The Role of the PGC1α Gly482Ser Polymorphism in Weight Gain due to Intensive Diabetes Therapy

The Diabetes Control and Complications Trial (DCCT) involved intensive diabetes therapy of subjects with type 1 diabetes mellitus (T1DM) for an average period of 6.5 years. A subset of these subjects gained excessive weight. We tested for association of polymorphisms in 8 candidate genes with the above trait. We found the Gly482Ser polymorphism in the peroxisome proliferator-activated receptor γ coactivator-1α (PGC1α) to be significantly associated with weight gain in males (P = .0045) but not in females. The Ser allele was associated with greater weight gain than the Gly allele (P = .005). Subjects with a family history of type 2 diabetes mellitus (T2DM) were more common among those who gained excessive weight. We conclude that T2DM and the Gly482Ser polymorphism in PGC1α contribute to the effect of intensive diabetes therapy on weight gain in males with T1DM.

[1]  A. Butte,et al.  Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[2]  P. Puigserver,et al.  Restoration of insulin-sensitive glucose transporter (GLUT4) gene expression in muscle cells by the transcriptional coactivator PGC-1 , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[3]  M. Jarvelin,et al.  A Common Variant in the FTO Gene Is Associated with Body Mass Index and Predisposes to Childhood and Adult Obesity , 2007, Science.

[4]  J. Weber,et al.  Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[5]  C. Bouchard,et al.  A glucocorticoid receptor gene marker is associated with abdominal obesity, leptin, and dysregulation of the hypothalamic-pituitary-adrenal axis. , 2000, Obesity research.

[6]  C. Dina,et al.  Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population. , 2002, Diabetes.

[7]  J. Brunzell,et al.  Abdominal obesity and dyslipidemia in the metabolic syndrome: importance of type 2 diabetes and familial combined hyperlipidemia in coronary artery disease risk. , 2004, The Journal of clinical endocrinology and metabolism.

[8]  P. Arner,et al.  Effect of the (C825T) Gbeta(3) polymorphism on adrenoceptor-mediated lipolysis in human fat cells. , 2002, Diabetes.

[9]  T. Hansen,et al.  Mutation analysis of peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) and relationships of identified amino acid polymorphisms to Type II diabetes mellitus , 2001, Diabetologia.

[10]  P. Puigserver,et al.  Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. , 2003, Endocrine reviews.

[11]  S. O’Rahilly,et al.  Meta-analysis of the Gly482Ser variant in PPARGC1A in type 2 diabetes and related phenotypes , 2006, Diabetologia.

[12]  M. Daly,et al.  PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes , 2003, Nature Genetics.

[13]  P A Cleary,et al.  Effect of excessive weight gain with intensive therapy of type 1 diabetes on lipid levels and blood pressure: results from the DCCT. Diabetes Control and Complications Trial. , 1998, JAMA.

[14]  M. Stumvoll,et al.  C825T polymorphism of the G protein beta3 subunit is associated with obesity but not with insulin sensitivity. , 2004, Obesity research.

[15]  N. Unwin,et al.  The N363S polymorphism of the glucocorticoid receptor: potential contribution to central obesity in men and lack of association with other risk factors for coronary heart disease and diabetes mellitus. , 2001, The Journal of clinical endocrinology and metabolism.

[16]  M. Ehm,et al.  An autosomal genomic scan for loci linked to prediabetic phenotypes in Pima Indians. , 1998, The Journal of clinical investigation.

[17]  B. Paulweber,et al.  Peroxisome Proliferator-Activated Receptor-γ Coactivator-1 Gene Locus Associations With Obesity Indices in Middle-Aged Women , 2002 .

[18]  C. Dina.  New insights into the genetics of body weight , 2008, Current opinion in clinical nutrition and metabolic care.

[19]  Y. Chagnon,et al.  A genome-wide scan for abdominal fat assessed by computed tomography in the Québec Family Study. , 2001, Diabetes.

