{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T10:37:20Z","timestamp":1790246240846,"version":"4.1.0"},"reference-count":42,"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>We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterize their association with intermediate phenotypes, and to investigate their role in type 2 diabetes (T2D) risk among normal-weight, overweight, and obese individuals. We investigated the association of genetic scores with euglycemic-hyperinsulinemic clamp\u2013 and oral glucose tolerance test\u2013based measures of insulin resistance and secretion and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight, and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M\/I value (\u03b2 in SDs per allele [95% CI], \u22120.03 [\u22120.04, \u22120.01]; P = 0.004). This score was associated with lower BMI (\u22120.01 [\u22120.01, \u22120.0]; P = 0.02) and gluteofemoral fat mass (\u22120.03 [\u22120.05, \u22120.02; P = 1.4 \u00d7 10\u22126) and with higher alanine transaminase (0.02 [0.01, 0.03]; P = 0.002) and \u03b3-glutamyl transferase (0.02 [0.01, 0.03]; P = 0.001). While the secretion score had a stronger association with T2D in leaner individuals (Pinteraction = 0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI or waist strata (Pinteraction &amp;gt; 0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size.<\/jats:p>","DOI":"10.2337\/db14-0319","type":"journal-article","created":{"date-parts":[[2014,6,20]],"date-time":"2014-06-20T06:59:58Z","timestamp":1403247598000},"page":"4378-4387","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":160,"title":["Common Genetic Variants Highlight the Role of Insulin Resistance and Body Fat Distribution in Type 2 Diabetes, Independent of Obesity"],"prefix":"10.2337","volume":"63","author":[{"given":"Robert A.","family":"Scott","sequence":"first","affiliation":[{"name":"MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge Biomedical Campus, University of Cambridge School of 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