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1. Renal Denervation Reverses Hepatic Insulin Resistance Induced by High-Fat Diet

Author

Iyer, Malini S, Bergman, Richard N, Korman, Jeremy E, Woolcott, Orison O, Kabir, Morvarid, Victor, Ronald G, Clegg, Deborah J, and Kolka, Cathryn

Subjects
Biomedical and Clinical Sciences, Nutrition, Digestive Diseases, Liver Disease, Obesity, Neurosciences, Oral and gastrointestinal, Animals, Catecholamines, Diet, High-Fat, Dogs, Gluconeogenesis, Glucose Clamp Technique, Hypoglycemia, Insulin, Insulin Resistance, Kidney, Liver, Liver X Receptors, Male, Real-Time Polymerase Chain Reaction, Renin, Sympathetic Nervous System, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences
Abstract

Activation of the sympathetic nervous system (SNS) constitutes a putative mechanism of obesity-induced insulin resistance. Thus, we hypothesized that inhibiting the SNS by using renal denervation (RDN) will improve insulin sensitivity (SI) in a nonhypertensive obese canine model. SI was measured using euglycemic-hyperinsulinemic clamp (EGC), before (week 0 [w0]) and after 6 weeks of high-fat diet (w6-HFD) feeding and after either RDN (HFD + RDN) or sham surgery (HFD + sham). As expected, HFD induced insulin resistance in the liver (sham 2.5 ± 0.6 vs. 0.7 ± 0.6 × 10-4 dL ⋅ kg-1 ⋅ min-1 ⋅ pmol/L-1 at w0 vs. w6-HFD [P < 0.05], respectively; HFD + RDN 1.6 ± 0.3 vs. 0.5 ± 0.3 × 10-4 dL ⋅ kg-1 ⋅ min-1 ⋅ pmol/L-1 at w0 vs. w6-HFD [P < 0.001], respectively). In sham animals, this insulin resistance persisted, yet RDN completely normalized hepatic SI in HFD-fed animals (1.8 ± 0.3 × 10-4 dL ⋅ kg-1 ⋅ min-1 ⋅ pmol/L-1 at HFD + RDN [P < 0.001] vs. w6-HFD, [P not significant] vs. w0) by reducing hepatic gluconeogenic genes, including G6Pase, PEPCK, and FOXO1. The data suggest that RDN downregulated hepatic gluconeogenesis primarily by upregulating liver X receptor α through the natriuretic peptide pathway. In conclusion, bilateral RDN completely normalizes hepatic SI in obese canines. These preclinical data implicate a novel mechanistic role for the renal nerves in the regulation of insulin action specifically at the level of the liver and show that the renal nerves constitute a new therapeutic target to counteract insulin resistance.

Published
2016

2. Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci

Author

Walford, Geoffrey A, Gustafsson, Stefan, Rybin, Denis, Stančáková, Alena, Chen, Han, Liu, Ching-Ti, Hong, Jaeyoung, Jensen, Richard A, Rice, Ken, Morris, Andrew P, Mägi, Reedik, Tönjes, Anke, Prokopenko, Inga, Kleber, Marcus E, Delgado, Graciela, Silbernagel, Günther, Jackson, Anne U, Appel, Emil V, Grarup, Niels, Lewis, Joshua P, Montasser, May E, Landenvall, Claes, Staiger, Harald, Luan, Jian’an, Frayling, Timothy M, Weedon, Michael N, Xie, Weijia, Morcillo, Sonsoles, Martínez-Larrad, María Teresa, Biggs, Mary L, Chen, Yii-Der Ida, Corbaton-Anchuelo, Arturo, Færch, Kristine, Gómez-Zumaquero, Juan Miguel, Goodarzi, Mark O, Kizer, Jorge R, Koistinen, Heikki A, Leong, Aaron, Lind, Lars, Lindgren, Cecilia, Machicao, Fausto, Manning, Alisa K, Martín-Núñez, Gracia María, Rojo-Martínez, Gemma, Rotter, Jerome I, Siscovick, David S, Zmuda, Joseph M, Zhang, Zhongyang, Serrano-Rios, Manuel, Smith, Ulf, Soriguer, Federico, Hansen, Torben, Jørgensen, Torben J, Linnenberg, Allan, Pedersen, Oluf, Walker, Mark, Langenberg, Claudia, Scott, Robert A, Wareham, Nicholas J, Fritsche, Andreas, Häring, Hans-Ulrich, Stefan, Norbert, Groop, Leif, O’Connell, Jeff R, Boehnke, Michael, Bergman, Richard N, Collins, Francis S, Mohlke, Karen L, Tuomilehto, Jaakko, März, Winfried, Kovacs, Peter, Stumvoll, Michael, Psaty, Bruce M, Kuusisto, Johanna, Laakso, Markku, Meigs, James B, Dupuis, Josée, Ingelsson, Erik, and Florez, Jose C

