Placental mesenchymal stem cells restore glucose and energy homeostasis in obesogenic adipocytes.

Obesity (Ob) depicts a state of energy imbalance(s) being characterized by the accumulation of excessive fat and which predisposes to several metabolic diseases. Mesenchymal stem cells (MSCs) represent a promising option for addressing obesity and its associated metabolic co-morbidities. The present study aims at assessing the beneficial effects of human placental MSCs (P-MSCs) in mitigating Ob-associated insulin resistance (IR) and mitochondrial dysfunction both in vivo and in vitro. Under obesogenic milieu, adipocytes showed a significant reduction in glucose uptake, and impaired insulin signaling with decreased expression of UCP1 and PGC1α, suggestive of dysregulated non-shivering thermogenesis vis-a-vis mitochondrial biogenesis respectively. Furthermore, obesogenic adipocytes demonstrated impaired mitochondrial respiration and energy homeostasis evidenced by reduced oxygen consumption rate (OCR) and blunted ATP/NAD+/NADP+ production respectively. Interestingly, co-culturing adipocytes with P-MSCs activated PI3K-Akt signaling, improved glucose uptake, diminished ROS production, enhanced mitochondrial OCR, improved ATP/NAD+/NADP+ production, and promoted beiging of adipocytes evidenced by upregulated expression of PRDM16, UCP1, and PGC1α expression. In vivo, P-MSCs administration increased the peripheral blood glucose uptake and clearance, and improved insulin sensitivity and lipid profile with a coordinated increase in the ratio of ATP/ADP and NAD+ and NADP+ in the white adipose tissue (WAT), exemplified in WNIN/GR-Ob obese mutant rats. In line with in vitro findings, there was a significant reduction in adipocyte hypertrophy, increased mitochondrial staining, and thermogenesis. Our findings advocate for a therapeutic application of P-MSCs for improving glucose and energy homeostasis, i.e., probably restoring non-shivering thermogenesis towards obesity management.

Blood glucose related adverse drug reaction of antitumor monoclonal antibodies: a retrospective analysis using Vigibase

Abstract On the increasing prevalence of using mAbs (monoclonal antibodies) in cancer therapy and the severe risk of hyperglycemia, we aimed to analyze the main clinical ADRs of mAbs, with a focus on adverse hyperglycemic events associated with currently clinically used mAbs. mAbs as well as target information were selected from Martinadale book and published articles. Drug approving information was collected from each government website, and ADR statistic data were collected from VigibaseR, comparing with Adverse Event Reporting System of US FDA. Top 10 mAbs were classified within listing in total ADR records, ADRs per year, hyperglycemic ADR records. Vigibase data were updated onto 15 Feb 2019. 20 mAbs were analyzed with 263217 ADR reports, wherein 16751 records on Metabolism and nutrition disorders and 1444 records on Glucose metabolism disorders. The geographic, age, gender distributions and annual ADR report numbers were listed respectively. Of the top 10, Rituximab, Bevacizumab and Nivolumab were on the top 3 in total ADR record and hyperglycemic record. Top 3 record results were similar in Vigibase and FDA database. It is of increasing importance for clinicians to be aware of early detection, patient management, or drug selection strategies when using mAbs, particularly within the high glycemic risk-reported mAbs, to improve the efficacy and tolerability of mAbs regiment and optimize patient outcomes.

Neuron-specific mitochondrial oxidative stress results in epilepsy, glucose dysregulation and a striking astrocyte response.

Mitochondrial superoxide (O2-) production is implicated in aging, neurodegenerative disease, and most recently epilepsy. Yet the specific contribution of neuronal O2- to these phenomena is unclear. Here, we selectively deleted superoxide dismutase-2 (SOD2) in neuronal basic helix-loop-helix transcription factor (NEX)-expressing cells restricting deletion to a subset of excitatory principle neurons primarily in the forebrain (cortex and hippocampus). This resulted in nSOD2 KO mice that lived into adulthood (2-3 months) with epilepsy, selective loss of neurons, metabolic rewiring and a marked mitohormetic gene response. Surprisingly, expression of an astrocytic gene, glial fibrillary acidic protein (GFAP) was significantly increased relative to WT. Further studies in rat primary neuron-glial cultures showed that increased mitochondrial O2-, specifically in neurons, was sufficient to upregulate GFAP. These results suggest that neuron-specific mitochondrial O2- is sufficient to drive a complex and catastrophic epileptic phenotype and highlights the ability of SOD2 to act in a cell-nonautonomous manner to influence an astrocytic response.

