Crosstalk between genetic variability of adiponectin and leptin, glucose-insulin system and subclinical atherosclerosis in patients with newly diagnosed type 2 diabetes. The Verona Newly Diagnosed Type 2 Diabetes Study 14

Abstract

Aim: To evaluate the relationship of genetic variability of adiponectin (ADIPOQ), leptin (LEP) and leptin receptor (LEPR) genes with glucose-insulin system and markers of subclinical atherosclerosis (ATS) in patients with newly diagnosed type 2 diabetes.

Materials and methods: In 794 subjects we performed: 1) euglycemic hyperinsulinemic clamp to assess insulin sensitivity; 2) mathematical modelling of a 5h-OGTT to estimate β-cell function; 3) resting ECG; 4) carotid artery and lower limb artery eco-doppler sonography to identify ATS; 5) genotyping of tag-SNPs within ADIPOQ, LEP and LEPR gene.

Results: Regression analyses showed: 1) adiponectin levels were negatively associated with BMI, waist-to-hip ratio and triglycerides and positively with HDL and insulin sensitivity (p-all<0.03); 2) leptin levels were positively associated with BMI, HDL-cholesterol and plasma triglycerides and negatively with insulin sensitivity (p-all<0.001). Two SNPs (rs1501299 and rs2241767) within ADIPOQ gene were associated with circulating levels of adiponectin. The ADIPOQ-GAACA haplotype was associated with plasma adiponectin (p=0.034; β=-0.24), ECG abnormalities (p=0.012; OR=2.76), carotid ATS (p=0.025; OR=2.00) and peripheral limb artery ATS (p=0.032; OR=1.90). The LEP-CTA haplotype showed an association with ischemic ECG abnormalities (p=0.017; OR=2.24). Finally, LEPR-GAACGG was associated with circulating leptin (p=0.005; β=-0.31) and worst β-cell function (p=0.023; β=-15.10). Omnibus haplotype analysis showed that ADIPOQ haplotypes were associated with levels of adiponectin and common carotid artery ATS, LEP with peripheral limb artery ATS, whereas LEPR haplotypes influenced circulating levels of leptin.

Conclusions: Results of this study reinforce knowledge on adipokines' role in regulating glucose metabolism; in particular highlighted the potential atherogenic role of leptin and the anti atherogenic role of adiponectin.

Keywords: beta-cell function; cardiovascular disease; diabetes complications; insulin secretion; type 2 diabetes mellitus.