Download files
Abstract
Type 2 diabetes (T2D) is a metabolic disorder characterised by the inability of β-cells to secrete enough insulin to maintain glucose homeostasis. Pancreatic β-cells secrete insulin in a biphasic manner, first and second phase insulin secretion, and loss of first phase insulin secretion is an independent predictor of T2D onset. Restoration of first phase insulin secretion has been shown to improve blood glucose in T2D by suppressing hepatic glucose production and priming insulin sensitive tissue to more readily take up glucose and has thus prompted numerous studies into its regulation. First phase insulin secretion is initiated primarily by the classical triggering pathway, a complex system comprised of multiple stimulatory signals. The aim of this study was to identify models of reduced first phase insulin secretion. Two models were identified high passage MIN6 cells and β-cells that have reduced or lack the transcription factor hypoxia inducible factor-1α (HIF-1α).
High passage MIN6 cells were shown to have reduced first phase insulin secretion while still retaining some second phase secretory capacity, similar to that seen in T2D patients early on in disease progression. When compared to functioning low passage MIN6 cells, high passage cells displayed an altered metabolic profile including significantly reduced intracellular ATP content, reduced glucose and lipid oxidation, reduced glucose uptake, and altered gene expression profile. The changes observed are also similar to that seen in the β-cells of T2D patients.
Mice lacking HIF-1α in the β-cells have reduced glucose tolerance and glucose stimulated first phase insulin secretion. These β-cells also have reduced intracellular ATP content. MIN6 cells with reduced HIF-1α display similar characteristics of reduced insulin first phase insulin and intracellular ATP content. Increasing HIF-1α with the iron chelator Deferasirox in mice on a high fat diet improved their glucose tolerance. The results of this study showed that HIF-1α is essential for normal β-cell function, contrary to previously published reports.