Endoplasmic reticulum stress-induced apoptosis in the development of diabetes: is there a role for adipose tissue and liver?

Diabetes mellitus (DM) is a multifactorial chronic metabolic disease characterized by hyperglycaemia. Several different mechanisms have been implicated in the development of the disease, including endoplasmic reticulum (ER) stress. ER stress is increasingly acknowledged as an important mechanism in the development of DM, not only for β-cell loss but also for insulin resistance. Accumulating evidence suggests that ER stress-induced apoptosis may be an important mode of β-cell loss and therefore important in the development of diabetes. Recent data also suggest a role of ER stress-induced apoptosis in liver and adipose tissue in relation to diabetes, but more extensive studies on human adipocyte and hepatocyte (patho)physiology and ER stress are needed to identify the exact interactions between environmental signals, ER stress and apoptosis in these organs

The renewable energy and energy efficiency potential of Waitakere City : a thesis presented in partial fulfilment of the requirements for the degree of Masters of Technology in Energy Management at Massey University

Electricity restrictions and blackouts have occurred in Waitakere City in the past and are likely to occur again in the future unless the city can become more self reliant by meeting, at least in part, the increasing energy requirements for what is one of the fastest growing cities in New Zealand. In this study the potentials for energy conservation, energy efficiency and renewable energy resources have been broadly quantified and assessed using desktop analysis of publicly available data for stationary final use energy systems (i.e. excluding transportation) within the geographical area of Waitakere City and adjoining waters. It was found that energy efficiency and energy conservation measures can consistently and predictably achieve overall energy savings and reduce daily and seasonal peak demand. The best renewable energy resource potential exists with solar and geothermal for heating applications and wave, offshore and inshore wind and tidal currents for electricity generation. There is very limited potential for hydro and bioenergy systems beyond what already exists. PV solar and land based wind power generation are currently only feasible for limited off-grid applications. This scoping study confirms the achievability of the vision expressed in Waitakere City Council's "Long Term Council Community Plan" (LTCCP) that by 2020 " Waitakere City will be an energy cell, not an energy sink. Air quality supports good health". A range of flagship projects have been identified to progress the achievement of this vision. Waitakere City Council can use this report as part of the development of a comprehensive energy management plan

Associations of C-reactive protein with measures of obesity, insulin resistance, and subclinical atherosclerosis in healthy, middle-aged women

Obesity, the insulin resistance syndrome, and atherosclerosis are closely linked and may all be determinants of an increased acute-phase response. In this study, we examined the relationship of C-reactive protein (CRP) with measures of obesity, variables of the insulin resistance syndrome, and intima-media thickness of the common carotid arteries in 186 healthy, middle-aged women selected from the general population. Associations were assessed by regression analysis. CRP was strongly associated with body mass index (BMI) and waist circumference. CRP was also associated with other variables of the insulin resistance syndrome, including blood pressure, insulin, high density lipoprotein cholesterol, triglycerides, apolipoprotein A1 (inversely), plasminogen activator inhibitor-1 antigen, and tissue-type plasminogen activator antigen. Associations between CRP and the variables of the insulin resistance syndrome disappeared after controlling for BMI but remained significant for plasminogen activator inhibitor-1 antigen only. The association of CRP with common carotid artery intima-media thickness was weak and limited to ever-smokers. BMI explained 29.7% of the variance of CRP, whereas common carotid artery intima-media thickness explained only 3.7%. The results of this population-based study indicate that adiposity is strongly associated with CRP in healthy, middle-aged women. In this population, BMI accounted for the relationship between CRP and other variables of the insulin resistance syndrome. Further studies should determine whether losing weight ameliorates the inflammatory state

Higher Plasma Soluble Receptor for Advanced Glycation End Products (sRAGE) Levels Are Associated With Incident Cardiovascular Disease and All-Cause Mortality in Type 1 Diabetes: A 12-Year Follow-Up Study

To investigate the associations of plasma levels of soluble receptor for advanced glycation end products (sRAGE) with incident cardiovascular disease (CVD) and allcause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal dysfunction, low-grade inflammation, arterial stiffness, and advanced glycation end products (AGEs). RESEARCH DESIGN AND METHODS - We prospectively followed 169 individuals with diabetic nephropathy and 170 individuals with persistent normoalbuminuria who were free of CVD at study entry and in whom levels of sRAGE and other biomarkers were measured at baseline. The median follow-up duration was 12.3 years (7.6 -12.5). RESULTS - The incidence of fatal and nonfatal CVD and allcause mortality increased with higher baseline levels of log-transformed sRAGE (Ln-sRAGE) independently of other CVD risk factors: hazard ratio (HR) 1.90 (95% CI 1.13-3.21) and 2.12 (1.26 -3.57) per 1-unit increase in Ln-sRAGE, respectively. Adjustments for estimated glomerular filtration rate (eGFRMDRD), but not or to a smaller extent for markers of endothelial dysfunction, low-grade inflammation, arterial stiffness, and AGEs, attenuated these associations to HR 1.59 (95% CI 0.91-2.77) for fatal and nonfatal CVD events and to 1.90 (1.09 -3.31) for all-cause mortality. In addition, in patients with nephropathy, the rate of decline of GFR was 1.38 ml/min/1.73 m2 per year greater per 1-unit increase of Ln-sRAGE at baseline (P = 0.036). CONCLUSIONS - Higher levels of sRAGE are associated with incident fatal and nonfatal CVD and all-cause mortality in individuals with type 1 diabetes. sRAGE-associated renal dysfunction may partially explain this association

L(+) and D(−) Lactate Are Increased in Plasma and Urine Samples of Type 2 Diabetes as Measured by a Simultaneous Quantification of L(+) and D(−) Lactate by Reversed-Phase Liquid Chromatography Tandem Mass Spectrometry

