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

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

Author information

1
Department of Medicine, Division of Endocrinology, Boston Children's Hospital, Boston, MA.
2
Departments of Medicine and Pediatrics, Harvard Medical School, Boston, MA.
3
Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA.
4
Diabetes Unit and Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA.
5
Department of Family Medicine and Public Health, University of California, San Diego, CA.
6
Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA.
7
Department of Medicine, Division of Endocrinology, Boston Children's Hospital, Boston, MA; joelh@broadinstitute.org david.ludwig@childrens.harvard.edu jcflorez@mgh.harvard.edu.
8
Departments of Medicine and Pediatrics, Harvard Medical School, Boston, MA; joelh@broadinstitute.org david.ludwig@childrens.harvard.edu jcflorez@mgh.harvard.edu.

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.

PMID:
29295838
PMCID:
PMC5937525
DOI:
10.1373/clinchem.2017.280727
[Indexed for MEDLINE]
Free PMC Article

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