| Title: | Genetic Evidence That Carbohydrate-Stimulated Insulin Secretion Leads to Obesity |
| Journal: | Clinical Chemistry |
| Published: | 1 Jan 2018 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/29295838/ |
| DOI: | https://doi.org/10.1373/clinchem.2017.280727 |
| URL: | https://academic.oup.com/clinchem/article-pdf/64/1/192/32642428/clinchem0192.pdf |
Publication 13726
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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.</p>
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.</p>
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.</p>
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.</p>
14 Keywords
- Body Mass Index
- Cohort Studies
- Dietary Carbohydrates
- Fasting
- Genome-Wide Association Study
- Glucose
- Humans
- Insulin Resistance
- Insulin Secretion
- Mendelian Randomization Analysis
- Models, Biological
- Obesity
- Polymorphism, Single Nucleotide
- Reproducibility of Results
9 Authors
- Christina M Astley
- Jennifer N Todd
- Rany M Salem
- Sailaja Vedantam
- Cara B Ebbeling
- Paul L Huang
- David S Ludwig
- Joel N Hirschhorn
- Jose C Florez
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