Insulin-dependent diabetes may occur in patients with cancers who are treated with checkpoint inhibitors (CPIs). We reviewed cases occurring over a 6-year period at two academic institutions and identified 27 patients in whom this developed, or an incidence of 0.9%. The patients had a variety of solid-organ cancers, but all had received either anti-PD-1 or anti-PD-L1 antibodies. Diabetes presented with ketoacidosis in 59%, and 42% had evidence of pancreatitis in the peridiagnosis period. Forty percent had at least one positive autoantibody and 21% had two or more. There was a predominance of HLA-DR4, which was present in 76% of patients. Other immune adverse events were seen in 70%, and endocrine adverse events in 44%. We conclude that autoimmune, insulin-dependent diabetes occurs in close to 1% of patients treated with anti-PD-1 or -PD-L1 CPIs. This syndrome has similarities and differences compared with classic type 1 diabetes. The dominance of HLA-DR4 suggests an opportunity to identify those at highest risk of these complications and to discover insights into the mechanisms of this adverse event.

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Thyroid dysfunction, either thyrotoxicosis or hypothyroidism, represents an important cardiovascular risk factor. Heart disease is the leading cause of death for men and women in the United States. Cardiovascular disease is multifactorial and many efforts have been made to assess precipitants for optimal guideline-based, primary, and secondary prevention. Thyroid hormone receptors are present in the myocardium and endothelium, and small alterations in its levels could have significant effects in cardiac function. Specifically, overt hypothyroidism is associated with an increased risk for atherosclerotic cardiovascular disease due to metabolic and hemodynamic effects. Several concomitant factors like impaired lipid profile, low-grade chronic inflammatory state, increased oxidative stress and increased insulin resistance enforce this relationship. The last decade has seen a renewed interest on the impact of subclinical hypothyroidism on the cardiovascular system and whether or not it should be treated. The aim of this review is to provide current evidence of the effect of thyroid hormone replacement, either with levothyroxine mono-therapy or in combination with liothyronine, on specific cardiovascular parameters.

Checkpoint inhibitors (CPIs) targeting programmed death-1(PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) have revolutionized cancer treatment but can trigger autoimmune complications including CPI-induced diabetes (CPI-DM), which occurs preferentially with PD-1 blockade. We found evidence of pancreatic inflammation in patients with CPI-DM with shrinkage of pancreases, increased pancreatic enzymes, and in a case from a patient who died with CPI-DM, peri-islet lymphocytic infiltration.In the NOD mouse model, anti-PD-L1 but not anti-CTLA-4 induces diabetes rapidly. RNA sequencing revealed that cytolytic IFNγ+ CD8+ T cells infiltrated islets with anti-PD-L1. Changes in β cells were predominantly driven by IFNγ and TNFα and included induction of a potentially novel β cell population with transcriptional changes suggesting dedifferentiation. IFNγ increased checkpoint ligand expression and activated apoptosis pathways in human β cells in vitro. Treatment with anti-IFNγ and anti-TNFα prevented CPI-DM in anti-PD-L1 treated NOD mice. CPIs targeting the PD-1/PD-L1 pathway result in transcriptional changes in β cells and immune infiltrates that may lead to the development of diabetes. Inhibition of inflammatory cytokines can prevent CPI-DM, suggesting a strategy for clinical application to prevent this complication.

Ferroptosis is an iron-dependent, oxidative form of cell death that is countered mainly by glutathione peroxidase 4 (GPX4) and the production of glutathione (GSH), which is formed from cysteine. The identification of the cancers that may benefit from pharmacological ferroptotic induction is just emerging. We recently demonstrated that inducing ferroptosis genetically or pharmacologically in MYCN-amplified neuroblastoma (NB) is a novel and effective way to kill these cells. MYCN increases iron metabolism and subsequent hydroxyl radicals through increased expression of the transferrin receptor 1 (TfR1) and low levels of the ferroportin receptor. To counter increased hydroxyl radicals, MYCN binds to the promoter of SLC3A2 (solute carrier family 3 member 2). SLC3A2 is a subunit of system Xc-, which is the cysteine-glutamate antiporter that exports glutamate and imports cystine. Cystine is converted to cysteine intracellularly. Here, we investigated other ways MYCN may increase cysteine levels. By performing metabolomics in a syngeneic NB cell line either expressing MYCN or GFP, we demonstrate that the transsulfuration pathway is activated by MYCN. Furthermore, we demonstrate that MYCN-amplified NB cell lines and tumors have higher levels of cystathionine beta-synthase (CBS), the rate-limiting enzyme in transsulfuration, which leads to higher levels of the thioether cystathionine (R-S-(2-amino-2-carboxyethyl)-l-homocysteine). In addition, MYCN-amplified NB tumors have high levels of methylthioadenosine phosphorylase (MTAP), an enzyme that helps salvage methionine following polyamine metabolism. MYCN directly binds to the promoter of MTAP. We propose that MYCN orchestrates both enhanced cystine uptake and enhanced activity of the transsulfuration pathway to counteract increased reactive oxygen species (ROS) from iron-induced Fenton reactions, ultimately contributing to a ferroptosis vulnerability in MYCN-amplified neuroblastoma.

OBJECTIVE To comprehensively compare the effects of a very low-carbohydrate, high-unsaturated/low-saturated fat diet (LC) with those of a high-unrefined carbohydrate , low-fat diet (HC) on glycemic control and cardiovascular disease (CVD) risk factors in type 2 diabetes (T2DM). RESEARCH DESIGN AND METHODS Obese adults (n = 115, BMI 34.4 6 4.2 kg/m 2 , age 58 6 7 years) with T2DM were randomized to a hypocaloric LC diet (14% carbohydrate [<50 g/day], 28% protein, and 58% fat [<10% saturated fat]) or an energy-matched HC diet (53% carbohydrate , 17% protein, and 30% fat [<10% saturated fat]) combined with structured exercise for 24 weeks. The outcomes measured were as follows: glycosylated hemoglobin (HbA 1c), glycemic variability (GV; assessed by 48-h continuous glucose monitoring), antiglycemic medication changes (antiglycemic medication effects score [MES]), and blood lipids and pressure. RESULTS A total of 93 participants completed 24 weeks. Both groups achieved similar completion rates (LC 79%, HC 82%) and weight loss (LC 212.0 6 6.3 kg, HC 211.5 6 5.5 kg); P ‡ 0.50. Blood pressure (29.8/27.3 6 11.6/6.8 mmHg), fasting blood glucose (21.4 6 2.3 mmol/L), and LDL cholesterol (20.3 6 0.6 mmol/L) decreased, with no diet effect (P ‡ 0.10). LC achieved greater reductions in triglyc-erides (20.5 6 0.5 vs. 20.1 6 0.5 mmol/L), MES (20.5 6 0.5 vs. 20.2 6 0.5), and GV indices; P £ 0.03. LC induced greater HbA 1c reductions (22.6 6 1.0% [228.4 6 10.9 mmol/mol] vs. 21.9 6 1.2% [220.8 6 13.1 mmol/mol]; P = 0.002) and HDL cholesterol (HDL-C) increases (0.2 6 0.3 vs. 0.05 6 0.2 mmol/L; P = 0.007) in participants with the respective baseline values HbA 1c >7.8% (62 mmol/mol) and HDL-C <1.29 mmol/L. CONCLUSIONS Both diets achieved substantial improvements for several clinical glycemic control and CVD risk markers. These improvements and reductions in GV and antiglycemic medication requirements were greatest with the LC compared with HC. This suggests an LC diet with low saturated fat may be an effective dietary approach for T2DM management if effects are sustained beyond 24 weeks.

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