Roles of microRNAs in carbohydrate and lipid metabolism disorders and their therapeutic potential.

MicroRNAs (miRNAs) are small (∼21 nucleotides), endogenous, non-coding RNA molecules implicated in the post-transcriptional gene regulation performed through target mRNA cleavage or translational inhibition. In recent years, several investigations have demonstrated that miRNAs are involved in regulating both carbohydrate and lipid homeostasis in humans and other organisms. Moreover, it has been observed that the dysregulation of these metabolism-related miRNAs leads to the development of several metabolic disorders, such as type 2 diabetes, obesity, nonalcoholic fatty liver, insulin resistance, and hyperlipidemia. Hence, in this current review, with the aim to impulse the research arena of the micro-transcriptome implications in vital metabolic pathways as well as to highlight the remarkable potential of miRNAs as therapeutic targets for metabolic disorders in humans, we provide an overview of the regulatory roles of metabolism-associated miRNAs in humans and murine models.

Glycine Improves Ischemic Stroke Through miR-19a-3p/AMPK/GSK-3ß/HO-1 Pathway.

PURPOSE: To explore the molecular mechanism of glycine in improving ischemic stroke. PATIENTS AND METHODS: The serum samples of patients with ischemic stroke and healthy people were compared. The ischemic stroke model of PC12 cells was established by oxygen-glucose deprivation (OGD). qPCR quantified miR-19a-3p and AMPK mRNA, and protein expression was detected by Western blot. MTT was used to detect cell activity. Flow cytometry was used to detect cells. Glucose metabolism kit was used to detect glucose intake and formation amount of lactic acid. RESULTS: Compared with the control group, OGD group (OGDG) showed lower cell activity and increased cell apoptosis. TNF-α, IL-1ßI, L-6, Caspase 3, Caspase 9 and Bax were up-regulated, and Glut1, HK2, LDHA, PDK1, PKM2 and Bcl2 were down-regulated. At the same time, glucose intake, formation amount of lactic acid and cell apoptosis rate were reduced, and AMPK/GSK-3ß/HO-1 pathway activity was down-regulated. Glycine could counteract the above phenomena in OGDG. miR-19a-3p and AMPK decreased and increased, respectively, during glycine therapy. AMPK was the target gene of miR-19a-3p. Rescue experiments demonstrated that glycine improved cell apoptosis, inflammatory response and glucose metabolism disorder of ischemic stroke through miR-19a-3p/AMPK/GSK-3ß/HO-1 pathway. CONCLUSION: Glycine improves ischemic stroke through miR-19a-3p/AMPK/GSK-3ß/HO-1 pathway.

Effect of Vanadium Complex with Enzymatic Hydrolysate of Soy Protein on Carbohydrate and Lipid Metabolism Disorders in Male Wistar Rats.

The effects of vanadium complex with enzymatic hydrolysate of soy protein (V-EHSPI) were studied in male Wistar rats with induced disorders of carbohydrate and lipid metabolism. The content of vanadium (IV) in the studied complex was 15.8 mg/g dry product. High-lipid high-carbohydrate diet was used to induce disorders of lipid and carbohydrate metabolism. Addition of vanadium in three different doses to the diet over 100-day experiment reduced body weight gain and the levels of glucose, insulin, leptin, and triglycerides. V-EHSPI produced beneficial effects on carbohydrate and lipid metabolism even in a dose 5 µg/kg body weight/day (calculated from the mean food consumption over the entire treatment period). Significant inhibition of growth and changes in the weight of organs in animals treated with V-EHSPI attested to toxicity of vanadium in the studied dose range.

The early history of GIP 1969-2000: From enterogastrone to major metabolic hormone.

This paper describes the early history of Gastric Inhibitory Polypeptide, better referred to simply as GIP, from its isolation by purification from a crude preparation of CCK-PZ (cholecystokinin/pancreozymin) to its recognition as a key play in the pathogenesis of obesity and other metabolic disorders far removed from the enterogastrone properties by which it was originally identified. Augmentation of glucose mediated insulin release, the incretin effect, was discovered soon after GIP was first isolated and only much later was its important role in the pathogenesis of obesity, through mechanism other than its insulin secretion, appreciated. Immunoassay - the method by which the concentration of GIP was measured in plasma until quite recently - was found to be flawed and to depend upon which specific epitope of the hormone an assay detected. This was especially true if it was an amino-acid sequence specific to porcine rather than human GIP. A further confounder was the discovery that much of the GIP measured by immunoassay was its biological antagonist produced by cleavage of its two N-terminal amino-acids in the circulation by the same dipeptidyl-peptidase as de-activates GLP-1. Potential use of synthetic agonistic and antagonistic GIP analogues in therapeutics was barely alluded to before year 2000.

