A caffeine pre-treatment and sole effect of bone-marrow mesenchymal stem cells-derived conditioned media on hyperglycemia-suppressed fertilization.

As a common metabolic disorder, hyperglycemia (HG) affects and disrupts the physiology of various systems in the body. Transplantation of mesenchymal stem cells (MSCs) has been used to control the complications of disease. Most of the therapeutic properties of MSCs are attributed to their secretome. This study aimed to investigate the effects of conditioned media extracted from sole or caffeine pre-treated bone-marrow-derived MSCs on hyperglycemia-induced detrimental impact on some aspects of reproduction. The HG was induced by intraperitoneally injection of streptozotocin (65 mg/kg) and nicotinamide (110 mg/kg). Twenty-four male Wistar rats (190 ± 20 g) were divided into control, HG, and the hyperglycemic groups receiving conditioned media of proliferated MSCs solely (CM) or MSCs pre-treated with caffeine (CCM). During the 49-day treatment, body weight and blood glucose were measured weekly. Finally, HbA1c, spermatogenesis development, sperm count, morphology, viability, motility, chromatin condensation, and DNA integrity were examined. Also, testicular total antioxidant capacity (TAC), malondialdehyde, sperm fertilization potential, and pre-implantation embryo development were evaluated. A one-way ANOVA and Tukey's post-hoc tests were used to analyze the quantitative data. The p < 0.05 was considered statistically significant. The CM and with a higher efficiency, the CCM remarkably (p < 0.05) improved body weight and HG-suppressed spermatogenesis, enhanced sperm parameters, chromatin condensation, DNA integrity, and TAC, reduced HbA1c, sperm abnormalities, and malondialdehyde, and significantly improved pre-implantation embryo development versus HG group. The conditioned media of MSCs solely (CM) and more effectively after pre-treatment of MSCs with caffeine (CCM) could improve spermatogenesis development, sperm quality, pre-implantation embryo development, and testicular global antioxidant potential during hyperglycemia.

Endothelial thioredoxin interacting protein (TXNIP) modulates endothelium-dependent vasorelaxation in hyperglycemia.

Endothelial dysfunction, hallmarked by an imbalance between vasoconstriction and vasorelaxation, is associated with diabetes. Thioredoxin Interacting protein (TXNIP), controlled by an exquisitely glucose sensitive gene, is increasingly recognized for its role in diabetes. However, the role of TXNIP in modulating diabetes-related endothelial dysfunction remains unclear. To elucidate the role of TXNIP, we generated two novel mouse strains; endothelial-specific TXNIP knockout (EKO) and a Tet-O inducible, endothelial-specific TXNIP overexpression (EKI). Hyperglycemia was induced by streptozotocin (STZ) treatment in floxed control (fl/fl) and EKO mice. Doxycycline (DOX) was given to EKI mice to induce endothelial TXNIP overexpression. The ablation of endothelial TXNIP improved glucose tolerance in EKO mice. Acetylcholine-induced, endothelium-dependent vasorelaxation was impaired in STZ-treated fl/fl mice while this STZ impaired vasorelaxation was attenuated in EKO mice. Hyperglycemia induction of NLRP3 and reductions in Akt and eNOS phosphorylation were also mitigated in EKO mice. Overexpression of endothelial TXNIP did not impair glucose tolerance in DOX-treated EKI mice, however induction of endothelial TXNIP led to impaired vasorelaxation in EKI mice. This was associated with increased NLRP3 and reduced Akt and eNOS activation. In conclusion, deletion of endothelial TXNIP is protective against and overexpression of endothelial TXNIP induces endothelial dysfunction; thus, endothelial TXNIP plays a critical role in modulating endothelial dysfunction.

A Hyperglycemic Microenvironment Inhibits Tendon-to-Bone Healing through the let-7b-5p/CFTR Pathway.

