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The pancreatic islets are composed of discrete hormone-producing cells that orchestrate systemic glucose homeostasis. Here we identify subsets of beta cells using a single-cell transcriptomic approach. One subset of beta cells marked by high CD63 expression is enriched for the expression of mitochondrial metabolism genes and exhibits higher mitochondrial respiration compared with CD63lo beta cells. Human and murine pseudo-islets derived from CD63hi beta cells demonstrate enhanced glucose-stimulated insulin secretion compared with pseudo-islets from CD63lo beta cells. We show that CD63hi beta cells are diminished in mouse models of and in humans with type 2 diabetes. Finally, transplantation of pseudo-islets generated from CD63hi but not CD63lo beta cells into diabetic mice restores glucose homeostasis. These findings suggest that loss of a specific subset of beta cells may lead to diabetes. Strategies to reconstitute or maintain CD63hi beta cells may represent a potential anti-diabetic therapy.

BACKGROUND. Obesity is the foremost risk factor in the development of endometrial cancer (EC). However, the impact of obesity on the response to immune checkpoint inhibitors (ICI) in EC remains poorly understood. This retrospective study investigates the association among BMI, body fat distribution, and clinical and molecular characteristics of EC patients treated with ICI. METHODS. We analyzed progression-free survival (PFS) and overall survival (OS) in EC patients treated with ICI, categorized by BMI, fat-mass distribution, and molecular subtypes. Incidence of immune-related adverse events (irAEs) after ICI was also assessed based on BMI status. RESULTS. 524 EC patients were included in the study. Overweight and obese patients exhibited a significantly prolonged PFS and OS compared with normal BMI patients after treatment with ICI. Multivariable Cox’s regression analysis confirmed the independent association of overweight and obesity with improved PFS and OS. Elevated visceral adipose tissue (VAT) was identified as a strong independent predictor for improved PFS to ICI. Associations between obesity and OS/PFS were particularly significant in the copy number-high/TP53abnormal (CN-H/TP53abn) EC molecular subtype. Finally, obese patients demonstrated a higher irAE rate compared with normal BMI individuals. CONCLUSION. Obesity is associated with improved outcomes to ICI in EC patients and a higher rate of irAEs. This association is more pronounced in the CN-H/TP53abn EC molecular subtype. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is characterized by insulin resistance and a gradual loss of pancreatic beta cell mass and function.sup.1,2. Currently, there are no therapies proven to prevent beta cell loss and some, namely insulin secretagogues, have been linked to accelerated beta cell failure, thereby limiting their use in type 2 diabetes.sup.3,4. The adipokine adipsin/complement factor D controls the alternative complement pathway and generation of complement component C3a, which acts to augment beta cell insulin secretion.sup.5. In contrast to other insulin secretagogues, we show that chronic replenishment of adipsin in diabetic db/db mice ameliorates hyperglycemia and increases insulin levels while preserving beta cells by blocking dedifferentiation and death. Mechanistically, we find that adipsin/C3a decreases the phosphatase Dusp26; forced expression of Dusp26 in beta cells decreases expression of core beta cell identity genes and sensitizes to cell death. In contrast, pharmacological inhibition of DUSP26 improves hyperglycemia in diabetic mice and protects human islet cells from cell death. Pertaining to human health, we show that higher concentrations of circulating adipsin are associated with a significantly lower risk of developing future diabetes among middle-aged adults after adjusting for body mass index (BMI). Collectively, these data suggest that adipsin/C3a and DUSP26-directed therapies may represent a novel approach to achieve beta cell health to treat and prevent type 2 diabetes. Targeting the adipokine adipsin and its downstream pathway may provide an approach for preservation of beta cell loss in type 2 diabetes., Author(s): Nicolás Gómez-Banoy [sup.1] , J. Sawalla Guseh [sup.2] , Ge Li [sup.3] , Alfonso Rubio-Navarro [sup.1] , Tong Chen [sup.1] , BreAnne Poirier [sup.1] , Gregory Putzel [sup.4] , [...]