Prevalence and progression of carbohydrate disorders in patients with pheochromocytoma/paraganglioma: retrospective single-center study.

BACKGROUND: Carbohydrate disorders are the most frequent metabolic disorders, affecting a significant proportion of patients with pheochromocytoma. OBJECTIVE: A retrospective study assessed the prevalence and progression of carbohydrate disorders in 204 patients (92 men, 112 women) with histologically proven pheochromocytoma diagnosed in a single specialized tertiary center during a 40-year period (1978-2017). One hundred were followed-up after tumor removal. RESULTS: Carbohydrate disorders were diagnosed in 49.5% of cases: 30.4% with diabetes and, 19.1% prediabetes. Subjects with carbohydrate disorders had significantly greater age at diagnosis and higher 24-hour urine metanephrine and normetanephrine concentrations than those with normal glucose tolerance. One-third of patients with diabetes achieved good glycemic control under oral treatment (54% on metformin monotherapy). One-third of patients overall required preoperative insulin treatment. Postoperative follow-up (100 patients; 5-year mean duration) showed reduced prevalence of diabetes (13% vs. 33%; P=0.0007) and prediabetes (12% vs. 24%; P=0.027). Almost 60% of subjects initially diagnosed with carbohydrate disorders recovered normal glucose tolerance after surgery; these subjects had significantly higher preoperative urine metanephrine/normetanephrine levels than those with persistent diabetes/prediabetes. Correlation analysis revealed a moderate negative relationship between urine metanephrine/normetanephrine concentration and the outcome of the carbohydrate disorders (Spearmen's Rho=-0.507; P=0.013). There was no significant difference according to pre- or postoperative prevalence of obesity (15% vs. 16%; P=0.845) or dyslipidemia (46% vs. 39%; P=0.316). CONCLUSIONS: Carbohydrate disorders affect approximately 50% of pheochromocytoma patients; 30% develop overt diabetes, which may be the only clinical manifestation in some rare cases. Pheochromocytoma-related diabetes is more likely to affect patients with predominant adrenaline secretion. It is often easy to control and usually requires oral antidiabetic treatment. Reversibility of carbohydrate disorders depend on severity, preoperative metanephrine level, age and weight.

Postmortem Analysis of Vitreous Humor For Detection of Antemortem Disorders in Glucose Metabolism. An Old Method Revisited.

It has been estimated that 15% up to one third of cases of deaths due to diabetic ketoacidosis occur in individuals with so far unknown diabetes. Moreover, cardiac arrhythmias that occur during nocturnal hypoglycaemia include bradycardia and ectopics that may provoke lethal arrhythmias. As postmortem capillary glucose concentrations have no diagnostic value, the postmortem forensic proof of hyperglycaemia or hypoglycaemia remains a challenge. The established but rarely applied method of postmortem determination of glucose and lactate in vitreous humor with or without calculation of the sum formula of Traub could provide reliable exclusion or proof of severe antemortem disorders in glucose metabolism. To date, diagnostic puncture of vitreous humor is more established for the postmortem detection of diabetic ketoacidosis than for the exclusion or proof of lethal hypoglycaemia. Vitreous humor is protected from postmortem degradation and contamination due to its isolated localization. The autolytic process in vitreous humor is considerably delayed compared to blood or liquor. In vitreous humor also the triggering agent of hypoglycaemia (insulin, insulin analogues) is easier to be detected than in blood since insulins are very unstable in postmortem blood. Furthermore, parameters of long term glycaemic control such as 1,5-anhydroglucitol, HbA1c and fructosamine can be determined in vitreous humor. However, limitations and interference factors of this method should be carefully considered. So far, clinical diabetology has taken no broad notice of this useful forensic procedure.

p53-dependent transcriptional suppression of BAG3 protects cells against metabolic stress via facilitation of p53 accumulation.

