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

Genetic variation in thioredoxin interacting protein (TXNIP) is associated with hypertriglyceridaemia and blood pressure in diabetes mellitus

Aims Thioredoxin interacting protein (TXNIP) is an attractive candidate gene for diabetes or diabetic dyslipidaemia, since TXNIP is the strongest glucose-responsive gene in pancreatic B-cells, TXNIP deficiency in a mouse model is associated with hyperlipidaemia and TXNIP is located in the 1q21-1q23 chromosomal Type 2 diabetes mellitus (DM) locus. We set out to investigate whether metabolic effects of TXNIP that were previously reported in a murine model are also relevant in human Type 2 DM. Methods The frequency distribution of a 3' UTR single nucleotide polymorphism (SNP) in TXNIP was investigated in subjects with normal glucose tolerance (NGT; n = 379), impaired glucose tolerance (IGT; n = 228) and Type 2 DM (n = 230). Metabolic data were used to determine the effect of this SNP on parameters associated with lipid and glucose metabolism. Results The frequency of the TXNIP variation did not differ between groups, but within the group of diabetic subjects, carriers of the TXNIP-T variant had 1.6-fold higher triglyceride concentrations (P = 0.015; n = 136) and a 5.5-mmHg higher diastolic blood pressure (P = 0.02; n = 212) than homozygous carriers of the common C-allele, whereas in non-diabetic subjects fasting glucose was 0.26 mmol/l lower (P = 0.002; n = 478) in carriers of the T-allele. Moreover, a significant interaction between plasma glucose concentrations and TXNIP polymorphism on plasma triglycerides was observed (P = 0.012; n = 544). Conclusion This is the first report to implicate TXNIP in a human disorder of energy metabolism, Type 2 diabetes. The effect of TXNIP on triglycerides is influenced by plasma glucose concentrations, suggesting that the biological relevance of TXNIP variations may be particularly relevant in recurrent episodes of hyperglycaemia

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

Glucose Variability Assessed with Continuous Glucose Monitoring:Reliability, Reference Values, and Correlations with Established Glycemic Indices-The Maastricht Study

Background: Glucose variability (GV) measured by continuous glucose monitoring (CGM) has become an accepted marker of glycemic control. Nevertheless, several methodological aspects of GV assessment require further study. We, therefore, investigated the minimum number of days needed to reliably measure GV, assessed GV reference values, and studied the correlation of GV with established glycemic indices (i.e., HbA(1c), seven-point oral glucose tolerance test [OGTT]-derived indices). Methods: We used cross-sectional data from The Maastricht Study, an observational population-based cohort enriched with type 2 diabetes. Participants with more than 48 h of CGM (iPro2; Medtronic) were included for analysis (n = 851; age: 60 +/- 9years; 49% women; 23% type 2 diabetes). We used mean sensor glucose (MSG), standard deviation (SD), and coefficient of variation (CV) as CGM-derived indices (the latter two for GV quantification). We calculated reliability using the Spearman-Brown prophecy formula, established reference values by calculating 2.5th-97.5th percentiles, and studied correlations using Spearman's rho. Results: Sufficient reliability (R > 0.80) was achieved with two (MSG and SD), or three monitoring days (CV). The reference ranges, assessed in individuals with normal glucose metabolism (n = 470), were 90.5-120.6 mg/dL (MSG), 7.9-24.8 mg/dL (SD), and 7.74%-22.45% (CV). For MSG, the strongest correlation was found with fasting plasma glucose (rho = 0.65 [0.61; 0.69]); for SD, with the 1-h OGTT value (rho = 0.61 [0.56; 0.65]); and for CV, with both the incremental glucose peak (IGP) during the OGTT (rho = 0.50 [0.45; 0.55]) and the 1-h OGTT value (rho = 0.50 [0.45; 0.55]). Conclusions: The reliability findings and reference values are relevant for studies that aim to investigate CGM-measured GV. One-hour OGTT and IGP values can be used as GV indices when CGM is unavailable

Activating transcription factor 6 polymorphisms and haplotypes are associated with impaired glucose homeostasis and type 2 diabetes in dutch Caucasians

Context: Activating transcription factor 6 (ATF6) is critical for initiation and full activation of the unfolded protein response. An association between genetic variation in ATF6 and type 2 diabetes (DM2) was recently reported in Pima Indians. Objectives: To investigate the broader significance of this association for DM2, replication studies in distinct ethic populations are required. We investigated ATF6 for its association with DM2 in Dutch Caucasians. Design/Setting: A genetic association study was conducted at an academic research laboratory. Study Participants: Two independent Dutch cohorts were studied. Cohort 1 (n = 154) was used to evaluate genetic variation in the ATF6 gene in relation to glucose homeostasis in the general population. Cohort 2 (n = 798) consisted of patients with DM2, impaired glucose tolerance, impaired fasting glucose, and normoglycemic control subjects, and was used to investigate ATF6 polymorphisms for their contribution to disturbed glucose homeostasis and DM2. Main Outcome Measures: There were 16 tag single nucleotide polymorphisms genotyped in all subjects of both cohorts. Those single nucleotide polymorphisms included three nonsynonymous coding variants and captured all common allelic variation of ATF6. Results: Our data show that common ATF6 variants are associated with elevated glucose levels in the general population (cohort 1, P = 0.005-0.05). Furthermore, the majority of these variants, and haplotypes thereof, were significantly associated with impaired fasting glucose, impaired glucose tolerance, and DM2 ( cohort 2, P = 0.006-0.05). Associated variants differ from those identified in Pima Indians. Conclusions: Our results strengthen the evidence that one or more variants in ATF6 are associated with disturbed glucose homeostasis and DM2

