Body mass index and adiposity influence responses to immune checkpoint inhibition in endometrial cancer.

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/TP53abnormal (CN-H/TP53abn) 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/TP53abn 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).

Body mass index and adiposity influence responses to immune checkpoint inhibition in endometrial cancer.

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/TP53abnormal (CN-H/TP53abn) 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/TP53abn 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).

Spatiotemporal regulation of GIPR signaling impacts glucose homeostasis as revealed in studies of a common GIPR variant.

OBJECTIVE: Glucose-dependent insulinotropic polypeptide (GIP) has a role in controlling postprandial metabolic tone. In humans, a GIP receptor (GIPR) variant (Q354, rs1800437) is associated with a lower body mass index (BMI) and increased risk for Type 2 Diabetes. To better understand the impacts of GIPR-Q354 on metabolism, it is necessary to study it in an isogeneic background to the predominant GIPR isoform, E354. To accomplish this objective, we used CRISPR-CAS9 editing to generate mouse models of GIPR-Q354 and GIPR-E354. Here we characterize the metabolic effects of GIPR-Q354 variant in a mouse model (GIPR-Q350). METHODS: We generated the GIPR-Q350 mice for in vivo studies of metabolic impact of the variant. We isolated pancreatic islets from GIPR-Q350 mice to study insulin secretion ex vivo. We used a ß-cell cell line to understand the impact of the GIPR-Q354 variant on the receptor traffic. RESULTS: We found that female GIPR-Q350 mice are leaner than littermate controls, and male GIPR-Q350 mice are resistant to diet-induced obesity, in line with the association of the variant with reduced BMI in humans. GIPR-Q350 mice of both sexes are more glucose tolerant and exhibit an increased sensitivity to GIP. Postprandial GIP levels are reduced in GIPR-Q350 mice, revealing feedback regulation that balances the increased sensitivity of GIP target tissues to secretion of GIP from intestinal endocrine cells. The increased GIP sensitivity is recapitulated ex vivo during glucose stimulated insulin secretion assays in islets. Generation of cAMP in islets downstream of GIPR activation is not affected by the Q354 substitution. However, post-activation traffic of GIPR-Q354 variant in ß-cells is altered, characterized by enhanced intracellular dwell time and increased localization to the Trans-Golgi Network (TGN). CONCLUSIONS: Our data link altered intracellular traffic of the GIPR-Q354 variant with GIP control of metabolism. We propose that this change in spatiotemporal signaling underlies the physiologic effects of GIPR-Q350/4 and GIPR-E350/4 in mice and humans. These findings contribute to a more complete understanding of the impact of GIPR-Q354 variant on glucose homeostasis that could perhaps be leveraged to enhance pharmacologic targeting of GIPR for the treatment of metabolic disease.

A beta cell subset with enhanced insulin secretion and glucose metabolism is reduced in type 2 diabetes.

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.

Maladaptive positive feedback production of ChREBPß underlies glucotoxic ß-cell failure.

Preservation and expansion of ß-cell mass is a therapeutic goal for diabetes. Here we show that the hyperactive isoform of carbohydrate response-element binding protein (ChREBPß) is a nuclear effector of hyperglycemic stress occurring in ß-cells in response to prolonged glucose exposure, high-fat diet, and diabetes. We show that transient positive feedback induction of ChREBPß is necessary for adaptive ß-cell expansion in response to metabolic challenges. Conversely, chronic excessive ß-cell-specific overexpression of ChREBPß results in loss of ß-cell identity, apoptosis, loss of ß-cell mass, and diabetes. Furthermore, ß-cell "glucolipotoxicity" can be prevented by deletion of ChREBPß. Moreover, ChREBPß-mediated cell death is mitigated by overexpression of the alternate CHREBP gene product, ChREBPα, or by activation of the antioxidant Nrf2 pathway in rodent and human ß-cells. We conclude that ChREBPß, whether adaptive or maladaptive, is an important determinant of ß-cell fate and a potential target for the preservation of ß-cell mass in diabetes.

Hyperglycemia in acute COVID-19 is characterized by insulin resistance and adipose tissue infectivity by SARS-CoV-2.

