Residual [beta] cell function and monogenic variants in long-duration type 1 diabetes patients

BACKGROUND. In the Joslin Medalist Study (Medalists), we determined whether significant associations exist between [beta] cell function and pathology and clinical characteristics. METHODS. Individuals with type 1 diabetes (T1D) for 50 or more years underwent evaluation including HLA analysis, basal and longitudinal autoantibody (AAb) status, and [beta] cell function by a mixed-meal tolerance test (MMTT) and a hyperglycemia/ arginine clamp procedure. Postmortem analysis of pancreases from 68 Medalists was performed. Monogenic diabetes genes were screened for the entire cohort. RESULTS. Of the 1019 Medalists, 32.4% retained detectable C-peptide levels (>0.05 ng/mL, median: 0.21 ng/mL). In those who underwent a MMTT (n = 516), 5.8% responded with a doubling of baseline C-peptide levels. Longitudinally (n = 181, median: 4 years), C-peptide levels increased in 12.2% (n = 22) and decreased in 37% (n = 67) of the Medalists. Among those with repeated MMTTs, 5.4% (3 of 56) and 16.1% (9 of 56) had waxing and waning responses, respectively. Thirty Medalists with baseline C-peptide levels of 0.1 ng/mL or higher underwent the clamp procedure, with [HLA.sup.-]/[AAb.sup.-] and [HLA.sup.+]/[AAb.sup.-] Medalists being most responsive. Postmortem examination of pancreases from 68 Medalists showed that all had scattered insulin-positive cells; 59 additionally had few insulin-positive cells within a few islets; and 14 additionally had lobes with multiple islets with numerous insulin-positive cells. Genetic analysis revealed that 280 Medalists (27.5%) had monogenic diabetes variants; in 80 (7.9%) of these Medalists, the variants were classified as 'likely pathogenic' (rare exome variant ensemble learner [REVEL] >0.75). CONCLUSION. All Medalists retained insulin-positive [beta] cells, with many responding to metabolic stimuli even after 50 years of T1D. The Medalists were heterogeneous with respect to [beta] cell function, and many with [HLA.sup.+] diabetes risk alleles also had monogenic diabetes variants, indicating the importance of genetic testing for clinically diagnosed T1D. FUNDING. Funding for this work was provided by the Dianne Nunnally Hoppes Fund; the Beatson Pledge Fund; the NIH, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); and the American Diabetes Association (ADA).
Introduction Pancreatic [beta] cell depletion attributed to autoimmunity is the hallmark of type 1 diabetes (T1D). However, recent studies have shown that residual [beta] cells may exist despite very long-duration [...]