Diabetes is the result of having an inadequate supply of functional insulin-producing β-cells. Efforts in research and development that focused on using systemic pathway to induce β-cell regeneration have had limited clinical success. Emerging studies implicate local islet molecular and cellular factors in pancreatic β-cell homeostasis. Intraislet endothelial cells (IECs), a key ally of pancreatic β-cells, secrete factors that could affect β-cell survival and insulin production. Fibroblast growth factor (FGF) 21 is an endocrine hormone that regulates energy homeostasis and insulin sensitivity. The function of endogenous FGF-21 derived from ECs is undefined in diabetes. With a loss-of-function approach, this study sought to determine the role of EC-FGF-21 in pancreatic β-cell homeostasis in STZ-induced diabetic mice and high-fat diet (HFD)-induced obese mice. Mice with EC-specific deletion of FGF-21 gene (EC-FKO) were generated by crossing Tie2-Cre mice with FGF-21loxP mice. In 8-to-10-week-old male mice (n=15/group) treated with STZ (50 mg/kg, i.p. for consecutive 5d and killed 4 weeks later), EC-FKO vs. wild type C57BL/6J (WT) mice displayed more severe hyperglycemia, degeneration of insulin-producing β-cells, and expansion of glucagon-producing α-cells. Both groups showed similar changes in pancreatic Glut2 and PARP1 protein levels and vascular density. In 8-to-10-week-old WT male mice (n=15/group) fed an HFD (TestDiet: 60% energy from fat) for 16 weeks, obesity and insulin resistance developed, along with lipid accumulation in the islet and compensatory expansion of β-cell mass, all of which were worsened, except for less β-cell mass expansion, in EC-FKO mice. Our latest immunofluorescent data showed a significant reduction of IEC-FGF-21 protein staining in WT mice treated with STZ or HFD vs. non-treated mice. Our findings suggest that EC-FGF-21 is required to maintain β-cell homeostasis under stress conditions. Loss of IEC-FGF-21 may contribute, at least in part, to β-cell degeneration in diabetes.
M. Li: None. M. Qian: None. J. Xu: None.
National Institutes of Health