Solid tumour frequently undergoes metabolic stress during tumour development because of inadequate blood supply and the high nutrient expenditure. p53 is activated by glucose limitation and maintains cell survival via triggering metabolic checkpoint. However, the exact downstream contributors are not completely identified. BAG3 is a cochaperone with multiple cellular functions and is implicated in metabolic reprogramming of pancreatic cancer cells. The current study demonstrated that glucose limitation transcriptionally suppressed BAG3 expression in a p53-dependent manner. Importantly, hinderance of its down-regulation compromised cellular adaptation to metabolic stress triggered by glucose insufficiency, supporting that BAG3 might be one of p53 downstream contributors for cellular adaptation to metabolic stress. Our data showed that ectopic BAG3 expression suppressed p53 accumulation via direct interaction under metabolic stress. Thereby, the current study highlights the significance of p53-mediated BAG3 suppression in cellular adaptation to metabolic stress via facilitating p53 accumulation.

[Bone microarchitecture and other body composition parameters in patients with overweight or obesity grouped by glucose metabolism disorders]. / Microarquitectura ósea y otros parámetros de composición corporal en pacientes con sobrepeso u obesidad agrupados según alteraciones del metabolismo hidrocarbonado.

INTRODUCTION: Introduction: obesity and DM-2 decrease trabecular bone mass even though cortical bone increase may coexist. Another common finding is presarcopenia/sarcopenia, possibly due to insulin resistance and oxidative stress. It remains to be clarified whether these changes depend on either early (prediabetes) or late (established DM) glucidic alterations, or rather they would be linked predominantly by excess fat mass in obese patients Objectives: to evaluate and compare body composition parameters (bone, muscle and adipose-visceral tissues) in overweight/obese patients grouped by whether or not they present glucidic metabolism disorders. Analyze if there are differences between FRAX vs FRAX adjusted to trabecular bone score TBS in both groups. Methods: sixteen overweight/obese patients were included. In all of them clinical-anthropometric evaluation, bioimpedance, DXA and analysis were performed. They were grouped by glycemia as: a) normal; b) impaired fasting glycemia (IFG); and c) DM-2. Non-parametric tests were performed. Results: no statistically significant differences were found among groups regarding bone microarchitecture, muscle mass or visceral fat. The IFG group showed the highest average muscle mass and visceral fat. Then, patients were reclassified in only two groups, normal glycemia in group 1 and altered glycemia in group 2 (IFG and DM-2), and statistically significant differences were found at the expense of lower trabecular bone microarchitecture in group 2 (p = 0.031) and phosphorus lower levels in group 1 (p = 0.042). Conclusions: in our study, the bone microarchitecture is impaired in patients with altered glycemia and obesity. Studies with larger sample size are needed to establish when these changes take place in the natural evolution of diabetes.

INTRODUCCIÓN: Introducción: la obesidad y la diabetes mellitus tipo 2 (DM-2) disminuyen el entramado trabecular óseo aun cuando puede coexistir aumento del hueso cortical. Otro hallazgo en común es la presarcopenia/sarcopenia secundaria posiblemente a la insulinorresistencia y el estrés oxidativo. Queda por aclarar si estos cambios dependen fundamentalmente de las alteraciones glucídicas precoces (pre DM-2) o tardías (DM-2 establecida), o más bien estarían vinculadas de forma predominante por el exceso de masa grasa en individuos obesos. Objetivos: evaluar y comparar parámetros de composición corporal (compartimentos óseo, muscular y adiposo-visceral) en pacientes con sobrepeso/obesidad agrupados según presenten o no alteraciones glucídicas. Analizar si existen diferencias comparando FRAX vs. FRAX ajustado a trabecular bone score (TBS) en ambos grupos. Métodos: se incluyeron 16 pacientes con sobrepeso/obesidad. A todos se les realizó evaluación clínica-antropométrica, bioimpedanciometría, absorciometría de rayos X de energía dual o densitometría ósea (DXA) y análisis, y se les agrupó según glucemia en tres grupos: a) normal; b) glucemia basal alterada en ayunas (GBA); y c) DM-2. Para el análisis estadístico empleamos pruebas no paramétricas. Resultados: no se encontraron diferencias estadísticamente significativas en los grupos respecto a microarquitectura ósea, masa muscular o grasa visceral. El grupo GBA mostró el mayor promedio de masa muscular y grasa visceral. Tras reclasificar en solo dos grupos, glucemia normal en el grupo 1 y glucemia alterada en el grupo 2 (GBA y DM-2), encontramos diferencias estadísticamente significativas con detrimento de la microarquitectura ósea trabecular en el grupo 2 (p = 0,031) y cifras de fósforo con niveles inferiores en el grupo 1 (p = 0,42). Conclusiones: en nuestro estudio, la microarquitectura ósea está deteriorada en pacientes con glucemia alterada y obesos. Hacen falta estudios con mayor tamaño muestral para establecer en qué momento se instauran estos cambios en la evolución natural de la diabetes.

