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Diabetologia
Published in: Diabetologia 6/2013

01-06-2013 | Article

Systematic evaluation of validated type 2 diabetes and glycaemic trait loci for association with insulin clearance

Authors: M. O. Goodarzi, X. Guo, J. Cui, M. R. Jones, T. Haritunians, A. H. Xiang, Y.-D. I. Chen, K. D. Taylor, T. A. Buchanan, W. A. Hsueh, L. J. Raffel, J. I. Rotter

Published in: Diabetologia | Issue 6/2013

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Abstract

Aims/hypothesis

Insulin clearance is a highly heritable trait, for which few quantitative trait loci have been discovered. We sought to determine whether validated type 2 diabetes and/or glycaemic trait loci are associated with insulin clearance.

Methods

Hyperinsulinaemic–euglycaemic clamps were performed in two Hispanic-American family cohorts totalling 1329 participants in 329 families. The Metabochip was used to fine-map about 50 previously identified loci for type 2 diabetes, fasting glucose, fasting insulin, 2 h glucose or HbA1c. This resulted in 17,930 variants, which were tested for association with clamp-derived insulin clearance via meta-analysis of the two cohorts.

Results

In the meta-analysis, 38 variants located within seven loci demonstrated association with insulin clearance (p < 0.001). The top signals for each locus were rs10241087 (DGKB/TMEM195 [TMEM195 also known as AGMO]) (p = 4.4 × 10−5); chr1:217605433 (LYPLAL1) (p = 3.25 × 10−4); rs2380949 (GLIS3) (p = 3.4 × 10−4); rs55903902 (FADS1) (p = 5.6 × 10−4); rs849334 (JAZF1) (p = 6.4 × 10−4); rs35749 (IGF1) (p = 6.7 × 10−4); and rs9460557 (CDKAL1) (p = 6.8 × 10−4).