Subjects
Biomedical and Clinical Sciences, Genetics, Prevention, Human Genome, Diabetes, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Chemokines, CC, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Insulin Receptor Substrate Proteins, Insulin Resistance, Male, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-bcl-2, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences
Abstract

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10(-11)), rs12454712 (BCL2; P = 2.7 × 10(-8)), and rs10506418 (FAM19A2; P = 1.9 × 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.

Published
2016

3. Improved Performance of Dynamic Measures of Insulin Response Over Surrogate Indices to Identify Genetic Contributors of Type 2 Diabetes: The GUARDIAN Consortium

Author

Palmer, Nicholette D, Wagenknecht, Lynne E, Langefeld, Carl D, Wang, Nan, Buchanan, Thomas A, Xiang, Anny H, Allayee, Hooman, Bergman, Richard N, Raffel, Leslie J, Chen, Yii-Der Ida, Haritunians, Talin, Fingerlin, Tasha, Goodarzi, Mark O, Taylor, Kent D, Rotter, Jerome I, Watanabe, Richard M, and Bowden, Donald W

Subjects
Biomedical and Clinical Sciences, Genetics, Diabetes, Metabolic and endocrine, Adult, Aged, Blood Glucose, Diabetes Mellitus, Type 2, Female, Glucose Tolerance Test, Homeostasis, Humans, Insulin, Insulin Resistance, Male, Middle Aged, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences
Abstract

Type 2 diabetes (T2D) is a heterogeneous disorder with contributions from peripheral insulin resistance and β-cell dysfunction. For minimization of phenotypic heterogeneity, quantitative intermediate phenotypes characterizing basal glucose homeostasis (insulin resistance and HOMA of insulin resistance [HOMAIR] and of β-cell function [HOMAB]) have shown promise in relatively large samples. We investigated the utility of dynamic measures of glucose homeostasis (insulin sensitivity [SI] and acute insulin response [AIRg]) evaluating T2D-susceptibility variants (n = 57) in Hispanic Americans from the GUARDIAN Consortium (n = 2,560). Basal and dynamic measures were genetically correlated (HOMAB-AIRg: ρG = 0.28-0.73; HOMAIR-SI: ρG = -0.73 to -0.83) with increased heritability for the dynamic measure AIRg Significant association of variants with dynamic measures (P < 8.77 × 10(-4)) was observed. A pattern of superior performance of AIRg was observed for well-established loci including MTNR1B (P = 9.46 × 10(-12)), KCNQ1 (P = 1.35 × 10(-4)), and TCF7L2 (P = 5.10 × 10(-4)) with study-wise statistical significance. Notably, significant association of MTNR1B with AIRg (P < 1.38 × 10(-9)) was observed in a population one-fourteenth the size of the initial discovery cohort. These observations suggest that basal and dynamic measures provide different views and levels of sensitivity to discrete elements of glucose homeostasis. Although more costly to obtain, dynamic measures yield significant results that could be considered physiologically "closer" to causal pathways and provide insight into the discrete mechanisms of action.

