title: Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes.
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.
authors.affiliation: 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.
authors.forename: Tiinamaija
authors.initials: T
authors.lastname: Tuomi
authors.affiliation: Unit of Molecular Metabolism, Lund University Diabetes Centre, Lund SE-205 02, Sweden.
authors.forename: Cecilia L F
authors.initials: CLF
authors.lastname: Nagorny
authors.affiliation: Unit of Molecular Metabolism, Lund University Diabetes Centre, Lund SE-205 02, Sweden.
authors.forename: Pratibha
authors.initials: P
authors.lastname: Singh
authors.affiliation: Unit of Diabetes and Celiac Disease, Lund University Diabetes Centre, Lund SE-205 02, Sweden.
authors.forename: Hedvig
authors.initials: H
authors.lastname: Bennet
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Uppsala SE-751 23, Sweden.
authors.forename: Qian
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Uppsala SE-751 23, Sweden.
authors.forename: Ida
authors.initials: I
authors.lastname: Alenkvist
authors.affiliation: 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.
authors.forename: Bo
authors.initials: B
authors.lastname: Isomaa
authors.affiliation: Folkhälsan Research Center, Helsinki FI-00250, Finland.
authors.forename: Bjarne
authors.initials: B
authors.lastname: Östman
authors.affiliation: Folkhälsan Research Center, Helsinki FI-00250, Finland; Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki FI-00014, Finland.
authors.forename: Johan
authors.initials: J
authors.lastname: Söderström
authors.affiliation: Institute of Behavioural Sciences, University of Helsinki, Helsinki FI-00014, Finland.
authors.forename: Anu-Katriina
authors.initials: AK
authors.lastname: Pesonen
authors.affiliation: Institute of Behavioural Sciences, University of Helsinki, Helsinki FI-00014, Finland.
authors.forename: Silja
authors.initials: S
authors.lastname: Martikainen
authors.affiliation: Institute of Behavioural Sciences, University of Helsinki, Helsinki FI-00014, Finland.
authors.forename: Katri
authors.initials: K
authors.lastname: Räikkönen
authors.affiliation: Folkhälsan Research Center, Helsinki FI-00250, Finland.
authors.forename: Tom
authors.initials: T
authors.lastname: Forsén
authors.affiliation: 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.
authors.forename: Liisa
authors.initials: L
authors.lastname: Hakaste
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Almgren
authors.affiliation: Unit of Diabetes and Endocrinology, Lund University Diabetes Centre, Lund SE-205 02, Sweden.
authors.forename: Petter
authors.initials: P
authors.lastname: Storm
authors.affiliation: Unit of Diabetes and Endocrinology, Lund University Diabetes Centre, Lund SE-205 02, Sweden.
authors.forename: Olof
authors.initials: O
authors.lastname: Asplund
authors.affiliation: Unit of Neuroendocrine Cell Biology, Lund University Diabetes Centre, Lund SE-205 02, Sweden.
authors.forename: Liliya
authors.initials: L
authors.lastname: Shcherbina
authors.affiliation: Unit of Diabetes and Celiac Disease, Lund University Diabetes Centre, Lund SE-205 02, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Fex
authors.affiliation: Unit of Diabetes and Endocrinology, Lund University Diabetes Centre, Lund SE-205 02, Sweden.
authors.forename: João
authors.initials: J
authors.lastname: Fadista
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Uppsala SE-751 23, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Tengholm
authors.affiliation: Unit of Neuroendocrine Cell Biology, Lund University Diabetes Centre, Lund SE-205 02, Sweden.
authors.forename: Nils
authors.initials: N
authors.lastname: Wierup
authors.affiliation: 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.
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.affiliation: Unit of Molecular Metabolism, Lund University Diabetes Centre, Lund SE-205 02, Sweden. Electronic address: hindrik.mulder@med.lu.se.
authors.forename: Hindrik
authors.initials: H
authors.lastname: Mulder
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D005947:Glucose / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D008550:Melatonin / Q000378:metabolism* / Q000494:pharmacology; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D044094:Receptors, Melatonin / Q000235:genetics; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007328:Insulin; D044094:Receptors, Melatonin; D000242:Cyclic AMP; D005947:Glucose; D008550:Melatonin
keywords: RNA sequencing; gene targeting; insulin; islets; recall-by-genotype