BackgroundAdvances in cancer immunotherapy have generated encouraging results in multiple malignancies refractory to standard chemotherapies. As the use of immune checkpoint inhibitors (ICI) proliferates, the incidence of autoimmune side effects associated with these agents, termed immune related adverse events (irAE), is expected to increase. The frequency of significant irAE in ICI treated patients is about 10–20% and early recognition is critical to prevent serious morbidity and even mortality. New onset autoimmune diabetes mellitus (DM) associated with immune checkpoint inhibitor treatment is extremely rare, occurring in less than 1% of patients. Autoimmune DM often presents as diabetic ketoacidosis, a medical emergency requiring immediate treatment. We describe the first reported case of a patient with lung cancer who developed autoimmune diabetes after nivolumab treatment and was found to have three diabetes related (islet) autoantibodies present before ICI treatment and seroconversion of another after ICI treatment and onset of autoimmune DM.Case PresentationA 34 year old African American woman with metastatic non-small cell lung cancer (NSCLC) was treated with nivolumab in the second line setting after disease progression following standard chemoradiation therapy. After receiving two doses of nivolumab, the patient developed abrupt onset of hyperglycemia and diabetic ketoacidosis. Autoimmune diabetes was diagnosed on the basis of undetectable C-peptide levels, seropositivity of three diabetes related (islet) autoantibodies and absolute insulin dependence. The patient eventually required use of continuous subcutaneous insulin infusion (insulin pump) due to erratic glycemic excursions and multiple readmissions for DKA. Human leucocyte antigen (HLA) genoyping revealed none of the high risk haplotypes associated with the development of type 1 diabetes. Interestingly, a frozen blood sample obtained prior to treatment with nivolumab tested positive for three of the four diabetes related (islet) autoantibodies despite no prior history of diabetes and no family history of diabetes. Notably, at the time of manuscript preparation, the patient is without evidence of NSCLC recurrence with no further treatment since the nivolumab therapy.ConclusionNew onset autoimmune diabetes mellitus associated with nivolumab has been described only in case reports and occurs at rates of < 1% in the large clinical trials which garnered FDA approval in the second line setting for NSCLC. As ICI use continues to expand across a wide variety of malignancies, clinicians must maintain a high index of suspicion for irAE, including autoimmune DM and other endocrinopathies. A multidisciplinary team and thorough education of the patient are recommended to optimize management of new onset adult autoimmune DM. Our patient may have been at greater risk for the development of ICI related autoimmune diabetes due to the presence of three diabetes related autoantibodies prior to therapy; however, about half of the reported cases of autoimmune DM aft...

Paracellular permeability is mediated by the epithelial cell tight junction. Studies in intestinal and other epithelia have suggested that the activity of src family kinases (SFKs) increases epithelial paracellular permeability through its action on the tight junction protein, occludin, but the involvement of SFKs and occludin in regulation of renal epithelial paracellular permeability is unclear. In this study, the role of SFKs in regulation of renal epithelial paracellular permeability and the involvement of occludin protein in this regulatory event was examined in two renal epithelial cell lines, LLC-PK(1) (proximal tubule-like) and MDCK (distal tubule-like). The effect of broad spectrum SFK inhibitors on paracellular permeability of calcein and fluorescein-dextran3000 were examined. SFK inhibitor treatment increased paracellular movement of both compounds in both renal epithelial cell lines. The SFK inhibitor effect was concentration-dependent and, at low concentrations, was not associated with cell damage/death. Response to SFK inhibitors was acquired progressively after cell populations attained confluence suggesting maturation of the regulatory mechanism. Increased paracellular permeability was not associated with dramatic changes in total cell content of occludin protein, its partitioning between detergent-soluble and -insoluble fractions, or its subcellular localization. Further, the SFK-induced increase in paracellular permeability was unaffected by either occludin protein overexpression or occludin protein knockdown. These results demonstrate that SFK activity decreases paracellular permeability of renal epithelial cells, as opposed to its effect in intestinal epithelial cells, and that this regulation is not mediated by occludin protein.

This pilot multi-center, open-label, randomized trial determined the safety and efficacy of exenatide alone or in combination with basal insulin in medicine and surgery patients with type 2 diabetes (T2D). A total of 150 patients with blood glucose (BG) between 140-400 mg/dl on home therapy with oral agents or insulin ≤ 0.5 U/kg/day were treated with exenatide, exenatide+basal, or basal-bolus (BB) regimen. Exenatide was started at 5 mcg BID, basal insulin at 0.25 U/kg/d, and BB at 0.5 U/kg/d given half as glargine and half as lispro before meals. At discharge, pre-admission therapy was restarted and patients were randomized to exenatide (titrated to 10 mcg BID) or basal insulin, and followed for up to 3 months. The combination of exenatide and basal insulin resulted in lower hospital mean daily BG and higher proportion of target BG 70-180 mg/dl compared to exenatide or BB, p&lt;0.01 (Table). There were no differences in hospital hypoglycemia, gastrointestinal (GI) adverse events or study withdrawal between groups. After discharge, there was no difference in BG control (p=0.65) but exenatide group had more GI adverse events (p&lt;0.001) compared to basal group.Exenatide (n=47)Exe+Basal (n=51)Basal-Bolus (n=52)P valueRandomization BG, mg/dl196±61195±51201±580.91Admission HbA1c, %8.9±2.28.3±2.08.5±1.70.22Length-of-stay, days, median Q1-Q34.0 (2.0-8.0)5.0 (3.0-7.0)4.0 (2.0-5.0)0.23Mean daily BG, days 2-10, mg/dl177±41154±39166±400.01BG at target 70-180 mg/dl, %61±3978±3163±310.02BG &lt; 54 mg/dl, n (%)0 (0)1 (2.1)2 (4.1)0.77Nausea/vomiting, n (%)5 (10.6)5 (9.8)1 (1.9)0.17Withdrawal due to AE, n (%)3 (6.4)0 (0)0 (0)0.029Post-Discharge DataExenatide (n= 48)Basal Insulin (n= 55)Mean daily BG, mg/dl156±63141.±270.65BG &lt; 54 mg/dl, n (%)*4 (10)4 (11)1.0Hospital re-admission, n (%)17%13%0.59Nausea/vomiting, n (%)20 (53)1 (3)&lt;0.001Withdrawal due to AE, n (%)5 (13)0 (0)0.05HbA1c at 3 months, %8.2±1.97.3±10.07 These preliminary results indicate that inpatient and post-discharge treatment with exenatide in combination with basal insulin is safe and effective for the management of general medicine and surgery patients with T2D. Disclosure M. Fayfman: None. D.L. Mize: None. D.J. Rubin: Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc.. I. Anzola: None. M.A. Urrutia: None. C. Ramos: None. F.J. Pasquel: Consultant; Self; Merck Sharp & Dohme Corp., Sanofi, Boehringer Ingelheim Pharmaceuticals, Inc.. J. Haw: None. P. Vellanki: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. H. Wang: None. K.E. Joyce: None. A. Karunakaran: None. B.S. Albury: None. R. Weaver: None. L. Viswanathan: None. S. Jaggi: None. R.J. Galindo: None. G.E. Umpierrez: Research Support; Self; Sanofi US, Merck & Co., Inc., Novo Nordisk Inc., AstraZeneca. Advisory Panel; Self; Sanofi, Intarcia Therapeutics, Inc..

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