Isoform-specific Roles of Prolyl-Hydroxylases in the Regulation of β-cell Insulin Secretion during Diet-Induced Obesity in Males

Abstract

Type 2 diabetes affects approximately 480 million individuals worldwide and is associated with impaired tissue insulin sensitivity and β-cell dysfunction. Although there has been much research into nutrient-regulated insulin secretion and the progression to β-cell dysfunction in type 2 diabetes, the story is still incomplete. Hypoxia-inducible factor prolyl 4-hydroxylases (PHDs) are α-ketoglutarate dioxygenases commonly known to regulate hypoxia-inducible factor-1α (HIF-1α). Unique expression profiles of PHD1, PHD2 and PHD3 isozymes suggest isoform-specific roles in α-ketoglutarate-sustained insulin secretion. Our laboratory recently showed a role for β-cell PHD1 and PHD3 in insulin secretion, and previous research suggests that PHD2 may play a role in obesity-induced metabolic dysfunction. This thesis focuses on possible roles that β-cell PHDs may play in moderating the interrelationship between defective nutrient-sustained insulin secretion and obesity-induced β-cell dysfunction. We placed β-cell-specific PHD1, PHD2 or PHD3 knockout mice on a high-fat diet to explore the roles of PHD isoforms in regulating β-cell function under diet-induced obesity. β-cell-specific PHD1 knockout mice did not display any unique obesity-induced metabolic phenotypes compared to high-fat diet-fed control mice. β-cell-specific PHD3 knockout mice on the high-fat diet experienced increased weight gain compared to high-fat diet-fed control mice. However, despite increased fasting blood glucose levels, they showed no exacerbated impairments to in vivo glucose homeostasis and plasma lipid profiles. β-cell-specific PHD2 knockout mice resisted high-fat diet-induced obesity and showed improved in vivo glucose homeostasis combined with minor alterations in their plasma lipid profile. The lack of obesity-induced metabolic dysfunction in β-cell-specific PHD2 knockout mice could be explained by enhanced β-cell mass and ex vivo glucose-stimulated insulin secretion. Overall, β-cell-specific PHD2 knockout mice have ameliorated glucose homeostasis and β-cell function during obesity, potentially due to PHD2’s role in discouraging HIF-1α stability during metabolic stress.