Published
2016

4. Genetic Variants Associated With Quantitative Glucose Homeostasis Traits Translate to Type 2 Diabetes in Mexican Americans: The GUARDIAN (Genetics Underlying Diabetes in Hispanics) Consortium

Author

Palmer, Nicholette D, Goodarzi, Mark O, Langefeld, Carl D, Wang, Nan, Guo, Xiuqing, Taylor, Kent D, Fingerlin, Tasha E, Norris, Jill M, Buchanan, Thomas A, Xiang, Anny H, Haritunians, Talin, Ziegler, Julie T, Williams, Adrienne H, Stefanovski, Darko, Cui, Jinrui, Mackay, Adrienne W, Henkin, Leora F, Bergman, Richard N, Gao, Xiaoyi, Gauderman, James, Varma, Rohit, Hanis, Craig L, Cox, Nancy J, Highland, Heather M, Below, Jennifer E, Williams, Amy L, Burtt, Noel P, Aguilar-Salinas, Carlos A, Huerta-Chagoya, Alicia, Gonzalez-Villalpando, Clicerio, Orozco, Lorena, Haiman, Christopher A, Tsai, Michael Y, Johnson, W Craig, Yao, Jie, Rasmussen-Torvik, Laura, Pankow, James, Snively, Beverly, Jackson, Rebecca D, Liu, Simin, Nadler, Jerry L, Kandeel, Fouad, Chen, Yii-Der I, Bowden, Donald W, Rich, Stephen S, Raffel, Leslie J, Rotter, Jerome I, Watanabe, Richard M, and Wagenknecht, Lynne E

Subjects
Biomedical and Clinical Sciences, Obesity, Clinical Research, Diabetes, Human Genome, Genetics, Metabolic and endocrine, Blood Glucose, Databases, Factual, Diabetes Mellitus, Type 2, Gene Expression Regulation, Genetic Variation, Genome, Genome-Wide Association Study, Genotype, Hispanic or Latino, Homeostasis, Humans, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences
Abstract

Insulin sensitivity, insulin secretion, insulin clearance, and glucose effectiveness exhibit strong genetic components, although few studies have examined their genetic architecture or influence on type 2 diabetes (T2D) risk. We hypothesized that loci affecting variation in these quantitative traits influence T2D. We completed a multicohort genome-wide association study to search for loci influencing T2D-related quantitative traits in 4,176 Mexican Americans. Quantitative traits were measured by the frequently sampled intravenous glucose tolerance test (four cohorts) or euglycemic clamp (three cohorts), and random-effects models were used to test the association between loci and quantitative traits, adjusting for age, sex, and admixture proportions (Discovery). Analysis revealed a significant (P < 5.00 × 10(-8)) association at 11q14.3 (MTNR1B) with acute insulin response. Loci with P < 0.0001 among the quantitative traits were examined for translation to T2D risk in 6,463 T2D case and 9,232 control subjects of Mexican ancestry (Translation). Nonparametric meta-analysis of the Discovery and Translation cohorts identified significant associations at 6p24 (SLC35B3/TFAP2A) with glucose effectiveness/T2D, 11p15 (KCNQ1) with disposition index/T2D, and 6p22 (CDKAL1) and 11q14 (MTNR1B) with acute insulin response/T2D. These results suggest that T2D and insulin secretion and sensitivity have both shared and distinct genetic factors, potentially delineating genomic components of these quantitative traits that drive the risk for T2D.

Published
2015

5. Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity

Author

Dimas, Antigone S, Lagou, Vasiliki, Barker, Adam, Knowles, Joshua W, Mägi, Reedik, Hivert, Marie-France, Benazzo, Andrea, Rybin, Denis, Jackson, Anne U, Stringham, Heather M, Song, Ci, Fischer-Rosinsky, Antje, Boesgaard, Trine Welløv, Grarup, Niels, Abbasi, Fahim A, Assimes, Themistocles L, Hao, Ke, Yang, Xia, Lecoeur, Cécile, Barroso, Inês, Bonnycastle, Lori L, Böttcher, Yvonne, Bumpstead, Suzannah, Chines, Peter S, Erdos, Michael R, Graessler, Jurgen, Kovacs, Peter, Morken, Mario A, Narisu, Narisu, Payne, Felicity, Stancakova, Alena, Swift, Amy J, Tönjes, Anke, Bornstein, Stefan R, Cauchi, Stéphane, Froguel, Philippe, Meyre, David, Schwarz, Peter EH, Häring, Hans-Ulrich, Smith, Ulf, Boehnke, Michael, Bergman, Richard N, Collins, Francis S, Mohlke, Karen L, Tuomilehto, Jaakko, Quertemous, Thomas, Lind, Lars, Hansen, Torben, Pedersen, Oluf, Walker, Mark, Pfeiffer, Andreas FH, Spranger, Joachim, Stumvoll, Michael, Meigs, James B, Wareham, Nicholas J, Kuusisto, Johanna, Laakso, Markku, Langenberg, Claudia, Dupuis, Josée, Watanabe, Richard M, Florez, Jose C, Ingelsson, Erik, McCarthy, Mark I, Prokopenko, Inga, and Investigators, on behalf of the MAGIC

