Genetic Evidence That Carbohydrate-Stimulated Insulin Secretion Leads to Obesity

• Published in: Clinical chemistry (Baltimore, Md.) Vol. 64; no. 1; pp. 192 - 200
• Main 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
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.01.2018
• Subjects: Body Mass Index; Body size; Body weight; Body weight gain; Carbohydrates; Cardiology; Cohort Studies; Dietary Carbohydrates - administration & dosage; Fasting; Genetic diversity; Genetic variance; Genome-Wide Association Study; Glucose; Glucose - administration & dosage; Humans; Hyperinsulinemia; Insulin; Insulin Resistance; Insulin secretion; Insulin Secretion - genetics; Mendelian Randomization Analysis; Models, Biological; Obesity; Obesity - genetics; Obesity - metabolism; Polymorphism, Single Nucleotide; Randomization; Reproducibility of Results; Secretion; Sensitivity analysis; Studies
• ISSN: 0009-9147; 1530-8561
• DOI: 10.1373/clinchem.2017.280727

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. 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. Higher genetically determined insulin-30 was strongly associated with higher BMI (β = 0.098, = 2.2 × 10 ), 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. 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.