Pancreatic surgery and tertiary pancreatitis services warrant provision for support from a specialist diabetes team.

Pancreatic surgery units undertake several complex operations, albeit with considerable morbidity and mortality, as is the case for the management of complicated acute pancreatitis or chronic pancreatitis. The centralisation of pancreatic surgery services, with the development of designated large-volume centres, has contributed to significantly improved outcomes. In this editorial, we discuss the complex associations between diabetes mellitus (DM) and pancreatic/periampullary disease in the context of pancreatic surgery and overall management of complex pancreatitis, highlighting the consequential needs and the indispensable role of specialist diabetes teams in support of tertiary pancreatic services. Type 3c pancreatogenic DM, refers to DM developing in the setting of exocrine pancreatic disease, and its identification and management can be challenging, while the glycaemic control of such patients may affect their course of treatment and outcome. Adequate preoperative diabetes assessment is warranted to aid identification of patients who are likely to need commencement or escalation of glucose lowering therapy in the postoperative period. The incidence of new onset diabetes after pancreatic resection is widely variable in the literature, and depends on the type and extent of pancreatic resection, as is the case with pancreatic parenchymal loss in the context of severe pancreatitis. Early involvement of a specialist diabetes team is essential to ensure a holistic management. In the current era, large volume pancreatic surgery services commonly abide by the principles of enhanced recovery after surgery, with inclusion of provisions for optimisation of the perioperative glycaemic control, to improve outcomes. While various guidelines are available to aid perioperative management of DM, auditing and quality improvement platforms have highlighted deficiencies in the perioperative management of diabetic patients and areas of required improvement. The need for perioperative support of diabetic patients by specialist diabetes teams is uniformly underlined, a fact that becomes clearly more prominent at all different stages in the setting of pancreatic surgery and the management of complex pancreatitis. Therefore, pancreatic surgery and tertiary pancreatitis services must be designed with a provision for support from specialist diabetes teams. With the ongoing accumulation of evidence, it would be reasonable to consider the design of specific guidelines for the glycaemic management of these patients.

Type 2 Diabetes Mellitus and Efficacy Outcomes from Immune Checkpoint Blockade in Patients with Cancer.

PURPOSE: No evidence exists as to whether type 2 diabetes mellitus (T2DM) impairs clinical outcome from immune checkpoint inhibitors (ICI) in patients with solid tumors. EXPERIMENTAL DESIGN: In a large cohort of ICI recipients treated at 21 institutions from June 2014 to June 2020, we studied whether patients on glucose-lowering medications (GLM) for T2DM had shorter overall survival (OS) and progression-free survival (PFS). We used targeted transcriptomics in a subset of patients to explore differences in the tumor microenvironment (TME) of patients with or without diabetes. RESULTS: A total of 1,395 patients were included. Primary tumors included non-small cell lung cancer (NSCLC; 54.7%), melanoma (24.7%), renal cell (15.0%), and other carcinomas (5.6%). After multivariable analysis, patients on GLM (n = 226, 16.2%) displayed an increased risk of death [HR, 1.29; 95% confidence interval (CI),1.07-1.56] and disease progression/death (HR, 1.21; 95% CI, 1.03-1.43) independent of number of GLM received. We matched 92 metformin-exposed patients with 363 controls and 78 patients on other oral GLM or insulin with 299 control patients. Exposure to metformin, but not other GLM, was associated with an increased risk of death (HR, 1.53; 95% CI, 1.16-2.03) and disease progression/death (HR, 1.34; 95% CI, 1.04-1.72). Patients with T2DM with higher pretreatment glycemia had higher neutrophil-to-lymphocyte ratio (P = 0.04), while exploratory tumoral transcriptomic profiling in a subset of patients (n = 22) revealed differential regulation of innate and adaptive immune pathways in patients with T2DM. CONCLUSIONS: In this study, patients on GLM experienced worse outcomes from immunotherapy, independent of baseline features. Prospective studies are warranted to clarify the relative impact of metformin over a preexisting diagnosis of T2DM in influencing poorer outcomes in this population.

Diagnostic criteria and proposed management of immune-related endocrinopathies following immune checkpoint inhibitor therapy for cancer.

Checkpoint inhibitors are now widely used in the management of many cancers. Endocrine toxicity is amongst the most common side effects. These endocrinopathies differ from most other immune-related toxicities in frequently being irreversible and rarely requiring cessation of checkpoint inhibitor therapy. This review considers an approach to the presentation and diagnosis of endocrinopathies, compared to classical endocrine diagnosis, suggesting improvements to classification and treatment based on fundamental endocrine principles. These will help to align management with other similar endocrine conditions and standardise the diagnosis and reporting of endocrine toxicity of checkpoint inhibitors to improve both endocrine and oncological care. In particular, the importance of considering any inflammatory phase (such as painful thyroiditis or hypophysitis resulting in the pituitary enlargement), from the endocrine consequences (transient hyperthyroidism followed by hypothyroidism, pan-hypopituitarism or isolated adrenocorticotrophic hormone deficiency), is highlighted. It is also important to consider the potential confounder of exogenous corticosteroids in adrenal suppression.

