Experimental Diabetes Research最新文献

Purpose: We examined the impact of diabetes and hyperglycemia on cancer-specific survival of patients with metastatic or recurrent breast cancer (BC).

Methods: We performed a retrospective analysis of 265 patients with advanced BC receiving palliative chemotherapy. BC-specific mortality was compared for diabetic and nondiabetic patients as well as for patients that presented hyperglycemia during treatment.

Results: No difference was observed between the diabetic and nondiabetic patients in terms of overall survival (OS). A difference in OS was observed between nondiabetic patients and diabetic patients who had hyperglycemia. The OS was greater in diabetic patients with proper metabolic control than diabetic patients with hyperglycemia. The risk of death was higher in patients with mean glucose levels >130 mg/dL during treatment. Several factors were associated with poor OS: tumor stage, hormone-receptor-negative tumors, HER2 negative disease, multiple metastatic sites, presence of visceral metastases, and mean glucose >130 mg/dL.

Conclusion: Elevated glucose levels are associated with a poor outcome in diabetic and nondiabetic patients in contrast to patients with normoglycemic levels, conferring an elevated risk of death. According to these results, clinicians should monitor glucose levels during treatment for advanced breast cancer disease and take action to maintain normal glucose levels.

Aim: The aim of this study is to investigate the relationship between the common C49620T polymorphism in the sulfonylurea receptor (SUR1) gene and glucose metabolism, β-cell secretory function and insulin resistance in women with a history of gestational diabetes (GDM).

Material and methods: Study group included 199 women, diagnosed GDM within the last 5-12 years and control group of comparable 50 women in whom GDM was excluded during pregnancy. Blood glucose and insulin levels were measured during oral glucose tolerance test. Indices of insulin resistance (HOMA-IR) and β-cell function (HOMA %B) were calculated. In all patients, the C49620T polymorphism in intron 15 of the SUR1 gene was determined.

Results: The distribution of the studied polymorphism in the two groups did not differ from each other (χ(2) = 0.34, P = 0.8425). No association between the distribution of polymorphisms and coexisting glucose metabolism disorders (χ(2) = 7,13, P = 0, 3043) was found. No association was also observed between the polymorphism and HOMA %B or HOMA-IR.

Conclusions: The polymorphism C49620T in the SUR1 gene is not associated with insulin resistance and/or insulin secretion in women with a history of GDM and does not affect the development of GDM, or the development of glucose intolerance in the studied population.

Background: The Vanilloid subfamily of transient receptor potential (TRPV) ion channels has been widely implicated in detecting osmotic and mechanical stress. In the current study, we examine the functional expression of TRPV4 channels in cell volume regulation in cells of the human collecting duct.

Methods: Western blot analysis, siRNA knockdown, and microfluorimetry were used to assess the expression and function of TRPV4 in mediating Ca²⁺-dependent mechanical stimulation within a novel system of the human collecting duct (HCD).

Results: Native and siRNA knockdown of TRPV4 protein expression was confirmed by western blot analysis. Touch was used as a cell-directed surrogate for osmotic stress. Mechanical stimulation of HCD cells evoked a transient increase in [Ca²⁺](i) that was dependent upon thapsigargin-sensitive store release and Ca²⁺ influx. At 48 hrs, high glucose and mannitol (25 mM) reduced TRPV4 expression by 54% and 24%, respectively. Similar treatment doubled SGK1 expression. Touch-evoked changes were negated following TRPV4 knockdown.

Conclusion: Our data confirm expression of Ca²⁺-dependent TRPV4 channels in HCD cells and suggest that a loss of expression in response to high glucose attenuates the ability of the collecting duct to exhibit regulatory volume decreases, an effect that may contribute to the pathology of fluid and electrolyte imbalance as observed in diabetic nephropathy.

Objective: To investigate the effect of ezetimibe on the insulin secretion in db/db mice.

Methods: The db/db diabetic mice aged 8 weeks were randomly assigned into 2 groups and intragastrically treated with ezetimibe or placebo for 6 weeks. The age matched db/m mice served as controls. At the end of experiment, glucose tolerance test was performed and then the pancreas was collected for immunohistochemistry. In addition, in vitro perfusion of pancreatic islets was employed for the detection of insulin secretion in the first phase.

Results: In the ezetimibe group, the fasting blood glucose was markedly reduced, and the total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were significantly lowered when compared with those in the control group (P < 0.05). At 120 min after glucose tolerance test, the area under curve in the ezetimibe group was significantly smaller than that in the control group (P < 0.05), but the AUC(INS0-30) was markedly higher. In vitro perfusion of pancreatic islets revealed the first phase insulin secretion was improved. In addition, the insulin expression in the pancreas in the ezetimibe group was significantly increased as compared to the control group.

Conclusion: Ezetimibe can improve glucose tolerance, recover the first phase insulin secretion, and protect the function of β cells in mice.

