The multifaceted nature of diabetes mellitus induced by checkpoint inhibitors.

Immune checkpoint inhibitors (CPI) are increasingly being used in oncology, and many autoimmune side effects have been described. Diabetes mellitus (DM) has been reported in approximately 1% of subjects treated with programmed cell death-1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors, alone or in association with CTLA-4 inhibitors. In the present mini-review, we aimed to describe different clinical pictures and pathophysiology associated with these forms of diabetes. Data on CPI-related DM was gathered from the largest case series in the literature and from our centre dedicated to immunotherapy complications (ImmuCare-Hospices Civils de Lyon). Most cases are acute autoimmune insulin-dependent diabetes which are similar to fulminant diabetes (extremely acute onset with concomitant near-normal HbA1c levels). Other cases, however, have a phenotype close to type 2 diabetes or appear as a decompensation of previously known type 2 diabetes. The occurrence of diabetes can also be a complication of autoimmune pancreatitis induced by CPI use. Finally, two cases of diabetes in a context of autoimmune lipoatrophy have recently been described. Regarding the wide variety of CPI-induced diabetes, the discovery of a glucose disorder under CPI should motivate specialised care for aetiological diagnosis and appropriate treatment.

Diabetes mellitus induced by PD-1 and PD-L1 inhibitors: description of pancreatic endocrine and exocrine phenotype.

AIMS: 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. METHODS: We analyzed the data of six subjects treated with immunotherapy who presented acute diabetes. RESULTS: 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. CONCLUSIONS: 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.

Protective effects of alpha-lipoic acid against beta-cell damage in streptozotocin induced diabetes In rats / 中华胰腺病杂志

Objective To investigate the protective effects of alpha-lipoie acid (ALA) against beta-cell damage in streptozotocin (STZ)-induced diabetes in rats. Methods Thirty SD rats were randomly divided into three groups: normal control (NC) group, STZ group and ALA + STZ group, with 10 rats in each group. mg/kg, intraperitoneal injection), till the end of the study (4 weeks later). Blood glucose were measured every 3 days after STZ injection. Malondialdehyde (MDA) and reduced glutathione (GSH) levels were measured in pancreatic homogenates. Pancreatic beta-cells were examined by immunohistocbemical methods, Results STZ induced a significant increase of the level of blood glucose. Body weight of rats in ALA + STZ group was (341±26)g, which significantly lower than (368±3)g in NC group, and high than (301±2)g in STZ group with stas(P < 0. 05). Meanwhile the MDA levels in STZ group and NC group were(1.22 ± 0. 14) and(0.57 ± 0.04)nmoL/mg prot, respectively, and there was significant difference between the two groups (P < 0.05) ; the GSH levels in STZ group and NC group were(16.54 ± 1.10) and(25.46 ± 0.62) mg/g prot (P < 0.05), respectively; degeneration of islet cells and decreased blood glucose were observed in STZ + ALA-pretreated rats; MDA level in pancreatic homogenates was(0.72 ± 0. 23)nmoL/mg prot, which was significantly lower than that in STZ group (P < 0.05) ; the GSH level was (35.33 ± 2.66) mg/g prot, which was significantly higher than that in STZ group (P < 0.05) ; increased staining of insulin and preservation of islet ceils functions were more obvious in the STZ + ALA-pretreated rats. Conclusions ALA exerted its protective effect through reducing the oxidative stress and preserving pancreatic beta-cell integrity.