Investigating the association between fasting insulin, erythrocytosis and HbA1c through Mendelian randomization and observational analyses

Abstract

Background: Insulin resistance (IR)/hyperinsulinemia (HI), are early abnormalities in the etiology of prediabetes (preT2D) and type 2 diabetes (T2D). IR/HI also associate with increased erythrocytosis. Hemoglobin A1c (HbA1c) is commonly used to diagnose and monitor preT2D/T2D, but can be influenced by erythrocytosis independent of glycemi. Methods: We undertook bidirectional Mendelian randomization (MR), in individuals of European ancestry, to investigate potential causal associations between increased fasting insulin adjusted for BMI (FI), erythrocytosis and its non-glycemic impact on HbA1c. We investigated the association between Triglyceride-glucose index (TGI), a surrogate measure of IR/HI, and glycation gap (difference between measured HbA1c and predicted HbA1c derived from linear regression of fasting glucose) in people with normoglycemia and preT2D. Results: Inverse variance weighted MR (IVWMR) suggests increased FI increases haemoglobin (b=0.54+/-0.09, p=2.7 x 10-10), red cell count (RCC, b=0.54+/-0.12, p=5.38x10-6) and reticulocyte (RETIC, b=0.70+/-0.15, p=2.18x10-6). Multivariable MR indicates increased FI does not impact HbA1c (b=0.23+/-0.16, p=0.162) but reduces HbA1c after adjustment for T2D (b=0.31+/-0.13, p=0.016). Increased haemoglobin (b=0.03+/-0.01, p=0.02), RCC (b=0.02+/-0.01, p=0.04) and RETIC (b=0.03+/-0.01, p=0.002) might modestly increase FI. Increased TGI associates with decreased glycation gap, i.e. measured HbA1c was lower than expected based on fasting glucose, (b=-0.09+0.009, p<0.0001) in people with preT2D but not in normoglycemia (b=0.02+0.007, p<0.0001). Conclusions: MR suggests increased FI increases erythrocytosis and might potentially decrease HbA1c by non-glycemic effects. Increased TGI, a surrogate measure of increased FI, associates with lower-than-expected HbA1 in people with preT2D. These findings merit confirmatory studies to evaluate its clinical significance.