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Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge.

ABSTRACT: Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, beta (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 x 10(-15)). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 x 10(-17); ratio of insulin to glucose area under the curve, P = 1.3 x 10(-16)) and diminished incretin effect (n = 804; P = 4.3 x 10(-4)). We also identified variants at ADCY5 (rs2877716, P = 4.2 x 10(-16)), VPS13C (rs17271305, P = 4.1 x 10(-8)), GCKR (rs1260326, P = 7.1 x 10(-11)) and TCF7L2 (rs7903146, P = 4.2 x 10(-10)) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 x 10(-18)).

SUBMITTER: Saxena R

PROVIDER: S-EPMC2922003 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge.

Saxena Richa R Hivert Marie-France MF Langenberg Claudia C Tanaka Toshiko T Pankow James S JS Vollenweider Peter P Lyssenko Valeriya V Bouatia-Naji Nabila N Dupuis Josée J Jackson Anne U AU Kao W H Linda WH Li Man M Glazer Nicole L NL Manning Alisa K AK Luan Jian'an J Stringham Heather M HM Prokopenko Inga I Johnson Toby T Grarup Niels N Boesgaard Trine W TW Lecoeur Cécile C Shrader Peter P O'Connell Jeffrey J Ingelsson Erik E Couper David J DJ Rice Kenneth K Song Kijoung K Andreasen Camilla H CH Dina Christian C Köttgen Anna A Le Bacquer Olivier O Pattou François F Taneera Jalal J Steinthorsdottir Valgerdur V Rybin Denis D Ardlie Kristin K Sampson Michael M Qi Lu L van Hoek Mandy M Weedon Michael N MN Aulchenko Yurii S YS Voight Benjamin F BF Grallert Harald H Balkau Beverley B Bergman Richard N RN Bielinski Suzette J SJ Bonnefond Amelie A Bonnycastle Lori L LL Borch-Johnsen Knut K Böttcher Yvonne Y Brunner Eric E Buchanan Thomas A TA Bumpstead Suzannah J SJ Cavalcanti-Proença Christine C Charpentier Guillaume G Chen Yii-Der Ida YD Chines Peter S PS Collins Francis S FS Cornelis Marilyn M J Crawford Gabriel G Delplanque Jerome J Doney Alex A Egan Josephine M JM Erdos Michael R MR Firmann Mathieu M Forouhi Nita G NG Fox Caroline S CS Goodarzi Mark O MO Graessler Jürgen J Hingorani Aroon A Isomaa Bo B Jørgensen Torben T Kivimaki Mika M Kovacs Peter P Krohn Knut K Kumari Meena M Lauritzen Torsten T Lévy-Marchal Claire C Mayor Vladimir V McAteer Jarred B JB Meyre David D Mitchell Braxton D BD Mohlke Karen L KL Morken Mario A MA Narisu Narisu N Palmer Colin N A CN Pakyz Ruth R Pascoe Laura L Payne Felicity F Pearson Daniel D Rathmann Wolfgang W Sandbaek Annelli A Sayer Avan Aihie AA Scott Laura J LJ Sharp Stephen J SJ Sijbrands Eric E Singleton Andrew A Siscovick David S DS Smith Nicholas L NL Sparsø Thomas T Swift Amy J AJ Syddall Holly H Thorleifsson Gudmar G Tönjes Anke A Tuomi Tiinamaija T Tuomilehto Jaakko J Valle Timo T TT Waeber Gérard G Walley Andrew A Waterworth Dawn M DM Zeggini Eleftheria E Zhao Jing Hua JH Illig Thomas T Wichmann H Erich HE Wilson James F JF van Duijn Cornelia C Hu Frank B FB Morris Andrew D AD Frayling Timothy M TM Hattersley Andrew T AT Thorsteinsdottir Unnur U Stefansson Kari K Nilsson Peter P Syvänen Ann-Christine AC Shuldiner Alan R AR Walker Mark M Bornstein Stefan R SR Schwarz Peter P Williams Gordon H GH Nathan David M DM Kuusisto Johanna J Laakso Markku M Cooper Cyrus C Marmot Michael M Ferrucci Luigi L Mooser Vincent V Stumvoll Michael M Loos Ruth J F RJ Altshuler David D Psaty Bruce M BM Rotter Jerome I JI Boerwinkle Eric E Hansen Torben T Pedersen Oluf O Florez Jose C JC McCarthy Mark I MI Boehnke Michael M Barroso Inês I Sladek Robert R Froguel Philippe P Meigs James B JB Groop Leif L Wareham Nicholas J NJ Watanabe Richard M RM

Nature genetics 20100117 2

Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, beta (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 x 10(-15)). The GIPR A-allele carriers also showed decreas ...[more]

PMID: 20081857

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Project description:ObjectiveGlucose-dependent insulinotropic polypeptide (GIP) has a role in controlling postprandial metabolic tone. In humans, a GIP receptor (GIPR) variant (Q354, rs1800437) is associated with a lower body mass index (BMI) and increased risk for Type 2 Diabetes. To better understand the impacts of GIPR-Q354 on metabolism, it is necessary to study it in an isogeneic background to the predominant GIPR isoform, E354. To accomplish this objective, we used CRISPR-CAS9 editing to generate mouse models of GIPR-Q354 and GIPR-E354. Here we characterize the metabolic effects of GIPR-Q354 variant in a mouse model (GIPR-Q350).MethodsWe generated the GIPR-Q350 mice for in vivo studies of metabolic impact of the variant. We isolated pancreatic islets from GIPR-Q350 mice to study insulin secretion ex vivo. We used a β-cell cell line to understand the impact of the GIPR-Q354 variant on the receptor traffic.ResultsWe found that female GIPR-Q350 mice are leaner than littermate controls, and male GIPR-Q350 mice are resistant to diet-induced obesity, in line with the association of the variant with reduced BMI in humans. GIPR-Q350 mice of both sexes are more glucose tolerant and exhibit an increased sensitivity to GIP. Postprandial GIP levels are reduced in GIPR-Q350 mice, revealing feedback regulation that balances the increased sensitivity of GIP target tissues to secretion of GIP from intestinal endocrine cells. The increased GIP sensitivity is recapitulated ex vivo during glucose stimulated insulin secretion assays in islets. Generation of cAMP in islets downstream of GIPR activation is not affected by the Q354 substitution. However, post-activation traffic of GIPR-Q354 variant in β-cells is altered, characterized by enhanced intracellular dwell time and increased localization to the Trans-Golgi Network (TGN).ConclusionsOur data link altered intracellular traffic of the GIPR-Q354 variant with GIP control of metabolism. We propose that this change in spatiotemporal signaling underlies the physiologic effects of GIPR-Q350/4 and GIPR-E350/4 in mice and humans. These findings contribute to a more complete understanding of the impact of GIPR-Q354 variant on glucose homeostasis that could perhaps be leveraged to enhance pharmacologic targeting of GIPR for the treatment of metabolic disease.

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Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge.

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Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge.

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