Subjects
Biomedical and Clinical Sciences, Genetics, Diabetes, Autoimmune Disease, Clinical Research, Prevention, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Alleles, Cluster Analysis, Diabetes Mellitus, Type 2, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Insulin, Insulin Resistance, Insulin Secretion, Insulin-Secreting Cells, Male, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Transcription Factors, MAGIC Investigators, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences
Abstract

Patients with established type 2 diabetes display both β-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.

Published
2014

6. Comprehensive Association Study of Type 2 Diabetes and Related Quantitative Traits With 222 Candidate Genes

Author

Gaulton, Kyle J, Willer, Cristen J, Li, Yun, Scott, Laura J, Conneely, Karen N, Jackson, Anne U, Duren, William L, Chines, Peter S, Narisu, Narisu, Bonnycastle, Lori L, Luo, Jingchun, Tong, Maurine, Sprau, Andrew G, Pugh, Elizabeth W, Doheny, Kimberly F, Valle, Timo T, Abecasis, Gonçalo R, Tuomilehto, Jaakko, Bergman, Richard N, Collins, Francis S, Boehnke, Michael, and Mohlke, Karen L

Subjects
Biomedical and Clinical Sciences, Biotechnology, Diabetes, Genetics, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Adult, Aged, Diabetes Mellitus, Type 2, Female, Finland, Gene Frequency, Genes, p53, Genetic Predisposition to Disease, Genotype, Glucose Transporter Type 2, Humans, Male, Middle Aged, Nuclear Respiratory Factor 1, Phosphoric Diester Hydrolases, Polymorphism, Single Nucleotide, Potassium Channels, Inwardly Rectifying, Pyrophosphatases, Quantitative Trait, Heritable, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences
Abstract

ObjectiveType 2 diabetes is a common complex disorder with environmental and genetic components. We used a candidate gene-based approach to identify single nucleotide polymorphism (SNP) variants in 222 candidate genes that influence susceptibility to type 2 diabetes.Research design and methodsIn a case-control study of 1,161 type 2 diabetic subjects and 1,174 control Finns who are normal glucose tolerant, we genotyped 3,531 tagSNPs and annotation-based SNPs and imputed an additional 7,498 SNPs, providing 99.9% coverage of common HapMap variants in the 222 candidate genes. Selected SNPs were genotyped in an additional 1,211 type 2 diabetic case subjects and 1,259 control subjects who are normal glucose tolerant, also from Finland.ResultsUsing SNP- and gene-based analysis methods, we replicated previously reported SNP-type 2 diabetes associations in PPARG, KCNJ11, and SLC2A2; identified significant SNPs in genes with previously reported associations (ENPP1 [rs2021966, P = 0.00026] and NRF1 [rs1882095, P = 0.00096]); and implicated novel genes, including RAPGEF1 (rs4740283, P = 0.00013) and TP53 (rs1042522, Arg72Pro, P = 0.00086), in type 2 diabetes susceptibility.ConclusionsOur study provides an effective gene-based approach to association study design and analysis. One or more of the newly implicated genes may contribute to type 2 diabetes pathogenesis. Analysis of additional samples will be necessary to determine their effect on susceptibility.

