Genetic Evidence That Carbohydrate-Stimulated Insulin Secretion Leads to Obesity. (4th January 2020)

• Record Type: Journal Article
• Authors: Astley, Christina M; Todd, Jennifer N; Salem, Rany M; Vedantam, Sailaja; Ebbeling, Cara B; Huang, Paul L; Ludwig, David S; Hirschhorn, Joel N; Florez, Jose C
• Is Part Of: Clinical chemistry. Volume 64:Number 1(2018)
• Page Start: 192
• Page End: 200
• Publication Date: 2020-01-04
• Subjects: Clinical chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Biochimie -- Périodiques; Diagnostics biologiques -- Périodiques; Biochemistry; Clinical chemistry; Pharmaceutical chemistry; Biochemistry; Laboratory Techniques and Procedures; Klinische chemie; Periodicals; 616.075605
• DOI: 10.1373/clinchem.2017.280727
• Languages: English
• ISSNs: 0009-9147

Abstract

Abstract: BACKGROUND: A fundamental precept of the carbohydrate–insulin model of obesity is that insulin secretion drives weight gain. However, fasting hyperinsulinemia can also be driven by obesity-induced insulin resistance. We used genetic variation to isolate and estimate the potentially causal effect of insulin secretion on body weight. METHODS: Genetic instruments of variation of insulin secretion [assessed as insulin concentration 30 min after oral glucose (insulin-30)] were used to estimate the causal relationship between increased insulin secretion and body mass index (BMI), using bidirectional Mendelian randomization analysis of genome-wide association studies. Data sources included summary results from the largest published metaanalyses of predominantly European ancestry for insulin secretion (n = 26037) and BMI (n = 322154), as well as individual-level data from the UK Biobank (n = 138541). Data from the Cardiology and Metabolic Patient Cohort study at Massachusetts General Hospital (n = 1675) were used to validate genetic associations with insulin secretion and to test the observational association of insulin secretion and BMI. RESULTS: Higher genetically determined insulin-30 was strongly associated with higher BMI (β = 0.098, P = 2.2 × 10 −21 ), consistent with a causal role in obesity. Similar positive associations were noted in sensitivity analyses using other genetic variants as instrumental variables. By contrast, higher genetically determined BMI was not associated with insulin-30. CONCLUSIONS: Mendelian randomization analyses provide evidence for a causal relationship of glucose-stimulated insulin secretion on body weight, consistent with the carbohydrate–insulin model of obesity.