Individuals infected with SARS-CoV-2 who also display hyperglycemia suffer from longer hospital stays, higher risk of developing acute respiratory distress syndrome (ARDS), and increased mortality. Nevertheless, the pathophysiological mechanism of hyperglycemia in COVID-19 remains poorly characterized. Here, we show that hyperglycemia is similarly prevalent among patients with ARDS independent of COVID-19 status. Yet among patients with ARDS and COVID-19, insulin resistance is the prevalent cause of hyperglycemia, independent of glucocorticoid treatment, which is unlike patients with ARDS but without COVID-19, where pancreatic beta cell failure predominates. A screen of glucoregulatory hormones revealed lower levels of adiponectin in patients with COVID-19. Hamsters infected with SARS-CoV-2 demonstrated a strong antiviral gene expression program in the adipose tissue and diminished expression of adiponectin. Moreover, we show that SARS-CoV-2 can infect adipocytes. Together these data suggest that SARS-CoV-2 may trigger adipose tissue dysfunction to drive insulin resistance and adverse outcomes in acute COVID-19.

Hyperglycemia in Acute COVID-19 is Characterized by Adipose Tissue Dysfunction and Insulin Resistance.

COVID-19 has proven to be a metabolic disease resulting in adverse outcomes in individuals with diabetes or obesity. Patients infected with SARS-CoV-2 and hyperglycemia suffer from longer hospital stays, higher risk of developing acute respiratory distress syndrome (ARDS), and increased mortality compared to those who do not develop hyperglycemia. Nevertheless, the pathophysiological mechanism(s) of hyperglycemia in COVID-19 remains poorly characterized. Here we show that insulin resistance rather than pancreatic beta cell failure is the prevalent cause of hyperglycemia in COVID-19 patients with ARDS, independent of glucocorticoid treatment. A screen of protein hormones that regulate glucose homeostasis reveals that the insulin sensitizing adipokine adiponectin is reduced in hyperglycemic COVID-19 patients. Hamsters infected with SARS-CoV-2 also have diminished expression of adiponectin. Together these data suggest that adipose tissue dysfunction may be a driver of insulin resistance and adverse outcomes in acute COVID-19.

Adipsin preserves beta cells in diabetic mice and associates with protection from type 2 diabetes in humans.

Type 2 diabetes is characterized by insulin resistance and a gradual loss of pancreatic beta cell mass and function1,2. 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 diabetes3,4. The adipokine adipsin/complement factor D controls the alternative complement pathway and generation of complement component C3a, which acts to augment beta cell insulin secretion5. 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.

Adipokines as key players in ß cell function and failure.

The growing prevalence of obesity and its related metabolic diseases, mainly Type 2 diabetes (T2D), has increased the interest in adipose tissue (AT) and its role as a principal metabolic orchestrator. Two decades of research have now shown that ATs act as an endocrine organ, secreting soluble factors termed adipocytokines or adipokines. These adipokines play crucial roles in whole-body metabolism with different mechanisms of action largely dependent on the tissue or cell type they are acting on. The pancreatic ß cell, a key regulator of glucose metabolism due to its ability to produce and secrete insulin, has been identified as a target for several adipokines. This review will focus on how adipokines affect pancreatic ß cell function and their impact on pancreatic ß cell survival in disease contexts such as diabetes. Initially, the "classic" adipokines will be discussed, followed by novel secreted adipocyte-specific factors that show therapeutic promise in regulating the adipose-pancreatic ß cell axis.

Screening tests for distal symmetrical polyneuropathy in Latin American patients with type 2 diabetes mellitus

ABSTRACT Objective This cross sectional study intended to evaluate two bedside tests (Neuropad and VibraTip) as screening tools for distal symmetrical polyneuropathy (DSPN) in Latin American patients with type 2 diabetes mellitus (T2D). Subjects and methods Ninety-three Colombian patients diagnosed with T2D were recruited. Anthropometric variables, glycemic control parameters, lipid profile and renal function were assessed for each patient. DSPN was defined by a Michigan Neuropathy Screening Instrument (MNSI) clinical score greater than 2. Both Neuropad and Vibratip tests were applied to each patient. Contingency analyses were performed to evaluate the diagnostic power of both tools. Results The prevalence of DSPN determined clinically by MNSI was 25.8%. DSPN in these patients was associated with age, worsening renal function, and insulin treatment. The sensitivity and specificity of the Neuropad test for DSPN was 66.6% and 63% respectively. Its negative predictive value (NPV) was 84.6%. The VibraTip test exhibited a sensitivity of 54.1% and specificity of 91.3%, with a NPV of 85.1%. Conclusion Neuropad and VibraTip are reliable screening tools for DSPN in Latin American population. VibraTip presents a considerable diagnostic power for DSPN in this population. Further studies regarding the cost-effectiveness of these tools in clinical practice are needed.

Screening tests for distal symmetrical polyneuropathy in Latin American patients with type 2 diabetes mellitus.