Published
2008

13. Mendelian Randomization Studies Do Not Support a Causal Role for Reduced Circulating Adiponectin Levels in Insulin Resistance and Type 2 Diabetes

Author

Yaghootkar, Hanieh, Lamina, Claudia, Scott, Robert A., Dastani, Zari, Hivert, Marie-France, Warren, Liling L., Stancáková, Alena, Buxbaum, Sarah G., Lyytikäinen, Leo-Pekka, Henneman, Peter, Wu, Ying, Cheung, Chloe Y.Y., Pankow, James S., Jackson, Anne U., Gustafsson, Stefan, Zhao, Jing Hua, Ballantyne, Christie M., Xie, Weijia, Bergman, Richard N., Boehnke, Michael, el Bouazzaoui, Fatiha, Collins, Francis S., Dunn, Sandra H., Dupuis, Josee, Forouhi, Nita G., Gillson, Christopher, Hattersley, Andrew T., Hong, Jaeyoung, Kähönen, Mika, Kuusisto, Johanna, Kedenko, Lyudmyla, Kronenberg, Florian, Doria, Alessandro, Assimes, Themistocles L., Ferrannini, Ele, Hansen, Torben, Hao, Ke, Häring, Hans, Knowles, Joshua W., Lindgren, Cecilia M., Nolan, John J., Paananen, Jussi, Pedersen, Oluf, Quertermous, Thomas, Smith, Ulf, Lehtimäki, Terho, Liu, Ching-Ti, Loos, Ruth J.F., McCarthy, Mark I., Morris, Andrew D., Vasan, Ramachandran S., Spector, Tim D., Teslovich, Tanya M., Tuomilehto, Jaakko, van Dijk, Ko Willems, Viikari, Jorma S., Zhu, Na, Langenberg, Claudia, Ingelsson, Erik, Semple, Robert K., Sinaiko, Alan R., Palmer, Colin N.A., Walker, Mark, Lam, Karen S.L., Paulweber, Bernhard, Mohlke, Karen L., van Duijn, Cornelia, Raitakari, Olli T., Bidulescu, Aurelian, Wareham, Nick J., Laakso, Markku, Waterworth, Dawn M., Lawlor, Debbie A., Meigs, James B., Richards, J. Brent, and Frayling, Timothy M.

Published
2013
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18. Detailed Physiologic Characterization Reveals Diverse Mechanisms for Novel Genetic Loci Regulating Glucose and Insulin Metabolism in Humans

Author

Ingelsson, Erik, Langenberg, Claudia, Hivert, Marie-France, Prokopenko, Inga, Lyssenko, Valeriya, Dupuis, Josée, Mägi, Reedik, Sharp, Stephen, Jackson, Anne U., Assimes, Themistocles L., Shrader, Peter, Knowles, Joshua W., Zethelius, Björn, Abbasi, Fahim A., Bergman, Richard N., Bergmann, Antje, Berne, Christian, Boehnke, Michael, Bonnycastle, Lori L., Bornstein, Stefan R., Buchanan, Thomas A., Bumpstead, Suzannah J., Böttcher, Yvonne, Chines, Peter, Collins, Francis S., Cooper, Cyrus C., Dennison, Elaine M., Erdos, Michael R., Ferrannini, Ele, Fox, Caroline S., Graessler, Jürgen, Hao, Ke, Isomaa, Bo, Jameson, Karen A., Kovacs, Peter, Kuusisto, Johanna, Laakso, Markku, Ladenvall, Claes, Mohlke, Karen L., Morken, Mario A., Narisu, Narisu, Nathan, David M., Pascoe, Laura, Payne, Felicity, Petrie, John R., Sayer, Avan A., Schwarz, Peter E., Scott, Laura J., Stringham, Heather M., Stumvoll, Michael, Swift, Amy J., Syvänen, Ann-Christine, Tuomi, Tiinamaija, Tuomilehto, Jaakko, Tönjes, Anke, Valle, Timo T., Williams, Gordon H., Lind, Lars, Barroso, Inês, Quertermous, Thomas, Walker, Mark, Wareham, Nicholas J., Meigs, James B., McCarthy, Mark I., Groop, Leif, Watanabe, Richard M., and Florez, Jose C.

Published
2010
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26. Evidence of interaction between PPARG2 and HNF4A contributing to variation in insulin sensitivity in Mexican Americans

Author

Black, Mary Helen, Fingerlin, Tasha E., Allayee, Hooman, Zhang, Weiming, Xiang, Anny H., Trigo, Enrique, Hartiala, Jaana, Lehtinen, Allison B., Haffner, Steven M., Bergman, Richard N., McEachin, Richard C., Kjos, Siri L., Lawrence, Jean M., Buchanan, Thomas A., and Watanabe, Richard M.

