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

Abstract

AbstractBackgroundInsulin 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.MethodsWe 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.ResultsInverse variance weighted MR (IVWMR) suggests increased FI increases haemoglobin (b=0.54+/-0.09, p=2.7 × 10-10), red cell count (RCC, b=0.54+/-0.12, p=5.38×10-6) and reticulocyte (RETIC, b=0.70+/-0.15, p=2.18×10-6). 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).ConclusionsMR 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.