Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis

The effect of a sodium glucose cotransporter 2 inhibitor (SGLT2i) in reducing heart failure hospitalization in the EMPA-REG OUTCOMES trial has raised the possibility of using these agents to treat established heart failure. We hypothesize that osmotic diuresis induced by SGLT2 inhibition, a distinctly different diuretic mechanism than other diuretic classes, results in greater electrolyte-free water clearance, and ultimately in greater fluid clearance from the interstitial fluid (IF) space than from the circulation, potentially resulting in congestion relief with minimal impact on blood volume, arterial filling, and organ perfusion. We utilize a mathematical model to illustrate that electrolyte-free water clearance results in a greater reduction in IF volume compared to blood volume, and that this difference may be mediated by peripheral sequestration of osmotically inactive sodium. By coupling the model with data on plasma and urinary sodium and water in healthy subjects administered either the SGLT2i dapagliflozin or loop diuretic bumetanide, we predict that dapagliflozin produces a 2-fold greater reduction in IF volume compared to blood volume, while the reduction in IF volume with bumetanide is only 78% of the reduction in blood volume. Heart failure is characterized by excess fluid accumulation, in both the vascular compartment and interstitial space, yet many heart failure patients have arterial underfilling due to low cardiac output, which may be aggravated by conventional diuretic treatment. Thus, we hypothesize that by reducing IF volume to a greater extent than blood volume, SGLT2 inhibitors might provide better control of congestion without reducing arterial filling and perfusion

Anti-inflammatory and antioxidant properties of HDLs are impaired in type 2 diabetes.

ObjectiveIn mice, 4F, an apolipoprotein A-I mimetic peptide that restores HDL function, prevents diabetes-induced atherosclerosis. We sought to determine whether HDL function is impaired in type 2 diabetic (T2D) patients and whether 4F treatment improves HDL function in T2D patient plasma in vitro.Research design and methodsHDL anti-inflammatory function was determined in 93 T2D patients and 31 control subjects as the ability of test HDLs to inhibit LDL-induced monocyte chemotactic activity in human aortic endothelial cell monolayers. The HDL antioxidant properties were measured using a cell-free assay that uses dichlorofluorescein diacetate. Oxidized fatty acids in HDLs were measured by liquid chromatography-tandem mass spectrometry. In subgroups of patients and control subjects, the HDL inflammatory index was repeated after incubation with L-4F.ResultsThe HDL inflammatory index was 1.42 ± 0.29 in T2D patients and 0.70 ± 0.19 in control subjects (P < 0.001). The cell-free assay was impaired in T2D patients compared with control subjects (2.03 ± 1.35 vs. 1.60 ± 0.80, P < 0.05), and also HDL intrinsic oxidation (cell-free assay without LDL) was higher in T2D patients (1,708 ± 739 vs. 1,233 ± 601 relative fluorescence units, P < 0.001). All measured oxidized fatty acids were significantly higher in the HDLs of T2D patients. There was a significant correlation between the cell-free assay values and the content of oxidized fatty acids in HDL fractions. L-4F treatment restored the HDL inflammatory index in diabetic plasma samples (from 1.26 ± 0.17 to 0.71 ± 0.11, P < 0.001) and marginally affected it in healthy subjects (from 0.81 ± 0.16 to 0.66 ± 0.10, P < 0.05).ConclusionsIn patients with T2D, the content of oxidized fatty acids is increased and the anti-inflammatory and antioxidant activities of HDLs are impaired

Meta‐analysis of the association between sodium‐glucose co‐transporter‐2 inhibitors and risk of skin cancer among patients with type 2 diabetes

A slight increase in melanoma risk was observed among sodium‐glucose co‐transporter‐2 (SGLT‐2) inhibitor users in the regular reports. However, the association remains uncertain. To address this issue, we performed a systematic search of electronic databases up to May 2, 2018 and a meta‐analysis of 21 randomized controlled trials (RCTs) involving 20 308 patients. We did not find a significant increase in risk of melanoma among SGLT‐2 inhibitor users (Peto odds ratio [OR], 2.17; 95% confidence interval [CI], 0.80‐5.89; I2, 0%). Similar results were observed in the subgroup analyses according to the type of SGLT‐2 inhibitor, type of control, ages of patients, race/ethnicity, and trial durations. For non‐melanoma skin cancer risk, no significant difference was observed when all trials were combined (Peto OR, 0.70; 95% CI, 0.47‐1.07; I2, 0%), while a significantly decreased risk was observed among trials with duration <52 weeks (Peto OR, 0.12; 95% CI, 0.02‐0.59; I2, 0%). No evidence of publication bias was detected in the analyses. Current evidence from RCTs did not support a significantly increased risk of skin cancer associated with SGLT‐2 inhibitors

Bariatric surgery as a treatment of type 2 diabetes

Obesity has reached epidemic proportions, predisposing to the development of type 2 diabetes and cardiovascular diseases. Weight loss is a major objective, although often difficult to achieve with medical treatments. Bariatric surgery has proven its efficacy in obtaining marked and sustained weight loss, and is also associated with a significant improvement in insulin resistance, beta cell function, lipid metabolism, blood pressure and even diabetes remission. We examined the long-term effect of Roux-en-Y gastric bypass (RYGB, a predominantly restrictive procedure) in a patient with uncontrolled type 2 diabetes. One year after surgery, the patient had lost 30% of initial weight with a significant improvement in blood pressure, withdrawal of cholesterol-lowering therapy, complete remission of diabetes