Dysglycemia and the Density of the Coronary Vasa Vasorum.

OBJECTIVE: This study was conducted to determine the relationship between dysglycemia and the coronary artery vasa vasorum density. RESEARCH DESIGN AND METHODS: The left anterior descending coronary artery was removed from 57 deceased individuals during autopsy, and the capillaries in the vessel wall were identified using fluorescent immunohistochemical staining. HbA1c was determined in postmortem whole blood for each individual. The density of the vasa vasorum in the intima-media and the adventitia was manually quantified and recorded by readers unaware of the individual's other characteristics. RESULTS: The individuals with diabetes had a lower density of the coronary vasa vasorum than those without diabetes. The higher the HbA1c, the lower the density of these vessels in the adventitia and entire vessel wall. CONCLUSIONS: Dysglycemia-induced damage to the vasa vasorum may promote ischemic heart disease in people with diabetes.

Genetic and Environmental Contributions to Variation in the Posterior Communicating Collaterals of the Circle of Willis.

Variation in blood flow mediated by the posterior communicating collateral arteries (PComs) contributes to variation in the severity of tissue injury in obstructive disease. Evidence in animals and humans indicates that differences in the extent of PComs, i.e., their anatomic lumen diameter and whether they are present bilaterally, unilaterally, or absent, are a major factor. These differences arise during development since they are present at birth. However, the causal mechanisms are unknown. We used angiography after maximal dilation to examine involvement of genetic, environmental, and stochastic factors. The extent of PComs varied widely among seven genetically diverse strains of mice. Like pial collaterals in the microcirculation, aging and hypertension reduced PCom diameter, while in contrast, obesity, hyperlipidemia, metabolic syndrome, and diabetes mellitus had no effect. Naturally occurring intrauterine growth restriction had no effect on extent of PCom or pial collaterals in the adult. The number and diameter of PComs evidenced much larger apparent stochastic-dependent variation than pial collaterals. In addition, both PComs underwent flow-mediated outward remodeling after unilateral permanent MCA occlusion that varied with genetic background and was greater on the ipsilesional side. These findings indicate that variation in the number and diameter of PCom collateral arteries arises from stochastic factors and naturally occurring genetic variants that differ from those that cause variation in pial collateral arterioles. Environmental factors also contribute: aging and hypertension reduce PCom diameter. Our results suggest possible sources of variation of PComs in humans and provide information relevant when studying mouse models of occlusive cerebrovascular disease.

Age- and Brain Region-Specific Changes of Glucose Metabolic Disorder, Learning, and Memory Dysfunction in Early Alzheimer's Disease Assessed in APP/PS1 Transgenic Mice Using 18F-FDG-PET.

Alzheimer's disease (AD) is a leading cause of dementia worldwide, associated with cognitive deficits and brain glucose metabolic alteration. However, the associations of glucose metabolic changes with cognitive dysfunction are less detailed. Here, we examined the brains of APP/presenilin 1 (PS1) transgenic (Tg) mice aged 2, 3.5, 5 and 8 months using 18F-labed fluorodeoxyglucose (18F-FDG) microPET to assess age- and brain region-specific changes of glucose metabolism. FDG uptake was calculated as a relative standardized uptake value (SUVr). Morris water maze (MWM) was used to evaluate learning and memory dysfunction. We showed a glucose utilization increase in multiple brain regions of Tg mice at 2 and 3.5 months but not at 5 and 8 months. Comparisons of SUVrs within brains showed higher glucose utilization than controls in the entorhinal cortex, hippocampus, and frontal cortex of Tg mice at 2 and 3.5 months but in the thalamus and striatum at 3.5, 5 and 8 months. By comparing SUVrs in the entorhinal cortex and hippocampus, Tg mice were distinguished from controls at 2 and 3.5 months. In MWM, Tg mice aged 2 months shared a similar performance to the controls (prodromal-AD). By contrast, Tg mice failed training tests at 3.5 months but failed all MWM tests at 5 and 8 months, suggestive of partial or complete cognitive deficits (symptomatic-AD). Correlation analyses showed that hippocampal SUVrs were significantly correlated with MWM parameters in the symptomatic-AD stage. These data suggest that glucose metabolic disorder occurs before onset of AD signs in APP/PS1 mice with the entorhinal cortex and hippocampus affected first, and that regional FDG uptake increase can be an early biomarker for AD. Furthermore, hippocampal FDG uptake is a possible indicator for progression of Alzheimer's cognition after cognitive decline, at least in animals.

