In:
Clinical Chemistry, Oxford University Press (OUP), Vol. 64, No. 1 ( 2018-01-01), p. 192-200
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0009-9147
,
1530-8561
DOI:
10.1373/clinchem.2017.280727
Language:
English
Publisher:
Oxford University Press (OUP)
Publication Date:
2018
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