Influence of Insulin Receptor Single Nucleotide Polymorphisms on Glycaemic Control and Formation of Anti-Insulin Antibodies in Diabetes Mellitus

Abstract

Single nucleotide polymorphisms (SNPs) in insulin and insulin receptor genes may influence the interaction between the two molecules, as may anti-insulin antibodies (IAs), commonly found in patients with type 1 diabetes mellitus (T1D) or type 2 diabetes mellitus (T2D) treated with exogenous insulin. We examined the impact of two SNPs in the human insulin gene (INS), rs3842752 and rs689, and two in the insulin receptor gene (INSR) rs2245649 and rs2229429, on disease susceptibility, glycaemic control, and IAs formation in 100 T1D patients and 101 T2D patients treated with insulin. 79 individuals without diabetes were typed as healthy controls. The minor alleles of rs3842752 and rs689 in INS protected against T1D (OR: 0.50, p = 0.01 and OR: 0.44; p = 0.002, respectively). The minor alleles of both rs2245649 and rs2229429 in INSR were risk factors for poor glycaemic control (HbA1c ≥ 80 mmol/mol) in T1D (OR: 5.35, p = 0.009 and OR: 3.10, p = 0.01, respectively). Surprisingly, the minor alleles of rs2245649 and rs2229429 in INSR associated strongly with the absence of IAs in T1D (OR = 0.28, p = 0.008 and OR = 0.30, p = 0.002, respectively). In conclusion, the minor alleles of the investigated INS SNPs protect against T1D, and the minor alleles of the investigated INSR SNPs are associated with poor glycaemic control and the absence of IAs in T1D.

Keywords: anti-insulin antibodies (IAs) single nucleotide polymorphisms (SNPs); diabetes; glycaemic control; insulin receptor.

Figure 1

Serum HbA1c levels by INSR SNPs genotypes. HbA1c levels (mmol/mol) of patients with T1D (n = 82, white bars) and patients with T2D (n = 92, grey bars) by genotype distribution of (A) INSR rs2245649 and (B) rs2229429. Trend test was performed with linear regression, adjusted for age, sex, BMI, and insulin dosage.

Figure 2

Serum sIR levels by HbA1c levels and INSR SNPs genotypes. Shown are serum sIR levels of patients with T1D (n = 82, white bars) and patients with T2D (n = 94, grey bars) in relation to (A) HbA1c levels (mmol/mol), (B) INSR rs2245649 and (C) INSR rs2229429. Trend tests and comparisons between T1D and T2D were performed with linear regression, adjusted for age and sex, * p ≤ 0.05.

Figure 3

Anti-insulin antibody (IA) titres by INSR SNPs genotype. Shown are IA titres for patients with T1D (n = 100, white bars) and patients with T2D (n = 101, grey bars) in relation to the genotype distributions for (A) INSR rs2245649 and (B) rs2229429. Trend test performed by logistic regression with adjustment for age and sex. Trend tests and comparisons between T1D and T2D by genotype were performed with linear regression, adjusted for age and sex, ** p ≤ 0.01.