title: PINK1 deficiency in β-cells increases basal insulin secretion and improves glucose tolerance in mice.
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.
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Deas
authors.forename: Kaisa
authors.initials: K
authors.lastname: Piipari
authors.forename: Asif
authors.initials: A
authors.lastname: Machhada
authors.forename: Abi
authors.initials: A
authors.lastname: Li
authors.forename: Ana
authors.initials: A
authors.lastname: Gutierrez-del-Arroyo
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Withers
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
authors.forename: Andrey Y
authors.initials: AY
authors.lastname: Abramov
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D011494:Protein Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D002118:Calcium; D005947:Glucose; D007328:Insulin; D011494:Protein Kinases; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000099202:PTEN-Induced Putative Kinase
keywords: PINK1; Parkinson's disease; diabetes; insulin; β-cells