Fucosylated AGP glycopeptides as biomarkers of HNF1A-Maturity onset diabetes of the young.

AIMS: We previously demonstrated that antennary fucosylated N-glycans on plasma proteins are regulated by HNF1A and can identify cases of Maturity-Onset Diabetes of the Young caused by HNF1A variants (HNF1A-MODY). Based on literature data, we further postulated that N-glycans with best diagnostic value mostly originate from alpha-1-acid glycoprotein (AGP). In this study we analyzed fucosylation of AGP in subjects with HNF1A-MODY and other types of diabetes aiming to evaluate its diagnostic potential. METHODS: A recently developed LC-MS method for AGP N-glycopeptide analysis was utilized in two independent cohorts: a) 466 subjects with different diabetes subtypes to test the fucosylation differences, b) 98 selected individuals to test the discriminative potential for pathogenic HNF1A variants. RESULTS: Our results showed significant reduction in AGP fucosylation associated to HNF1A-MODY when compared to other diabetes subtypes. Additionally, ROC curve analysis confirmed significant discriminatory potential of individual fucosylated AGP glycopeptides, where the best performing glycopeptide had an AUC of 0.94 (95% CI 0.90-0.99). CONCLUSIONS: A glycopeptide based diagnostic tool would be beneficial for patient stratification by providing information about the functionality of HNF1A. It could assist the interpretation of DNA sequencing results and be a useful addition to the differential diagnostic process.

Maturity onset diabetes of the young type 2 (MODY2): Insight from an extended family.

AIMS: To assess long-term outcome of patients with maturity onset diabetes of the young, type 2 (MODY2) in a unique large cohort of patients with the same genetic and environmental background. METHODS: We prospectively evaluated 162 patients aged 5 to 82 years, belonging to the same extended family living in the same village. All patients underwent molecular testing for the glucokinase (GCK) gene mutation identified in the proband, and were categorized into three groups (MODY2, type 2 diabetes and controls). RESULTS: The 5.5-year-old proband had the c.1278_1286del mutation in the GCK and was diagnosed with MODY2. Forty-two out of 162 participants were positive for the mutation and 39 had type 2 diabetes. Patients were followed for a mean 10.2 ± 3.7 years (range 0-14). Mean fasting blood glucose and HbA1c increased significantly over the years in MODY2 patients (133 vs. 146 mg/dL; 6.9% vs. 8.2%, respectively). Increase in HbA1c occurred only in the obese/overweight subgroups. Twenty-five percent of MODY2 patients developed diabetes complications, all were above 40 years of age. CONCLUSIONS: Although MODY2 commonly has a benign disease course, weight gain is a risk factor for diabetes complications, requiring life-long follow-up and in some patients, medical intervention.