Background. Plasma and urinary levels of D-lactate have been linked to the presence of diabetes. Previously developed techniques have shown several limitations to further evaluate D-lactate as a biomarker for this condition. Methods. D- and L-lactate were quantified using ultraperformance liquid chromatography tandem mass spectrometry with labelled internal standard. Samples were derivatized with diacetyl-L-tartaric anhydride and separated on a C18-reversed phase column. D- and L-lactate were analysed in plasma and urine of controls, patients with inflammatory bowel disease (IBD), and patients with type 2 diabetes (T2DM). Results. Quantitative analysis of D- and L-lactate was achieved successfully. Calibration curves were linear (r2 > 0.99) over the physiological and pathophysiological ranges. Recoveries for urine and plasma were between 96% and 113%. Inter- and intra-assay variations were between 2% and 9%. The limits of detection of D-lactate and L-lactate in plasma were 0.7 μmol/L and 0.2 μmol/L, respectively. The limits of detection of D-lactate and L-lactate in urine were 8.1 nmol/mmol creatinine and 4.4 nmol/mmol creatinine, respectively. Plasma and urinary levels of D- and L-lactate were increased in patients with IBD and T2DM as compared with controls. Conclusion. The presented method proved to be suitable for the quantification of D- and L-lactate and opens the possibility to explore the use of D-lactate as a biomarker

Impact of type 2 diabetes and the metabolic syndrome on myocardial structure and microvasculature of men with coronary artery disease

<p>Abstract</p> <p>Background</p> <p>Type 2 diabetes and the metabolic syndrome are associated with impaired diastolic function and increased heart failure risk. Animal models and autopsy studies of diabetic patients implicate myocardial fibrosis, cardiomyocyte hypertrophy, altered myocardial microvascular structure and advanced glycation end-products (AGEs) in the pathogenesis of diabetic cardiomyopathy. We investigated whether type 2 diabetes and the metabolic syndrome are associated with altered myocardial structure, microvasculature, and expression of AGEs and receptor for AGEs (RAGE) in men with coronary artery disease.</p> <p>Methods</p> <p>We performed histological analysis of left ventricular biopsies from 13 control, 10 diabetic and 23 metabolic syndrome men undergoing coronary artery bypass graft surgery who did not have heart failure or atrial fibrillation, had not received loop diuretic therapy, and did not have evidence of previous myocardial infarction.</p> <p>Results</p> <p>All three patient groups had similar extent of coronary artery disease and clinical characteristics, apart from differences in metabolic parameters. Diabetic and metabolic syndrome patients had higher pulmonary capillary wedge pressure than controls, and diabetic patients had reduced mitral diastolic peak velocity of the septal mitral annulus (E'), consistent with impaired diastolic function. Neither diabetic nor metabolic syndrome patients had increased myocardial interstitial fibrosis (picrosirius red), or increased immunostaining for collagen I and III, the AGE Nε-(carboxymethyl)lysine, or RAGE. Cardiomyocyte width, capillary length density, diffusion radius, and arteriolar dimensions did not differ between the three patient groups, whereas diabetic and metabolic syndrome patients had reduced perivascular fibrosis.</p> <p>Conclusions</p> <p>Impaired diastolic function of type 2 diabetic and metabolic syndrome patients was not dependent on increased myocardial fibrosis, cardiomyocyte hypertrophy, alteration of the myocardial microvascular structure, or increased myocardial expression of Nε-(carboxymethyl)lysine or RAGE. These findings suggest that the increased myocardial fibrosis and AGE expression, cardiomyocyte hypertrophy, and altered microvasculature structure described in diabetic heart disease were a consequence, rather than an initiating cause, of cardiac dysfunction.</p

Особливості синтаксичної організації художньої прози Редьярда Кіплінга

Статья посвящена исследованию синтаксических конструкций, с помощью которых в художественной прозе Редьярда Киплинга отображаются особенности английской и индийской культур.Стаття присвячена дослідженню синтаксичних конструкцій, за допомогою яких у художній прозі Редьярда Кіплінга відображено особливості англійської та індійської культур.The article is dedicated to the investigation of the main syntactic constractions with the help of which in the prose of Rudyard Kipling there are depicted the peculiarities of English and Indian cultures

Dietary advanced glycation endproducts (AGEs) increase their concentration in plasma and tissues, result in inflammation and modulate gut microbial composition in mice; evidence for reversibility

Scope: Dietary advanced glycation endproducts (AGEs) are associated with negative biological effects, possibly due to accumulation in plasma and tissues and through modulation of inflammation and gut microbiota. Whether these biological consequences are reversible by limiting dietary AGE intake is unknown. Methods and results: Young healthy C57BL/6 mice were fed a standard chow (n = 10) or a baked chow high AGE-diet (n = 10) (~1.8–6.9 fold increased protein-bound Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl) lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1)) for 10 weeks or a switch diet with baked chow for 5 weeks followed by 5 weeks of standard chow (n = 10). We assessed accumulation of AGEs in plasma, kidney, and liver and measured inflammatory markers and gut microbial composition. After 10 weeks of baked chow, a substantial panel of AGEs were increased in plasma, liver, and kidney. These increases were normalized after the switch diet. The inflammatory z-score increased after the baked chow diet. Gut microbial composition differed significantly between groups, with enriched Dubosiella spp. dominating these alterations. Conclusion: A high AGE-diet led to an increase of AGEs in plasma, kidney, and liver and to more inflammation and modification of the gut microbiota. These effects were reversed or discontinued by a diet lower in AGEs.Peer reviewe