Subjects
Mexican Americans -- Health aspects -- Genetic aspects, Insulin -- Genetic aspects -- Health aspects, DNA binding proteins -- Health aspects -- Genetic aspects, Health
Abstract

OBJECTIVE--We hypothesized that interaction between PPARG2 Pro12Ala and variants in the promoter region of HNF4A are associated with type 2 diabetes--related quantitative traits in Mexican-American families of a proband with previous gestational diabetes. RESEARCH DESIGN AND METHODS--The BetaGene project genotyped PPARG2 Pro12Ala and nine HNF4A single nucleotide polymorphisms (SNPs) in 473 individuals in 89 families. Members of the proband generation had fasting glucose RESULTS--Neither PPARG2 Pro12Ala nor any of the nine HNF4A SNPs were independently associated with type 2 diabetes-related quantitative traits. However, the interaction between PPARG2 Pro12Ala and HNF4A rs2144908 was significantly associated with both insulin sensitivity ([S.sub.I]) (Bonferroni P = 0.0006) and 2-h insulin (Bonferroni P = 0.039). Subjects with at least one PPARG2 Ala allele and homozygous for the HNF4A rs2144908 A allele had 40% higher [S.sub.I] compared with individuals with at least one G allele. [S.sub.I] did not vary by rs2144908 genotype among PPARG2 Pro/Pro. The interaction result for [S.sub.I] was replicated by the Insulin Resistance Atherosclerosis Family Study (P = 0.018) in their San Antonio sample (n = 484) where subjects with at least one PPARG2 Ala allele and homozygous for the HNF4A rs2144908 A allele had a 29% higher [S.sub.I] compared with individuals with at least one G allele. However, the interaction was not replicated in their San Luis Valley sample (n = 496; P = 0.401). CONCLUSIONS--Together, these results suggest that variation in PPARG2 and HNF4A may interact to regulate insulin sensitivity in Mexican Americans at risk for type 2 diabetes., Mexican-American women with previous gestational diabetes mellitus (GDM) exhibit significant β-cell dysfunction and are at high risk for developing type 2 diabetes (1-3). Moreover, their risk for future type 2 [...]

Published
2008

27. Screening of 134 Single Nucleotide Polymorphisms (SNPs) Previously Associated With Type 2 Diabetes Replicates Association With 12 SNPs in Nine Genes

Author

Willer, Cristen J., Bonnycastle, Lori L., Conneely, Karen N., Duren, William L., Jackson, Anne U., Scott, Laura J., Narisu, Narisu, Chines, Peter S., Skol, Andrew, Stringham, Heather M., Petrie, John, Erdos, Michael R., Swift, Amy J., Enloe, Sareena T., Sprau, Andrew G., Smith, Eboni, Tong, Maurine, Doheny, Kimberly F., Pugh, Elizabeth W., Watanabe, Richard M., Buchanan, Thomas A., Valle, Timo T., Bergman, Richard N., Tuomilehto, Jaakko, Mohlke, Karen L., Collins, Francis S., and Boehnke, Michael

Published
2007

29. Common Variants in Maturity-Onset Diabetes of the Young Genes Contribute to Risk of Type 2 Diabetes in Finns

Author

Bonnycastle, Lori L., Willer, Cristen J., Conneely, Karen N., Jackson, Anne U., Burrill, Cecily P., Watanabe, Richard M., Chines, Peter S., Narisu, Narisu, Scott, Laura J., Enloe, Sareena T., Swift, Amy J., Duren, William L., Stringham, Heather M., Erdos, Michael R., Riebow, Nancy L., Buchanan, Thomas A., Valle, Timo T., Tuomilehto, Jaakko, Bergman, Richard N., Mohlke, Karen L., Boehnke, Michael, and Collins, Francis S.