BACKGROUND: Tendon-to-bone healing is a difficult process in treatment of rotator cuff tear (RCT). In addition, diabetes is an important risk factor for poor tendon-to-bone healing. Therefore, we investigated the specific mechanisms through which diabetes affects tendon-to-bone healing by regulating the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). METHODS: Tendon-derived stem cells (TDSCs) were extracted from rats after which their proliferative capacities were evaluated by the MTT assay. The expression levels of CFTR and tendon-related markers were determined by qRT-PCR. Then, bioinformatics analyses and dual luciferase reporter gene assays were used to identify miRNAs with the ability to bind CFTR mRNA. Finally, CFTR was overexpressed in TDSCs to validate the specific mechanisms through which the high glucose microenvironment inhibits tendon-to-bone healing. RESULTS: The high glucose microenvironment downregulated mRNA expression levels of tendon-related markers and CFTR in TDSCs cultured with different glucose concentrations. Additionally, bioinformatics analyses revealed that let-7b-5p may be regulated by the high glucose microenvironment and can regulate CFTR levels. Moreover, a dual luciferase reporter gene assay was used to confirm that let-7b-5p targets and binds CFTR mRNA. Additional experiments also confirmed that overexpressed CFTR effectively reversed the negative effects of the hyperglycaemic microenvironment and upregulation of let-7b-5p on TDSC proliferation and differentiation. These findings imply that the hyperglycemic microenvironment inhibits CFTR transcription and, consequently, proliferation and differentiation of TDSCs in vitro by upregulating let-7b-5p. CONCLUSIONS: A hyperglycemic microenvironment inhibits TDSC proliferation in vitro via the let-7b-5p/CFTR pathway, and this is a potential mechanism in diabetes-induced poor tendon-to-bone healing.

Megakaryocytes Mediate Hyperglycemia-Induced Tumor Metastasis.

High blood glucose has long been established as a risk factor for tumor metastasis, yet the molecular mechanisms underlying this association have not been elucidated. Here we describe that hyperglycemia promotes tumor metastasis via increased platelet activity. Administration of glucose, but not fructose, reprogrammed the metabolism of megakaryocytes to indirectly prime platelets into a prometastatic phenotype with increased adherence to tumor cells. In megakaryocytes, a glucose metabolism-related gene array identified the mitochondrial molecular chaperone glucose-regulated protein 75 (GRP75) as a trigger for platelet activation and aggregation by stimulating the Ca2+-PKCα pathway. Genetic depletion of Glut1 in megakaryocytes blocked MYC-induced GRP75 expression. Pharmacologic blockade of platelet GRP75 compromised tumor-induced platelet activation and reduced metastasis. Moreover, in a pilot clinical study, drinking a 5% glucose solution elevated platelet GRP75 expression and activated platelets in healthy volunteers. Platelets from these volunteers promoted tumor metastasis in a platelet-adoptive transfer mouse model. Together, under hyperglycemic conditions, MYC-induced upregulation of GRP75 in megakaryocytes increases platelet activation via the Ca2+-PKCα pathway to promote cancer metastasis, providing a potential new therapeutic target for preventing metastasis. SIGNIFICANCE: This study provides mechanistic insights into a glucose-megakaryocyte-platelet axis that promotes metastasis and proposes an antimetastatic therapeutic approach by targeting the mitochondrial protein GRP75.

Hyperglycemia exacerbates cadmium-induced glomerular nephrosis.

Current research suggests that cadmium (Cd) exposure may be associated with the progression of diabetic nephropathy; however, the details of this relationship are insufficiently understood. The present study investigated the effects of elevated glucose on Cd-induced toxicity to glomerular cells using in vitro and in vivo models, and it demonstrated that Cd exposure and the hyperglycemia of diabetes acting together increased the risk of developing glomerular nephrosis. In vitro, human podocytes were exposed to a DMEM low-glucose media without (control), or with Cd (as CdCl2), or a high-glucose media plus Cd. The CCK-8, ROS, apoptosis, and mitochondrial transmembrane potential (ΔΨm) assays showed that human podocytes exposed to Cd in a high-glucose media had greater degrees of injury compared with cells treated with Cd at low (euglycemic)-glucose levels. In vivo, diabetic hyperglycemia was induced by streptozotocin in 8-week-old male C57BL/6 mice to which either CdCl2 or saline (control) was intraperitoneally injected twice weekly for 24 weeks. Compared with euglycemic saline-treated controls, the diabetic mice exposed to Cd demonstrated decreased body weight and increased blood urea nitrogen levels along with histopathological renal architecture changes including collagen fiber accumulation. The results of this study supported the hypothesis that hyperglycemia plus Cd exposure increases the risk of damage to glomerular podocytes compared with Cd exposure in euglycemia.

Association between glucose intolerance and chemotherapy-induced lung injury in patients with lung cancer and interstitial lung disease.

