About a third of people who have lived with a diagnosis of type 1 diabetes for over 50 years still maintain detectable C-peptide production, and a small proportion have another form of diabetes that could signal their ability to come off insulin altogether, new research suggests.
Those were among several novel findings from the Joslin Medalist Study of 1019 people who have lived with a documented diagnosis of type 1 diabetes for over 50 years, including pathologic data from 68 who have died.
The report was published online July 2 in the Journal of Clinical Investigationby Marc Gregory Yu, MD, of the Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts, and colleagues.
"The findings from this prospective clinical, genetic, and pathological study clearly show that most individuals with type 1 diabetes retain insulin-positive beta cells, with many of these individuals responding to metabolic stimuli even after 50 years of type 1 diabetes," Yu and colleagues write.
The results suggest that some of the Medalists may have been misdiagnosed with type 1 diabetes rather than a form of monogenic diabetes, and, in a small number of cases, people might be able to stop taking insulin and switch to an oral glucose-lowering medication, they note.
"Individuals found to have high levels of C-peptide, despite their longstanding type 1 diabetes, may benefit from both human leukocyte antigen (HLA) risk allele evaluation and monogenic diabetes screening, as these may help dictate the ideal course of treatment," Yu and colleagues say.
"To a greater extent, monogenic diabetes screening may benefit individuals with long-duration type 1 diabetes, regardless of serum C-peptide levels," they add.
In an accompanying editorial, Fabrizio Barbetti, MD, Bambino Gesù Children's Hospital IRCCS, Rome, Italy, and Simeon I. Taylor, MD, University of Maryland School of Medicine, Baltimore, describe the specific subpopulations of people with type 1 diabetes they say could benefit from screening for monogenic diabetes.
"It would be a remarkable outcome if identification of genetic variants in monogenic diabetes genes enabled a subpopulation of Medalist patients to switch to an oral drug rather than insulin," they add.
And according to a statement issued by the Joslin Institute, the investigators expect to launch a clinical trial within months to see if the Medalists with the pathogenic variants might be able to switch from insulin to oral medications to manage their diabetes.
"This will be the first clinical study looking at the administration of oral drugs in an older population with monogenic diabetes," Yu says.
Medalists Study a "Truly Remarkable Achievement"
Joslin awards bronze medals to people who have lived with a diagnosis of type 1 diabetes for at least 50 years.
Commenting on the study overall, Barbetti and Taylor say: "It is a truly remarkable achievement for a single center to have conducted thorough investigations of such a large number of patients with type 1 diabetes and such impressive longevity."
In the new analysis, Yu and colleagues examined 1019 Medalists, of whom slightly more than half were female (55%) and who were a median age of 65 years at first study visit, a median age of 11 years at type 1 diabetes diagnosis, and had median type 1 diabetes duration of 53 years.
All were screened for monogenic diabetes genes that can affect beta-cell function. Other tests included HLA analysis, basal and longitudinal autoantibody status, and beta-cell function by both mixed-meal tolerance test (MMTT) and hyperglycemia/arginine clamp procedures, as well as C-peptide testing.
Analysis of pancreases from the 68 who died was performed post-mortem.
Medalists Are Heterogeneous
Positivity for autoantibodies was found in 43.6% of the 1019 patients, and detectable C-peptide levels (> 0.05 ng/mL) in 32.4% (median, 0.21 ng/mL).
Among the 516 participants who underwent an MMTT, approximately 6% responded, defined as at least a doubling of baseline C-peptide levels, with a median response of 0.35 ng/mL. However, the presence or absence of a C-peptide response was not associated with clinical characteristics, such as HbA1c or prevalence of diabetes-related complications.
Among 181 who returned for a second MMTT after a median 4.1 years, 60% changed from having detectable baseline C-peptide levels to undetectable levels. But interestingly, 9% with baseline undetectable levels actually increased to a detectable level.
And of 30 Medalists with baseline detectable C-peptide levels who underwent the clamp procedure, 46.7% were responsive (defined again as a doubling or greater of baseline C-peptide). Those who were negative for type 1 diabetes-related autoantibodies were more likely to respond.
This therefore indicates that "some patients were still able to respond to metabolic stimuli despite long-term insulin dependence," state Barbetti and Taylor in their editorial.
They note that the authors emphasize the possibility that the small number of residual functioning beta cells, which had escaped autoimmune destruction, could somehow be "rejuvenated," with the hope of restoring insulin secretion even after decades of type 1 diabetes.
And the postmortem analysis of pancreata from Medalists showed that "despite more than 50 years of autoimmune attack, insulin-positive beta cells were detected by immunohistopathology in all 68 patients" they add.
Overall, the Medalist cohort was highly heterogeneous, and genetic testing suggested that several patients would fall into categories other than type 1 diabetes, "and may be able to transfer to other therapy options," the editorialists reiterate.
Who to Screen for Monogenic Diabetes
Barbetti and Taylor continue, "Given the data from this Joslin Medalist study, such genetic screening is most likely to be productive in patients who are negative for HLA risk alleles."
"Furthermore, as exemplified by [three of the research subjects] who carry pathogenic mutations, the diagnosis of [monogenic diabetes] should be suspected in patients diagnosed with type 1 diabetes who show detectable C-peptide levels during fasting that increase after an [MMTT]."
"Despite the fact that these patients have done extremely well using insulin for more than 50 years, insulin therapy requires considerable effort on the part of patients," they observe. "Therefore, when it is possible to achieve good metabolic control with a sulfonylurea, patients with monogenic diabetes tend to welcome the change to an oral drug."
The study was funded by the Dianne Nunnally Hoppes Fund; Beatson Pledge Fund; NIH-NIDDK, and American Diabetes Association. Yu and Barbetti had no disclosures. Taylor has served as a paid consultant for Ionis Pharmaceuticals and is an inventor on patents for the use of metreleptin as a treatment for lipodystrophy and use of fusion proteins containing fibronectin-derived serum albumin-binding domains to extend the pharmacokinetics of therapeutic proteins.
J Clin Invest. Published online July 2, 1019. Article, Editorial
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