Genotype-phenotype correlations and response to glucose lowering therapy in subjects with HNF1β associated diabetes.

AIMS: Molecular defects of hepatic nuclear factor 1β (HNF1β) are associated with multiorgan disease (renal disease, pancreatic hypoplasia, and genital tract anomalies) in addition to diabetes. We examined the phenotypic features, insulin secretory response to glucose, and response to treatment in subjects with HNF1β-MODY (MODY 5).

METHODS

Twelve subjects with HNF1β-MODY were phenotyped in detail. A 2-h oral glucose tolerance test was performed to establish insulin secretory response with glucose, insulin and C-peptide measurements taken at baseline and 30 min intervals. Clinical follow-up occurred bi-annually.

RESULTS

Ten of 12 subjects had diabetes with mean age of onset of 30.2 ± 15.5 years, fasting glucose of 9.7 ± 4.6 mmol/L and HbA1c of 60.9 ± 17.1 mmol/mol (7.7 ± 1.6%). Renal and/or pancreatic morphological abnormalities were found in 9 subjects. Mean fasting C-peptide (0.5 ± 0.4 nmol/L) and AUC C-peptide (1.5 ± 1.0 nmol/L/120 min) were reduced in our cohort with 4 subjects demonstrating marked insulin deficiency. OGIS was reduced at 290.2 ± 67.0 ml min-1 m-2. 6/10 subjects were on insulin therapy at initial diagnosis and 8/10 at last clinical follow-up. Mean insulin dose at last clinical follow-up was 0.45 ± 0.23units/kg/day. 5 subjects on insulin were trialled on sulphonylurea therapy, and none was successfully weaned off insulin.

CONCLUSIONS

Diagnosing HNF1β-MODY in a diabetes clinic is challenging due to its variable phenotype and variable age of onset. β-Cell dysfunction and insulin resistance contribute to diabetes in HNF1β-MODY. No subjects successfully transitioned to sulphonylurea. Early initiation of insulin therapy would be suitable to achieve glycaemic control. This emphasizes the importance of genetic testing for monogenic forms of diabetes to guide personalized treatment.