title: Glucose-Raising Polymorphisms in the Human Clock Gene Cryptochrome 2 (CRY2) Affect Hepatic Lipid Content.
abstract: Circadian rhythms govern vital functions. Their disruption provokes metabolic imbalance favouring obesity and type-2 diabetes. The aim of the study was to assess the role of clock genes in human prediabetes. To this end, genotype-phenotype associations of 121 common single nucleotide polymorphisms (SNPs) tagging ARNTL, ARNTL2, CLOCK, CRY1, CRY2, PER1, PER2, PER3, and TIMELESS were assessed in a study population of 1,715 non-diabetic individuals metabolically phenotyped by 5-point oral glucose tolerance tests. In subgroups, hyperinsulinaemic-euglycaemic clamps, intravenous glucose tolerance tests, and magnetic resonance imaging/spectroscopy were performed. None of the tested SNPs was associated with body fat content, insulin sensitivity, or insulin secretion. Four CRY2 SNPs were associated with fasting glycaemia, as reported earlier. Importantly, carriers of these SNPs' minor alleles revealed elevated fasting glycaemia and, concomitantly, reduced liver fat content. In human liver tissue samples, CRY2 mRNA expression was directly associated with hepatic triglyceride content. Our data may point to CRY2 as a novel switch in hepatic fuel metabolism promoting triglyceride storage and, concomitantly, limiting glucose production. The anti-steatotic effects of the glucose-raising CRY2 alleles may explain why these alleles do not increase type-2 diabetes risk.
authors.affiliation: Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany.|German Center for Diabetes Research (DZD), Tübingen, Germany.
authors.forename: Fausto
authors.initials: F
authors.lastname: Machicao
authors.affiliation: Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany.|German Center for Diabetes Research (DZD), Tübingen, Germany.|Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Peter
authors.affiliation: Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany.|German Center for Diabetes Research (DZD), Tübingen, Germany.|Department of Diagnostic and Interventional Radiology, Section on Experimental Radiology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Machann
authors.affiliation: Department of General, Visceral, and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Ingmar
authors.initials: I
authors.lastname: Königsrainer
authors.affiliation: Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany.|German Center for Diabetes Research (DZD), Tübingen, Germany.|Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Böhm
authors.affiliation: Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany.|German Center for Diabetes Research (DZD), Tübingen, Germany.|Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Stefan Zoltan
authors.initials: SZ
authors.lastname: Lutz
authors.affiliation: Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany.|German Center for Diabetes Research (DZD), Tübingen, Germany.|Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Heni
authors.affiliation: Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany.|German Center for Diabetes Research (DZD), Tübingen, Germany.|Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany.|Department of Internal Medicine, Division of Nutritional and Preventive Medicine, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Fritsche
authors.affiliation: Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany.|German Center for Diabetes Research (DZD), Tübingen, Germany.|Department of Diagnostic and Interventional Radiology, Section on Experimental Radiology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Fritz
authors.initials: F
authors.lastname: Schick
authors.affiliation: Department of General, Visceral, and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Königsrainer
authors.affiliation: Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany.|German Center for Diabetes Research (DZD), Tübingen, Germany.|Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Stefan
authors.affiliation: Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany.|German Center for Diabetes Research (DZD), Tübingen, Germany.|Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.affiliation: Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany.|German Center for Diabetes Research (DZD), Tübingen, Germany.|Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Staiger
mesh_terms: D000328:Adult; D056931:Cryptochromes / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: C538966:CRY2 protein, human; D056931:Cryptochromes; D005947:Glucose