Conclusions/interpretation

While the majority of validated loci for type 2 diabetes and related traits do not appear to influence insulin clearance in Hispanics, several of these loci do show evidence of association with this trait. It is therefore possible that these loci could have pleiotropic effects on insulin secretion, insulin sensitivity and insulin clearance.
Appendix
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Literature
1.
Kim SP, Ellmerer M, Kirkman EL, Bergman RN (2007) Beta-cell "rest" accompanies reduced first-pass hepatic insulin extraction in the insulin-resistant, fat-fed canine model. Am J Physiol Endocrinol Metab 292:E1581–E1589PubMedCrossRef
2.
Lee CC, Haffner SM, Wagenknecht LE et al (2012) Insulin clearance and the incidence of type 2 diabetes in Hispanics and African Americans: the IRAS family study. Diabetes Care. doi:10.​2337/​dc12-1316
3.
Haffner SM, Stern MP, Watanabe RM, Bergman RN (1992) Relationship of insulin clearance and secretion to insulin sensitivity in non-diabetic Mexican Americans. Eur J Clin Invest 22:147–153PubMedCrossRef
4.
Osei K, Schuster DP (1994) Ethnic differences in secretion, sensitivity, and hepatic extraction of insulin in black and white Americans. Diabet Med 11:755–762PubMedCrossRef
5.
Rudovich NN, Rochlitz HJ, Pfeiffer AF (2004) Reduced hepatic insulin extraction in response to gastric inhibitory polypeptide compensates for reduced insulin secretion in normal-weight and normal glucose tolerant first-degree relatives of type 2 diabetic patients. Diabetes 53:2359–2365PubMedCrossRef
6.
Goodarzi MO, Taylor KD, Guo X et al (2005) Variation in the gene for muscle-specific AMP deaminase is associated with insulin clearance, a highly heritable trait. Diabetes 54:1222–1227PubMedCrossRef
7.
Guo X, Cui J, Jones MR et al (2012) Insulin clearance: confirmation as a highly heritable trait, and genome-wide linkage analysis. Diabetologia 55:2183–2192PubMedCrossRef
8.
Sladek R, Rocheleau G, Rung J et al (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445:881–885PubMedCrossRef
9.
Zeggini E, Weedon MN, Lindgren CM et al (2007) Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316:1336–1341PubMedCrossRef
10.
Scott LJ, Mohlke KL, Bonnycastle LL et al (2007) A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316:1341–1345PubMedCrossRef
11.
Saxena R, Voight BF, Lyssenko V et al (2007) Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316:1331–1336PubMedCrossRef
12.
Pivovarova O, Nikiforova VJ, Pfeiffer AF, Rudovich N (2009) The influence of genetic variations in HHEX gene on insulin metabolism in the German MESYBEPO cohort. Diabetes Metab Res Rev 25:156–162PubMedCrossRef
13.
Rudovich N, Pivovarova O, Fisher E et al (2009) Polymorphisms within insulin-degrading enzyme (IDE) gene determine insulin metabolism and risk of type 2 diabetes. J Mol Med 87:1145–1151PubMedCrossRef
14.
Johnson AD, Handsaker RE, Pulit SL, Nizzari MM, O'Donnell CJ, de Bakker PI (2008) SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics 24:2938–2939PubMedCrossRef
15.
Altshuler D, Hirschhorn JN, Klannemark M et al (2000) The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 26:76–80PubMedCrossRef
16.
Tschritter O, Fritsche A, Stefan N et al (2003) Increased insulin clearance in peroxisome proliferator-activated receptor gamma2 Pro12Ala. Metabolism 52:778–783PubMedCrossRef
17.
Voight BF, Kang HM, Ding J et al (2012) The Metabochip, a custom genotyping array for genetic studies of metabolic, cardiovascular, and anthropometric traits. PLoS Genet 8:e1002793PubMedCrossRef
18.
Xiang AH, Azen SP, Raffel LJ et al (2001) Evidence for joint genetic control of insulin sensitivity and systolic blood pressure in Hispanic families with a hypertensive proband. Circulation 103:78–83PubMedCrossRef
19.
DeFronzo RA, Tobin JD, Andres R (1979) Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237:E214–E223PubMed
20.
Gunderson KL, Steemers FJ, Ren H et al (2006) Whole-genome genotyping. Methods Enzymol 410:359–376PubMedCrossRef
21.
Morris AP, Voight BF, Teslovich TM et al (2012) Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet 44:981–990PubMedCrossRef
22.
Scott RA, Lagou V, Welch RP et al (2012) Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. Nat Genet 44:991–1005PubMedCrossRef
23.
Bryc K, Velez C, Karafet T et al (2010) Colloquium paper: genome-wide patterns of population structure and admixture among Hispanic/Latino populations. Proc Natl Acad Sci U S A 107(Suppl 2):8954–8961PubMedCrossRef
24.
Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38:904–909PubMedCrossRef
25.
Chen MH, Yang Q (2010) GWAF: an R package for genome-wide association analyses with family data. Bioinformatics 26:580–581PubMedCrossRef
26.
Willer CJ, Li Y, Abecasis GR (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26:2190–2191PubMedCrossRef
27.
Gamboa-Melendez MA, Huerta-Chagoya A, Moreno-Macias H et al (2012) Contribution of common genetic variation to the risk of type 2 diabetes in the Mexican Mestizo population. Diabetes 61:3314–3321PubMedCrossRef
28.
Cruz M, Valladares-Salgado A, Garcia-Mena J et al (2010) Candidate gene association study conditioning on individual ancestry in patients with type 2 diabetes and metabolic syndrome from Mexico City. Diabetes Metab Res Rev 26:261–270PubMedCrossRef
29.
Campbell DD, Parra MV, Duque C et al (2012) Amerind ancestry, socioeconomic status and the genetics of type 2 diabetes in a Colombian population. PLoS One 7:e33570PubMedCrossRef
30.
Palmer ND, Goodarzi MO, Langefeld CD et al (2008) Quantitative trait analysis of type 2 diabetes susceptibility loci identified from whole genome association studies in the Insulin Resistance Atherosclerosis Family Study. Diabetes 57:1093–1100PubMedCrossRef
