Genes associated with obesity in patients with atypical diabetes
Main Article Content
Abstract
Diabetes Mellitus has a high prevalence in Uruguay and around the world. It presents different and complex clinical characteristics and very frequently diagnosis is a challenge for treating physicians. In previous works we described an atypical diabetic population showing genetic variations as HLA and non-HLA related to type 1 diabetes, presenting also type 2 diabetes clinical features. In the present work we studied variations in four genes (IRS-1, PPAR-γ2, ENPP-1 and UCP-2) associated with obesity and diabetes.
We studied 155 patients from two healthcare centers in Montevideo, Uruguay. We divided them into two populations as per type 2 diabetes criterion (84 patients) and atypical diabetes criterion (71 patients). We analyzed SNPs rs1801278, rs1801282, rs1044498 and rs659366 in genes IRS-1, PPAR-γ2, ENPP-1 and UCP-2, respectively.
Significant differences in SNP, IRS-1 and UCP-2 were found. No significant polymorphism variations were found in PPAR-γ2 and ENPP-1.
Our results would be in accordance with the evidence regarding the lack of correlation between genotype and phenotype in atypical diabetes patients, as there are differences in some of the susceptibility and protective variants for obesity and diabetes in genes involved in insulin resistance and faulty beta cells.
On the other hand, other variants would be partaken by both populations, determining the phenotypic characteristics they have in common. Genetic studies could serve not only for the identification of this type of patients but also to optimize their treatment.
Article Details
How to Cite
SOUTO, Jorge.
Genes associated with obesity in patients with atypical diabetes.
Medical Research Archives, [S.l.], v. 2, n. 9, nov. 2015.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/406>. Date accessed: 24 nov. 2024.
Keywords
diabetes; SNP; obesity; atypical diabetes
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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Almind K, Frederiksen SK, Ahlgren MG, Urhammer S, Hansen T, Clausen JO, et al. Rapid communication Common amino acid substitutions in insulin receptor substrate-4 are not associated with Type II diabetes mellitus or insulin resistance. Diabetologia. 1998;41:969–74.
Andersen G, Dalgaard LT, Justesen JM, Anthonsen S, Nielsen T, Thørner LW, Witte D, Jørgensen T, Clausen JO, Lauritzen T, Holmkvist J, Hansen T, Pedersen O. The frequent UCP2 -866G>A polymorphism protects against insulin resistance and is associated with obesity: a study of obesity and related metabolic traits among 17 636 Danes. Inter J Obesity. 2013;37(2):175-81.
Ashcroft FM, Rorsman P. Diabetes mellitus and the β cell: the last ten years. Cell. 2012;148(6):1160–71.
Bell CG, Walley AJ, Froguel P. The genetics of human obesity. Nat Rev Genet. 2005;6(3):221–34.
Bonnefond A, Durand E, Sand O, De Graeve F, Gallina S, Busiah K, et al. Molecular diagnosis of neonatal diabetes mellitus using next-generation sequencing of the whole exome. PLoS One. 2010;5(10):e13630.
Bonnefond A, Froguel P. Rare and Common Genetic Events in Type 2 Diabetes: What Should Biologists Know? Cell Metab 2015;21(3):357–68.
Buzzetti R, Petrone A, Ribaudo MC, Alemanno I, Zavarella S, Mein CA, Maiani F, Tiberti C, Baroni MG, Vecci E, Arca M, Leonetti F, Di Mario U. The common PPAR-gamma2 Pro12Ala variant is associated with greater insulin sensitivity. Eur J Hum Genet. 2004 Dec;12 (12):1050-4.
Chan CB, Saleh MC, Koshkin V, Wheeler MB. Uncoupling Protein 2 and Islet Function. Diabetes. 2004;53(February):S136–42.
Chistiakov DA, Potapov VA, Khodirev DS, Shamkhalova MS, Shestakova MV, Nosikov VN. The PPARγPro12Ala variant is associated with insulin sensitivity in Russian normoglycaemic and type 2 diabetic subjects. Diabetes & Vascular Disease Research. 2010;7(1): 56–62.
Das SK ES. NIH Public Access. Cellscience. 2006;2(4):100–31.
Diano S, Horvath TL. Mitochondrial uncoupling protein 2 (UCP2) in glucose and lipid metabolism. Trends Mol Med 2012;18(1):52–8.