PURPOSE: Cytotoxic chemotherapy-induced lung injury is a fatal complication in patients with lung cancer and interstitial lung disease (ILD). We aimed to evaluate the association between hyperglycemia and this form of lung injury in patients with lung cancer concomitant with ILD. METHODS: From 1147 patients with advanced lung cancer, we retrospectively enrolled 98 patients with ILD whose hemoglobin A1c (HbA1c) levels were measured, and investigated the association between HbA1c levels and cytotoxic chemotherapy-induced lung injury. In 73 patients whose serum samples were retained, we measured serum levels of advanced glycation end products (AGE) and assessed the association of AGE levels with HbA1c levels and cytotoxic chemotherapy-induced lung injury. RESULTS: The incidence of cytotoxic chemotherapy-induced lung injury was significantly higher in patients with HbA1c levels ≥ 5.8% than in those with HbA1c levels < 5.8%, but not in those with HbA1c levels ≥ 6.5% than in those with HbA1c levels < 6.5%. The multivariate logistic regression model revealed that HbA1c level ≥ 5.8% was a significant risk factor for this complication [odds ratio 3.178 (95% confidence interval 1.057-9.556), P = 0.040]. In addition, serum AGE levels were significantly higher in patients with HbA1c levels ≥ 5.8% than in those with HbA1c levels < 5.8% [median (interquartile range); 0.129 (0.023-0.290) and 0.474 (0.213-1.109) µg/mL, P = 0.001]. CONCLUSION: Glucose intolerance (e.g., HbA1c level ≥ 5.8%) may be a risk factor of cytotoxic chemotherapy-induced lung injury, which might be associated with elevated AGE production due to hyperglycemia.

A longitudinal study of the antilipolytic effect of insulin in women following bariatric surgery.

Insulin resistance of glucose utilization is fully restored following BMI normalization after bariatric surgery. We investigated if this also pertains to insulin-induced effects on fatty acid handling. Forty-three women with obesity (OB) were investigated before and 2 years after Roux-en-Y gastric by-pass when BMI was <30 kg/m2 (PO) and compared with 26 never obese women (NO). The Adipo-IR index was used as measure of insulin antilipolytic sensitivity. Changes (delta) in circulating glycerol and fatty acid levels during hyperinsulinemic euglycemic clamp represented the insulin maximum antilipolytic effect. Overall fatty acid utilization was reflected by delta fatty acids minus 3 × delta glycerol. Adipo-IR was higher in OB than in NO and PO (p < 0.0001), the latter two groups having similar values. Insulin lowered glycerol levels by about 70% in all groups, but delta glycerol was 30% larger in PO than in NO (p = 0.04). Delta adds and adds utilization were similar in all groups. We conclude that women with obesity, whose BMI is normalized after bariatric surgery, have improved maximum in vivo antilipolytic effect of insulin above expected in absolute but not relative terms as regards glycerol changes, while the handling of circulating fatty acids is changed to the normal state.

The effect of the menstrual cycle and hyperglycaemia on hormonal and metabolic responses during exercise.

PURPOSE: Variations in substrate metabolism have been identified in women during continuous steady-state aerobic exercise performed at the same relative intensity throughout discrete phases of the menstrual cycle, although some evidence exists that this is abolished when carbohydrate is ingested. This investigation examined the effects of a supraphysiologic exogenous glucose infusion protocol, administered during two phases of the menstrual cycle (follicular and luteal) in eumenorrheic women to identify differences between metabolic, hormonal and substrate oxidative responses. METHODS: During the experimental conditions, blood glucose was infused intravenously at rates to "clamp" blood glucose at 10 mM in seven healthy females (age 20 ± 1 y, mass 55.0 ± 4.1 kg, [Formula: see text] 40.0 ± 1.8 ml/kg/min). Following 30 min of seated rest, participants exercised on a cycle ergometer for 90 min at 60% [Formula: see text]. During the rest period and throughout exercise, blood metabolites and hormones were collected at regular intervals, in addition to expired air for the measurement of substrate oxidation. RESULTS: Significant differences between ovarian hormones and menstrual phase were identified, with estrogen significantly higher during the luteal phase compared to the follicular phase (213.28 ± 30.70 pmol/l vs 103.86 ± 13.85 pmol/l; p = 0.016), and for progesterone (14.23 ± 4.88 vs 2.11 ± 0.36 nmol/l; p = 0.042). However, no further significance was identified in any of the hormonal, metabolite or substrate utilisation patterns between phases. CONCLUSION: These data demonstrate that the infusion of a supraphysiological glucose dose curtails any likely metabolic influence employed by the fluctuation of ovarian hormones in eumenorrheic women during moderate exercise.

