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Diabetes New Target

Ryota Saito, Maiko Hoshi, Akihiro Kato, Chikako Ishikawa, Toshiya Komatsu
A number of (Z)-4-arylmethylene-1H-imidazol-5(4H)-ones, which are related to the fluorescent chromophore of the Aequorea green fluorescent protein (GFP), have been synthesized and evaluated their in vitro inhibitory activity against recombinant human aldose reductase for the first time. The GFP chromophore model 1a, with a p-hydroxy group on the 4-benzylidene and a carboxymethyl group on the N1 position, exhibited strong bioactivity with an IC50 value of 0.36 μM. This efficacy is higher than that of sorbinil, a known highly potent aldose reductase inhibitor...
October 8, 2016: European Journal of Medicinal Chemistry
Christoph Nowak, Samira Salihovic, Andrea Ganna, Stefan Brandmaier, Taru Tukiainen, Corey D Broeckling, Patrik K Magnusson, Jessica E Prenni, Rui Wang-Sattler, Annette Peters, Konstantin Strauch, Thomas Meitinger, Vilmantas Giedraitis, Johan Ärnlöv, Christian Berne, Christian Gieger, Samuli Ripatti, Lars Lind, Nancy L Pedersen, Johan Sundström, Erik Ingelsson, Tove Fall
Insulin resistance (IR) and impaired insulin secretion contribute to type 2 diabetes and cardiovascular disease. Both are associated with changes in the circulating metabolome, but causal directions have been difficult to disentangle. We combined untargeted plasma metabolomics by liquid chromatography/mass spectrometry in three non-diabetic cohorts with Mendelian Randomization (MR) analysis to obtain new insights into early metabolic alterations in IR and impaired insulin secretion. In up to 910 elderly men we found associations of 52 metabolites with hyperinsulinemic-euglycemic clamp-measured IR and/or β-cell responsiveness (disposition index) during an oral glucose tolerance test...
October 2016: PLoS Genetics
Chiranjit Ghosh, Santanu Mandal, Gourab D Banik, Abhijit Maity, Prabuddha Mukhopadhyay, Shibendu Ghosh, Manik Pradhan
The inability to envisage the acute onset and progression of type 1 diabetes (T1D) has been a major clinical stumbling block and an important area of biomedical research over the last few decades. Therefore there is a pressing need to develop a new and an effective strategy for early detection of T1D and to precisely distinguish T1D from type 2 diabetes (T2D). Here we describe the precise role of the enzymatic activity of carbonic anhydrase (CA) in erythrocytes in the pathogenesis of T1D and T2D. We show that CA activities are markedly altered during metabolism of T1D and T2D and this facilitates to the oxygen-18 ((18)O) isotopic fractionations of breath CO2...
October 21, 2016: Scientific Reports
Kenji Sugawara, Kohei Honda, Yoshie Reien, Norihide Yokoi, Chihiro Seki, Harumi Takahashi, Kohtaro Minami, Ichiro Mori, Akio Matsumoto, Haruaki Nakaya, Susumu Seino
Insulin secretagogues are used for treatment of type 2 diabetes. We attempted to discover novel small molecules to stimulate insulin secretion by using in silico similarity search using sulfonylureas as query, followed by measurement of insulin secretion. Among 38 compounds selected by in silico similarity search, we found three diphenylsemicarbazides and one quinolone that stimulate insulin secretion. We focused on compound 8 (C8), which had the strongest insulin-secreting effect. Based on the structure-activity relationship of C8-derivatives, we identified diphenylthiosemicarbazide (DSC) 108 as the most potent secretagogue...
2016: PloS One
X H Sun, M S Yin, Y L Mu
Objective: To investigate the alterations of mTOR signaling pathway and autophagy in the development of type 2 diabetes and early diabetic cardiomyopathy and to study their roles in pathogenesis of diabetic myocardium. Methods: A type 2 diabetes rat model was established by injection of streptozocin after five-week of high fat diet. The rats were randomly divided into control group, experiment group of 2 weeks and experiment group of 4 weeks. Alterations of mTOR, p-mTOR, S6K1, Beclin-1 and LC3-Ⅱ expression in myocardium were determined by Western blot and immunohistochemistry...
