Intima-media thickness and endothelial dysfunction in GCK and HNF1A-MODY patients

Abstract

Objective: Mutations in the glucokinase (GCK) gene, along with hepatocyte nuclear factor 1A (HNF1A) gene mutations, are the most frequent cause of maturity-onset diabetes of the young (MODY). GCK-MODY patients are typically characterized by a moderate fasting hyperglycemia; however, little is known about atherosclerosis and intermediate-related phenotypes in these subjects. Design: To examine carotid artery intima-media thickness (IMT) and endothelial function assessed by brachial artery flow-mediated dilatation (FMD) in GCK gene mutations carriers and HNF1A-MODY. Methods: A total of 64 subjects with GCK gene mutations, and 52 HNF1A gene mutation carriers as well as 53 nondiabetic controls were examined. IMT and FMD were assessed by ultrasonography. Appropriate statistical tests were performed to assess differences between the groups, and multivariate linear regression was done for the association with IMT and FMD. Results: The clinical characteristics of all groups were similar with the mean age at examination of 35.1, 41.1, and 39.5 years for GCK, HNF1A and the control group respectively. The highest mean IMT value was in the HNF1A-MODY group: 7.0G1.4 mm, whereas it reached 6.3G1.4 mm in GCK mutation carriers and 6.3G1.3 mm in controls (PZ0.008). After adjustment for possible clinical and biochemical cofounders, IMT remained higher in HNF1A-MODY patients as compared with GCK-MODY patients (PZ0.02) and controls (PZ0.0003). FMD was significantly lower in HNF1A (9.9G4.6%) and GCK-MODY (11.1G4.6%) patients in comparison with controls (13.9G4.7%; PZ0.0001). After adjustment, FMD remained lower in HNF1A-MODY (PZ0.0005) and GCK-MODY patients (PZ0.01) as compared with controls. Conclusions: Both examined MODY groups demonstrated evidence of endothelial dysfunction. In addition, HNF1-MODY patients seem to be more prone to an early atherosclerotic phenotype.

Quality of life assessment in patients with HNF1A-MODY and GCK-MODY

“…We attempted to contact all adult patients who had been registered in our MODY patient database over approximately the last 15 years [11]. We initially considered 130 diabetic patients with HNF1A-MODY and 128 subjects with GCK-MODY mutations.…”

“…The pathogenicity of mutations was determined based on earlier published reports, DNA sequencedifference biological character, and co-segregation with diabetes within the families. The ascertainment criteria and genetic testing procedures for MODY were as previously described [11]. Subjects were defined as having T1DM if they had typical clinical symptoms at diagnosis, an insulin therapy requirement from the beginning of the disease, and were diagnosed prior to the age of 30 with diabetes.…”

A single dose of dapagliflozin, an SGLT-2 inhibitor, induces higher glycosuria in GCK- and HNF1A-MODY than in type 2 diabetes mellitus

“…They usually do not develop advanced chronic microvascular complications of diabetes, although, the prevalence of background retinopathy is rather high, reaching 30% according to British data [12]. Moreover, there is also some evidence on abnormalities in surrogate cardiovascular outcomes in GCK mutation carriers [13]. Therefore, clinicians would probably consider initiation of treatment in some GCK-MODY patients.…”

Assessment of Newly Proposed Clinical Criteria to IdentifyHNF1AMODY in Patients with an Initial Diagnosis of Type 1 or Type 2 Diabetes Mellitus

“…Subjects diagnosed with either T1DM or T2DM were preselected and ascertained as previously defined [ 6 , 7 ]. All patients underwent molecular testing at the Department of Metabolic Diseases, Medical College, Jagiellonian University, Krakow, Poland [ 8 ]. The study was approved by the Bioethical Committee of Jagiellonian University.…”