Elevated miR-130a/miR130b/miR-152 expression reduces intracellular ATP levels in the pancreatic beta cell.
MicroRNAs have emerged as important players of gene regulation with significant impact in diverse disease processes. In type-2 diabetes, in which impaired insulin secretion is a major factor in disease progression, dysregulated microRNA expression in the insulin-secreting pancreatic beta cell has been widely-implicated. Here, we show that miR-130a-3p, miR-130b-3p, and miR-152-3p levels are elevated in the pancreatic islets of hyperglycaemic donors, corroborating previous findings about their upregulation in the islets of type-2 diabetes model Goto-Kakizaki rats. We demonstrated negative regulatory effects of the three microRNAs on pyruvate dehydrogenase E1 alpha (PDHA1) and on glucokinase (GCK) proteins, which are both involved in ATP production. Consequently, we found both proteins to be downregulated in the Goto-Kakizaki rat islets, while GCK mRNA expression showed reduced trend in the islets of type-2 diabetes donors. Overexpression of any of the three microRNAs in the insulin-secreting INS-1 832/13 cell line resulted in altered dynamics of intracellular ATP/ADP ratio ultimately perturbing fundamental ATP-requiring beta cell processes such as glucose-stimulated insulin secretion, insulin biosynthesis and processing. The data further strengthen the wide-ranging influence of microRNAs in pancreatic beta cell function, and hence their potential as therapeutic targets in type-2 diabetes.
Islet Cell Exocytosis, Department of Clinical Sciences-Malmö, Lund University, Malmö, 205 02, Sweden.|Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.
Jones K
JK
Ofori
Islet Cell Exocytosis, Department of Clinical Sciences-Malmö, Lund University, Malmö, 205 02, Sweden.|Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.
Vishal A
VA
Salunkhe
Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.|Molecular Metabolism, Department of Clinical Sciences-Malmö, Lund University, Malmö, 20502, Sweden.
Annika
A
Bagge
Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.|Molecular Metabolism, Department of Clinical Sciences-Malmö, Lund University, Malmö, 20502, Sweden.
Neelanjan
N
Vishnu
Islet Cell Exocytosis, Department of Clinical Sciences-Malmö, Lund University, Malmö, 205 02, Sweden.|Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.
Mototsugu
M
Nagao
Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.|Molecular Metabolism, Department of Clinical Sciences-Malmö, Lund University, Malmö, 20502, Sweden.
Hindrik
H
Mulder
Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.|Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, 1211, Switzerland.
Claes B
CB
Wollheim
Islet Cell Exocytosis, Department of Clinical Sciences-Malmö, Lund University, Malmö, 205 02, Sweden.|Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.
Lena
L
Eliasson
Islet Cell Exocytosis, Department of Clinical Sciences-Malmö, Lund University, Malmö, 205 02, Sweden.|Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.
Jonathan L S
JL
Esguerra
D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005786:Gene Expression Regulation; D020868:Gene Silencing; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats
D007328:Insulin; D035683:MicroRNAs; D012333:RNA, Messenger; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D005947:Glucose