to controls, without affecting the islet morphology and identity of the ß-cells. Under both basal and metabolically stimulated pregnancy states, ß-cell proliferation and mass were comparable in ST5 OE and control animals. Furthermore, there was no detectable difference in ß-cell proliferation between ST5 OE and control animals in response to STZ-induced ß-cell loss. CONCLUSIONS: We successfully derived an inducible bitransgenic mouse model to overexpress ST5 specifically in ß-cells. However, our findings demonstrate that ST5 overexpression by itself has no mitogenic effect on the adult ß-cell under basal and metabolically challenged states.

Regulation of fasted blood glucose by resistin.

The association between obesity and diabetes supports an endocrine role for the adipocyte in maintaining glucose homeostasis. Here we report that mice lacking the adipocyte hormone resistin exhibit low blood glucose levels after fasting, due to reduced hepatic glucose production. This is partly mediated by activation of adenosine monophosphate-activated protein kinase and decreased expression of gluconeogenic enzymes in the liver. The data thus support a physiological function for resistin in the maintenance of blood glucose during fasting. Remarkably, lack of resistin diminishes the increase in post-fast blood glucose normally associated with increased weight, suggesting a role for resistin in mediating hyperglycemia associated with obesity.