Involvement of senescence marker protein-30 in glucose metabolism disorder and non-alcoholic fatty liver disease.

Senescence marker protein-30 (SMP30) was found to decrease in the liver, kidneys and lungs of mice during aging. SMP30 is a pleiotropic protein that acts to protect cells from apoptosis by enhancing plasma membrane Ca(2+) -pump activity and is bona fide gluconolactonase (EC 3.1.1.17) that participates in the penultimate step of the vitamin C biosynthetic pathway. For the past several years, we have obtained strong evidence showing the close relationship between SMP30, glucose metabolism disorder and non-alchoholic fatty liver disease in experiments with SMP30 knockout mice. Emerging proof links the following abnormalities: (i) the reduction of SMP30 by aging and/or excessive dietary fat or genetic deficiency causes a loss of Ca(2+) pumping activity, which impairs acute insulin release in pancreatic ß-cells, initiates inflammatory responses with oxidative stress and endoplasmic reticulum stress in non-alchoholic steatohepatitis, exacerbates renal tubule damage, and introduces tubulointerstitial inflammation and fibrosis in diabetic nephropathy; (ii) vitamin C insufficiency also impairs acute insulin secretion in pancreatic ß-cells by a mechanism distinct from that of the SMP30 deficiency; and (iii) the increased oxidative stress by concomitant deficiencies of SMP30, superoxide dismutase 1 and vitamin C similarly causes hepatic steatosis. Here, we review recent advances in our understanding of SMP30 in glucose metabolism disorder and non-alchoholic fatty liver disease.

Potential effect of chronic Helicobacter pylori infection on glucose metabolism of Mongolian gerbils.

AIM: To assess the effect of Helicobacter pylori (H. pylori) infection on metabolic parameters in Mongolian gerbils. METHODS: A total of 40 male, 5- to 8-wk-old, specific-pathogen-free Mongolian gerbils (30-50 g) were randomly allocated into two groups: a control group (n = 20) and an H. pylori group (n = 20). After a two-week acclimation period, the control group was administered Brucella broth and the H. pylori group was challenged intra-gastrically five times every other day with approximately 10(9)/CFU H. pylori ATCC43504 (CagA+, VacA+). Each group was then divided into two subgroups, which were sacrificed at either 6 or 12 mo. The control and H. pylori subgroups each contained 10 Mongolian gerbils. Body weight, abdominal circumference, and body length were measured, and body mass index (BMI) and Lee's index were calculated. Biochemical assays were used to detect serum indexes, including glucose, glycated hemoglobin (GHb), glycated hemoglobin A1c (HbA1c), triacylglycerol, and total cholesterol, using an automatic biochemistry analyzer. Inflammatory cytokines, including interleukin (IL)-1ß, IL-2, IL-4, IL-10, IL-12, tumor necrosis factor-α (TNF-α) and interferon (IFN)-γ, were assayed using ELISA. The expression of insulin and insulin-like growth factor 1 (IGF-1) was detected by immunohistochemistry, and islet apoptosis was measured using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. RESULTS: At each time point, body weight, abdominal circumference, BMI, and Lee's index were increased after H. pylori infection. However, these differences were not significant. H. pylori infection significantly increased the GHb (5.45 ± 0.53 vs 4.98 ± 0.22, P < 0.05) and HbA1c (4.91 ± 0.61 vs 4.61 ± 0.15, P < 0.05) levels at 12 mo. We observed no significant differences in serum biochemical indexes, including fasting blood glucose, triacylglycerol and total cholesterol, at 6 or 12 mo after infection. H. pylori infection significantly increased the expression of IGF-1 (P < 0.05). Insulin levels from the pancreas and the apoptotic rate of islet ß-cells remained unchanged. Also, we observed no significant differences among cytokines levels, including IL-1ß, IL-2, IL-4, IL-10, IL-12, TNF-α and IFN-γ. IL-4 was the only exception, which increased at 6 (44.36 ± 25.17 vs 17.38 ± 3.47, P < 0.05) and 12 mo (33.41 ± 10.00 vs 18.91 ± 5.31, P < 0.05) after H. pylori infection. CONCLUSION: Long-term H. pylori infection is significantly associated with high levels of HbA1c in Mongolian gerbils, indicating a potential role of H. pylori infection in glucose dysregulation.

