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.

Disclosure

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.

Funding

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

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.