Review of SGLT2i for the Treatment of Renal Complications: Experience in Patients with and Without T2D

The management of type 2 diabetes (T2D) involves decreasing plasma glucose levels and reducing cardiovascular and microvascular complications. Diabetic kidney disease (DKD), defined as presence of albuminuria, impaired glomerular filtration, or both, is an insidious microvascular complication of diabetes that generates a substantial personal and clinical burden. The progressive reduction in renal function and increased albuminuria results in an increase of cardiovascular events. Thus, patients with DKD require exhaustive control of the associated cardiovascular risk factors. People with diabetes and renal impairment have fewer options of antidiabetic drugs because of contraindications, adverse effects, or altered pharmacokinetics. Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) reduce blood glucose concentrations by blocking the uptake of sodium and glucose in the proximal tubule and promoting glycosuria, and these agents now have an important role in the management of T2D. The results of several cardiovascular outcomes trials suggested that SGLT2i are associated with improvements in renal endpoints in addition to their reduction in cardiovascular events and mortality, which represents a major advance in the care of this population. The dedicated kidney outcomes trials have confirmed the renoprotective action of SGLT2i across different glomerular filtration and albuminuria values, even in patients with non-diabetic chronic kidney disease. Notably, this improvement in kidney function may indirectly benefit cardiac function through multifaceted interorgan cross talk, which can break the cardiorenal vicious circle linked to T2D. In this article, we briefly review the different mechanisms of action that may explain the renal beneficial effects of SGLT2i and disclose the results of the key renal outcome trials and the subsequent update of related clinical guidelines

A surgical model of short bowel syndrome induces a long-lasting increase in pancreatic beta-cell mass

Several surgical techniques are used nowadays as a severe treatment for obesity and diabetes mellitus type 2. These techniques are aggressive due to drastic changes in the nutrient flow and non-reversible modifications on the digestive tube. In this paper we present the effects of a massive intestinal resection on the pancreas. Results have shown that short bowel technique is less aggressive to normal anatomy and physiology of the intestinal tract than Gastric bypass or biliopancreatic diversion (e.g.). In this paper we reproduce a model of short bowel syndrome (SIC), with similar surgical conditions and clinical complications as seen in human cases. This work was conducted on normal Wistar rats, with no other concurrent factors, in order to determine the effects on normal pancreas islets. We measured pancreatic implications by histomorphometric studies, which included beta-cell mass by immunocytochemistry, and apoptosis/proliferation test with TUNEL technique and Ki-67. Briefly, we reported on an increased relative area of the islets of the pancreas, as well as an increase in the average size of islets in the SIC versus the control group. Furthermore we stated that this increase in size of the pancreatic islets is due to the mechanisms of proliferation of beta cells in animals undergoing SIC. These goals could reveal a direct influence of surgical modification of the digestive tract over the pancreatic beta cell homeostasis. In this sense, there are many potential stimulators of intestinal adaptation, including peptide hormones and growth components which are associated or involved as effectors of the endocrine pancreas

Madness at the Hospital of Innocents of Seville (1436-1840)

En el presente trabajo se estudia el funcionamiento y desarrollo histórico del Hospital de San Cosme y San Damián, la primera y más antigua de las instituciones existentes en Sevilla cuya función principal era la de «curar a los pobres enfermos faltos de juicio». Concretamente se estudia el origen, la evolución y significación del hospital a lo largo de los siglos, así como la información disponible acerca de los ingresos, patologías y tratamientos que constan en la documentación. También se exploran las competencias y funciones de las diferentes figuras que formaban parte del servicio a los enfermos.This article studies the functioning and the historical development of the Hospital de San Cosme y San Damián, the first and oldest institution of Seville which main function was «healing the insane without sense». Specifically, we study the origin, evolution and significance of the hospital through the centuries, as well as the available information regarding admissions, pathologies and treatment contained in the documentation. Moreover we explore the responsibilities and roles of the people who were part of the assistance to the insane

Coenzyme Q10 therapy

For a number of years, coenzyme Q10 (CoQ10) was known for its key role in mitochondrial bioenergetics; later studies demonstrated its presence in other subcellular fractions and in blood plasma, and extensively investigated its antioxidant role. These 2 functions constitute the basis for supporting the clinical use of CoQ10. Also, at the inner mitochondrial membrane level, CoQ10 is recognized as an obligatory cofactor for the function of uncoupling proteins and a modulator of the mitochondrial transition pore. Furthermore, recent data indicate that CoQ 10 affects the expression of genes involved in human cell signaling, metabolism and transport, and some of the effects of CoQ10 supplementation may be due to this property. CoQ10 deficiencies are due to autosomal recessive mutations, mitochondrial diseases, aging-related oxidative stress and carcinogenesis processes, and also statin treatment. Many neurodegenerative disorders, diabetes, cancer, and muscular and cardiovascular diseases have been associated with low CoQ10 levels as well as different ataxias and encephalomyopathies. CoQ10 treatment does not cause serious adverse effects in humans and new formulations have been developed that increase CoQ10 absorption and tissue distribution. Oral administration of CoQ10 is a frequent antioxidant strategy in many diseases that may provide a significant symptomatic benefit.This work was supported by grants (FIS PI10/00543, FIS EC08/00076) from the Ministerio de Sanidad, Spain, and Fondo Europeo de Desarrollo Regional (FEDER-Unión Europea); Servicio Andaluz de Salud-Junta de Andalucía (SAS 111242); Proyecto de Investigación de Excelencia de la Junta de Andalucía (CTS-5725); and by AEPMI (Asociación de Enfermos de Patología Mitocondrial), FEEL (Fundación Española de Enfermedades Lisosomales) and ALBA Andalucía (Federación Andaluza de Fibromialgia y Fatiga Crónica).Peer Reviewe

