Genetic determinants of circulating GIP and GLP-1 concentrations

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Almgren , P , Lindqvist , A , Krus , U , Hakaste , L , Ottosson-Laakso , E , Asplund , O , Sonestedt , E , Prasad , R B , Laurila , E , Orho-Melander , M , Melander , O , Tuomi , T , Holst , J J , Nilsson , P M , Wierup , N , Groop , L & Ahlqvist , E 2017 , ' Genetic determinants of circulating GIP and GLP-1 concentrations ' , JCI INSIGHT , vol. 2 , no. 21 , 93306 . https://doi.org/10.1172/jci.insight.93306

Title: Genetic determinants of circulating GIP and GLP-1 concentrations
Author: Almgren, Peter; Lindqvist, Andreas; Krus, Ulrika; Hakaste, Liisa; Ottosson-Laakso, Emilia; Asplund, Olof; Sonestedt, Emily; Prasad, Rashmi B.; Laurila, Esa; Orho-Melander, Marju; Melander, Olle; Tuomi, Tiinamaija; Holst, Jens Juul; Nilsson, Peter M.; Wierup, Nils; Groop, Leif; Ahlqvist, Emma
Contributor: University of Helsinki, Endokrinologian yksikkö
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
Date: 2017-11-21
Number of pages: 13
Belongs to series: JCI INSIGHT
ISSN: 2379-3708
URI: http://hdl.handle.net/10138/299215
Abstract: The secretion of insulin and glucagon from the pancreas and the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) from the gastrointestinal tract is essential for glucose homeostasis. Several novel treatment strategies for type 2 diabetes (T2D) mimic GLP-1 actions or inhibit incretin degradation (DPP4 inhibitors), but none is thus far aimed at increasing the secretion of endogenous incretins. In order to identify new potential therapeutic targets for treatment of T2D, we performed a meta-analysis of a GWAS and an exome-wide association study of circulating insulin, glucagon, GIP, and GLP-1 concentrations measured during an oral glucose tolerance test in up to 7,828 individuals. We identified 6 genome-wide significant functional loci associated with plasma incretin concentrations in or near the SLC5A1 (encoding SGLT1), GIPR, ABO, GLP2R, F13A1, and HOXD1 genes and studied the effect of these variants on mRNA expression in pancreatic islet and on metabolic phenotypes. Immunohistochemistry showed expression of GIPR, ABO, and HOXD1 in human enteroendocrine cells and expression of ABO in pancreatic islets, supporting a role in hormone secretion. This study thus provides candidate genes and insight into mechanisms by which secretion and breakdown of GIP and GLP-1 are regulated.
Subject: GENOME-WIDE ASSOCIATION
GLUCAGON-LIKE PEPTIDE-1
BODY-MASS INDEX
INSULIN-RESISTANCE
MALMO DIET
CHOLESTEROL ABSORPTION
MOLECULAR-MECHANISMS
GLUCOSE-ABSORPTION
FASTING GLUCOSE
LOCI
3111 Biomedicine
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