Genetic Evidence That Carbohydrate-Stimulated Insulin Secretion Leads to Obesity

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.

Figure 1. Overview of bidirectional Mendelian randomization

(A) Forward analysis estimates the causal effect of insulin secretion on obesity; (B) reverse analysis estimates the causal effect of obesity on insulin secretion. Key assumptions: (1) variants are reliably associated with the intermediate trait, (2) variants affect the outcome only through the intermediate trait, and (3) variants are independent of confounders.

Figure 2. Study overview

We developed and validated instrument sets for glucose-stimulated insulin secretion (GSIS) (A) and body mass index (BMI) (B) using published genome-wide association study data and independent data sets. Three GSIS sets were assembled using narrow and broad trait definitions (insulin-30 or any GSIS) with stringent and relaxed signficiance thresholds (P ≤ 5×10⁻⁸ or 5×10⁻⁵). Instrument sets were used to estimate causal association in the bidirectional Mendelian randomization analyses. SNPs, single nucleotide polymorphisms; Insulin-30, insulin concentration 30 min after oral glucose.

Figure 3. Mendelian randomization effect estimates

Estimates of higher insulin concentration 30 min after oral glucose on body mass index (BMI), using three different instrument sets (insulin-30-stringent, insulin-30-relaxed, and glucose-stimulated insulin secretion [GSIS]-stringent). GIANT, Genetic Investigation of Anthropometric Traits consortium; UKB, United Kingdom Biobank; SE, standard error; SD, standard deviation. “This is an un-copyedited authored manuscript copyrighted by the American Association for Clinical Chemistry (AACC). This may not be duplicated or reproduced, other than for personal use or within the rule of ‘Fair Use of Copyrighted Materials’ (section 107, Title 17, U.S. Code) without permission of the copyright owner, AACC. The AACC disclaims any responsibility or liability for errors or omissions in this version of the manuscript or in any version derived from it by the National Institutes of Health or other parties. The final publisher-authenticated version of the article is available at http://www.clinchem.org.”