Genetic determinants of circulating GIP and GLP-1 concentrations
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Genetic determinants of circulating GIP and GLP-1 concentrations. / 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.
In: JCI insight, Vol. 2, No. 21, e93306, 02.11.2017.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Genetic determinants of circulating GIP and GLP-1 concentrations
AU - Almgren, Peter
AU - Lindqvist, Andreas
AU - Krus, Ulrika
AU - Hakaste, Liisa
AU - Ottosson-Laakso, Emilia
AU - Asplund, Olof
AU - Sonestedt, Emily
AU - Prasad, Rashmi B
AU - Laurila, Esa
AU - Orho-Melander, Marju
AU - Melander, Olle
AU - Tuomi, Tiinamaija
AU - Holst, Jens Juul
AU - Nilsson, Peter M
AU - Wierup, Nils
AU - Groop, Leif
AU - Ahlqvist, Emma
PY - 2017/11/2
Y1 - 2017/11/2
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1172/jci.insight.93306
DO - 10.1172/jci.insight.93306
M3 - Journal article
C2 - 29093273
VL - 2
JO - JCI Insight
JF - JCI Insight
SN - 2379-3708
IS - 21
M1 - e93306
ER -
ID: 189624585