Residual β cell function and monogenic variants in long-duration type 1 diabetes patients

Abstract

BACKGROUND. In the Joslin Medalist Study (Medalists), we determined whether significant associations exist between β 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 β 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-/AAband HLA + /AAb-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 β cells, with many responding to metabolic stimuli even after 50 years of T1D. The Medalists were heterogeneous with respect to β cell function, and many with HLA + diabetes risk alleles also had monogenic diabetes variants, indicating the importance of genetic testing for clinically diagnosed T1D.

Preserved C-peptide secretion is associated with fewer low-glucose events and lower glucose variability on flash glucose monitoring in adults with type 1 diabetes

“…In the DCCT, preserved C-peptide secretion was associated with lower rates of severe hypoglycaemia [7], fewer diabetes complications, lower HbA 1c and lower insulin doses [8], although these associations were mostly observed in the intensive treatment arm. These associations were not noted in the recent Joslin Medalist Study which assessed individuals with long-standing type 1 diabetes [5]. Preservation of C-peptide has been associated with lower self-reported rates of symptomatic, asymptomatic and severe hypoglycaemia, although not with measures of impaired awareness, in a number of observational studies [9][10][11].…”

“…Significant residual C-peptide secretion is more likely in those diagnosed in adulthood, ranging from 36% within the first 5 years to 22% up to 20 years post diagnosis [3], with evidence of stabilisation after an exponential fall in the first 7 years [4]. Even after 50 years of type 1 diabetes, 32.4% of individuals retain detectable C-peptide levels (>16 pmol/l) [5]. Evidence from the DCCT suggests that intensive therapy may prolong the duration of C-peptide persistence [6].…”

Prediction algorithms: pitfalls in interpreting genetic variants of autosomal dominant monogenic diabetes

“…Recently published examples involving monogenic diabetes demonstrate how pathogenicity prediction algorithms can be very inaccurate for predicting which genetic variants are likely causal of dominant monogenic disease (1)(2)(3)(4). Here, we highlight the potential pitfalls of variant classification and how they can be avoided.…”

“…A recent study used a bioinformatic algorithm to identify 88 "likely pathogenic" monogenic diabetes variants in 80 individuals (8.6%) from a cohort of 1019 individuals with type 1 diabetes for 50 or more years (4). Application of the widely used American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) standards and guidelines (5) classifies only nine of these 88 variants as likely pathogenic or pathogenic variants that would be reported by our clinical diagnostic laboratory as likely causative of the patients' diabetes.…”

From immunohistological to anatomical alterations of human pancreas in type 1 diabetes: New concepts on the stage

“…Although some donors with elevated C‐peptide levels showed most numerous insulin‐positive islets, it was reported that this was not always the case, with some subjects showing solely scattered singlet/doublet cells and high values of serum C‐peptide or vice versa. These results suggest that even though the presence of insulin‐positive islets in several donors with long‐standing T1D positively correlated with pre‐mortem C‐peptide values (indicating a fully functional phenotype), the scenario is heterogeneous, and the function of residual β‐cells (both scattered and within islets) should be further studied …”