Apoptotic microtubules delimit an active caspase free area in the cellular cortex during the execution phase of apoptosis

This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License.Apoptotic microtubule network (AMN) is organized during apoptosis, forming a cortical structure beneath plasma membrane, which has an important role in preserving cell morphology and plasma membrane permeability. The aim of this study was to examine the role of AMN in maintaining plasma membrane integrity during the execution phase of apoptosis. We demonstrated in camptothecin-induced apoptosis in H460 cells that AMN delimits an active caspase free area beneath plasma membrane that permits the preservation of cellular cortex and transmembrane proteins. AMN depolymerization in apoptotic cells by a short exposure to colchicine allowed active caspases to reach the cellular cortex and cleave many key proteins involved in plasma membrane structural support, cell adhesion and ionic homeostasis. Cleavage of cellular cortex and plasma membrane proteins, such as α-spectrin, paxilin, focal adhesion kinase (FAK), E-cadherin and integrin subunit β4 was associated with cell collapse and cell detachment. Otherwise, cleavage-mediated inactivation of calcium ATPase pump (PMCA-4) and Na(+)/Ca(2+) exchanger (NCX) involved in cell calcium extrusion resulted in calcium overload. Furthermore, cleavage of Na(+)/K(+) pump subunit β was associated with altered sodium homeostasis. Cleavage of cell cortex and plasma membrane proteins in apoptotic cells after AMN depolymerization increased plasma permeability, ionic imbalance and bioenergetic collapse, leading apoptotic cells to secondary necrosis. The essential role of caspase-mediated cleavage in this process was demonstrated because the concomitant addition of colchicine that induces AMN depolymerization and the pan-caspase inhibitor z-VAD avoided the cleavage of cortical and plasma membrane proteins and prevented apoptotic cells to undergo secondary necrosis. Furthermore, the presence of AMN was also critical for proper phosphatidylserine externalization and apoptotic cell clearance by macrophages. These results indicate that AMN is essential to preserve an active caspase free area in the cellular cortex of apoptotic cells that allows plasma membrane integrity during the execution phase of apoptosis.This work was supported by FIS PI10/00543 grant, FIS EC08/00076 grant, Ministerio de Sanidad, Spain and Fondo Europeo de Desarrollo Regional (FEDER-Unión Europea), SAS 111242 grant, Servicio Andaluz de Salud Junta de Andalucía, Proyecto de Investigación de Excelencia de la Junta de Andalucía CTS-5725, and by AEPMI (Asociación de Enfermos de Patología Mitocondrial).Peer reviewe

Long-term effects in bone mineral density after different bariatric procedures in patients with type 2 diabetes: outcomes of a randomized clinical trial

There is scant evidence of the long-term effects of bariatric surgery on bone mineral density (BMD). We compared BMD changes in patients with severe obesity and type 2 diabetes (T2D) 5 years after randomization to metabolic gastric bypass (mRYGB), sleeve gastrectomy (SG) and greater curvature plication (GCP). We studied the influence of first year gastrointestinal hormone changes on final bone outcomes. Forty-five patients, averaging 49.4 (7.8) years old and body mass index (BMI) 39.4 (1.9) kg/m(2), were included. BMD at lumbar spine (LS) was lower after mRYGB compared to SG and GCP: 0.89 [0.82;0.94] vs. 1.04 [0.91;1.16] vs. 0.99 [0.89;1.12],p= 0.020. A higher percentage of LS osteopenia was present after mRYGB 78.6% vs. 33.3% vs. 50.0%, respectively. BMD reduction was greater in T2D remitters vs. non-remitters. Weight at fifth year predicted BMD changes at the femoral neck (FN) (adjustedR(2): 0.3218;p= 0.002), and type of surgery (mRYGB) and menopause predicted BMD changes at LS (adjustedR(2): 0.2507;p< 0.015). In conclusion, mRYGB produces higher deleterious effects on bone at LS compared to SG and GCP in the long-term. Women in menopause undergoing mRYGB are at highest risk of bone deterioration. Gastrointestinal hormone changes after surgery do not play a major role in BMD outcomes

Role of adipose tissue GLP-1R expression in metabolic improvement after bariatric surgery in patients with type 2 diabetes