Hepatitis C virus infection and type 1 and type 2 diabetes mellitus

Hepatitis C virus (HCV) infection and diabetes mellitus are two major public health problems that cause devastating health and financial burdens worldwide. Diabetes can be classified into two major types: type 1 diabetes mellitus (T1DM) and T2DM. T2DM is a common endocrine disorder that encompasses multifactorial mechanisms, and T1DM is an immunologically mediated disease. Many epidemiological studies have shown an association between T2DM and chronic hepatitis C (CHC) infection. The processes through which CHC is associated with T2DM seem to involve direct viral effects, insulin resistance, proinflammatory cytokines, chemokines, and other immune-mediated mechanisms. Few data have been reported on the association of CHC and T1DM and reports on the potential association between T1DM and acute HCV infection are even rarer. A small number of studies indicate that interferon-α therapy can stimulate pancreatic autoimmunity and in certain cases lead to the development of T1DM. Diabetes and CHC have important interactions. Diabetic CHC patients have an increased risk of developing cirrhosis and hepatocellular carcinoma compared with non-diabetic CHC subjects. However, clinical trials on HCV-positive patients have reported improvements in glucose metabolism after antiviral treatment. Further studies are needed to improve prevention policies and to foster adequate and cost-effective programmes for the surveillance and treatment of diabetic CHC patients

GLP-1 and glucose tolerance after sleeve gastrectomy in morbidly obese subjects with type 2 diabetes.

Although GLP-1 has been suggested as a major factor for the marked improvement of glucose tolerance commonly seen after sleeve gastrectomy (SG), several observations challenge this hypothesis. To better understand the role of GLP-1 in the remission of type 2 diabetes mellitus (T2DM) long term after SG in humans, we conducted two separate cross-sectional studies: 1) the GLP-1 response to a standardized mixed liquid meal (SMLM) was compared in subjects with T2DM antedating SG but with different long-term (>2 years) T2DM outcomes (remission, relapse, or lack of remission) (study 1) and 2) the effect of GLP-1 receptor blockade with exendin (9-39) on glucose tolerance was examined in subjects with T2DM antedating surgery, who had undergone SG and presented with long-term T2DM remission (study 2). In study 1, we observed a comparable GLP-1 response to the SMLM regardless of the post-SG outcome of T2DM. In study 2, the blockade of GLP-1 action resulted in impaired insulin secretion but limited deterioration of glucose tolerance. Thus, our data suggest the enhanced GLP-1 secretion observed long term after SG is neither sufficient nor critical to maintain normal glucose tolerance in subjects with T2DM antedating the surgery

Intersection between metabolic dysfunction, high fat diet consumption, and brain aging

Deleterious neurochemical, structural, and behavioral alterations are a seemingly unavoidable aspect of brain aging. However, the basis for these alterations, as well as the basis for the tremendous variability in regards to the degree to which these aspects are altered in aging individuals, remains to be elucidated. An increasing number of individuals regularly consume a diet high in fat, with high‐fat diet consumption known to be sufficient to promote metabolic dysfunction, although the links between high‐fat diet consumption and aging are only now beginning to be elucidated. In this review we discuss the potential role for age‐related metabolic disturbances serving as an important basis for deleterious perturbations in the aging brain. These data not only have important implications for understanding the basis of brain aging, but also may be important to the development of therapeutic interventions which promote successful brain aging.Fil: Uranga, Romina Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Bruce Keller, Annadora J.. State University of Louisiana; Estados UnidosFil: Morrison, Christopher D.. State University of Louisiana; Estados UnidosFil: Fernandez Kim, Sun Ok. State University of Louisiana; Estados UnidosFil: Ebenezer, Philip J.. State University of Louisiana; Estados UnidosFil: Zhang, Le. State University of Louisiana; Estados UnidosFil: Dasuri, Kalavathi. State University of Louisiana; Estados UnidosFil: Keller, Jeffrey N.. State University of Louisiana; Estados Unido

Differential expression profile of CXCR3 splicing variants is associated with thyroid neoplasia. Potential role in papillary thyroid carcinoma oncogenesis?

Indexación: Scopus.Papillary thyroid cancer (PTC) is the most prevalent endocrine neoplasia. The increased incidence of PTC in patients with thyroiditis and the frequent immune infiltrate found in PTC suggest that inflammation might be a risk factor for PTC development. The CXCR3-ligand system is involved in thyroid inflammation and CXCR3 has been found upregulated in many tumors, suggesting its pro-tumorigenic role under the inflammatory microenvironment. CXCR3 ligands (CXCL4, CXCL9, CXCL10 and CXCL11) trigger antagonistic responses partly due to the presence of two splice variants, CXCR3A and CXCR3B. Whereas CXCR3A promotes cell proliferation, CXCR3B induces apoptosis. However, the relation between CXCR3 variant expression with chronic inflammation and PTC development remains unknown. Here, we characterized the expression pattern of CXCR3 variants and their ligands in benign tumors and PTC. We found that CXCR3A and CXCL10 mRNA levels were increased in non-metastatic PTC when compared to non-neoplastic tissue. This increment was also observed in a PTC epithelial cell line (TPC-1). Although elevated protein levels of both isoforms were detected in benign and malignant tumors, the CXCR3A expression remained greater than CXCR3B and promoted proliferation in Nthy-ori-3-1 cells. In non-metastatic PTC, inflammation was conditioning for the CXCR3 ligands increased availability. Consistently, CXCL10 was strongly induced by interferon gamma in normal and tumor thyrocytes. Our results suggest that persistent inflammation upregulates CXCL10 expression favoring tumor development via enhanced CXCR3A-CXCL10 signaling. These findings may help to further understand the contribution of inflammation as a risk factor in PTC development and set the basis for potential therapeutic studies.http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=23502&path[]=7402