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Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes

Tuomi, Tiinamaija; Nagorny, Cecilia L F LU ; Singh, Pratibha LU ; Bennet, Hedvig LU ; Yu, Qian; Alenkvist, Ida; Isomaa, Bo; Östman, Bjarne; Söderström, Johan and Pesonen, Anu Katriina, et al. (2016) In Cell Metabolism 23(6). p.1067-1077
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)

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.

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@misc{236111f6-c294-47c4-b5b0-31e30f7be313,
  abstract     = {<p>Type 2 diabetes (T2D) is a global pandemic. Genome-wide association studies (GWASs) have identified &gt;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.</p>},
  author       = {Tuomi, Tiinamaija and Nagorny, Cecilia L F and Singh, Pratibha and Bennet, Hedvig and Yu, Qian and Alenkvist, Ida and Isomaa, Bo and Östman, Bjarne and Söderström, Johan and Pesonen, Anu Katriina and Martikainen, Silja and Räikkönen, Katri and Forsén, Tom and Hakaste, Liisa and Almgren, Peter and Storm, Petter and Asplund, Olof and Shcherbina, Liliya and Fex, Malin and Fadista, João and Tengholm, Anders and Wierup, Nils and Groop, Leif and Mulder, Hindrik},
  issn         = {1550-4131},
  keyword      = {gene targeting,insulin,islets,recall-by-genotype,RNA sequencing},
  language     = {eng},
  month        = {06},
  number       = {6},
  pages        = {1067--1077},
  publisher    = {ARRAY(0x887bff0)},
  series       = {Cell Metabolism},
  title        = {Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes},
  url          = {http://dx.doi.org/10.1016/j.cmet.2016.04.009},
  volume       = {23},
  year         = {2016},
}