We aimed to explore the relationship between GLP-1 receptor (GLP-1R) expression in adipose tissue (AT) and incretin secretion, glucose homeostasis and weight loss, in patients with morbid obesity and type 2 diabetes undergoing bariatric surgery. RNA was extracted from subcutaneous (SAT) and visceral (VAT) AT biopsies from 40 patients randomized to metabolic gastric bypass, sleeve gastrectomy or greater curvature plication. Biochemical parameters, fasting plasma insulin, glucagon and area under the curve (AUC) of GLP-1 following a standard meal test were determined before and 1 year after bariatric surgery. GLP-1R expression was higher in VAT than in SAT. GLP-1R expression in VAT correlated with weight (r = -0.453, p = 0.008), waist circumference (r = -0.494, p = 0.004), plasma insulin (r = -0.466, p = 0.007), and systolic blood pressure (BP) (r = -0.410, p = 0.018). At 1 year, GLP-1R expression in VAT was negatively associated with diastolic BP (r = -0.361, p = 0.039) and, following metabolic gastric bypass, with the increase of GLP-1 AUC, (R-2 = 0.46, p = 0.038). Finally, GLP-1R in AT was similar independently of diabetes outcomes and was not associated with weight loss after surgery. Thus, GLP-1R expression in AT is of limited value to predict incretin response and does not play a role in metabolic outcomes after bariatric surgery

A specific gut microbiota signature is associated with an enhanced GLP-1 and GLP-2 secretion and improved metabolic control in patients with type 2 diabetes after metabolic Roux-en-Y gastric bypass

ObjectiveTo determine changes in incretins, systemic inflammation, intestinal permeability and microbiome modifications 12 months after metabolic RYGB (mRYGB) in patients with type 2 diabetes (T2D) and their relationship with metabolic improvement.Materials and methodsProspective single-center non-randomized controlled study, including patients with class II-III obesity and T2D undergoing mRYGB. At baseline and one year after surgery we performed body composition measurements, biochemical analysis, a meal tolerance test (MTT) and lipid test (LT) with determination of the area under the curve (AUC) for insulin, C-peptide, GLP-1, GLP-2, and fasting determinations of succinate, zonulin, IL-6 and study of gut microbiota.ResultsThirteen patients aged 52.6 ± 6.5 years, BMI 39.3 ± 1.4 kg/m2, HbA1c 7.62 ± 1.5% were evaluated. After mRYGB, zonulin decreased and an increase in AUC after MTT was observed for GLP-1 (pre 9371 ± 5973 vs post 15788 ± 8021 pM, P&lt;0.05), GLP-2 (pre 732 ± 182 vs post 1190 ± 447 ng/ml, P&lt;0.001) and C- peptide, as well as after LT. Species belonging to Streptococaceae, Akkermansiacea, Rickenellaceae, Sutterellaceae, Enterobacteriaceae, Oscillospiraceae, Veillonellaceae, Enterobacterales_uc, and Fusobacteriaceae families increased after intervention and correlated positively with AUC of GLP-1 and GLP-2, and negatively with glucose, HbA1c, triglycerides and adiposity markers. Clostridium perfringens and Roseburia sp. 40_7 behaved similarly. In contrast, some species belonging to Lachnospiraceae, Erysipelotricaceae, and Rumnicocaceae families decreased and showed opposite correlations. Higher initial C-peptide was the only predictor for T2D remission, which was achieved in 69% of patients.ConclusionsPatients with obesity and T2D submitted to mRYGB show an enhanced incretin response, a reduced gut permeability and a metabolic improvement, associated with a specific microbiota signature

The MEDESS-GIB database: Tracking the Atlantic water inflow

On 9 September 2014, an intensive drifter deployment was carried out in the Strait of Gibraltar. In the frame of the MEDESS-4MS Project (EU MED Program), the MEDESS-GIB experiment consisted of the deployment of 35 satellite tracked drifters, mostly of CODE-type, equipped with temperature sensor sampling at a rate of 30min. Drifters were distributed along and on both sides of the Strait of Gibraltar. The MEDESS-GIB deployment plan was designed as to ensure quasi-synoptic spatial coverage. To this end, four boats covering an area of about 680NM2 in 6h were coordinated. As far as these authors know, this experiment is the most important exercise in the area in terms of number of drifters released. Collected satellite-tracked data along drifter trajectories have been quality controlled and processed to build the presented MEDESS-GIB database. This paper reports the MEDESS-GIB data set that comprises drifter trajectories, derived surface currents and in situ SST measurements collected along the buoys tracks. This series of data is available through the PANGAEA (Data Publisher for Earth and Environmental Science) repository, with the following doi:10.1594/PANGAEA.853701. Likewise, the MEDESS-GIB data will be incorporated as part of the Copernicus Marine historical products. The MEDESS-GIB data set provides a complete Lagrangian view of the surface inflow of Atlantic waters through the Strait of Gibraltar and thus, very useful data for further studies on the surface circulation patterns in the Alboran Sea, and their links with one of the most energetic Mediterranean Sea flows: the Algerian Current