OBJECTIVE: This cross sectional study intended to evaluate two bedside tests (Neuropad and VibraTip) as screening tools for distal symmetrical polyneuropathy (DSPN) in Latin American patients with type 2 diabetes mellitus (T2D). SUBJECTS AND METHODS: Ninety-three Colombian patients diagnosed with T2D were recruited. Anthropometric variables, glycemic control parameters, lipid profile and renal function were assessed for each patient. DSPN was defined by a Michigan Neuropathy Screening Instrument (MNSI) clinical score greater than 2. Both Neuropad and Vibratip tests were applied to each patient. Contingency analyses were performed to evaluate the diagnostic power of both tools. RESULTS: The prevalence of DSPN determined clinically by MNSI was 25.8%. DSPN in these patients was associated with age, worsening renal function, and insulin treatment. The sensitivity and specificity of the Neuropad test for DSPN was 66.6% and 63% respectively. Its negative predictive value (NPV) was 84.6%. The VibraTip test exhibited a sensitivity of 54.1% and specificity of 91.3%, with a NPV of 85.1%. CONCLUSION: Neuropad and VibraTip are reliable screening tools for DSPN in Latin American population. VibraTip presents a considerable diagnostic power for DSPN in this population. Further studies regarding the cost-effectiveness of these tools in clinical practice are needed.

Genetic Manipulation with Viral Vectors to Assess Metabolism and Adipose Tissue Function.

Viral vectors have become widely used tools for genetic manipulation of adipose tissues to understand the biology and function of adipocytes in metabolism. There are a number of different viral vectors commonly used: retrovirus, lentivirus, adenovirus, and adeno-associated virus (AAV). Here, we review examples from the literature and describe methods to transduce adipocytes and adipose tissues using retrovirus, lentivirus, adenovirus, and AAV to ascertain gene function in adipose biology.

[MicroRNAs: circulating biomarkers in type 2 Diabetes Mellitus and physical exercise]. / MicroRNAs: Marcadores séricos en diabetes mellitus tipo 2 y ejercicio físico.

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.

Soluble tumor necrosis factor receptor 1 is associated with diminished estimated glomerular filtration rate in colombian patients with type 2 diabetes.

AIMS: The tumor necrosis factor α (TNF-α) family of inflammatory molecules plays a crucial role in the pathogenesis of type 2 diabetes mellitus (DM2) complications. TNF-α soluble receptors 1 (sTNFR1) and 2 (sTNFR2) have been associated with chronic kidney disease in DM2 patients. This cross-sectional study intended to determine serum concentrations of sTNFR1 and sTNFR2 in Colombian patients and correlated them with various clinical variables, especially kidney function. METHODS: 92 Colombian patients with DM2 were recruited. Anthropometric variables, glycemic control parameters, lipid profile and renal function were assessed for each patient. Levels of sTNFR1 and sTNFR2 were determined using ELISA. Patients were stratified in two groups according to reduced estimated glomerular filtration rate (eGFR) (<60ml/min/1.73m(2)) and normal eGFR (≥60ml/min/1.73m(2)). RESULTS: Significantly elevated levels of sTNFR1 and sTNFR2 were observed in the diminished versus normal eGFR group. Also, significant differences were noticed between both groups in haemoglobin A1c (HbA1c) values, percentage of hypertensive subjects treated with angiotensin receptor blocker (ARB) and subjects treated with metformin. No differences were observed regarding body mass index (BMI), albuminuria and lipid profile. Multivariable linear regression analysis revealed that sTNFR1 alone showed a significant association with low eGFR (p=0.009). However, after adjusting for age, the association weakens. Moreover, sTNFR1 and sTNFR2 showed a linear negative correlation with eGFR (r=-0.448, p<0.001 and r=-0.376, p<0.001, respectively). A positive correlation was also seen between sTNFR1 and HbA1c, whereas a negative correlation between both sTNFRs and high-density lipoprotein (HDL) cholesterol was found. CONCLUSION: Elevated levels of sTNFRs, especially sTNFR1, are associated with loss of kidney function in Hispanic patients with DM2. Future studies should focus on social and genetic determinants of inflammation and their association with CKD in this ethnicity.

MicroRNAs: Marcadores séricos en diabetes mellitus tipo 2 y ejercicio físico / MicroRNAs: circulating biomarkers in type 2 Diabetes Mellitus and physical exercise

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.

Changes to circulating inflammatory cytokines in response to moderate exercise.

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-1ß (IL-1ß) - 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-1ß 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-1ß 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.