OR34-06 Gliclazide Restores Appropriate Glucagon Suppression During OGTT In MODY3 & MODY1 Patients: Results Of The “Glucagon In MODY” Study

Abstract

Abstract Disclosure: I.I. Spiliotis: None. L. Anguelova: None. F. Kavvoura: None. K. Owen: None. Diabetes is a multi-hormone disorder involving both insufficient insulin secretion and aberrant glucagon secretion. MODY (Maturity Onset Diabetes of the Young) is a subgroup of diabetes which is caused by mutations in specific genes including HNF1A (MODY3) and HNF4A (MODY1). Most MODY3 or MODY1 patients are managed in the UK with the sulfonylurea gliclazide at a starting dose of around 20-40mg (vs. 80mg - 320mg daily for managing type 2 diabetes). It remains unclear clear why this population is particularly sensitive to gliclazide, and there is limited information on glucagon levels in these patients. The ”Glucagon in MODY” study was a non-randomized interventional pilot study (NCT03246828), aiming to investigate whether fasting and post-prandial glucagon levels are raised in MODY3 & MODY1 patients, and whether gliclazide treatment leads to more physiological glucose-induced glucagon suppression in this population. Methods: We recruited 10 patients from MODY clinics, whose diabetes was managed with gliclazide +/- metformin only at the time of the study. They each underwent a 2h 75g oral glucose tolerance test (OGTT) before and after omitting their gliclazide for 3 days. Blood samples were taken at 30min intervals for glucose, c-peptide and glucagon. Paired t-test was used to compare baseline fasting values on and off gliclazide, and two-way repeated measures ANOVA with post-hoc multiple comparisons was used to compare the OGTT timepoints versus baseline. Results: Study population characteristics were as follows (median ±CI): age 46±9.8, 6 females, BMI 23.9±1.1, HbA1c 52.5±13.6mmol/mol, gliclazide dose 60±29mg per day; 6 MODY3 and 4 MODY1. Fasting blood glucose values were significantly elevated off gliclazide (p<0.001) and rose by an average of 10mmol/L during the OGTT, as expected in this population; however two-way ANOVA did not show a significant difference on vs. off gliclazide. Neither fasting c-peptide nor glucagon values were significantly different on vs. off gliclazide, and while c-peptide rose in both groups, glucagon levels were only suppressed at 60min on gliclazide (p=0.035). When c-peptide and glucagon values were corrected for blood glucose levels during the OGTT, there was no significant change from baseline in c-peptide values on vs off gliclazide. However, glucagon values were significantly decreased on gliclazide from 60min onwards (p<0.01), and there was no correlation with corrected c-peptide values (p=0.2). Conclusion: In our limited study population of 6 MODY3 and 4 MODY1 patients, gliclazide appears to restore appropriate glucose-induced glucagon suppression during a 75g OGTT, which is not related to changes in c-peptide levels. This suggests that pancreatic alpha-cell regulation may be a previously unrecognized mechanism by which sulfonylurea treatment improves glycemic control in MODY. Presentation: Sunday, June 18, 2023