October 8, 2016: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
Mengjing Wang, Jason Chou, Yongen Chang, Wei L Lau, Uttam Reddy, Connie M Rhee, Jing Chen, Chuanming Hao, Kamyar Kalantar-Zadeh
In the management of patients with chronic kidney diseases (CKD), a low-protein diet usually refers to a diet with protein intake of 0.6 to 0.8 grams per kilogram of body weight per day (g/kg/day) and should include at least 50% high-biologic-value protein. It may be supplemented with essential acids or nitrogen- free ketoanalogues if <0.6 g/kg/d. Low-protein diet can reduce proteinuria especially in non-diabetic CKD patients. In hypoalbuminemic patients it may lead to an increase in serum albumin level...
October 19, 2016: Panminerva Medica
Eda Cengiz, Peiyao Cheng, Katrina J Ruedy, Craig Kollman, William V Tamborlane, Georgeanna J Klingensmith, Robin L Gal, Janet Silverstein, Joyce Lee, Maria J Redondo, Roy W Beck
OBJECTIVE: Current data are limited on the course of type 1 diabetes (T1D) in children and adolescents through the first few years of diabetes. The Pediatric Diabetes Consortium T1D new onset (NeOn) Study was undertaken to prospectively assess natural history and clinical outcomes in children treated at 7 US diabetes centers from the time of diagnosis. This paper describes clinical outcomes in the T1D NeOn cohort during the first 3 years postdiagnosis. RESULTS: A total of 1048 participants (mean age 9...
October 19, 2016: Pediatric Diabetes
Peter Nilsson
A number of chronic disease conditions tend to cluster in families with an increased risk in first-degree relatives, but also an increased risk in second-degree relatives. This fact is most often referred to as the heritability (heredity) of these diseases and explained by the influence of genetic factors, or shared environment, even if the more specific details or mechanism leading to disease are not known. New methods have to be explored in screening studies and register linkage studies to define and measure consequences of a positive family history of disease...
September 2016: Journal of Hypertension
Mohan Raizada
Hypertension (HTN) is the most prevalent modifiable risk for cardiovascular disease (CVD) and disorders directly influencing CVD (i.e. obesity, diabetes, chronic kidney disease, obstructive sleep apnea, etc.). About one billion people worldwide have HTN, with American adults having 90% lifetime risk of developing HTN. Despite aggressive campaign for lifestyle changes and advances in drug therapy, HTN remains an immense health, emotional, and economic challenge. This is due, in part, to the fact that ∼50% of HTN patients' blood pressure remains uncontrolled and ∼20% of HTN patients are resistant to or require > antihypertensive drugs...
September 2016: Journal of Hypertension
Michel E Safar
Mid-life elevated BP is classically associated with a raised systemic vascular resistance. A classical interpretation of the association between aortic stiffness and blood pressure (BP) invokes hypertension as a simple form of premature aging that increases stress on the arterial wall and accelerates age-related stiffening of the aorta. Recent clinical and experimental data have called into question the directionality of this sequence of events associating stiffness and hypertension.Therefore an initial abnormality in stiffness may antedate and contribute initially to the pathogenesis of hypertension, namely isolated systolic hypertension...
September 2016: Journal of Hypertension
Daniel W Jones
Hypertension and Chronic Kidney Disease are both common. The vast majority of patients with chronic kidney disease (CKD) have hypertension. Hypertension can be both a cause and a result of CKD. Many patients with CKD, both diabetic and non-diabetic have overt proteinuria (>300 mg/day). Patients with proteinuria are at higher risk for progression of kidney disease and for atherosclerosis. Because patients with CKD are often excluded from hypertension trials with hard outcomes, there has been until recently less data than ideal to consider in making decisions...
September 2016: Journal of Hypertension
David John Webb
Treatment-resistant hypertension (TRH) is defined as the failure to achieve an office BP target of <140/90 mmHg (<130/80 mmHg in patients with chronic kidney disease (CKD) or diabetes) in patients with hypertension (HT), despite adherence to at least 3 antihypertensive medications at optimal tolerated doses, ideally including a diuretic (Calhoun et al., Circulation 2008). TRH identifies patients with hard-to-treat HT, who might benefit from specialist investigation and treatment. Although some studies put the prevalence of TRH as >10%, these levels may be inflated by white-coat hypertension and poor adherence...
September 2016: Journal of Hypertension
Ernesto Schiffrin
Hypertension has been defined by the levels of BP above which lowering BP will reduce the cardiovascular risk associated with elevated BP. This level has been classically 140/90 mmHg on the basis of actuarial data from the insurance industry. However, we now know that cardiovascular risk rises progressively from levels as low as 115/75 mmHg upward with a doubling of the incidence of both coronary heart disease and stroke for every 20/10-mmHg increment of BP. In uncomplicated hypertension without cardiovascular risk factors or target organ damage, there is little randomized clinical trial evidence that lowering SBP of <160 mmHg reduces cardiovascular risk...