Di Paola R, Caporarello N, Marucci A, Dimatteo C, Iadicicco C, Del Guerra S, et al. ENPP1 affects insulin action and secretion: evidences from in vitro studies. PLoS One 2011;6(5):e19462.
Fabregat M, Fernandez M, Javiel G, Vitarella G, Mimbacas A. The Genetic Profile from HLA and Non-HLA Loci Allows Identification of Atypical Type 2 Diabetes Patients. J Diab Res 2015; 1-6 Article ID 485132
Fernández M, Fabregat M, Javiel G, Mimbacas A. HLA alleles may serve as a tool to discriminate atypical type 2 diabetic patients. World J Diabetes 2014;5(5):711–6.
Frederiksen L, Brodbaek K, Fenger M, Jorgensen T, Borch-Johnsen K, Madsbad S, Urhammer SA. Studies of the Pro12Ala Polymorphism of the PPAR-Gene in the Danish MONICA Cohort: Homozygosityof the Ala Allele Confers a Decreased Risk of the Insulin Resistance Syndrome. The Journal of Clinical Endocrinology & Metabolism. 2002;87(8): 3989–3992.
Freeman H, Cox RD. Type-2 diabetes: a cocktail of genetic discovery. Hum Mol Genet. 2006;15 Spec No(2):R202–9.
Gable DR, Stephens JW, Cooper JA, Miller GJ, Humphries SE. Variation in the UCP2-UCP3 Gene Cluster Predicts the Development of Type 2 Diabetes in Healthy Middle-Aged Men. Diabetes 2006; 55(5):1504–11.
Gao Z, He Qing, Peng Bailu, Chiao P YJ. Regulation of nuclear translocation of HDAC3 by IKB α is required for TNF-inhibition of PPAR γ function. J Biol Chem. 2006;281(7):4540–7.
Ghoussaini M, Meyre D, Lobbens S, Charpentier G, Clément K, Charles MA, Tauber M,Weill J, Froguel P. Implication of the Pro12Ala polymorphism of the PPAR-gamma 2 gene in type 2 diabetes and obesity in the French population. BMC Medical Genetics. 2005;6:1-8.
Gonzalez Sanchez JL, Serrano Rıos M, Fernandez Perez C, Laakso M, Martınez Larrad MT. Effect of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor g-2 gene on adiposity, insulin sensitivity and lipid profile in the Spanish population. European Journal of Endocrinology. 2002;147: 495–501.
Gurnell M, Savage DB, Chatterjee VK, O'Rahilly S. The metabolic syndrome: peroxisome proliferator-activated receptor gamma and its therapeutic modulation. Journal of Clinical Endocrinology and Metabolism. 2003 Jun;88(6): 2412-21.
He W. PPARγ2 Pro12Ala Polymorphism and Human Health. PPAR Research. 2009; 2009:849538.
Ho JS, Germer S, Tam CH, So WY, Martin M, Ma RC, Chan JC, Ng MC. Association of the PPARG Pro12Ala polymorphism with type 2 diabetes and incident coronary heart disease in a Hong Kong Chinese population. Diabetes Research and Clinical Practice. 2012;97(3): 483-91.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care net. 2012;35(6):1364–79.
Ježek P, Dlasková A, Plecitá-Hlavatá L. Redox homeostasis in pancreatic β cells. Oxid Med Cell Longev. 2012; 2012:932838.
Li Li-xin, Skorpen F, Egeberg K, Jørgensen IH, Grill V. Induction of Uncoupling Protein 2 mRNA in beta-cells is stimulated by oxidation of fatty acids but not nutrient oversupply. Endocrinology. 2002;143(4):1371–7.
Liew CW, Bochenski J, Kawamori D, Hu J, Leech CA, Wanic K, Malecki M, Warram JH, Qi L, Krolewski AS, Kulkarni RN.The pseudokinase tribbles homolog 3 interacts with ATF4 to negatively regulate insulin exocytosis in human and mouse beta cells. J Clin Invest. 2010;120(8):2876-88.
Luo JZ, Luo L. American ginseng stimulates insulin production and prevents apoptosis through regulation of uncoupling protein-2 in cultured beta cells. Evid Based Complement Alternat Med. 2006;3(3):365–72.
Lyssenko V, Almgren P, Anevski D, Orho-Melander M, Sjögren M, Saloranta C, et al. Genetic prediction of future type 2 diabetes. PLoS Med. 2005;2(12):e345.
