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Cell Metab. 2016 Jun 14;23(6):1067-1077. doi: 10.1016/j.cmet.2016.04.009. Epub 2016 May 12.

Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes.

Author information

1
Endocrinology, Abdominal Center, Helsinki University Hospital, Helsinki FI-00014, Finland; Folkhälsan Research Center, Helsinki FI-00250, Finland; Diabetes and Obesity Research Program, Research Programs Unit, University of Helsinki, Helsinki FI-00014, Finland; Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki FI-00014, Finland.
2
Unit of Molecular Metabolism, Lund University Diabetes Centre, Lund SE-205 02, Sweden.
3
Unit of Diabetes and Celiac Disease, Lund University Diabetes Centre, Lund SE-205 02, Sweden.
4
Department of Medical Cell Biology, Uppsala University, Uppsala SE-751 23, Sweden.
5
Folkhälsan Research Center, Helsinki FI-00250, Finland; Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki FI-00014, Finland; Department of Social Services and Health Care, Jakobstad FI-68601, Finland.
6
Folkhälsan Research Center, Helsinki FI-00250, Finland.
7
Folkhälsan Research Center, Helsinki FI-00250, Finland; Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki FI-00014, Finland.
8
Institute of Behavioural Sciences, University of Helsinki, Helsinki FI-00014, Finland.
9
Endocrinology, Abdominal Center, Helsinki University Hospital, Helsinki FI-00014, Finland; Folkhälsan Research Center, Helsinki FI-00250, Finland; Diabetes and Obesity Research Program, Research Programs Unit, University of Helsinki, Helsinki FI-00014, Finland.
10
Institute of Behavioural Sciences, University of Helsinki, Helsinki FI-00014, Finland; Unit of Diabetes and Endocrinology, Lund University Diabetes Centre, Lund SE-205 02, Sweden.
11
Unit of Diabetes and Endocrinology, Lund University Diabetes Centre, Lund SE-205 02, Sweden.
12
Unit of Neuroendocrine Cell Biology, Lund University Diabetes Centre, Lund SE-205 02, Sweden.
13
Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki FI-00014, Finland; Unit of Diabetes and Endocrinology, Lund University Diabetes Centre, Lund SE-205 02, Sweden.
14
Unit of Molecular Metabolism, Lund University Diabetes Centre, Lund SE-205 02, Sweden. Electronic address: hindrik.mulder@med.lu.se.

Abstract

Type 2 diabetes (T2D) is a global pandemic. Genome-wide association studies (GWASs) have identified >100 genetic variants associated with the disease, including a common variant in the melatonin receptor 1 b gene (MTNR1B). Here, we demonstrate increased MTNR1B expression in human islets from risk G-allele carriers, which likely leads to a reduction in insulin release, increasing T2D risk. Accordingly, in insulin-secreting cells, melatonin reduced cAMP levels, and MTNR1B overexpression exaggerated the inhibition of insulin release exerted by melatonin. Conversely, mice with a disruption of the receptor secreted more insulin. Melatonin treatment in a human recall-by-genotype study reduced insulin secretion and raised glucose levels more extensively in risk G-allele carriers. Thus, our data support a model where enhanced melatonin signaling in islets reduces insulin secretion, leading to hyperglycemia and greater future risk of T2D. The findings also imply that melatonin physiologically serves to inhibit nocturnal insulin release.

KEYWORDS:

RNA sequencing; gene targeting; insulin; islets; recall-by-genotype

PMID:
27185156
DOI:
10.1016/j.cmet.2016.04.009
[Indexed for MEDLINE]
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