Genetic Evidence That Carbohydrate-Stimulated Insulin Secretion Leads to Obesity

Clin Chem. 2018 Jan;64(1):192-200. doi: 10.1373/clinchem.2017.280727.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Body Mass Index
  • Cohort Studies
  • Dietary Carbohydrates / administration & dosage*
  • Fasting
  • Genome-Wide Association Study
  • Glucose / administration & dosage
  • Humans
  • Insulin Resistance
  • Insulin Secretion / genetics*
  • Mendelian Randomization Analysis*
  • Models, Biological
  • Obesity / genetics*
  • Obesity / metabolism*
  • Polymorphism, Single Nucleotide
  • Reproducibility of Results


  • Dietary Carbohydrates
  • Glucose