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Hindrik Mulder

Hindrik Mulder

Principal investigator

Hindrik Mulder

Elevated miR-130a/miR130b/miR-152 expression reduces intracellular ATP levels in the pancreatic beta cell

Author

  • Jones K. Ofori
  • Vishal A. Salunkhe
  • Annika Bagge
  • Neelanjan Vishnu
  • Mototsugu Nagao
  • Hindrik Mulder
  • Claes B. Wollheim
  • Lena Eliasson
  • Jonathan L S Esguerra

Summary, in English

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.

Department/s

  • Diabetes - Islet Cell Exocytosis
  • Diabetes - Molecular Metabolism
  • EXODIAB: Excellence of Diabetes Research in Sweden

Publishing year

2017-03-23

Language

English

Publication/Series

Scientific Reports

Volume

7

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Endocrinology and Diabetes
  • Cell and Molecular Biology

Status

Published

Research group

  • Diabetes - Islet Cell Exocytosis
  • Diabetes - Molecular Metabolism

ISBN/ISSN/Other

  • ISSN: 2045-2322