Hyperglycaemia following immune checkpoint inhibitor therapy-Incidence, aetiology and assessment

Aims We systematically studied the presence of hyperglycaemia during treatment with Immune Checkpoint Inhibitors (ICPI) for cancer, in those with and without diabetes at baseline, and determined the cause of new-onset hyperglycaemia, Methods Retrospective review of electronic records of those receiving an ICPI for melanoma, lung or renal cancer. Results Overall, 959 participants were included. In this study, 103 had diabetes at baseline (10.7%). Those with lung cancer had the highest frequency of diabetes; 131 people had hyperglycaemia (defined as at least one glucose ≥11.1 mmol/L) in the year after starting an ICPI. The incidence was 55% in those with diabetes at baseline, and 8.6% in those without baseline diabetes. Among 74 with new-onset hyperglycaemia (without pre-existing diabetes) 76% was attributable to steroid induced diabetes, with 9.5% due to ICPI Induced diabetes resembling type 1 diabetes. Conclusions Hyperglycaemia is common in persons receiving an ICPI for cancer, including 8.6% of those without known diabetes. While much of this is due to glucocorticoid use, care is needed to avoid missing those with ICPI-induced diabetes who are at risk of diabetic ketoacidosis, which is a medical emergency

Perilipin Overexpression in White Adipose Tissue Induces a Brown Fat-Like Phenotype

Background: Perilipin A (PeriA) exclusively locates on adipocyte lipid droplets and is essential for lipid storage and lipolysis. Previously, we reported that adipocyte specific overexpression of PeriA caused resistance to diet-induced obesity and resulted in improved insulin sensitivity. In order to better understand the biological basis for this observed phenotype, we performed additional studies in this transgenic mouse model. Methodology and Principal Findings: When compared to control animals, whole body energy expenditure was increased in the transgenic mice. Subsequently, we performed DNA microarray analysis and real-time PCR on white adipose tissue. Consistent with the metabolic chamber data, we observed increased expression of genes associated with fatty acid β-oxidation and heat production, and a decrease in the genes associated with lipid synthesis. Gene expression of Pgc1a, a regulator of fatty acid oxidation and Ucp1, a brown adipocyte specific protein, was increased in the white adipose tissue of the transgenic mice. This observation was subsequently verified by both Western blotting and histological examination. Expression of RIP140, a regulator of white adipocyte differentiation, and the lipid droplet protein FSP27 was decreased in the transgenic mice. Importantly, FSP27 has been shown to control gene expression of these crucial metabolic regulators. Overexpression of PeriA in 3T3-L1 adipocytes also reduced FSP27 expression and diminished lipid droplet size. Conclusions: These findings demonstrate that overexpression of PeriA in white adipocytes reduces lipid droplet size by decreasing FSP27 expression and thereby inducing a brown adipose tissue-like phenotype. Our data suggest that modulation of lipid droplet proteins in white adipocytes is a potential therapeutic strategy for the treatment of obesity and its related disorders

Glycaemic control in people with type 2 diabetes mellitus during and after cancer treatment: A systematic review and meta-analysis

