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Genetic Evidence That Carbohydrate-Stimulated Insulin Secretion Leads to Obesity.

  • Author(s): 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
  • et al.

Published Web Location

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5937525/
No data is associated with this publication.
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.

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