Published
2006

46. Hepatic lipase gene variant--514C>T is associated with lipoprotein and insulin sensitivity response to regular exercise: the HERITAGE Family Study

Author

Teran-Garcia, Margarita, Santoro, Nicola, Rankinen, Tuomo, Bergeron, Jean, Rice, Treva, Leon, Arthur S., Rao, D.C., Skinner, James S., Bergman, Richard N., Despres, Jean-Pierre, and Bouchard, Claude

Subjects
Lipoproteins -- Observations, Proteolipids -- Observations, Insulin resistance -- Observations, Exercise -- Observations, Health
Abstract

We investigated the associations between the hepatic lipase gene (LIPC) -514C>T polymorphism and lipases, lipoproteins, and insulin sensitivity ([S.sub.i]) responses to exercise training. Hepatic lipase and lipoprotein lipase activities, plasma lipoprotein levels, and [S.sub.i] were measured in the sedentary state and post-exercise training in the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study (n = 662). The LIPC -514C allele frequency was 0.516 (blacks) and 0.796 (whites). Baseline and post-exercise training hepatic lipase activities were 40% higher in CC homozygotes (P < 0.0001) in both races. Black CC homozygotes had lower baseline lipoprotein lipase activity, HDL cholesterol, HD[L.sub.3], and apolipoprotein (apo)A-1 concentrations. White CC homozygotes had lower baseline HDL cholesterol, apoA-1, LDL cholesterol, and apoB levels that remained low post-exercise training. Baseline [S.sub.i] was not associated with the LIPC genotypes. However, training-induced improvements in [S.sub.i] both in blacks and whites were greater in CC homozygotes (+1.25 [+ or -] 0.2 and +0.22 [+ or -] 0.2 [micro]U x min-1 x [ml.sup.-1]) than in the TT genotype (+0.27 [+ or -] 0.3 and -0.97 [+ or -] 0.3 [micro]U x [min.sup.-1] x [ml.sup.-1]) (P = 0.008 and P = 0.002, respectively). The LIPC -514C allele was associated with higher hepatic lipase activity in sedentary and physically active states and better [S.sub.i] responses to regular exercise both in black and white individuals. The benefits from an exercise program on [S.sub.i] are likely to be substantial in the general population given the high frequency of the LIPC -514C allele, particularly in whites., Hepatic lipase hydrolyzes triglyceride and phospholipids from high-, intermediate-, and low-density lipoproteins, transforming them into smaller and denser particles, and promotes the cellular uptake of HDL cholesterol (1). The hepatic [...]

Published
2005

48. Genetic Variation Near the Hepatocyte Nuclear Factor-4α Gene Predicts Susceptibility to Type 2 Diabetes

Author

Silander, Kaisa, Mohlke, Karen L., Scott, Laura J., Peck, Erin C., Hollstein, Pablo, Skol, Andrew D., Jackson, Anne U., Deloukas, Panagiotis, Hunt, Sarah, Stavrides, George, Chines, Peter S., Erdos, Michael R., Narisu, Narisu, Conneely, Karen N., Li, Chun, Fingerlin, Tasha E., Dhanjal, Sharanjeet K., Valle, Timo T., Bergman, Richard N., Tuomilehto, Jaakko, Watanabe, Richard M., Boehnke, Michael, and Collins, Francis S.

Published
2004

49. A Large Set of Finnish Affected Sibling Pair Families With Type 2 Diabetes Suggests Susceptibility Loci on Chromosomes 6, 11, and 14

Author

Silander, Kaisa, Scott, Laura J., Valle, Timo T., Mohlke, Karen L., Stringham, Heather M., Wiles, Kerry R., Duren, William L., Doheny, Kimberly F., Pugh, Elizabeth W., Chines, Peter, Narisu, Narisu, White, Peggy P., Fingerlin, Tasha E., Jackson, Anne U., Li, Chun, Ghosh, Soumitra, Magnuson, Victoria L., Colby, Kimberly, Erdos, Michael R., Hill, Jason E., Hollstein, Pablo, Humphreys, Kathleen M., Kasad, Roshni A., Lambert, Jessica, Lazaridis, Konstantinos N., Lin, George, Morales-Mena, Anabelle, Patzkowski, Kristin, Pfahl, Carrie, Porter, Rachel, Rha, David, Segal, Leonid, Suh, Yong D., Tovar, Jason, Unni, Arun, Welch, Christian, Douglas, Julie A., Epstein, Michael P., Hauser, Elizabeth R., Hagopian, William, Buchanan, Thomas A., Watanabe, Richard M., Bergman, Richard N., Tuomilehto, Jaakko, Collins, Francis S., and Boehnke, Michael

Published
2004

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