31.
Ingelsson E, Langenberg C, Hivert MF et al (2010) Detailed physiologic characterization reveals diverse mechanisms for novel genetic Loci regulating glucose and insulin metabolism in humans. Diabetes 59:1266–1275PubMedCrossRef
32.
Boesgaard TW, Grarup N, Jorgensen T, Borch-Johnsen K, Hansen T, Pedersen O (2010) Variants at DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci are associated with reduced glucose-stimulated beta cell function in middle-aged Danish people. Diabetologia 53:1647–1655PubMedCrossRef
33.
Kirchhoff K, Machicao F, Haupt A et al (2008) Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion. Diabetologia 51:597–601PubMedCrossRef
34.
Grarup N, Andersen G, Krarup NT et al (2008) Association testing of novel type 2 diabetes risk alleles in the JAZF1, CDC123/CAMK1D, TSPAN8, THADA, ADAMTS9, and NOTCH2 loci with insulin release, insulin sensitivity, and obesity in a population-based sample of 4,516 glucose-tolerant middle-aged Danes. Diabetes 57:2534–2540PubMedCrossRef
35.
Stancakova A, Pihlajamaki J, Kuusisto J et al (2008) Single-nucleotide polymorphism rs7754840 of CDKAL1 is associated with impaired insulin secretion in nondiabetic offspring of type 2 diabetic subjects and in a large sample of men with normal glucose tolerance. J Clin Endocrinol Metab 93:1924–1930PubMedCrossRef
36.
Groenewoud MJ, Dekker JM, Fritsche A et al (2008) Variants of CDKAL1 and IGF2BP2 affect first-phase insulin secretion during hyperglycaemic clamps. Diabetologia 51:1659–1663PubMedCrossRef
37.
Dupuis J, Langenberg C, Prokopenko I et al (2010) New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42:105–116PubMedCrossRef
38.
Duckworth WC, Bennett RG, Hamel FG (1998) Insulin degradation: progress and potential. Endocr Rev 19:608–624PubMedCrossRef
39.
Wei FY, Suzuki T, Watanabe S et al (2011) Deficit of tRNA(Lys) modification by Cdkal1 causes the development of type 2 diabetes in mice. J Clin Invest 121:3598–3608PubMedCrossRef
40.
Kang HS, Kim YS, ZeRuth G et al (2009) Transcription factor Glis3, a novel critical player in the regulation of pancreatic beta-cell development and insulin gene expression. Mol Cell Biol 29:6366–6379PubMedCrossRef
41.
Meier JJ, Veldhuis JD, Butler PC (2005) Pulsatile insulin secretion dictates systemic insulin delivery by regulating hepatic insulin extraction in humans. Diabetes 54:1649–1656PubMedCrossRef
42.
Kim YS, Nakanishi G, Lewandoski M, Jetten AM (2003) GLIS3, a novel member of the GLIS subfamily of Kruppel-like zinc finger proteins with repressor and activation functions. Nucleic Acids Res 31:5513–5525PubMedCrossRef
43.
Barrett JC, Clayton DG, Concannon P et al (2009) Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 41:703–707PubMedCrossRef
44.
Quaranta M, Burden AD, Griffiths CE et al (2009) Differential contribution of CDKAL1 variants to psoriasis, Crohn's disease and type II diabetes. Genes Immun 10:654–658PubMedCrossRef
45.
Kumashiro N, Erion DM, Zhang D et al (2011) Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A 108:16381–16385PubMedCrossRef
46.
Araya J, Rodrigo R, Pettinelli P, Araya AV, Poniachik J, Videla LA (2010) Decreased liver fatty acid delta-6 and delta-5 desaturase activity in obese patients. Obesity (Silver Spring) 18:1460–1463CrossRef
47.
Vessby B, Gustafsson IB, Tengblad S, Boberg M, Andersson A (2002) Desaturation and elongation of fatty acids and insulin action. Ann N Y Acad Sci 967:183–195PubMedCrossRef
48.
Chambers JC, Zhang W, Sehmi J et al (2011) Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat Genet 43:1131–1138PubMedCrossRef
49.
Fox CS, Liu Y, White CC et al (2012) Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women. PLoS Genet 8:e1002695PubMedCrossRef
50.
Bille DS, Banasik K, Justesen JM et al (2011) Implications of central obesity-related variants in LYPLAL1, NRXN3, MSRA, and TFAP2B on quantitative metabolic traits in adult Danes. PLoS One 6:e20640PubMedCrossRef
51.
Speliotes EK, Yerges-Armstrong LM, Wu J et al (2011) Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet 7:e1001324PubMedCrossRef
52.
Heid IM, Jackson AU, Randall JC et al (2010) Meta-analysis identifies 13 new loci associated with waist–hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Genet 42:949–960PubMedCrossRef
53.
Dastani Z, Hivert MF, Timpson N et al (2012) Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals. PLoS Genet 8:e1002607PubMedCrossRef
54.
Goodarzi MO, Cui J, Chen YD, Hsueh WA, Guo X, Rotter JI (2011) Fasting insulin reflects heterogeneous physiological processes: role of insulin clearance. Am J Physiol Endocrinol Metab 301:E402–E408PubMedCrossRef
55.
Arafat AM, Mohlig M, Weickert MO, Schofl C, Spranger J, Pfeiffer AF (2010) Improved insulin sensitivity, preserved beta cell function and improved whole-body glucose metabolism after low-dose growth hormone replacement therapy in adults with severe growth hormone deficiency: a pilot study. Diabetologia 53:1304–1313PubMedCrossRef
56.
Belfiore A, Frasca F, Pandini G, Sciacca L, Vigneri R (2009) Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr Rev 30:586–623PubMedCrossRef
Metadata
Title
Systematic evaluation of validated type 2 diabetes and glycaemic trait loci for association with insulin clearance
Authors
M. O. Goodarzi
X. Guo
J. Cui
M. R. Jones
T. Haritunians
A. H. Xiang
Y.-D. I. Chen
K. D. Taylor
T. A. Buchanan
W. A. Hsueh
L. J. Raffel
J. I. Rotter
Publication date
01-06-2013
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 6/2013
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-013-2880-6

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