The Metaflammatory and Immunometabolic Role of Macrophages and Microglia in Diabetic Retinopathy.

Emergent studies reveal the roles of inflammatory cells and cytokines in the development of diabetic retinopathy (DR), which is gradually portrayed as a chronic inflammatory disease accompanied by metabolic disorder. Through the pathogenesis of DR, macrophages or microglia play a critical role in the inflammation, neovascularization, and neurodegeneration of the retina. Conventionally, macrophages are generally divided into M1 and M2 phenotypes which mainly rely on glycolysis and oxidative phosphorylation, respectively. Recently, studies have found that nutrients (including glucose and lipids) and metabolites (such as lactate), can not only provide energy for cells, but also act as signaling molecules to regulate the function and fate of cells. In this review, we discussed the intrinsic correlations among the metabolic status, polarization, and function of macrophage/microglia in DR. Hyperglycemia and hyperlipidemia could induce M1-like and M2-like macrophages polarization in different phases of DR. Targeting the regulation of microglial metabolic profile might be a promising therapeutic strategy to modulate the polarization and function of macrophages/microglia, thus attenuating the progression of DR.

Pathophysiological Characteristics Linking Type 2 Diabetes Mellitus and Colorectal Neoplasia.

A substantial body of literature has provided evidence that type 2 diabetes mellitus (T2DM) and colorectal neoplasia share several common factors. Both diseases are among the leading causes of death worldwide and have an increasing incidence. In addition to usual risk factors such as sedentary lifestyle, obesity, and family history, common pathophysiological mechanisms involved in the development of these diseases have been identified. These include changes in glucose metabolism associated with adipose tissue dysfunction including insulin resistance resulting to hyperinsulinemia and chronic hyperglycemia. In addition to altered glucose metabolism, abdominal obesity has been associated with accented carcinogenesis with chronic subclinical inflammation. An increasing number of studies have recently described the role of the gut microbiota in metabolic diseases including T2DM and the development of colorectal cancer (CRC). Due to the interconnectedness of different pathophysiological processes, it is not entirely clear which factor is crucial in the development of carcinogenesis in patients with T2DM. The aim of this work is to review the current knowledge on the pathophysiological mechanisms of colorectal neoplasia development in individuals with T2DM. Here, we review the potential pathophysiological processes involved in the onset and progression of colorectal neoplasia in patients with T2DM. Uncovering common pathophysiological characteristics is essential for understanding the nature of these diseases and may lead to effective treatment and prevention.

Hyperglycaemia-Induced Contractile Dysfunction and Apoptosis in Cardiomyocyte-Like Pulsatile Cells Derived from Mouse Embryonic Stem Cells.

Hyperglycaemia, a key metabolic abnormality in diabetes mellitus, is implicated in pathological cardiogenesis during embryological development. However, the underlying mechanisms and potential therapeutic targets remain unknown. We, therefore, studied the effect of hyperglycaemia on mouse embryonic stem cell (mESC) cardiac differentiation. The mESCs were differentiated via embryoid body (EB) formation and cultured under conditions with baseline (25 mM) or high (50 mM) glucose. Time-lapse microscopy images of pulsatile mESCs and Ca2+ transients were recorded. Biomarkers of cellular changes were detected using immunocytochemistry, terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) assay, and Western blot analyses. Differentiated, spontaneously beating mESCs stained positive for cardiac troponin T, α-actinin 2, myosin heavy chain, and connexin 43. Hyperglycaemia decreased the EB diameter and number of beating EBs as well as the cellular amplitude of contraction, the Ca2+ transient, and the contractile response to caffeine (1 mM), but had no effect on the expression of the sarco-endoplasmic reticulum calcium transport ATPase 2 (SERCA 2). Furthermore, hyperglycaemia decreased the expression of B cell lymphoma 2 (Bcl-2) and increased the expression of cytoplasmic cytochrome c and the number of TUNEL-positive cells, but had no effect on the expression of one of the mitochondrial fusion regulatory proteins, optic atrophy protein 1 (OPA1). Overall, hyperglycaemia suppressed the mESC cardiomyocyte-like differentiation and induced contractile dysfunction. The results are consistent with mechanisms involving abnormal Ca2+ handling and mitochondrial-dependent apoptosis, factors which represent potential therapeutic targets in developmental diabetic cardiac disease.