Background Cancer and Diabetes Mellitus (DM) are leading causes of death worldwide and the prevalence of both is escalating. People with co-morbid cancer and DM have increased morbidity and premature mortality compared with cancer patients with no DM. The reasons for this are likely to be multifaceted but will include the impact of hypo/hyperglycaemia and diabetes therapies on cancer treatment and disease progression. A useful step toward addressing this disparity in treatment outcomes is to establish the impact of cancer treatment on diabetes control. Aim The aim of this review is to identify and analyse current evidence reporting glycaemic control (HbA1c) during and after cancer treatment. Methods Systematic searches of published quantitative research relating to comorbid cancer and type 2 diabetes mellitus were conducted using databases, including Medline, Embase, PsychINFO, CINAHL and Web of Science (February 2017). Full text publications were eligible for inclusion if they: were quantitative, published in English language, investigated the effects of cancer treatment on glycaemic control, reported HbA1c (%/mmols/mol) and included adult populations with diabetes. Means, standard deviations and sample sizes were extracted from each paper; missing standard deviations were imputed. The completed datasets were analysed using a random effects model. A mixed-effects analysis was undertaken to calculate mean HbA1c (%/mmols/mol) change over three time periods compared to baseline. Results The available literature exploring glycaemic control post-diagnosis was mixed. There was increased risk of poor glycaemic control during this time if studies of surgical treatment for gastric cancer are excluded, with significant differences between baseline and 12 months (p < 0.001) and baseline and 24 months (p = 0.002). Conclusion We found some evidence to support the contention that glycaemic control during and/or after non-surgical cancer treatment is worsened, and the reasons are not well defined in individual studies. Future studies should consider the reasons why this is the case

Predicting development of ipilimumab-induced hypophysitis: utility of T4 and TSH index but not TSH.

PURPOSE: Ipilimumab, a monoclonal antibody inhibiting CLTA-4, is an established treatment in metastatic melanoma, either alone or in combination with nivolumab, and results in immune mediated adverse events, including endocrinopathy. Hypophysitis is one of the most common endocrine abnormalities. An early recognition of hypophysitis may prevent life threatening consequences of hypopituitarism; therefore, biomarkers to predict which patients will develop hypophysitis would have clinical utility. Recent studies suggested that a decline in TSH may serve as an early marker of IH. This study was aimed at assessing the utility of thyroid function tests in predicting development of hypophysitis. METHODS: A retrospective cohort study was performed for all patients (n = 308) treated with ipilimumab either as a monotherapy or in combination with nivolumab for advanced melanoma at the Royal Marsden Hospital from 2010 to 2016. Thyroid function tests, other pituitary function tests and Pituitary MRIs were used to identify those with hypophysitis. RESULTS AND CONCLUSIONS: Ipilimumab-induced hypophysitis (IH) was diagnosed in 25 patients (8.15%). A decline in TSH was observed in hypophysitis cohort during the first three cycles but it did not reach statistical significance (P = 0.053). A significant fall in FT4 (P < 0.001), TSH index (P < 0.001) and standardised TSH index (P < 0.001) prior to cycles 3 and 4 in hypophysitis cohort was observed. TSH is not useful in predicting development of IH. FT4, TSH index and standardised TSH index may be valuable but a high index of clinical suspicion remains paramount in early detection of hypophysitis

Human fetal mesenchymal stem cells differentiate into brown and white adipocytes: a role for ERRalpha in human UCP1 expression

We investigated the ability of fetal mesenchymal stem cells (fMSCs) to differentiate into brown and white adipocytes and compared the expression of a number of marker genes and key regulatory factors. We showed that the expression of key adipocyte regulators and markers during differentiation is similar to that in other human and murine adipocyte models, including induction of PPARγ2 and FABP4. Notably, we found that the preadipocyte marker, Pref-1, is induced early in differentiation and then declines markedly as the process continues, suggesting that fMSCs first acquire preadipocyte characteristics as they commit to the adipogenic lineage, prior to their differentiation into mature adipocytes. After adipogenic induction, some stem cell isolates differentiated into cells resembling brown adipocytes and others into white adipocytes. Detailed investigation of one isolate showed that the novel brown fat-determining factor PRDM16 is expressed both before and after differentiation. Importantly, these cells exhibited elevated basal UCP-1 expression, which was dependent on the activity of the orphan nuclear receptor ERRα, highlighting a novel role for ERRα in human brown fat. Thus fMSCs represent a useful in vitro model for human adipogenesis, and provide opportunities to study the stages prior to commitment to the adipocyte lineage. They also offer invaluable insights into the characteristics of human brown fat. © 2010 IBCB, SIBS, CAS All rights reserved