Obesity and diabetes contribute to cardiovascular disease and alter cytokine profile. The cytokine, tumour necrosis factor alpha (TNFα), activates a protective signalling cascade during ischaemic postconditioning (IPostC). However, most successful clinical studies with IPostC have not included obese and/or diabetic patients. We aimed to investigate the influence of TNFα on the outcome of IPostC in obese or diabetic mice. TNF knockout or wildtype mice were fed for 11 weeks with a high carbohydrate diet (HCD) to induce modest obesity. Diabetes was induced in a separate group by administration of a single intraperitoneal injection of streptozotocin. Hearts were then isolated and subjected to ischaemia (35 min of global ischaemia) followed by 45 min of reperfusion. HCD increased body weight, plasma insulin and leptin levels while the glucose level was unchanged. In streptozotocin-treated mice, blood glucose, plasma leptin and insulin were altered. Control, obese or diabetic mice were protected with IPostC in wiltype animals. In TNF knockout mice, IPostC failed to protect control and diabetic hearts while a slight protection was observed in obese hearts. Our data confirm a bidirectional role for TNFα associated with the severity of concomitant comorbidities and suggest that diabetic and/or modestly obese patients may still benefit from IPostC.

Renal hypertrophy and accumulation of extracellular matrix proteins are among cardinal manifestations of diabetic nephropathy. TGF beta system has been implicated in the pathogenesis of these manifestations. Among signaling pathways activated in the kidney in diabetes, mTOR- (mammalian target of rapamycin-)regulated pathways are pivotal in orchestrating high glucose-induced production of ECM proteins leading to functional and structural changes in the kidney culminating in adverse outcomes. Understanding signaling pathways that influence individual matrix protein expression could lead to the development of new interventional strategies. This paper will highlight some of the diverse components of the signaling network stimulated by hyperglycemia with an emphasis on extracellular matrix protein metabolism in the kidney in diabetes.

Cardiovascular disease (CVD) is the major cause of mortality in individuals with diabetes mellitus. However the molecular and cellular mechanisms that predispose individuals with diabetes to the development and progression of atherosclerosis, the underlying cause of most CVD, are not understood. This paper summarizes the current state of our knowledge of pathways and mechanisms that may link diabetes and hyperglycemia to atherogenesis. We highlight recent work from our lab, and others', that supports a role for ER stress in these processes. The continued investigation of existing pathways, linking hyperglycemia and diabetes mellitus to atherosclerosis, and the identification of novel mechanisms and targets will be important to the development of new and effective antiatherosclerotic therapies tailored to individuals with diabetes.

Objective: The aim of this study was to evaluate the association between the Trp64Arg polymorphism in the beta3-adrenergic receptor gene (ADRB3: rs4994) and BMI and serological and anthropometric data in healthy Japanese.

Methods: Healthy Japanese recruited in a large-scale integrated manufacturing facility in Japan (N = 1355; age: 37.25 ± 9.43; BMI: 22.86 ± 3.46) were eligible for analysis. The anthropometric data and serological data were measured during a comprehensive health check, and a self-reporting questionnaire was used to assess lifestyle habits (current exercise, smoking status, alcohol intake, and working style) and weight at age 20. Genotyping for the ADRB3 polymorphism was performed by PCR-RFLP method.

Results: Among 1355 participants, the genotype frequencies of the Trp/Trp, Trp/Arg, and Arg/Arg variants were 920 (67.9%), 394 (29.1%), and 41 (3.05%), respectively. In the multivariate analysis, a multiple linear regression model in men for the adjustment of age, drinking habits, smoking habits, exercise habits, working status and serological measurements statistically showed an overall weak significance between annual BMI gain from age 20 and age, LDL or ADRB3 polymorphism.

Conclusions: The level of LDL, age, and ADRB3 polymorphism (Arg/Arg genotype) were statistically associated with annual BMI gain in Japanese men.

Objective: Oxidative stress is considered to be the main factor in the development of diabetic complications and tissue injury. our objective was to investigate and compare the oxidant/antioxidant conditions and detoxification mechanisms of the liver, lung, kidney, cardiac tissues, and mitochondria of rats with diabetes induced by streptozocin (STZ).

Methods: Rats with diabetes induced by streptozocin were anesthetized by administering 90 mg/kg ketamine hydrochloride and 3 mg/kg xylazine hydrochloride. Thoracic cavities were incised open; liver, lung, kidney, and cardiac tissues were removed and stored at -70°C. All samples were homogenized and mitochondrial fractions were separated. Total Antioxidant Status (TAS), Total Oxidant Status (TOS), Oxidative Stress Index (OSI), Paraoxonase (PON), Arylesterase, Catalase (Cat), Malondialdehyde (MDA), and Glutathion-S-transferase were measured in each fraction.

Results: MDA and TOS levels were significantly increased in liver tissues, and T OS and OSI were increased in the mitochondrial fractions of diabetic rats. These increases were not statistically significant compared to the control group. No significant differences were determined in the antioxidant and GST activities.

Conclusion: According to our results, oxidative stress has not developed in rats with diabetes induced by streptozocin. The detoxification system was induced; however, this induction did not differ significantly from the controls.