Diabetes and cancer: Optimising glycaemic control.

Diabetes and cancer are both common and increasingly prevalent conditions, but emerging epidemiological evidence confirms that the risk of developing a number of common cancers is increased in those with type 2 diabetes. The risk of cancer in type 1 diabetes is less clearly defined, and therefore this review focuses on type 2 diabetes. Emerging evidence also supports an influence of diabetes on outcomes of cancer treatment. However, this relationship is bi-directional, with cancer and its treatment impacting on glucose control, whereas there is also emerging evidence indicating that diabetes care can deteriorate after a cancer diagnosis. Despite these clear links, there is a lack of evidence to guide clinicians in how to manage patients with diabetes during their cancer treatment. Although recent UK guidelines have started to address this, with the development of guidance for the management of hyperglycaemia in cancer, there is a clear need for wider guidance on the management of multi-morbidity during cancer, including diabetes and obesity, to incorporate nutritional management. We have therefore undertaken a narrative review of the evidence of links between type 2 diabetes and cancer incidence and outcomes, and discuss the challenges to diabetes care during cancer treatment.

Endocrine toxicity of cancer immunotherapy: clinical challenges.

Immune checkpoint inhibitors are now widely used in the treatment of multiple cancers. The major toxicities of these treatments are termed immune-related adverse events and endocrine dysfunction is common. Thyroid disease, hypopituitarism and a form of diabetes resembling type 1 diabetes are now all well described, with different patterns emerging with different checkpoint inhibitors. We review the presentation and management of the common endocrine immune-related adverse events, and discuss a number of recent advances in the understanding of these important, potentially life threatening toxicities. We also discuss some remaining dilemmas in management.

Immunotherapy-induced endocrinopathies: assessment, management and monitoring.

Immunotherapy with checkpoint inhibitors has transformed the treatment of cancer, but frequently results in immune-mediated adverse events affecting multiple organs, amongst which endocrine adverse events are frequent. The patterns of endocrine adverse events differ between inhibitors of the CTLA-4 and PD-1/PD-L1 pathways, but most frequently involve the thyroid and pituitary with insulin deficient diabetes also emerging as an important adverse event. These frequently result in long-lasting hormone deficiency requiring replacement. This review explores the mechanism of action of checkpoint inhibitors and details the expected endocrine adverse events and typical presentations. The effect of high-dose glucocorticoids therapy to treat nonendocrine adverse events is also discussed.

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 PPARgamma2 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 ERRalpha, highlighting a novel role for ERRalpha 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.

A functional interaction between RIP140 and PGC-1alpha regulates the expression of the lipid droplet protein CIDEA.

Nuclear receptors activate or repress target genes depending on the recruitment of coactivators or corepressors. The corepressor RIP140 and the PPAR coactivator 1alpha (PGC-1alpha) both play key roles in the regulated transcription of genes involved in energy homeostasis. We investigated the roles of RIP140 and PGC-1alpha in controlling the expression of CIDEA, an important regulatory factor in adipose cell function and obesity. Ectopically expressed CIDEA surrounded lipid droplets in brown adipocytes and induced the formation of lipid droplets in nonadipogenic cell lines. The expression and promoter activity of CIDEA was repressed by RIP140 and induced by PGC-1alpha, mediated through the binding of estrogen-related receptor alpha and NRF-1 to their cognate binding sites. Importantly, we demonstrate that RIP140 interacts directly with PGC-1alpha and suppresses its activity. The direct antagonism of PGC-1alpha by RIP140 provides a mechanism for regulating target gene transcription via nuclear receptor-dependent and -independent pathways.

Role of nuclear receptor coregulators in metabolism.

Understanding the molecular regulation of metabolism will lead to a better understanding of the pathogenesis and treatment of common metabolic conditions, including obesity and diabetes. Nuclear receptors are a family of transcription factors, many of which play major roles in regulating metabolic genes in key tissues. They function by recruiting coregulators to the promoters of metabolic genes that can either activate or repress transcription. This review examines the roles of these coregulators in the control of metabolism in adipose tissue and skeletal muscle, and discusses how they result in coordinated and regulated control of metabolic pathways. In particular, the ligand-dependent recruitment of both coactivators and corepressors has potential implications for the treatment of obesity and diabetes.