Longitudinal progression of diabetes mellitus in Wolfram syndrome: The Washington University Wolfram Research Clinic experience

Abstract

Objective: (1) Describe the progression of diabetes mellitus over time in an observational study of Wolfram syndrome, a rare, genetic, neurodegenerative disorder, which often includes diabetes mellitus and is typically diagnosed during childhood or adolescence. (2) Determine whether C-peptide could be used as a marker of diabetes progression in interventional trials for Wolfram syndrome.

Methods: N = 44 (25F/19M) participants with genetically confirmed Wolfram syndrome attended the Washington University Wolfram Research Clinic annually from 2010 to 2019. Medical history, physical examinations, blood sampling, and questionnaires were used to collect data about diabetes mellitus and other components of Wolfram syndrome. Beta-cell function was assessed by determination of C-peptide during a mixed meal tolerance test. Random coefficients models evaluated the rate of progression of C-peptide over time, and power analyses were used to estimate the number of subjects needed to detect a change in C-peptide decline during an intervention trial.

Results: 93.2% of patients had diabetes mellitus. Mean HbA1c across all study visits was 7.9%. C-peptide significantly decreased with increasing duration of diabetes mellitus (p < 0.0001); an optimal break point in C-peptide decline was identified to occur between 0.1 and 2.3 years after diabetes mellitus diagnosis. Twenty patients per group (active vs. control) were estimated to be needed to detect a 60% slowing of C-peptide decline during the first 2.3 years following diabetes diagnosis.

Conclusion: C-peptide declines over time in Wolfram syndrome and could potentially be used as a marker of diabetes progression in interventional studies for Wolfram syndrome, especially within the first 2 years after diabetes diagnosis.

Keywords: C-peptide; DIDMOAD; Hb A1c; neurodegenerative disease.

Figure 1.

Scatterplot of A) raw data for peak C-peptide and B) log-transformed data for peak C-peptide, over time (measured as diabetes duration at current clinic) in patients with diabetes mellitus. Each trajectory profile represents an individual participant’s peak C-peptide levels over time. Each dot represents an individual data point for peak C-peptide measured at a participant’s clinic visit with a line connecting data points for that participant over the duration of their diabetes mellitus. A) The dashed red line represents the time point at which diabetes began. The data to the left of the red line represents C-peptide levels for the participant who developed diabetes mellitus during the study. Pre-diabetes mellitus diagnosis data was not included in the random coefficients model. A&B) The purple arrow represents the optimal breakpoint (2.3 years) at which the slope for C-peptide decline changes.

Figure 1.

Scatterplot of A) raw data for peak C-peptide and B) log-transformed data for peak C-peptide, over time (measured as diabetes duration at current clinic) in patients with diabetes mellitus. Each trajectory profile represents an individual participant’s peak C-peptide levels over time. Each dot represents an individual data point for peak C-peptide measured at a participant’s clinic visit with a line connecting data points for that participant over the duration of their diabetes mellitus. A) The dashed red line represents the time point at which diabetes began. The data to the left of the red line represents C-peptide levels for the participant who developed diabetes mellitus during the study. Pre-diabetes mellitus diagnosis data was not included in the random coefficients model. A&B) The purple arrow represents the optimal breakpoint (2.3 years) at which the slope for C-peptide decline changes.