{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T15:19:51Z","timestamp":1783178391317,"version":"3.54.6"},"reference-count":41,"publisher":"American Diabetes Association","issue":"9","license":[{"start":{"date-parts":[[2022,6,24]],"date-time":"2022-06-24T00:00:00Z","timestamp":1656028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,9,1]]},"abstract":"<jats:p>Mendelian randomization (MR) suggests that postprandial hyperinsulinemia (unadjusted for plasma glucose) increases BMI, but its impact on cardiometabolic disease, a leading cause for mortality and morbidity in people with obesity, is not established. Fat distribution i.e., increased centripetal and\/or reduced femoro-gluteal adiposity, is causally associated with and better predicts cardiometabolic disease than BMI. We therefore undertook bidirectional MR to assess the effect of corrected insulin response (CIR) (insulin 30 min after a glucose challenge adjusted for plasma glucose) on BMI, waist-to-hip ratio (WHR), leg fat, type 2 diabetes (T2D), triglyceride (TG), HDL, liver fat, hypertension (HTN), and coronary artery disease (CAD) in people of European descent. Inverse variance\u2013weighted MR suggests a potential causal association between increased CIR and increased BMI (b = 0.048 \u00b1 0.02, P = 0.03), increased leg fat (b = 0.029 \u00b1 0.012, P = 0.01), reduced T2D (b = \u22120.73 \u00b1 0.15, P = 6 \u00d7 10\u22127, odds ratio [OR] 0.48 [95% CI 0.36\u20130.64]), reduced TG (b = \u22120.07 \u00b1 0.02, P = 0.003), and increased HDL (b = 0.04 \u00b1 0.01, P = 0.006) with some evidence of horizontal pleiotropy. CIR had neutral effects on WHR (b = 0.009 \u00b1 0.02, P = 0.69), liver fat (b = \u22120.08 \u00b1 0.04, P = 0.06), HTN (b = \u22120.001 \u00b1 0.004, P = 0.7, OR 1.00 [95% CI 0.99\u20131.01]), and CAD (b = \u22120.002 \u00b1 0.002, P = 0.48, OR 0.99 [95% CI 0.81\u20131.21]). T2D decreased CIR (b \u22120.22 \u00b1 0.04, P = 1.3 \u00d7 10\u22127), with no evidence that BMI, TG, HDL, liver fat, HTN, and CAD modulate CIR. In conclusion, we did not find evidence that increased CIR increases cardiometabolic disease. It might increase BMI with favorable fat distribution, reduce T2D, and improve lipids.<\/jats:p>","DOI":"10.2337\/db22-0138","type":"journal-article","created":{"date-parts":[[2022,6,24]],"date-time":"2022-06-24T05:11:56Z","timestamp":1656047516000},"page":"1880-1890","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":3,"title":["Insulin Response to Oral Glucose and Cardiometabolic Disease: A Mendelian Randomization Study to Assess Potential Causality"],"prefix":"10.2337","volume":"71","author":[{"given":"Anthony","family":"Nguyen","sequence":"first","affiliation":[{"name":"1Department of Medicine, University Health Network, and University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rana","family":"Khafagy","sequence":"additional","affiliation":[{"name":"1Department of Medicine, University Health Network, and University of Toronto, Toronto, Canada"},{"name":"2Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Canada"},{"name":"3Divisions of Epidemiology and Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ameena","family":"Meerasa","sequence":"additional","affiliation":[{"name":"1Department of Medicine, University Health Network, and University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delnaz","family":"Roshandel","sequence":"additional","affiliation":[{"name":"2Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew D.","family":"Paterson","sequence":"additional","affiliation":[{"name":"2Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Canada"},{"name":"3Divisions of Epidemiology and Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5167-2099","authenticated-orcid":false,"given":"Satya","family":"Dash","sequence":"additional","affiliation":[{"name":"1Department of Medicine, University Health Network, and University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2022,6,24]]},"reference":[{"key":"2022081918570945200_B1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/dom.14290","article-title":"Obesity as a multisystem disease: trends in obesity rates and obesity-related complications","volume":"23","author":"Sarma","year":"2021","journal-title":"Diabetes Obes Metab"},{"key":"2022081918570945200_B2","doi-asserted-by":"crossref","first-page":"2138","DOI":"10.1007\/s00125-021-05505-4","article-title":"On the causal relationships between hyperinsulinaemia, insulin resistance, obesity and dysglycaemia in type 2 diabetes","volume":"64","author":"Johnson","year":"2021","journal-title":"Diabetologia"},{"key":"2022081918570945200_B3","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1126\/science.aav0448","article-title":"Carbohydrates, insulin, and obesity","volume":"372","author":"Speakman","year":"2021","journal-title":"Science"},{"key":"2022081918570945200_B4","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1373\/clinchem.2017.280727","article-title":"Genetic evidence that carbohydrate-stimulated insulin secretion leads to obesity","volume":"64","author":"Astley","year":"2018","journal-title":"Clin Chem"},{"key":"2022081918570945200_B5","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.2337\/db20-0377","article-title":"Obesity is associated with increased basal and postprandial \u03b2-cell insulin secretion even in the absence of insulin resistance","volume":"69","author":"van Vliet","year":"2020","journal-title":"Diabetes"},{"key":"2022081918570945200_B6","doi-asserted-by":"crossref","first-page":"696","DOI":"10.2337\/diab.43.5.696","article-title":"Early changes in postprandial insulin secretion, not in insulin sensitivity, characterize juvenile obesity","volume":"43","author":"Le Stunff","year":"1994","journal-title":"Diabetes"},{"key":"2022081918570945200_B7","doi-asserted-by":"crossref","first-page":"e34408","DOI":"10.7554\/eLife.34408","article-title":"The MR-Base platform supports systematic causal inference across the human phenome","volume":"7","author":"Hemani","year":"2018","journal-title":"eLife"},{"key":"2022081918570945200_B8","first-page":"E214","article-title":"Glucose clamp technique: a method for quantifying insulin secretion and resistance","volume":"237","author":"DeFronzo","year":"1979","journal-title":"Am J Physiol"},{"key":"2022081918570945200_B9","doi-asserted-by":"crossref","first-page":"241","DOI":"10.2337\/diab.25.4.241","article-title":"Glucose tolerance and insulin release, a mathematical approach I. 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