Adhesion-mediated mechanosignaling forces mitohormesis.

Mitochondria control eukaryotic cell fate by producing the energy needed to support life and the signals required to execute programed cell death. The biochemical milieu is known to affect mitochondrial function and contribute to the dysfunctional mitochondrial phenotypes implicated in cancer and the morbidities of aging. However, the physical characteristics of the extracellular matrix are also altered in cancerous and aging tissues. Here, we demonstrate that cells sense the physical properties of the extracellular matrix and activate a mitochondrial stress response that adaptively tunes mitochondrial function via solute carrier family 9 member A1-dependent ion exchange and heat shock factor 1-dependent transcription. Overall, our data indicate that adhesion-mediated mechanosignaling may play an unappreciated role in the altered mitochondrial functions observed in aging and cancer.

Continuous glucose monitoring indices predict poor FEV1 recovery following cystic fibrosis pulmonary exacerbations.

BACKGROUND: Little is known about the effect of dysglycemia during cystic fibrosis pulmonary exacerbation (PEx) on recovery of FEV1 percentage predicted (ppFEV1) METHODS: Continuous glucose monitoring (CGM) was commenced at the time of admission to hospital for PEx and continued for 6 weeks. The CGM indices, percentage of time glucose greater than 7.8 mmol/L (%T>7.8) and mean glucose were evaluated as predictors of absolute ppFEV1 change following treatment of PEx. RESULTS: Of the 20 participants who completed the study 13 (65%) had cystic fibrosis related diabetes (CFRD). The mean of both CGM indices were highest during the first week of pulmonary exacerbation and continued to decline over the first 4 weeks at which point they plateaued. Using multivariate regression models, factors which were predictive of maximum attained ppFEV1 change over 6 weeks were %T>7.8, mean glucose, HbA1c and preadmission ppFEV1 change from baseline. These relationships were independent of a diagnosis of CFRD, which was not associated with ppFEV1 recovery. In a longitudinal model of ppFEV1 change at weeks 1, 2 and 6, the CGM index %T>7.8 approached significance as a predictive variable. CONCLUSIONS: Hyperglycemia during PEx in adult CF patients is associated with poorer ppFEV1 recovery. Conversely, there was no association observed between CFRD diagnosis and ppFEV1 improvement, suggesting that optimization of glycemic control in CFRD patients may positively influence recovery of lung function. Further clinical trials are required to evaluate the merits of intensive glycemic control in CFRD during PEx.

Endothelial response to glucose: dysfunction, metabolism, and transport.

The endothelial cell response to glucose plays an important role in both health and disease. Endothelial glucose-induced dysfunction was first studied in diabetic animal models and in cells cultured in hyperglycemia. Four classical dysfunction pathways were identified, which were later shown to result from the common mechanism of mitochondrial superoxide overproduction. More recently, non-coding RNA, extracellular vesicles, and sodium-glucose cotransporter-2 inhibitors were shown to affect glucose-induced endothelial dysfunction. Endothelial cells also metabolize glucose for their own energetic needs. Research over the past decade highlighted how manipulation of endothelial glycolysis can be used to control angiogenesis and microvascular permeability in diseases such as cancer. Finally, endothelial cells transport glucose to the cells of the blood vessel wall and to the parenchymal tissue. Increasing evidence from the blood-brain barrier and peripheral vasculature suggests that endothelial cells regulate glucose transport through glucose transporters that move glucose from the apical to the basolateral side of the cell. Future studies of endothelial glucose response should begin to integrate dysfunction, metabolism and transport into experimental and computational approaches that also consider endothelial heterogeneity, metabolic diversity, and parenchymal tissue interactions.

