Characterization of persistent beta-cell function in response to metabolic stimuli with HLA and monogenic genotypes and pancreatic morphology in a large group of people with long duration of type 1 diabetes (T1D) has not been reported. In the Joslin Medalist Study (“Medalists”), which enrolled people with ≥50 years of T1D (n=1019), we determined whether significant associations exist between beta-cell function, autoantibodies (AAb), islet morphology, and genetic risks for T1D and monogenic diabetes. In this cohort, 32% exhibited C-peptide>0.05 ng/mL while 44% had GAD/IA2 AAb. In those with mixed meal tolerance test (MMTT, n=516), 6% responded with doubling of baseline C-peptide, without a related change in AAb status. Longitudinally (n=181, over a median of 4 years), C-peptide levels increased in 12% (n=22) and decreased in 37% (n=67). Among those with repeated MMTT, 5% (3/56) and 16% (9/56) had similar waxing and waning responses, respectively. Postmortem examination of 68 Medalist pancreases showed that all contained scattered insulin-positive cells, with three categories: A) only scattered singlets/doublets (n=9); B) scattered plus few insulin-positive cells in some islets (n=45); and C) scattered plus some lobes with islets having many insulin-positive cells (n=14). 30 Medalists with baseline C-peptide ≥0.1 ng/mL underwent a hyperglycemic/arginine clamp, to which 47% responded. Genetic screen for monogenic diabetes on all Medalists studied with the clamp showed 10 exhibiting monogenic variants, with HLA-/AAb- and HLA+/AAb- Medalists responding most to stimuli.

In summary, these results show that all Medalists retained insulin-positive beta-cells, with many responding to metabolic stimuli even after 50 years of T1D. Medalists are heterogeneous with respect to beta-cell function and many with HLA+ diabetes risk alleles also have monogenic variants, indicating the importance of genetic testing for clinically-diagnosed T1D.


M. Yu: None. M.G. Pezzolesi: None. H.A. Keenan: Employee; Self; Sanofi Genzyme. D.M. Pober: None. Z. He: None. L.J. Tinsley: None. A. Doria: Research Support; Self; Sanofi-Aventis. S. Bonner-Weir: Advisory Panel; Spouse/Partner; Semma Therapeutics, Inc. G.L. King: Research Support; Self; Sanofi.


Nunnally Foundation; Beatson Pledge Fund; National Institute of Diabetes and Digestive and Kidney Diseases

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