[20]  O. Pedersen,et al.  A Gly482Ser missense mutation in the peroxisome proliferator-activated receptor gamma coactivator-1 is associated with altered lipid oxidation and early insulin secretion in Pima Indians. , 2003, Diabetes.

[21]  Jiandie D. Lin,et al.  An autoregulatory loop controls peroxisome proliferator-activated receptor γ coactivator 1α expression in muscle , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[22]  T. Kadowaki,et al.  A genetic variation in the PGC-1 gene could confer insulin resistance and susceptibility to Type II diabetes , 2002, Diabetologia.

[23]  E. Carlsson,et al.  Multiple environmental and genetic factors influence skeletal muscle PGC-1alpha and PGC-1beta gene expression in twins. , 2004, The Journal of clinical investigation.

[24]  H. Esterbauer,et al.  Human peroxisome proliferator activated receptor gamma coactivator 1 (PPARGC1) gene: cDNA sequence, genomic organization, chromosomal localization, and tissue expression. , 1999, Genomics.

[25]  Multiple environmental and genetic factors influence skeletal muscle PGC-1alpha and PGC-1beta gene expression in twins. , 2004 .

[26]  M. Laakso,et al.  Common polymorphisms of the PPAR-γ2 (Pro12Ala) and PGC-1α (Gly482Ser) genes are associated with the conversion from impaired glucose tolerance to type 2 diabetes in the STOP-NIDDM trial , 2004, Diabetologia.

[27]  G. Abecasis,et al.  A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants , 2007, Science.

[28]  W. Siffert.  G protein β3 subunit 825T allele, hypertension, obesity, and diabetic nephropathy , 2000 .

[29]  L. Rand,et al.  Magnitude and determinants of coronary artery disease in juvenile-onset, insulin-dependent diabetes mellitus. , 1987, The American journal of cardiology.

[30]  Johan Auwerx,et al.  A Pro12Ala substitution in PPARγ2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity , 1998, Nature Genetics.

[31]  S. Genuth,et al.  The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. , 1993, The New England journal of medicine.

[32]  B. Spiegelman.  Peroxisome Proliferator-Activated Receptor-Coactivator 1 ( PGC-1 ) : Transcriptional Coactivator and Metabolic Regulator , 2003 .

[33]  A. Shuldiner,et al.  Genes and pathophysiology of type 2 diabetes: more than just the Randle cycle all over again. , 2004, The Journal of clinical investigation.

[34]  M. Ridderstråle,et al.  Increased risk of obesity associated with the variant allele of the PPARGC1A Gly482Ser polymorphism in physically inactive elderly men , 2006, Diabetologia.

[35]  F. Jin,et al.  The Gly482Ser variant of the PPARGC1 gene is associated with Type 2 diabetes mellitus in northern Chinese, especially men , 2006, Diabetic medicine : a journal of the British Diabetic Association.

[36]  Eric S. Lander,et al.  The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes , 2000, Nature Genetics.

[37]  T. Olsson,et al.  Tissue-specific dysregulation of cortisol metabolism in human obesity. , 2001, The Journal of clinical endocrinology and metabolism.

[38]  J. Flier,et al.  A Transgenic Model of Visceral Obesity and the Metabolic Syndrome , 2001, Science.

[39]  B. Walker,et al.  Printed in U.S.A. Copyright © 2001 by The Endocrine Society Minireview: 11�-Hydroxysteroid Dehydrogenase Type 1— A Tissue-Specific Amplifier of Glucocorticoid Action* , 2000 .

[40]  P. Scherer,et al.  A haplotype at the adiponectin locus is associated with obesity and other features of the insulin resistance syndrome. , 2002, Diabetes.

[41]  J. Hokanson,et al.  Relationship of family history of type 2 diabetes, hypoglycemia, and autoantibodies to weight gain and lipids with intensive and conventional therapy in the Diabetes Control and Complications Trial. , 2003, Diabetes.

[42]  S. Lamberts,et al.  Polymorphisms in the glucocorticoid receptor gene and their associations with metabolic parameters and body composition. , 2004, Recent progress in hormone research.