Diabetes mellitus induced by PD-1 and PD-L1 inhibitors: description of pancreatic endocrine and exocrine phenotype
Programmed cell death-1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors restore antitumor immunity, but many autoimmune side-effects have been described. Diabetes mellitus is a rare complication, and little data concerning its pathophysiology and phenotype have been published. This study aimed to describe both pancreatic endocrine and exocrine functions, immunological features and change in pancreas volume in subjects with diabetes mellitus induced by PD-1 and PD-L1 inhibitors.
We analyzed the data of six subjects treated with immunotherapy who presented acute diabetes.
There were five men and one woman. Median age was 67 years (range 55–83). Three subjects were treated with nivolumab, two with pembrolizumab and one with durvalumab. Median time to diabetes onset after immunotherapy initiation was 4 months (range 2–13). Four patients presented fulminant diabetes (FD); none of these had type 1 diabetes (T1D)-related autoantibodies, none of them had T1D or FD-very high-risk HLA class II profiles. The bi-hormonal endocrine and exocrine pancreatic failure previously reported for one FD patient was not found in other FD subjects, but glucagon response was blunted in another FD patient. Pancreas volume was decreased at diabetes onset in 2 FD patients, and all patients presented a subsequent decrease of pancreas volume during follow-up.
In the patients presented herein, immunotherapy-induced diabetes was not associated with T1D-related autoantibodies. The hormonal and morphological analysis of the pancreatic glands of these six cases contributes to the understanding of the underlying and probably heterogeneous mechanisms. There is a need to find biomarkers to identify patients at risk to develop these new forms of diabetes at early stages of the process to prevent ketoacidosis and to evaluate preventive strategies.
KeywordsDiabetes mellitus Fulminant diabetes Autoimmune diabetes Immune checkpoint inhibitors side-effects Immunotherapy Programmed cell death-1 Anti-PD-1 Programmed death ligand 1 Anti-PD-L1 Pancreas volume Beta-cell pancreatic function Alpha-cell pancreatic function Exocrine pancreatic function Mixed meal test
We thank Philip Robinson (DRCI, Hospices Civils de Lyon) for help in manuscript preparation.
LM and CT collected clinical data and wrote the manuscript. LM, SR, JV, CCA and CT were clinicians in charge of managing patients’ endocrinopathies. AT analyzed the evolution of pancreas volume. NF tested autoantibodies. KC tested glucagon and C-peptide levels. SD analyzed the data, reviewed/edited the manuscript and contributed to the discussion. All authors gave final approval of the version to be published. CT is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Compliance with ethical standards
Conflict of interest
The authors declare that there is no duality of interest associated with this manuscript.
Research involving human participants and/or animals
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.
Informed consent was obtained from all patients for being included in the study.
- 7.Marchand L, Paulus V, Fabien N, Perol M, Thivolet C, Vouillarmet J et al (2017) Nivolumab-induced acute diabetes mellitus and hypophysitis in a patient with advanced pulmonary pleomorphic carcinoma with a prolonged tumor response. J Thorac Oncol 12(11):e182–e184 (PubMed PMID: 29074210)CrossRefGoogle Scholar
- 10.Gauci ML, Laly P, Vidal-Trecan T, Baroudjian B, Gottlieb J, Madjlessi-Ezra N et al (2017) Autoimmune diabetes induced by PD-1 inhibitor-retrospective analysis and pathogenesis: a case report and literature review. Cancer Immunol Immunother CII 66(11):1399–1410 (PubMed PMID: 28634815)CrossRefGoogle Scholar
- 13.Greenbaum CJ, Beam CA, Boulware D, Gitelman SE, Gottlieb PA, Herold KC et al (2012) Fall in C-peptide during first 2 years from diagnosis: evidence of at least two distinct phases from composite Type 1 Diabetes TrialNet data. Diabetes 61(8):2066–2073 (PubMed PMID: 22688329. Pubmed Central PMCID: 3402330)CrossRefGoogle Scholar
- 17.Sherr J, Tsalikian E, Fox L, Buckingham B, Weinzimer S, Tamborlane WV et al (2014) Evolution of abnormal plasma glucagon responses to mixed-meal feedings in youth with type 1 diabetes during the first 2 years after diagnosis. Diabetes Care 37(6):1741–1744 (PubMed PMID: 24696460. Pubmed Central PMCID: 4030093)CrossRefGoogle Scholar