Genetic determinants of circulating GIP and GLP-1 concentrations

Peter Almgren; Andreas Lindqvist; Ulrika Krus; Liisa Hakaste; Emilia Ottosson-Laakso; Olof Asplund; Emily Sonestedt; Rashmi B Prasad; Esa Laurila; Marju Orho-Melander; Olle Melander; Tiinamaija Tuomi; Jens Juul Holst; Peter M Nilsson; Nils Wierup; Leif Groop; Emma Ahlqvist

doi:10.1172/jci.insight.93306

Genetic determinants of circulating GIP and GLP-1 concentrations

Peter Almgren, Andreas Lindqvist, Ulrika Krus, Liisa Hakaste, Emilia Ottosson-Laakso, Olof Asplund, Emily Sonestedt, Rashmi B Prasad, Esa Laurila, Marju Orho-Melander, Olle Melander, Tiinamaija Tuomi, Jens Juul Holst, Peter M Nilsson, Nils Wierup, Leif Groop, Emma Ahlqvist

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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.

Originalsprog	Engelsk
Artikelnummer	e93306
Tidsskrift	JCI insight
Vol/bind	2
Udgave nummer	21
Antal sider	13
ISSN	2379-3708
DOI	https://doi.org/10.1172/jci.insight.93306
Status	Udgivet - 2 nov. 2017

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Genetic determinants of circulating GIP and GLP-1 concentrationsForlagets udgivne version, 394 KBLicens: Ikke-specificeret

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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, 2(21), [e93306]. https://doi.org/10.1172/jci.insight.93306

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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.",

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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

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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.

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Genetic determinants of circulating GIP and GLP-1 concentrations

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