Accelerated Progression of Prediabetes to Insulin-Dependent Diabetes After 9 Cycles of Nivolumab

Introduction: Diabetes mellitus have been reported in around 1% of patients receiving immune checkpoint inhibitors (ICI) resultingin immune checkpoint inhibitor induced diabetes mellitus (ICI-DM). 4 phenotypes of ICI-DM exist: acute autoimmuneinsulin-dependent diabetes, decompensation of prediabetes or type 2 diabetes, autoimmune pancreatitis, andautoimmune lipoatrophy. Clinical Case: A 52-year-old man was diagnosed with stage IIIb malignant melanoma. Two months following local excision, he wasstarted on nivolumab every 4 weeks planned for 1 year. His past medical history was significant for prediabetes,hypertension, obesity (BMI 33.27 kg/m²), primary hypogonadism, adult attention deficit disorder, obstructive sleepapnea, gastric ulcer, and gastroesophageal reflux disease. He denied tobacco use but reported semi-daily use ofmarijuana and alcohol. His baseline HbA1c was 6.0%. After the 8th cycle of nivolumab, he reported several bloodglucose readings in the 200 mg/dL range. He was thought to have progressed to type 2 diabetes and metformin wasstarted. Glipizide was added shortly thereafter due to persistent hyperglycemia. At the 9th cycle of nivolumab, hisHbA1c was 8.2%. In 1 week from this time, the patient developed abdominal pain, nausea, and persistent vomiting. Hewas found to be in DKA with blood glucose of 278 mg/dL, bicarbonate of 9.3 mmol/L, anion gap of 21, and arterial pHof 7.22. He was treated in the ICU per standard DKA care. His C-peptide was 0.5 ng/mL (reference 0.8–3.5) withconcomitant plasma glucose of 229 mg/dL. Autoantibody screening was negative including glutamic aciddecarboxylase antibody (anti-GAD), insulin antibody, insulin antigen-2 (IA-2) autoantibody, and zinc transporter 8antibody. The patient was discharged home on multiple daily injections of insulin but he struggled with diabetes carewhich proved to be of brittle nature requiring CGM use. Two months after completion of nivolumab treatment, thepatient reported epigastric abdominal pain with frequent nausea and occasional vomiting of few weeks duration. He wasdiagnosed with subacute pancreatitis based on symptoms and elevated lipase. There was no evidence of gallstones. Although immunotherapy-related pancreatitis was considered, we decided to try alcohol cessation first hoping to avoidthe need to use prednisone. Over several weeks, lipase normalized and his symptoms completely resolved. Conclusion: In this case, nivolumab resulted in progressive beta-cell failure and complete insulin dependence in a person with ahistory of prediabetes. Not all pancreatitis cases in the settings of immunotherapy use are immune-related adverseevents (irAE). Usual causes, e.g. alcohol, should still be considered. With cessation of alcohol, pancreatitis fullyresolved leading to avoidance of prednisone which would likely have worsened diabetes management in this patientwith brittle diabetes.

Inducible Pluripotent Stem Cells as a Potential Cure for Diabetes

Over the last century, diabetes has been treated with subcutaneous insulin, a discovery that enabled patients to forego death from hyperglycemia. Despite novel insulin formulations, patients with diabetes continue to suffer morbidity and mortality with unsustainable costs to the health care system. Continuous glucose monitoring, wearable insulin pumps, and closed-loop artificial pancreas systems represent an advance, but still fail to recreate physiologic euglycemia and are not universally available. Islet cell transplantation has evolved into a successful modality for treating a subset of patients with ‘brittle’ diabetes but is limited by organ donor supply and immunosuppression requirements. A novel approach involves generating autologous or immune-protected islet cells for transplant from inducible pluripotent stem cells to eliminate detrimental immune responses and organ supply limitations. In this review, we briefly discuss novel mechanisms for subcutaneous insulin delivery and define their shortfalls. We describe embryological development and physiology of islets to better understand their role in glycemic control and, finally, discuss cell-based therapies for diabetes and barriers to widespread use. In response to these barriers, we present the promise of stem cell therapy, and review the current gaps requiring solutions to enable widespread use of stem cells as a potential cure for diabetes.

Atypical hemolytic and uremic syndrome due to C3 mutation in pancreatic islet transplantation: a case report

Background We here report on the first observation of a C3 mutation that is related to atypical hemolytic and uremic syndrome (aHUS), which occurred in a pancreatic islet transplant patient. Immunosuppressive treatments, such as calcineurin inhibitors, have been linked to undesirable effects like nephrotoxicity. Case presentation A 40-year-old man with brittle diabetes, who was included in the TRIMECO trial, became insulin-independent 2 months after pancreatic islet transplantation. About 15 months after islet transplantation, the patient exhibited acute kidney injury due to aHUS. Despite plasma exchange and eculizumab treatment, the patient developed end-stage renal disease. A genetic workup identified a missense variant (p.R592Q) in the C3 gene. In vitro, this C3 variant had defective Factor I proteolytic activity with membrane proteins as cofactor proteins, which was thus classified as pathogenic. About 1 year after the aHUS episode, kidney transplantation was carried out under the protection of the specific anti-C5 monoclonal antibody eculizumab. The patient had normal kidney function, with preserved pancreatic islet function 4 years later. Conclusions Pancreatic islet transplantation could have triggered this aHUS episode, but this link needs to be clarified. Although prophylactic eculizumab maintains kidney allograft function, its efficacy still needs to be studied in larger populations.

Total Pancreatectomy is as Feasible and Safe as Pancreatico-duodenectomy

Background For many years total pancreatectomy (TP) had a notorious reputation due to the resulting brittle diabetes and pancreatic exocrine insufficiency, recent evidence suggests otherwise. The purpose of the current study is to evaluate the comparative perioperative results of TP and pancreatico-duodenectomy (PD).Methods The current study is a single center retrospective, case control study comparing the peri-operative outcomes of TP and PD over a period of 7 years for malignant and benign diseases of the pancreas. Primary and secondary measures of outcome were peri-operative mortality and morbidity respectively.Results 214 patients underwent pancreatic resection during the study period of which 35 patients underwent TP and 179 patients underwent PD. The two groups were homogenous in terms of demographics and clinical presentation. Mortality was not different between TP and PD and stands on 2.9% and 5% respectively (p-0.58). Overall complication rate was significantly lower in the TP group (17.1% vs. 55%, p<0.001) and the rate of major complications (Dindo-Clavien >3) was lower but did not reach statistical significance (2.9% vs. 11.2%, p-0.13).Conclusions Our study suggests that total pancreatectomy is not only feasible and safe, it might have better perioperative outcomes than PD with same mortality and reduced overall complication rate.