Aims We conducted a national survey to clarify the characteristics and clinical course of type 1 diabetes related to antiprogrammed cell death-1 therapy. Methods We analyzed the detailed data of 22 patients that were collected using a Japan Diabetes Society survey and a literature database search. Results Among the 22 patients, 11 (50.0%) met the criteria for fulminant type 1 diabetes and 11 (50.0%) met the criteria for acute-onset type 1 diabetes. The average patient age was 63 years. The mean duration between the date of the first anti-PD-1 antibody injection and development of type 1 diabetes was 155 days and ranged from 13 to 504 days. Flu-like symptoms, abdominal symptoms, and drowsiness were observed in 27.8, 31.6, and 16.7% patients, respectively. Mean ± standard deviation or median (first quartile-third quartile) glucose levels, HbA1c levels, urinary C-peptide immunoreactivity levels, and fasting serum C-peptide immunoreactivity levels were 617 ± 248 mg/dl, 8.1 ± 1.3%, 4.1 (1.4-9.4) μg/day, and 0.46 (0.20-0.70) ng/ml, respectively. Seventeen of 20 patients (85.0%) developed ketosis, and 7 of 18 patients (38.9%) developed diabetic ketoacidosis. Ten of 19 patients (52.6%) showed at least one elevated pancreatic enzyme level at the onset and two of seven patients showed this elevation before diabetes onset. Only one of 21 patients was anti-glutamic acid decarboxylase antibody positive. Conclusions Anti-programmed cell death-1 antibody-related type 1 diabetes varies from typical fulminant type 1 diabetes to acute-onset type 1 diabetes. However, diabetic ketoacidosis was frequently observed at the onset of diabetes. An appropriate diagnosis and treatment should be provided to avoid life-threatening metabolic alterations.

OBJECTIVE-Components of insulin/IGF-1 receptor-mediated signaling pathways in pancreatic ␤-cells have been implicated in the development of diabetes, in part through the regulation of ␤-cell mass in vivo. Studies in vitro have shown that the protein Ras homolog enriched in brain (Rheb) plays a key role as a positive upstream regulator of the mammalian target of rapamycin complex 1 (mTORC1) pathway in integrating inputs from nutrients and growth factors for cell growth. Our objective was to investigate the role of the mTORC1 pathway in the regulation of ␤-cell mass in vivo.RESEARCH DESIGN AND METHODS-We generated transgenic mice that overexpress Rheb in ␤-cells. We examined the activation of the mTORC1 pathway and its effects on ␤-cell mass, on glucose metabolism, and on protection against hyperglycemia.RESULTS-Immunoblots of islet extracts revealed that the phosphorylation levels of ribosomal protein S6 and eukaryotic initiation factor 4E binding protein 1, downstream effectors for mTORC1, were upregulated in transgenic ␤-cells. Immunostaining of the pancreatic sections with anti-phospho-S6 antibody confirmed upregulation of the mTORC1 pathway in ␤-cells in vivo. The mice showed improved glucose tolerance with higher insulin secretion. This arose from increased ␤-cell mass accompanied by increased cell size. The mice also exhibited resistance to hyperglycemia induced by streptozotocin and obesity.CONCLUSIONS-Activation of the mTORC1 pathway by Rheb led to increased ␤-cell mass in this mouse model without producing obvious unfavorable effects, giving a potential approach for the treatment of ␤-cell failure and diabetes. Diabetes

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