September 2016: Journal of Hypertension
Kazuomi Kario
Asians have specific characteristics of hypertension and related cardiovascular disease. Stroke is more common than coronary artery disease in Eastern Asian countries, while the coronary artery disease is more common than stroke in Western countries. The association slope between higher blood pressure (BP) and the risk of cardiovascular events is steeper in Asians than in Caucasians. This may partly explained by the recent result demonstrating that the morning BP surge in Asians is more extended (Hoshide, Kario, Parati et al...
September 2016: Journal of Hypertension
Masatsugu Horiuchi
Hypertensive patients have greater chances of such cardiovascular events as stroke, coronary heart disease, heart or renal failure, peripheral artery disease, and dementia. It is also well recognized that diabetes increases the cardiovascular risks in concert with hypertension. Therefore, main goals for an innovation of anti-hypertensive therapy would be to achieve further risk reduction by targeting the functional, metabolic, and structural alterations associated with hypertension. Professors Dzau and Braunwald et al proposed the concept of "the cardiovascular disease continuum" in 1991, and that hypertension may trigger the chain of events, leading to end-stage heart disease; however, this concept was quite new at that time, and there was some discussion whether "the cardiovascular disease continuum" is true or not...
September 2016: Journal of Hypertension
Om P Ganda, Joanna Mitri
Despite major advances, many patients with diabetes are currently achieving suboptimal control of lipids and blood pressure. The new cholesterol guidelines by the ACC/AHA have reignited the emphasis on more intensive treatment with statins in the population at high risk of CVD, including those with diabetes. While these guidelines do not include specific lipid goals, several other guidelines have retained previously defined risk-based LDL-C and non-HDL-C goals. More recent data indicate potential benefits in CVD outcomes with non-statin therapy added to statin therapy...
November 2016: Current Cardiology Reports
Munehiro Kitada, Yoshio Ogura, Daisuke Koya
Cardiovascular disease (CVD) due to atherosclerosis is the main cause of death in both the elderly and patients with metabolic diseases, including diabetes. Aging processes contribute to the pathogenesis of atherosclerosis. Calorie restriction (CR) is recognized as a dietary intervention for promoting longevity and delaying age-related diseases, including atherosclerosis. Sirt1, an NAD(+)-dependent deacetylase, is considered an anti-aging molecule and is induced during CR. Sirt1 deacetylates target proteins and is linked to cellular metabolism, the redox state and survival pathways...
October 15, 2016: Aging
Renu Vyas, Sanket Bapat, Esha Jain, Muthukumarasamy Karthikeyan, Sanjeev Tambe, Bhaskar D Kulkarni
In order to understand the molecular mechanism underlying any disease, knowledge about the interacting proteins in the disease pathway is essential. The number of revealed protein-protein interactions (PPI) is still very limited compared to the available protein sequences of different organisms. Experiment based high-throughput technologies though provide some data about these interactions, those are often fairly noisy. Computational techniques for predicting protein-protein interactions therefore assume significance...
September 30, 2016: Computational Biology and Chemistry
P Sneha, C George Priya Doss
The pace of anti-diabetic drug discovery is very slow in spite of increasing rate of prevalence of Type 2 Diabetes which remains a major public health concern. Though extensive research steps are taken in the past decade, yet craves for better of new treatment strategies to overcome the current scenario. One such general finding is the evolution of gliptins which discriminately inhibits DPP4 (Dipeptidyl peptidase-4) enzyme. Although the mechanism of action of gliptin is highly target oriented and accurate, still its long-term use stands unknown...
October 12, 2016: Life Sciences
Kelei Dong, Meiling Wu, Xiaomin Liu, Yanjie Huang, Dongyang Zhang, Yiting Wang, Liang-Jun Yan, Dongyun Shi
AMPK dysregulation contributes to the onset and development of type 2 diabetes (T2DM). AMPK is known to be activated by reactive oxygen species (ROS) and antioxidant interference. However the mechanism by which redox state mediates such contradictory result remains largely unknown. Here we used streptozotocin-high fat diet (STZ-HFD) induced-type 2 diabetic rats and cells lines (L02 and HEK 293) to explore the mechanism of redox-mediated AMPK activation. We show glutaredoxins (Grxs) concomitant with optimal ROS act as an essential mediator for AMPK activation...
October 12, 2016: Free Radical Biology & Medicine
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