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

Anthony Nguyen; Rana Khafagy; Habiba Hashemy; Kevin H M Kuo; Delnaz Roshandel; Andrew D Paterson; Satya Dash

doi:10.3389/fendo.2023.1146099

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

Front Endocrinol (Lausanne). 2023 Mar 17:14:1146099. doi: 10.3389/fendo.2023.1146099. eCollection 2023.

Authors

Anthony Nguyen¹, Rana Khafagy^{1

2

3}, Habiba Hashemy¹, Kevin H M Kuo^{4

5

6}, Delnaz Roshandel², Andrew D Paterson^{2

3}, Satya Dash¹

Affiliations

¹ Department of Medicine, University Health Network, University of Toronto, Toronto, ON, Canada.
² Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
³ Divisions of Epidemiology and Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
⁴ Division of Medical Oncology and Haematology, Department of Medicine, University Health Network, Toronto, ON, Canada.
⁵ Division of Haematology, Department of Medicine, University of Toronto, Toronto, ON, Canada.
⁶ Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.

Abstract

Background: Insulin resistance (IR) with associated compensatory hyperinsulinemia (HI) are early abnormalities in the etiology of prediabetes (preT2D) and type 2 diabetes (T2D). IR and HI also associate with increased erythrocytosis. Hemoglobin A1c (HbA1c) is commonly used to diagnose and monitor preT2D and T2D, but can be influenced by erythrocytosis independent of glycemia.

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 the triglyceride-glucose index (TGI), a surrogate measure of IR and 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) suggested that increased FI increases hemoglobin (Hb, 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 indicated that increased FI did not impact HbA1c (b=0.23 ± 0.16, p=0.162) but reduced HbA1c after adjustment for T2D (b=0.31 ± 0.13, p=0.016). Increased Hb (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. In the observational cohort, increased TGI associated 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 those with 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 HbA1c in people with preT2D. These findings merit confirmatory studies to evaluate their clinical significance.

Keywords: erythrocytosis; hemoglobin A1c; hyperinsulinemia; insulin resistance; type 2 diabetes (T2D).

Publication types

Observational Study
Research Support, Non-U.S. Gov't

MeSH terms

Blood Glucose
Carcinoma, Renal Cell*
Diabetes Mellitus, Type 2* / diagnosis
Diabetes Mellitus, Type 2* / genetics
Fasting
Glucose
Glycated Hemoglobin
Humans
Hyperinsulinism*
Insulin
Insulin Resistance*
Kidney Neoplasms*
Mendelian Randomization Analysis
Polycythemia* / genetics

Substances

Blood Glucose
Glucose
Glycated Hemoglobin
Insulin

Grants and funding

175041/CRUK_/Cancer Research UK/United Kingdom