Loss of CD24 in Mice Leads to Metabolic Dysfunctions and a Reduction in White Adipocyte Tissue.

CD24 is a glycophosphatidylinositol (GPI)-linked cell surface receptor that is involved in regulating the survival or differentiation of several different cell types. CD24 has been used to identify pre-adipocytes that are able to reconstitute white adipose tissue (WAT) in vivo. Moreover, we recently found that the dynamic upregulation of CD24 in vitro during early phases of adipogenesis is necessary for mature adipocyte development. To determine the role of CD24 in adipocyte development in vivo, we evaluated the development of the inguinal and interscapular subcutaneous WAT and the epididymal visceral WAT in mice with a homozygous deletion of CD24 (CD24KO). We observed a significant decrease in WAT mass of 40% to 74% in WAT mass from both visceral and subcutaneous depots in male mice, with no significant effect in female mice, compared to wild-type (WT) sex- and age-matched controls. We also found that CD24KO mice had increased fasting glucose and free fatty acids, decreased fasting insulin, and plasma leptin. No major differences were observed in the sensitivity to insulin or glucose, or in circulating triglycerides, total cholesterol, HDL-cholesterol, or LDL-cholesterol levels between WT and CD24KO mice. Challenging the CD24KO mice with either high sucrose (35%) or high fat (45%) diets that promote increased adiposity, increased WAT mass and fasting insulin, adiponectin and leptin levels, as well as reduced the sensitivity to insulin and glucose, to the levels of WT mice on the same diets. The CD24-mediated reduction in fat pad size was due to a reduction in adipocyte cell size in all depots with no significant reduction pre-adipocyte or adipocyte cell number. Thus, we have clearly demonstrated that the global absence of CD24 affects adipocyte cell size in vivo in a sex- and diet-dependent manner, as well as causing metabolic disturbances in glucose homeostasis and free fatty acid levels.

Thyroid volume in patients with glucose metabolism disorders.

OBJECTIVE: Thyroid volume and the prevalence of thyroid nodules are higher in patients with insulin resistance. A relationship between thyroid volume and glucose metabolism disorders (GMD) has not as yet been clarified. The present retrospective study aimed to investigate the association between GMD and thyroid volume. SUBJECTS AND METHODS: We investigated the data of 2,630 patients who were evaluated for thyroid biopsy in our hospital. The study population included 602 patients with GMD, 554 patients with diabetes mellitus (DM) and 1,474 patients with normal glucose metabolism as a control group. We obtained the levels of serum thyroid stimulating hormone (TSH) and the thyroid volumes of those patients retrospectively. RESULTS: The median ages for the control group, GMD group and DM group were 55 (15-91) years, 60 (27-97) years, and 65 (27-91) years respectively and there was a statistically significant difference between the groups with regard to age and gender (p<0.001). Levels of TSH were similar in all groups. The median total thyroid volumes for patients with DM and GMD were significantly higher than that of the control group [22.5 (3-202) mL, 20.2 (4-190) mL, and 19.2 (3-168) mL respectively, p≤0.001 for all parameters]. Also the median total thyroid volume for patients with DM was significantly higher than that of the GMD group (p<0.001). According to the correlation analysis, thyroid volume was significantly correlated with age (r=0.92, p<0.001) and TSH (r=0.435, p<0.001). Age, gender, TSH levels, GMD and DM diagnosis were independently correlated with thyroid volume. CONCLUSION: The thyroid gland is one of the target tissues of metabolic disorders. We reported a positive correlation between GMD/type 2 DM and thyroid volume. Further controlled, prospective, randomized studies on this subject are required to gain more information.