McGettrick AJ, Feener EP, Kahn CR. Human insulin receptor substrate-1 (IRS-1) polymorphism G972R causes IRS-1 to associate with the insulin receptor and inhibit receptor autophosphorylation. J Biol Chem. 2005;280(8):6441–6.
Marchetti P, Lupi R, Federici M, Marselli L, Masini M, Boggi U, et al. Insulin Secretory Function Is Impaired in Isolated. Diabetes. 2002;51:1419–24.
Marucci A, Cozzolino F, Dimatteo C, Monti M, Pucci P, Trischitta V, Di Paola R. Role of GALNT2 in the modulation of ENPP1 expression, and insulin signaling and action: GALNT2: a novel modulator of insulin signaling. Biochim Biophys Acta. 2013;1833(6):1388–95.
Mimbacas A, Pérez-Bravo F, Santos JL, Pisciottano C, Grignola R, Javiel G, et al. The association between HLA DQ genetic polymorphism and type 1 diabetes in a case-parent study conducted in an admixed population. Eur J Epidemiol. 2004;19(10):931–4.
Mimbacas A, Vitarella G, Souto J, Reyes AL, Farias J, Fernandez M, et al. The phenotype masks the genotype: A possible new expression of diabetes. J Pediatr Genet. 2012;1(2):131–4.
Mimbacas A, García L, Zorrilla P, Acosta M, Airaudo C, Ferrero R, et al. Genotype and phenotype correlations in diabetic patients in Uruguay. Genet Mol Res. 2009;8(4):1352–8.
Muoio DM, Newgard CB. Mechanisms of disease: molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes. Nat Rev Mol Cell Biol. 2008:193–205.
Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32(1):193–203.
Niessen M. On the role of IRS2 in the regulation of functional beta-cell mass. Arch Physiol Biochem. 2006;112(2):65-73.
Peraldi P, Hotamisligil GS, Buurman WA, White MF, Spiegelman BM. Tumor Necrosis Factor (TNF)-alpha inhibits insulin signaling through stimulation of the p55 TNF Receptor and Activation of Sphingomyelinase. J Biol Chem. 1996;271(22):13018–22.
Porzio O, Federici M, Hribal ML, Lauro D, Accili D, Lauro R, Borboni P, Sesti G. The Gly972→ Arg amino acid polymorphism in IRS-1 impairs insulin secretion in pancreatic β cells. J Clin Invest. 1999;104(3):357-64.
Qin LJ, Wen J, Qu YL, Huang QY. Lack of association of functional UCP2 -866G / A and Ala55Val polymorphisms and type 2 diabetes in the Chinese population based on a case-control study and a meta-analysis. Genet Mol Res. 2013;12(3):3324–34.
Royal College of Gerneral Practitioners. Coding, Classification and Diagnosis of Diabetes. NHS. 2011;1–56. Available from: www.diabetes.nhs.uk
Sasahara M, Nishi M, Kawashima H, Ueda K, Sakagashira S, Furuta H, et al. Uncoupling protein 2 promoter polymorphism 866G/A Affects Its Expression in beta-Cells and Modulates Clinical Profiles of Japanese Type 2 Diabetic Patients. Diabetes. 2004;53:482–5.
Sesti G, Federici M, Hribal ML, Lauro D, Sbraccia P, Lauro R. Defects of the insulin receptor substrate ( IRS ) system in human metabolic disorders. Faseb J. 2001;15:2099–111.
Sesti G, Cardellini M, Marini MA, Frontoni S, D'Adamo M, Del Guerra S, et al. A Common Polymorphism in the Promoter of UCP2 Glucose-Tolerant Subjects. Diabetes. 2003;52(May):1280–3.
Steenkamp DW, Alexanian SM, Sternthal E. Approach to the patient with atypical diabetes. CMAJ. 2014;186(9):678-84.
Stone MA, Camosso-Stefinovic J, Wilkinson J, de Lusignan S, Hattersley AT, Khunti K. Incorrect and incomplete coding and classification of diabetes: a systematic review. Diabet Med. 2010;27(5):491–7.
Vergotine Z, Yako YY, Kengne AP, Erasmus RT, Matsha TE. Proliferator-activated receptor gamma Pro12Ala interacts with the insulin receptor substrate 1 Gly972Arg and increase the risk of insulin resistance and diabetes in the mixed ancestry population from South Africa. BMC Genet. 2014;15:10.