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Background: Obesity is the foremost risk factor in the development of endometrial cancer (EC). However, the impact of obesity on the response to immune checkpoint inhibitors (ICI) in EC remains poorly understood. This retrospective study investigates the association between body mass index (BMI), body fat distribution, and clinical and molecular characteristics of EC patients treated with ICI., Methods: We analyzed progression-free survival (PFS) and overall survival (OS) in EC patients treated with ICI, categorized by BMI, fat mass distribution, and molecular subtypes. Incidence of immune-related adverse events (irAE) after ICI was also assessed based on BMI status., Results: 524 EC patients were included in the study. Overweight and obese patients exhibited a significantly prolonged PFS and OS compared to normal BMI patients after treatment with ICI. Multivariable Cox regression analysis confirmed the independent association of overweight and obesity with improved PFS and OS. Elevated visceral adipose tissue (VAT) was identified as a strong independent predictor for improved PFS to ICI. Associations between obesity and OS/PFS were particularly significant in the copy number-high/ TP53 abnormal (CN-H/ TP53 abn) EC molecular subtype. Finally, obese patients demonstrated a higher irAE rate compared to normal BMI individuals., Conclusion: Obesity is associated with improved outcomes to ICI in EC patients and a higher rate of irAEs. This association is more pronounced in the CN-H/ TP53 abn EC molecular subtype., Funding: NIH/NCI Cancer Center Support Grant P30CA008748 (MSK). K08CA266740 and MSK Gerstner Physician Scholars Program (J.C.O). RUCCTS Grant #UL1 TR001866 (N.G-B and C.S.J). Cycle for survival and Breast Cancer Research Foundation grants (B.W).

MicroRNAs are small, non-coding molecules with a crucial function in the cell´s biologic regulation. Circulating levels of miRNAs may be useful biomarkers in metabolic diseases such as type 2 Diabetes Mellitus (DM2), which alters the circulating concentrations of several types of miRNA. Specific serum profiles of these molecules have been identified in high-risk patients before the development of DM2 and its chronic complications. Most importantly, these profiles can be modified with physical exercise, which is crucial in the treatment of metabolic diseases. Acute physical activity alone can induce changes in tissue specific miRNAs, and responses are different in aerobic or non-aerobic training. Muscle and cardiovascular miRNAs, which may play an important role in the adap tation to exercise, are predominantly altered. Even further, there is a correlation between serum levels of miRNAs and fitness, suggesting a role for chronic exercise in their regulation. Thus, miRNAs are molecules of growing importance in exercise physiology, and may be involved in the mechanisms behind the beneficial effects of physical activity for patients with metabolic diseases.

Background: Regular physical activity improves the metabolic profile of patients, although the biological mechanisms involved are not clear yet. The anti-inflammatory effects of exercise are well known and are possibly related to its therapeutic properties. The aim of this study was to compare changes in the concentration of an anti-inflammatory cytokine - tumor necrosis factor soluble receptor-1 (sTNFR1) - and a pro-inflammatory cytokine - interleukin-1β (IL-1β) - during moderate physical exercise in sedentary versus athletic men., Methods: We analyzed serum inflammatory cytokine concentrations in 5 athletes and 5 sedentary men (aged 18 to 22): 1) 15 minutes and immediately before a 28-minute specifically-programmed moderate exercise session; 2) every 3 minutes during the exercise session; 3) 15 and 30 minutes after session completion., Results: We obtained serum sTNFR1 and IL-1β concentrations in 10 individuals. Both cytokines exhibited changes in their concentration during physical exercise: a significant increase in the concentration of sTNFR1 was observed in both the sedentary (P=0.0249) and the athlete (P=0.02172) groups. The levels of sTNFR1 were higher in the athlete group than in the sedentary group. No differences were observed in the IL-1β concentrations between the two groups., Conclusions: Serum concentration of the anti-inflammatory cytokine sTNFR1 increased during moderate physical exercise, and its levels were higher in athletes before, during and after physical activity. These findings are consistent with previous findings concerning the anti-inflammatory properties of exercise, and suggest that sTNFR1 has an important role in the anti-inflammatory environment following physical activity.