Gestational diabetes mellitus and obesity are related to persistent hyperglycemia in the postpartum period / Diabetes mellitus gestacional e obesidade estão relacionados à hiperglicemia persistente no período pós-parto

Abstract Objective To evaluate the obstetric and sociodemographic characteristics of gestational diabetic women who maintained hyperglycemia in the postpartum period (6-12 weeks postpartum). Methods This is a longitudinal cohort study with women who have had gestational diabetes and/or macrosomic children between March 1st, 2016 and March 1st, 2017. Between 6 and 12 weeks after birth, women who had gestational diabetes collected fasting glycemia, glucose tolerance test, and glycated hemoglobin results. The data were collected from medical records and during an interview in the first postpartum consultation. A statistical analysis was performed using frequency, percentage, Chi- Squared test, Fisher exact test, Mann-Whitney test, and multivariate Poisson regression. The significance level adopted for the statistical tests was 5%. Results One hundred and twenty-two women were included. Most of the women were younger than 35 years old (70.5%), white, multiparous, and with no history of gestational diabetes. Thirteen percent of the participants developed persistent hyperglycemia. A univariate analysis showed that maternal age above 35 years, being overweight, having grade 1 obesity and weight gain under 5 kg was related to the persistence of hyperglycemia in the postpartum period. Conclusion Maternal age above 35 years, obesity and overweight, and the diagnosis of gestational diabetes in the first trimester of pregnancy are associated with hyperglycemia during the postpartum period.

Resumo Objetivo Avaliar características sociodemográficas e obstétricas de mulheres com diabetes gestacional que mantêm hiperglicemia no período pós-parto (6-12 semanas pós-parto). Métodos Este é um estudo longitudinal de coorte com mulheres com diagnóstico de diabetes gestacional e/ou macrossomia fetal entre 1° de março de 2016 a 1° de março de 2017. As mulheres coletaram glicemia de jejum, teste de tolerância a glicose e hemoglobina glicada entre 6 a 12 semanas pós-parto. Os dados foram coletados de prontuários médicos e durante entrevista na primeira consulta de revisão pós-parto. Uma análise estatística foi realizada através do cálculo de frequências, porcentagens, teste do qui-quadrado, teste exato de Fisher, teste de Mann-Whitney e regressão multivariada de Poisson. A significância estatística adotada foi de 5%. Resultados Cento e vinte e duas mulheres foram incluídas. A maioria delas tinha menos de 35 anos de idade (70,5%), eram brancas, multíparas, e não tinham história de diabetes gestacional. Treze por cento das participantes desenvolveu hiperglicemia persistente. A análise univariada mostrou que os fatores relacionados com a persistência de hiperglicemia no período pós-natal foram: idade materna acima de 35 anos, sobrepeso, obesidade grau 1 e ganho de peso abaixo de 5 quilos. A análisemultivariada incluiu o diagnóstico no primeiro trimestre como fator de risco para hiperglicemia persistente. Conclusão Mulheres acima de 35 anos, obesidade, sobrepeso e diagnóstico de diabetes gestacional no primeiro trimestre estão relacionados com hiperglicemia persistente no período pós-parto.

Hyperglycemia-induced VEGF and ROS production in retinal cells is inhibited by the mTOR inhibitor, rapamycin.

Determine the impact of the mTOR inhibitor, rapamycin, on the hyperglycemia-induced expression of vascular endothelial growth factor (VEGF) and the production of reactive oxygen species (ROS) in retinal cells. Rats made hyperglycemic for 8 weeks by streptozotocin, as well as control rats, received i.p. rapamycin (1 mg/kg) for 3 days prior to immunostaining of their retinas with anti-VEGF and anti-glial fibrillary acidic protein (GFAP) and measuring retinal protein levels of VEGF and GFAP by Western blotting. In other experiments, flow cytometry analysis of ethidium fluorescence determined intracellular ROS levels in the absence or presence of rapamycin (1 µM) under normoglycemic (5.5 mM) and hyperglycemic (25 mM) conditions in a rat retinal Müller cell line (TR-MUL5) and primary human retinal microvascular endothelial cells (HRMECs). In the diabetic retina, VEGF was elevated and colocalized with the glial marker, GFAP, whose level was also elevated. Treatment with rapamycin inhibited the diabetes-induced VEGF and GFAP increases. We also found that raising extracellular glucose from 5.5 mM to 25 mM resulted in significant rapamycin-sensitive increases in the ROS levels of TR-MUL5 cells and HRMECs. In rat retina, rapamycin attenuates the diabetes-induced VEGF overexpression, and in cultured Müller cells and HRMECs, inhibits the hyperglycemia-induced boost ROS.

Diabetic Control Agents and Their Impact on Cardiac Surgery Patients: A Clinical Overview.