Villarroya F, Iglesias R, Giralt M. PPARs in the Control of Uncoupling Proteins Gene Expression. PPAR Res. 2007;2007:74364.
Wang X, Liu J, Ouyang Y, Fang M, Gao H, Liu L. The association between the Pro12Ala variant in the PPARγ2 gene and type 2 diabetes mellitus and obesity in a Chinese population. PLoS One. 2014;8(8): e71985.
Ye W, Reis a., Dubois-Laforgue D, Bellanne-Chantelot C, Timsit J, Velho G. Vitamin D receptor gene polymorphisms are associated with obesity in type 2 diabetic subjects with early age of onset. Eur J Endocrinol. 2001;145(2):181–6.
Ye Ji. NIH Public Access. Front Med. 2013;7(1):14–24.
Yoshiuchi I. Evidence of selection at insulin receptor substrate-1 gene loci. Acta Diabetol. 2013;50(5):775–9.
Almind K, Frederiksen SK, Ahlgren MG, Urhammer S, Hansen T, Clausen JO, et al. Rapid communication Common amino acid substitutions in insulin receptor substrate-4 are not associated with Type II diabetes mellitus or insulin resistance. Diabetologia. 1998;41:969–74.
Andersen G, Dalgaard LT, Justesen JM, Anthonsen S, Nielsen T, Thørner LW, Witte D, Jørgensen T, Clausen JO, Lauritzen T, Holmkvist J, Hansen T, Pedersen O. The frequent UCP2 -866G>A polymorphism protects against insulin resistance and is associated with obesity: a study of obesity and related metabolic traits among 17 636 Danes. Inter J Obesity. 2013;37(2):175-81.
Ashcroft FM, Rorsman P. Diabetes mellitus and the β cell: the last ten years. Cell. 2012;148(6):1160–71.
Bell CG, Walley AJ, Froguel P. The genetics of human obesity. Nat Rev Genet. 2005;6(3):221–34.
Bonnefond A, Durand E, Sand O, De Graeve F, Gallina S, Busiah K, et al. Molecular diagnosis of neonatal diabetes mellitus using next-generation sequencing of the whole exome. PLoS One. 2010;5(10):e13630.
Bonnefond A, Froguel P. Rare and Common Genetic Events in Type 2 Diabetes: What Should Biologists Know? Cell Metab 2015;21(3):357–68.
Buzzetti R, Petrone A, Ribaudo MC, Alemanno I, Zavarella S, Mein CA, Maiani F, Tiberti C, Baroni MG, Vecci E, Arca M, Leonetti F, Di Mario U. The common PPAR-gamma2 Pro12Ala variant is associated with greater insulin sensitivity. Eur J Hum Genet. 2004 Dec;12 (12):1050-4.
Chan CB, Saleh MC, Koshkin V, Wheeler MB. Uncoupling Protein 2 and Islet Function. Diabetes. 2004;53(February):S136–42.
Chistiakov DA, Potapov VA, Khodirev DS, Shamkhalova MS, Shestakova MV, Nosikov VN. The PPARγPro12Ala variant is associated with insulin sensitivity in Russian normoglycaemic and type 2 diabetic subjects. Diabetes & Vascular Disease Research. 2010;7(1): 56–62.
Das SK ES. NIH Public Access. Cellscience. 2006;2(4):100–31.
Diano S, Horvath TL. Mitochondrial uncoupling protein 2 (UCP2) in glucose and lipid metabolism. Trends Mol Med 2012;18(1):52–8.
Di Paola R, Caporarello N, Marucci A, Dimatteo C, Iadicicco C, Del Guerra S, et al. ENPP1 affects insulin action and secretion: evidences from in vitro studies. PLoS One 2011;6(5):e19462.
Fabregat M, Fernandez M, Javiel G, Vitarella G, Mimbacas A. The Genetic Profile from HLA and Non-HLA Loci Allows Identification of Atypical Type 2 Diabetes Patients. J Diab Res 2015; 1-6 Article ID 485132
Fernández M, Fabregat M, Javiel G, Mimbacas A. HLA alleles may serve as a tool to discriminate atypical type 2 diabetic patients. World J Diabetes 2014;5(5):711–6.
Frederiksen L, Brodbaek K, Fenger M, Jorgensen T, Borch-Johnsen K, Madsbad S, Urhammer SA. Studies of the Pro12Ala Polymorphism of the PPAR-Gene in the Danish MONICA Cohort: Homozygosityof the Ala Allele Confers a Decreased Risk of the Insulin Resistance Syndrome. The Journal of Clinical Endocrinology & Metabolism. 2002;87(8): 3989–3992.