Веб-ресурс для перегляду 3D моделей з використанням технології WebGL

У першому розділі досліджується актуальність проблеми, проводиться аналіз існуючих аналогів. Другий розділ присвячений формування мети дипломної роботи та задач проекту, вибору засобів реалізації та плануванню робіт. У третьому розділі виконується проектування веб-ресурсу, де наведені діаграми у нотації IDF0 та Use Case.Останній розділ присвячений детальному опису практичної реалізації проекту: виконання прототипування веб-сторінки, розмітка та форматування веб-ресурсу, налаштування та перевірка працездатності веб-браузера з WebGL, опис реакції на дії користувача, розробка функцій маніпуляцій над моделлю. Результатом проведеної роботи є розроблений веб-ресурс, який дозволяє користувачу обирати одну із чотирьох моделей для візуалізації на веб-сторінці та виконувати базові маніпуляції з нею

Upstream transcription factor 1 (USF1) in risk of type 2 diabetes:Association study in 2000 Dutch Caucasians

Type 2 diabetes shares substantial genetic and phenotypic overlap with familial combined hyperlipidemia. Upstream stimulatory factor 1 (USF7), a well-established susceptibility gene for familial combined hyperlipidemia, is postulated to be such a shared genetic determinant. We evaluated two established variants in familial combined hyperlipidemia (rs2073658 and rs3737787) for association with type 2 diabetes in two Dutch case-control samples (N=2011). The first case-control sample comprised 501 subjects with type 2 diabetes from the Breda cohort and 920 healthy blood bank donors of Dutch Caucasian origin. The second case-control sample included 211 subjects with type 2 diabetes, and 379 normoglycemic controls. SNP rs2073658 and SNP rs3737787 were in perfect linkage disequilibrium. In the first case-control sample, prevalence of the major allele was higher in patients than in controls (75% versus 71%, OR=1.25, p=0.018). A similar effect-size and -direction was observed in the second case-control sample (76% versus 72%, OR=1.22, p=0.16). A combined analysis strengthened the evidence for association (OR=1.23, p=0.006). Notably, the increased risk for type 2 diabetes could be ascribed to the major allele, and its high frequency translated to a substantial population attributable risk of 14.5%. In conclusion, the major allele of rs2073658 in the USF1 gene is associated with a modestly increased risk to develop type 2 diabetes in Dutch Caucasians, with considerable impact at the population level. (c) 2008 Elsevier Inc. All rights reserved

Association of Type 2 Diabetes, According to the Number of Risk Factors Within Target Range, With Structural Brain Abnormalities, Cognitive Performance, and Risk of Dementia

OBJECTIVE: Type 2 diabetes is associated with increased risks of cognitive dysfunction and brain abnormalities. The extent to which risk factor modification can mitigate these risks is unclear. We investigated the associations between incident dementia, cognitive performance, and brain abnormalities among individuals with type 2 diabetes, according to the number of risk factors on target, compared with control subjects without diabetes. RESEARCH DESIGN AND METHODS: Prospective data were from UK Biobank of 87,856 individuals (n = 10,663 diabetes, n = 77,193 control subjects; baseline 2006-2010), with dementia follow-up until February 2018. Individuals with diabetes were categorized according to the number of seven selected risk factors within the guideline-recommended target range (nonsmoking; guideline-recommended levels of glycated hemoglobin, blood pressure, BMI, albuminuria, physical activity, and diet). Outcomes were incident dementia, domain-specific cognitive performance, white matter hyperintensities, and total brain volume. RESULTS: After a mean follow-up of 9.0 years, 147 individuals (1.4%) with diabetes and 412 control subjects (0.5%) had incident dementia. Among individuals with diabetes, excess dementia risk decreased stepwise for a higher number of risk factors on target. Compared with control subjects (incidence rate per 1,000 person-years 0.62 [95% CI 0.56; 0.68]), individuals with diabetes who had five to seven risk factors on target had no significant excess dementia risk (absolute rate difference per 1,000 person-years 0.20 [-0.11; 0.52]; hazard ratio 1.32 [0.89; 1.95]). Similarly, differences in processing speed, executive function, and brain volumes were progressively smaller for a higher number of risk factors on target. These results were replicated in the Maastricht Study. CONCLUSIONS: Among individuals with diabetes, excess dementia risk, lower cognitive performance, and brain abnormalities decreased stepwise for a higher number of risk factors on target