Mendelian randomization analyses suggest a causal role for circulating GIP and IL-1RA levels in homeostatic model assessment-derived measures of β-cell function and insulin sensitivity in Africans without type 2 diabetes.

Background: In vitro and in vivo studies have shown that certain cytokines and hormones may play a role in the development and progression of type 2 diabetes (T2D). However, studies on their role in T2D in humans are scarce. We evaluated associations between 11 circulating cytokines and hormones with T2D among a population of sub-Saharan Africans and tested for causal relationships using Mendelian randomization (MR) analyses.

Methods: We used logistic regression analysis adjusted for age, sex, body mass index, and recruitment country to regress levels of 11 cytokines and hormones (adipsin, leptin, visfatin, PAI-1, GIP, GLP-1, ghrelin, resistin, IL-6, IL-10, IL-1RA) on T2D among Ghanaians, Nigerians, and Kenyans from the Africa America Diabetes Mellitus study including 2276 individuals with T2D and 2790 non-T2D individuals. Similar linear regression models were fitted with homeostatic modelling assessments of insulin sensitivity (HOMA-S) and β-cell function (HOMA-B) as dependent variables among non-T2D individuals (n = 2790). We used 35 genetic variants previously associated with at least one of these 11 cytokines and hormones among non-T2D individuals as instrumental variables in univariable and multivariable MR analyses. Statistical significance was set at 0.0045 (0.05/11 cytokines and hormones).

Results: Circulating GIP and IL-1RA levels were associated with T2D. Nine of the 11 cytokines and hormones (exceptions GLP-1 and IL-6) were associated with HOMA-S, HOMA-B, or both among non-T2D individuals. Two-stage least squares MR analysis provided evidence for a causal effect of GIP and IL-RA on HOMA-S and HOMA-B in multivariable analyses (GIP ~ HOMA-S β =  - 0.67, P-value = 1.88 × 10 and HOMA-B β = 0.59, P-value = 1.88 × 10; IL-1RA ~ HOMA-S β =  - 0.51, P-value = 8.49 × 10 and HOMA-B β = 0.48, P-value = 5.71 × 10). IL-RA was partly mediated via BMI (30-34%), but GIP was not. Inverse variance weighted MR analysis provided evidence for a causal effect of adipsin on T2D (multivariable OR = 1.83, P-value = 9.79 × 10), though these associations were not consistent in all sensitivity analyses.

Conclusions: The findings of this comprehensive MR analysis indicate that circulating GIP and IL-1RA levels are causal for reduced insulin sensitivity and increased β-cell function. GIP's effect being independent of BMI suggests that circulating levels of GIP could be a promising early biomarker for T2D risk. Our MR analyses do not provide conclusive evidence for a causal role of other circulating cytokines in T2D among sub-Saharan Africans.