Chronic hyperglycemia is associated with poor cardiovascular surgical outcomes due to microvascular and macrovascular complications. This is a major concern as over one third of cardiovascular surgical patients have diabetes mellitus which greatly increases their risk of experiencing adverse cardiovascular events. A literature review was performed to identify articles discussing the effects of anti-diabetic medications (ADMs) on cardiovascular outcomes and surgical mortality and morbidity rates. Optimizing perioperative glucose levels remains a key factor in producing good surgical outcomes. In addition, recognizing gender differences, increasing patient satisfaction, and implementing dedicated diabetic teams all improve surgical mortality and morbidity rates in the diabetic population.

Adipocyte lipolysis drives acute stress-induced insulin resistance.

Stress hyperglycemia and insulin resistance are evolutionarily conserved metabolic adaptations to severe injury including major trauma, burns, or hemorrhagic shock (HS). In response to injury, the neuroendocrine system increases secretion of counterregulatory hormones that promote rapid mobilization of nutrient stores, impair insulin action, and ultimately cause hyperglycemia, a condition known to impair recovery from injury in the clinical setting. We investigated the contributions of adipocyte lipolysis to the metabolic response to acute stress. Both surgical injury with HS and counterregulatory hormone (epinephrine) infusion profoundly stimulated adipocyte lipolysis and simultaneously triggered insulin resistance and hyperglycemia. When lipolysis was inhibited, the stress-induced insulin resistance and hyperglycemia were largely abolished demonstrating an essential requirement for adipocyte lipolysis in promoting stress-induced insulin resistance. Interestingly, circulating non-esterified fatty acid levels did not increase with lipolysis or correlate with insulin resistance during acute stress. Instead, we show that impaired insulin sensitivity correlated with circulating levels of the adipokine resistin in a lipolysis-dependent manner. Our findings demonstrate the central importance of adipocyte lipolysis in the metabolic response to injury. This insight suggests new approaches to prevent insulin resistance and stress hyperglycemia in trauma and surgery patients and thereby improve outcomes.

Glycaemia and hand grip strength in aging people: Guangzhou biobank cohort study.

BACKGROUND: There is a link between hyperglycemia and mechanical functions of muscle. However, existing evidence of the association between hyperglycemia and weaker muscle strength is limited and inconsistent. We examined whether glycemic status was associated with relative grip strength (RGS) in older Chinese. METHODS: In 2008-2012, 9180 participants (2516 men and 6664 women) from the Guangzhou Biobank Cohort Study had fasting and 2-h post-load glucose measured. Glycemic status was categorized as normoglycaemia, prediabetes (i.e., impaired fasting glucose and/or impaired glucose tolerance) and diabetes. RGS was assessed using a Jamar Hydraulic Hand Dynamometer divided by body mass index. General linear model was used to assess the association of glycemic status with RGS. RESULTS: After adjusting for age, smoking status, alcohol use, physical activity, health status, body fat percentage and waist circumference, in men, hyperglycemia was associated with a lower RGS, with the RGS being 1.38 (95% confidence interval (CI) = 1.34, 1.42) in normoglycaemia, 1.35 (95% CI = 1.30, 1.39) in prediabetes, 1.33 (95% CI = 1.29, 1.38) in newly diagnosed diabetes and 1.32 (95% CI = 1.27, 1.37) in known diabetes (P for trend < 0.001). The association of glycemic status with RGS was non-significant in women. Among the normoglycaemic group, no association was found between fasting glucose and RGS in men, whereas a significantly inverse association was found in women, with adjusted ß for RGS per mmol/l increase in fasting glucose being - 0.05 to - 0.04 (P values from 0.002 to 0.03). CONCLUSIONS: Higher fasting glucose was associated with reduced grip strength in a dose-response manner, and the association was significant even in women with normoglycaemia. Our findings suggest that lowering glucose across the whole range might be important in preserving muscle strength, especially in aging women.

Diabetes y COVID-19, una relación de ida y vuelta / Diabetes and COVID-19, one relation to go and comeback

Diabetic patients are at risk of developing unfavorably from SARS-COV19 disease, especially when they have poor glycemic control. On the other hand, in the case of diabetic patients with severe COVID, they evolve with severe hyperglycemia, often difficult to manage. Marked hyperglycemia has also been described in people without a known history of previous diabetes, even there have been reported cases of insulin-dependent diabetes debut in days after the disease. The aim of this review is to analyze possible mechanisms involved in the relationship between COVID-19 and DIABETES.