The Loss of ARNT/HIF1ß in Male Pancreatic ß-Cells Is Protective Against High-Fat Diet-Induced Diabetes.

ABSTRACT

The transcription factor aryl hydrocarbon receptor nuclear translocator (ARNT)/hypoxia-inducible factor (HIF)-1ß (ARNT/HIF1ß) plays a key role in maintaining ß-cell function and has been shown to be one of the most downregulated transcription factors in islets from patients with type 2 diabetes. We have shown a role for ARNT/HIF1ß in glucose sensing and insulin secretion in vitro and no defects in in vivo glucose homeostasis. To gain a better understanding of the role of ARNT/HIF1ß in the development of diabetes, we placed control (+/+/Cre) and ß-cell-specific ARNT/HIF1ß knockout (fl/fl/Cre) mice on a high-fat diet (HFD). Unlike the control (+/+/Cre) mice, HFD-fed fl/fl/Cre mice had no impairment in in vivo glucose tolerance. The lack of impairment in HFD-fed fl/fl/Cre mice was partly due to an improved islet glucose-stimulated NADPH/NADP+ ratio and glucose-stimulated insulin secretion. The effects of the HFD-rescued insulin secretion in fl/fl/Cre islets could be reproduced by treating low-fat diet (LFD)-fed fl/fl/Cre islets with the lipid signaling molecule 1-monoacylglcyerol. This suggests that the defects seen in LFD-fed fl/fl/Cre islet insulin secretion involve lipid signaling molecules. Overall, mice lacking ARNT/HIF1ß in ß-cells have altered lipid signaling in vivo and are resistant to an HFD's ability to induce diabetes.