PMID- 31264968 OWN - NLM STAT- MEDLINE DCOM- 20200526 LR - 20200526 IS - 1558-8238 (Electronic) IS - 0021-9738 (Print) IS - 0021-9738 (Linking) VI - 129 IP - 8 DP - 2019 Jul 2 TI - Residual beta cell function and monogenic variants in long-duration type 1 diabetes patients. PG - 3252-3263 LID - 127397 [pii] LID - 10.1172/JCI127397 [doi] AB - BACKGROUNDIn the Joslin Medalist Study (Medalists), we determined whether significant associations exist between beta cell function and pathology and clinical characteristics.METHODSIndividuals 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.RESULTSOf 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-/AAb- and 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).CONCLUSIONAll 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+ diabetes risk alleles also had monogenic diabetes variants, indicating the importance of genetic testing for clinically diagnosed T1D.FUNDINGFunding 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). FAU - Yu, Marc Gregory AU - Yu MG AD - Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA. AD - Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. FAU - Keenan, Hillary A AU - Keenan HA AD - Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA. AD - Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. FAU - Shah, Hetal S AU - Shah HS AD - Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA. AD - Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. FAU - Frodsham, Scott G AU - Frodsham SG AD - Division of Nephrology and Hypertension, University of Utah, Salt Lake City, Utah, USA. FAU - Pober, David AU - Pober D AD - Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA. FAU - He, Zhiheng AU - He Z AD - Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA. AD - Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. FAU - Wolfson, Emily A AU - Wolfson EA AD - Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA. FAU - D'Eon, Stephanie AU - D'Eon S AD - Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA. FAU - Tinsley, Liane J AU - Tinsley LJ AD - Clinic Administration, Joslin Diabetes Center, Boston, Massachusetts, USA. FAU - Bonner-Weir, Susan AU - Bonner-Weir S AD - Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA. AD - Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. FAU - Pezzolesi, Marcus G AU - Pezzolesi MG AD - Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA. AD - Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. AD - Division of Nephrology and Hypertension, University of Utah, Salt Lake City, Utah, USA. FAU - King, George Liang AU - King GL AD - Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA. AD - Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. LA - eng GR - DP3 DK094333/DK/NIDDK NIH HHS/United States GR - DP3 DK112192/DK/NIDDK NIH HHS/United States GR - P30 DK036836/DK/NIDDK NIH HHS/United States PT - Clinical Trial PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20190702 PL - United States TA - J Clin Invest JT - The Journal of clinical investigation JID - 7802877 RN - 0 (Autoantibodies) RN - 0 (C-Peptide) RN - 0 (HLA-A Antigens) SB - IM CIN - J Clin Invest. 2019 Jul 2;129(8):3045-3047. PMID: 31264970 MH - Adolescent MH - Aged MH - Autoantibodies/blood/genetics MH - C-Peptide/blood/genetics MH - Child MH - *Diabetes Mellitus, Type 1/blood/genetics/pathology MH - Female MH - Follow-Up Studies MH - Glucose Clamp Technique MH - HLA-A Antigens/blood/genetics MH - Humans MH - Insulin-Secreting Cells/*metabolism/pathology MH - Male MH - Middle Aged MH - Time Factors PMC - PMC6668678 OTO - NOTNLM OT - Beta cells OT - Diabetes OT - Endocrinology OT - Metabolism OT - Monogenic diseases COIS- Conflict of interest: GLK received a research grant from Sanofi-Aventis. EDAT- 2019/07/03 06:00 MHDA- 2020/05/27 06:00 PMCR- 2019/11/01 CRDT- 2019/07/03 06:00 PHST- 2019/01/19 00:00 [received] PHST- 2019/05/10 00:00 [accepted] PHST- 2019/07/03 06:00 [entrez] PHST- 2019/07/03 06:00 [pubmed] PHST- 2020/05/27 06:00 [medline] PHST- 2019/11/01 00:00 [pmc-release] AID - 127397 [pii] AID - 10.1172/JCI127397 [doi] PST - epublish SO - J Clin Invest. 2019 Jul 2;129(8):3252-3263. doi: 10.1172/JCI127397. eCollection 2019 Jul 2.