Thyroid volume in patients with glucose metabolism disorders / Volume da tiroide em pacientes com alterações do metabolismo da glicose

Objective Thyroid volume and the prevalence of thyroid nodules are higher in patients with insulin resistance. A relationship between thyroid volume and glucose metabolism disorders (GMD) has not as yet been clarified. The present retrospective study aimed to investigate the association between GMD and thyroid volume. Subjects and methods: We investigated the data of 2,630 patients who were evaluated for thyroid biopsy in our hospital. The study population included 602 patients with GMD, 554 patients with diabetes mellitus (DM) and 1,474 patients with normal glucose metabolism as a control group. We obtained the levels of serum thyroid stimulating hormone (TSH) and the thyroid volumes of those patients retrospectively. Results The median ages for the control group, GMD group and DM group were 55 (15‐91) years, 60 (27‐97) years, and 65 (27‐91) years respectively and there was a statistically significant difference between the groups with regard to age and gender (p<0.001). Levels of TSH were similar in all groups. The median total thyroid volumes for patients with DM and GMD were significantly higher than that of the control group [22.5 (3‐202) mL, 20.2 (4‐190) mL, and 19.2 (3‐168) mL respectively, p≤0.001 for all parameters]. Also the median total thyroid volume for patients with DM was significantly higher than that of the GMD group (p<0.001). According to the correlation analysis, thyroid volume was significantly correlated with age (r=0.92, p<0.001) and TSH (r=0.435, p<0.001). Age, gender, TSH levels, GMD and DM diagnosis were independently correlated with thyroid volume. Conclusion The thyroid gland is one of the target tissues of metabolic disorders. We reported a positive correlation between GMD/type 2 DM and thyroid volume. Further controlled, prospective, randomized studies on this subject are required to gain more information. .

Objetivo O volume da tiroide e a prevalência de nódulos tiroidianos são mais altos em pacientes com resistência à insulina. A relação entre o volume da tiroide e os transtornos do metabolismo da glicose (TMG) ainda não foi elucidada. O objetivo do presente estudo retrospectivo foi investigar a associação entre os TMG e o volume da tiroide. Sujeitos e métodos: Analisamos os dados de 2.630 pacientes que foram avaliados para biópsia de tiroide em nosso hospital. A população estudada incluiu 602 pacientes com TMG, 554 pacientes com diabetes melito (DM) e 1.474 pacientes com metabolismo normal da glicose, como grupo controle. As concentrações de hormônio tireoestimulante (TSH) e os volumes da tiroide para esses pacientes foram obtidos de forma retrospectiva. Resultados As idades medianas para o grupo controle, grupo TMG e grupo DM foram 55 (15‐91), 60 (27‐97) e 65 (27‐91) anos, respectivamente, e houve diferença estatisticamente significativa entre os grupos com relação à idade e ao gênero (p<0,001). Os níveis de TSH foram similares em todos os grupos. A mediana do volume total da tiroide para pacientes com DM e TMG foi significativamente maior do que para os pacientes do grupo controle [22,5 (3‐202) mL, 20,2 (4‐190) mL, e 19,2 (3‐168) mL, respectivamente, p≤0,001 para todos os parâmetros]. Além disso, a mediana do volume total da tiroide para pacientes com DM foi significativamente maior do que no grupo TMG (p<0,001). De acordo com a análise de correlação, o volume da tiroide foi significativamente correlacionado com a idade (r=0,92; p<0,001) e TSH (r=0,435; p<0,001). A idade, o gênero, a concentração de TSH e o diagnóstico de TMG e DM se correlacionaram com o volume da tiroide de forma independente. Conclusão A tiroide ...

Synthesis, characterization, and preclinical evaluation of new thiazolidin-4-ones substituted with p-chlorophenoxy acetic acid and clofibric acid against insulin resistance and metabolic disorder.

We synthesized twenty thiazolidin-4-one derivatives, which were then characterized by standard chromatographic and spectroscopic methods. From the in vitro glucose uptake assay, two compounds behaved as insulin sensitizers, where they enhanced glucose uptake in isolated rat diaphragm. In high-carbohydrate diet-induced insulin resistant mice, these two thiazolidin-4-ones attenuated hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and glucose intolerance. They raised the plasma leptin but did not reverse the diabetes-induced hypoadiponectinemia. Additionally, compound 3a reduced adiposity. The test compounds were also able to reverse the disturbed liver antioxidant milieu. To conclude, these two novel thiazolidin-4-ones modulated multiple mechanisms involved in metabolic disorders, reversing insulin resistance and thus preventing the development of type-2 diabetes.