Abstract
The Parkinson's disease (PD) gene, PARK6, encodes the PTEN-induced putative kinase 1 (PINK1) mitochondrial kinase, which provides protection against oxidative stress-induced apoptosis. Given the link between glucose metabolism, mitochondrial function and insulin secretion in β-cells, and the reported association of PD with type 2 diabetes, we investigated the response of PINK1-deficient β-cells to glucose stimuli to determine whether loss of PINK1 affected their function. We find that loss of PINK1 significantly impairs the ability of mouse pancreatic β-cells (MIN6 cells) and primary intact islets to take up glucose. This was accompanied by higher basal levels of intracellular calcium leading to increased basal levels of insulin secretion under low glucose conditions. Finally, we investigated the effect of PINK1 deficiency in vivo and find that PINK1 knockout mice have improved glucose tolerance. For the first time, these combined results demonstrate that loss of PINK1 function appears to disrupt glucose-sensing leading to enhanced insulin release, which is uncoupled from glucose uptake, and suggest a key role for PINK1 in β-cell function.
Highlights
Type 2 diabetes is a common metabolic disorder estimated to affect over 256 million adults worldwide [1]
To assess whether loss of PINK1 function would potentially have an effect on islet cell function, we sought to determine whether PINK1 was expressed in islet cells
Our results show that in the pancreas, normal b-cell function is impaired through PINK1 deficiency leading to higher basal levels of insulin secretion in vitro and a trend towards increased basal plasma insulin in vivo
Summary
Type 2 diabetes is a common metabolic disorder estimated to affect over 256 million adults worldwide [1]. The predominant mechanism underlying this disease is insulin resistance in peripheral metabolic tissues such as muscle, liver and adipose tissue accompanied by a relative deficit in insulin secretion [2,3]. The alpha (a) and beta (b) islet cells in the pancreas monitor blood glucose levels. When an increase in blood glucose is detected, these cells take up glucose via the GLUT2 glucose transporter leading to an increase in glucose metabolism within the cell [4].
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