Freeman H, Cox RD. Type-2 diabetes: a cocktail of genetic discovery. Hum Mol Genet. 2006;15 Spec No(2):R202–9.
Gable DR, Stephens JW, Cooper JA, Miller GJ, Humphries SE. Variation in the UCP2-UCP3 Gene Cluster Predicts the Development of Type 2 Diabetes in Healthy Middle-Aged Men. Diabetes 2006; 55(5):1504–11.
Gao Z, He Qing, Peng Bailu, Chiao P YJ. Regulation of nuclear translocation of HDAC3 by IKB α is required for TNF-inhibition of PPAR γ function. J Biol Chem. 2006;281(7):4540–7.
Ghoussaini M, Meyre D, Lobbens S, Charpentier G, Clément K, Charles MA, Tauber M,Weill J, Froguel P. Implication of the Pro12Ala polymorphism of the PPAR-gamma 2 gene in type 2 diabetes and obesity in the French population. BMC Medical Genetics. 2005;6:1-8.
Gonzalez Sanchez JL, Serrano Rıos M, Fernandez Perez C, Laakso M, Martınez Larrad MT. Effect of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor g-2 gene on adiposity, insulin sensitivity and lipid profile in the Spanish population. European Journal of Endocrinology. 2002;147: 495–501.
Gurnell M, Savage DB, Chatterjee VK, O'Rahilly S. The metabolic syndrome: peroxisome proliferator-activated receptor gamma and its therapeutic modulation. Journal of Clinical Endocrinology and Metabolism. 2003 Jun;88(6): 2412-21.
He W. PPARγ2 Pro12Ala Polymorphism and Human Health. PPAR Research. 2009; 2009:849538.
Ho JS, Germer S, Tam CH, So WY, Martin M, Ma RC, Chan JC, Ng MC. Association of the PPARG Pro12Ala polymorphism with type 2 diabetes and incident coronary heart disease in a Hong Kong Chinese population. Diabetes Research and Clinical Practice. 2012;97(3): 483-91.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care net. 2012;35(6):1364–79.
Ježek P, Dlasková A, Plecitá-Hlavatá L. Redox homeostasis in pancreatic β cells. Oxid Med Cell Longev. 2012; 2012:932838.
Li Li-xin, Skorpen F, Egeberg K, Jørgensen IH, Grill V. Induction of Uncoupling Protein 2 mRNA in beta-cells is stimulated by oxidation of fatty acids but not nutrient oversupply. Endocrinology. 2002;143(4):1371–7.
Liew CW, Bochenski J, Kawamori D, Hu J, Leech CA, Wanic K, Malecki M, Warram JH, Qi L, Krolewski AS, Kulkarni RN.The pseudokinase tribbles homolog 3 interacts with ATF4 to negatively regulate insulin exocytosis in human and mouse beta cells. J Clin Invest. 2010;120(8):2876-88.
Luo JZ, Luo L. American ginseng stimulates insulin production and prevents apoptosis through regulation of uncoupling protein-2 in cultured beta cells. Evid Based Complement Alternat Med. 2006;3(3):365–72.
Lyssenko V, Almgren P, Anevski D, Orho-Melander M, Sjögren M, Saloranta C, et al. Genetic prediction of future type 2 diabetes. PLoS Med. 2005;2(12):e345.
McGettrick AJ, Feener EP, Kahn CR. Human insulin receptor substrate-1 (IRS-1) polymorphism G972R causes IRS-1 to associate with the insulin receptor and inhibit receptor autophosphorylation. J Biol Chem. 2005;280(8):6441–6.
Marchetti P, Lupi R, Federici M, Marselli L, Masini M, Boggi U, et al. Insulin Secretory Function Is Impaired in Isolated. Diabetes. 2002;51:1419–24.
Marucci A, Cozzolino F, Dimatteo C, Monti M, Pucci P, Trischitta V, Di Paola R. Role of GALNT2 in the modulation of ENPP1 expression, and insulin signaling and action: GALNT2: a novel modulator of insulin signaling. Biochim Biophys Acta. 2013;1833(6):1388–95.
