Less but better: cardioprotective lipid profile of patients with GCK-MODY despite lower HDL cholesterol level

Wojciech Fendler,Maciej Banach,Agnieszka Szadkowska,Manfredi Rizzo,Malgorzata Urbanska-Kosinska,Maciej Borowiec,Karolina Antosik,Beata Malachowska,Magdalena Szopa,Maciej Malecki,Wojciech Mlynarski

doi:10.1007/s00592-014-0567-1

Abstract

Patients with diabetes caused by single-gene mutations generally exhibit an altered course of diabetes. Those with mutations of the glucokinase gene (GCK-MODY) show good metabolic control and low risk of cardiovascular complications despite paradoxically lowered high-density lipoprotein (HDL) cholesterol levels. In order to investigate the matter, we analyzed the composition of low-density lipoprotein (LDL) and HDL subpopulations in such individuals. The LipoPrint© system (Quantimetrix, USA) based on non-denaturing, linear polyacrylamide gel electrophoresis was used to separate and measure LDL and HDL subclasses in fresh-frozen serum samples from patients with mutations of glucokinase or HNF1A, type 1 diabetes (T1DM) and healthy controls. Fresh serum samples from a total of 37 monogenic diabetes patients (21 from GCK-MODY and 16 from HNF1A-MODY), 22 T1DM patients and 15 healthy individuals were measured in this study. Concentrations of the small, highly atherogenic LDL subpopulation were similar among the compared groups. Large HDL percentage was significantly higher in GCK-MODY than in control (p = 0.0003), T1DM (p = 0.0006) and HNF1A-MODY groups (p = 0.0246). Patients with GCK-MODY were characterized by significantly lower intermediate HDL levels than controls (p = 0.0003) and T1DM (p = 0.0005). Small, potentially atherogenic HDL content differed significantly with the GCK-MODY group showing concentrations of that subfraction from control (p = 0.0096), T1DM (p = 0.0193) and HNF1A-MODY (p = 0.0057) groups. Within-group heterogeneity suggested the existence of potential gene–gene or gene–environment interactions. GCK-MODY is characterized by a strongly protective profile of HDL cholesterol subpopulations. A degree of heterogeneity within the groups suggests the existence of interactions with other genetic or clinical factors.

Highlights

Dyslipidemia is considered as a traditional risk component for the metabolic syndrome, its qualitative aspects, genetically determined subfractions and variation in proatherogenic tendency have generated renewed interest and debate [1]
Large high-density lipoprotein (HDL) percentage was significantly higher in GCK-MODY than in control (p = 0.0003), T1DM (p = 0.0006) and HNF1A-MODY groups (p = 0.0246)
Patients with GCK-MODY were characterized by significantly lower intermediate HDL levels than controls (p = 0.0003) and T1DM (p = 0.0005)

Summary

Introduction

Dyslipidemia is considered as a traditional risk component for the metabolic syndrome, its qualitative aspects, genetically determined subfractions and variation in proatherogenic tendency have generated renewed interest and debate [1]. Acta Diabetol (2014) 51:625–632 were reported in diabetes caused by single-gene mutations in children and young adults [2, 3] These studies reported differences in apolipoprotein and HDL (high-density lipoprotein) cholesterol levels. Patients with diabetes caused by mutations of the glucokinase gene (GCKMODY), who generally do not experience increased risk of cardiovascular (CV) events despite being diagnosed with diabetes, were shown to have lower levels of HDL than healthy controls [3]. This somewhat counterintuitive observation leads us to investigate the detailed composition of low-density lipoprotein (LDL) and HDL subpopulations in sera of adolescents and young adults with diabetes of autoimmune and monogenic background. Should patients with GCK-MODY exhibit an altered composition of lipid subfractions, one may speculate that some of them would be candidates for the use of lipidlowering agents

Methods

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Conclusion