{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T16:34:11Z","timestamp":1792427651021,"version":"4.5.0"},"reference-count":35,"publisher":"American Diabetes Association","issue":"12","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,12,1]]},"abstract":"<jats:p>The mechanisms that predispose to hypertension, coronary artery disease (CAD), and type 2 diabetes (T2D) in individuals of normal weight are poorly understood. In contrast, in monogenic primary lipodystrophy\u2014a reduction in subcutaneous adipose tissue\u2014it is clear that it is adipose dysfunction that causes severe insulin resistance (IR), hypertension, CAD, and T2D. We aimed to test the hypothesis that common alleles associated with IR also influence the wider clinical and biochemical profile of monogenic IR. We selected 19 common genetic variants associated with fasting insulin\u2013based measures of IR. We used hierarchical clustering and results from genome-wide association studies of eight nondisease outcomes of monogenic IR to group these variants. We analyzed genetic risk scores against disease outcomes, including 12,171 T2D cases, 40,365 CAD cases, and 69,828 individuals with blood pressure measurements. Hierarchical clustering identified 11 variants associated with a metabolic profile consistent with a common, subtle form of lipodystrophy. A genetic risk score consisting of these 11 IR risk alleles was associated with higher triglycerides (\u03b2 = 0.018; P = 4 \u00d7 10\u221229), lower HDL cholesterol (\u03b2 = \u22120.020; P = 7 \u00d7 10\u221237), greater hepatic steatosis (\u03b2 = 0.021; P = 3 \u00d7 10\u22124), higher alanine transaminase (\u03b2 = 0.002; P = 3 \u00d7 10\u22125), lower sex-hormone-binding globulin (\u03b2 = \u22120.010; P = 9 \u00d7 10\u221213), and lower adiponectin (\u03b2 = \u22120.015; P = 2 \u00d7 10\u221226). The same risk alleles were associated with lower BMI (per-allele \u03b2 = \u22120.008; P = 7 \u00d7 10\u22128) and increased visceral-to-subcutaneous adipose tissue ratio (\u03b2 = \u22120.015; P = 6 \u00d7 10\u22127). Individuals carrying \u226517 fasting insulin\u2013raising alleles (5.5% population) were slimmer (0.30 kg\/m2) but at increased risk of T2D (odds ratio [OR] 1.46; per-allele P = 5 \u00d7 10\u221213), CAD (OR 1.12; per-allele P = 1 \u00d7 10\u22125), and increased blood pressure (systolic and diastolic blood pressure of 1.21 mmHg [per-allele P = 2 \u00d7 10\u22125] and 0.67 mmHg [per-allele P = 2 \u00d7 10\u22124], respectively) compared with individuals carrying \u22649 risk alleles (5.5% population). Our results provide genetic evidence for a link between the three diseases of the \u201cmetabolic syndrome\u201d and point to reduced subcutaneous adiposity as a central mechanism.<\/jats:p>","DOI":"10.2337\/db14-0318","type":"journal-article","created":{"date-parts":[[2014,7,21]],"date-time":"2014-07-21T21:32:56Z","timestamp":1405978376000},"page":"4369-4377","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":215,"title":["Genetic Evidence for a Normal-Weight \u201cMetabolically Obese\u201d Phenotype Linking Insulin Resistance, Hypertension, Coronary Artery Disease, and Type 2 Diabetes"],"prefix":"10.2337","volume":"63","author":[{"given":"Hanieh","family":"Yaghootkar","sequence":"first","affiliation":[{"name":"Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Scott","sequence":"additional","affiliation":[{"name":"MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles C.","family":"White","sequence":"additional","affiliation":[{"name":"Framingham Heart Study, National Heart, Lung, and Blood Institute, National Institutes of Health, Framingham, MA"},{"name":"Department of Biostatistics, Boston University School of Public Health, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Speliotes","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Gastroenterology, and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia B.","family":"Munroe","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg B.","family":"Ehret","sequence":"additional","affiliation":[{"name":"Cardiology Center, Geneva University Hospital, Geneva, Switzerland"},{"name":"Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua C.","family":"Bis","sequence":"additional","affiliation":[{"name":"Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline S.","family":"Fox","sequence":"additional","affiliation":[{"name":"Framingham Heart Study, National Heart, Lung, and Blood Institute, National Institutes of Health, Framingham, MA"},{"name":"Center for Population Studies, National Heart, Lung, and Blood Institute, National Institutes of Health, Framingham, MA"},{"name":"Division of Endocrinology, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Walker","sequence":"additional","affiliation":[{"name":"Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid B.","family":"Borecki","sequence":"additional","affiliation":[{"name":"Department of Genetics, Washington University School of Medicine, St. Louis, MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua W.","family":"Knowles","sequence":"additional","affiliation":[{"name":"Department of Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Yerges-Armstrong","sequence":"additional","affiliation":[{"name":"University of Maryland School of Medicine, Division of Endocrinology, Baltimore, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claes","family":"Ohlsson","sequence":"additional","affiliation":[{"name":"Center for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.B.","family":"Perry","sequence":"additional","affiliation":[{"name":"MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Chambers","sequence":"additional","affiliation":[{"name":"Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaspal S.","family":"Kooner","sequence":"additional","affiliation":[{"name":"Cardiovascular Science, National Heart and Lung Institute, Imperial College London, London, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nora","family":"Franceschini","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Langenberg","sequence":"additional","affiliation":[{"name":"MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge, U.K."},{"name":"Department of Epidemiology and Public Health, University College London, London, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-France","family":"Hivert","sequence":"additional","affiliation":[{"name":"Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, MA"},{"name":"General Medicine Division, Massachusetts General Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zari","family":"Dastani","sequence":"additional","affiliation":[{"name":"Departments of Human Genetics and Epidemiology and Biostatistics, McGill University, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Brent","family":"Richards","sequence":"additional","affiliation":[{"name":"Department of Twin Research and Genetic Epidemiology, King\u2019s College London, London, U.K."},{"name":"Department of Medicine, Human Genetics, Epidemiology, and Biostatistics, McGill University, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert K.","family":"Semple","sequence":"additional","affiliation":[{"name":"The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, U.K."},{"name":"The University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy M.","family":"Frayling","sequence":"additional","affiliation":[{"name":"Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2014,11,13]]},"reference":[{"key":"2022050211212490700_B1","doi-asserted-by":"crossref","first-page":"699","DOI":"10.2337\/diabetes.47.5.699","article-title":"The metabolically obese, normal-weight individual revisited","volume":"47","author":"Ruderman","year":"1998","journal-title":"Diabetes"},{"key":"2022050211212490700_B2","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1093\/ajcn\/34.8.1617","article-title":"The \u201cmetabolically-obese,\u201d normal-weight individual","volume":"34","author":"Ruderman","year":"1981","journal-title":"Am J Clin Nutr"},{"key":"2022050211212490700_B3"},{"key":"2022050211212490700_B4","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1210\/er.2010-0020","article-title":"Genetic syndromes of severe insulin resistance","volume":"32","author":"Semple","year":"2011","journal-title":"Endocr 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