Mimbacas A, Pérez-Bravo F, Santos JL, Pisciottano C, Grignola R, Javiel G, et al. The association between HLA DQ genetic polymorphism and type 1 diabetes in a case-parent study conducted in an admixed population. Eur J Epidemiol. 2004;19(10):931–4.
Mimbacas A, Vitarella G, Souto J, Reyes AL, Farias J, Fernandez M, et al. The phenotype masks the genotype: A possible new expression of diabetes. J Pediatr Genet. 2012;1(2):131–4.
Mimbacas A, García L, Zorrilla P, Acosta M, Airaudo C, Ferrero R, et al. Genotype and phenotype correlations in diabetic patients in Uruguay. Genet Mol Res. 2009;8(4):1352–8.
Muoio DM, Newgard CB. Mechanisms of disease: molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes. Nat Rev Mol Cell Biol. 2008:193–205.
Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32(1):193–203.
Niessen M. On the role of IRS2 in the regulation of functional beta-cell mass. Arch Physiol Biochem. 2006;112(2):65-73.
Peraldi P, Hotamisligil GS, Buurman WA, White MF, Spiegelman BM. Tumor Necrosis Factor (TNF)-alpha inhibits insulin signaling through stimulation of the p55 TNF Receptor and Activation of Sphingomyelinase. J Biol Chem. 1996;271(22):13018–22.
Porzio O, Federici M, Hribal ML, Lauro D, Accili D, Lauro R, Borboni P, Sesti G. The Gly972→ Arg amino acid polymorphism in IRS-1 impairs insulin secretion in pancreatic β cells. J Clin Invest. 1999;104(3):357-64.
Qin LJ, Wen J, Qu YL, Huang QY. Lack of association of functional UCP2 -866G / A and Ala55Val polymorphisms and type 2 diabetes in the Chinese population based on a case-control study and a meta-analysis. Genet Mol Res. 2013;12(3):3324–34.
Royal College of Gerneral Practitioners. Coding, Classification and Diagnosis of Diabetes. NHS. 2011;1–56. Available from: www.diabetes.nhs.uk
Sasahara M, Nishi M, Kawashima H, Ueda K, Sakagashira S, Furuta H, et al. Uncoupling protein 2 promoter polymorphism 866G/A Affects Its Expression in beta-Cells and Modulates Clinical Profiles of Japanese Type 2 Diabetic Patients. Diabetes. 2004;53:482–5.
Sesti G, Federici M, Hribal ML, Lauro D, Sbraccia P, Lauro R. Defects of the insulin receptor substrate ( IRS ) system in human metabolic disorders. Faseb J. 2001;15:2099–111.
Sesti G, Cardellini M, Marini MA, Frontoni S, D'Adamo M, Del Guerra S, et al. A Common Polymorphism in the Promoter of UCP2 Glucose-Tolerant Subjects. Diabetes. 2003;52(May):1280–3.
Steenkamp DW, Alexanian SM, Sternthal E. Approach to the patient with atypical diabetes. CMAJ. 2014;186(9):678-84.
Stone MA, Camosso-Stefinovic J, Wilkinson J, de Lusignan S, Hattersley AT, Khunti K. Incorrect and incomplete coding and classification of diabetes: a systematic review. Diabet Med. 2010;27(5):491–7.
Vergotine Z, Yako YY, Kengne AP, Erasmus RT, Matsha TE. Proliferator-activated receptor gamma Pro12Ala interacts with the insulin receptor substrate 1 Gly972Arg and increase the risk of insulin resistance and diabetes in the mixed ancestry population from South Africa. BMC Genet. 2014;15:10.
Villarroya F, Iglesias R, Giralt M. PPARs in the Control of Uncoupling Proteins Gene Expression. PPAR Res. 2007;2007:74364.
Wang X, Liu J, Ouyang Y, Fang M, Gao H, Liu L. The association between the Pro12Ala variant in the PPARγ2 gene and type 2 diabetes mellitus and obesity in a Chinese population. PLoS One. 2014;8(8): e71985.
Ye W, Reis a., Dubois-Laforgue D, Bellanne-Chantelot C, Timsit J, Velho G. Vitamin D receptor gene polymorphisms are associated with obesity in type 2 diabetic subjects with early age of onset. Eur J Endocrinol. 2001;145(2):181–6.
Ye Ji. NIH Public Access. Front Med. 2013;7(1):14–24.
Yoshiuchi I. Evidence of selection at insulin receptor substrate-1 gene loci. Acta Diabetol. 2013;50(5):775–9.