Sodium tungstate: Is it a safe option for a chronic disease setting,such as diabetes?

Diabetes is a complex metabolic disorder triggered by the deficient secretion of insulin by pancreatic β cells, the resistance of peripheral tissues to the action of the hormone, or both, and is characterized by chronic hyperglycemia leading to organ damage and failure. Tight glycemic control represents the best therapy to delay or stop progression of diabetes, with many antidiabetic drugs being commercially available nowadays. However, no ideal normoglycemic agent has been developed as yet, and those already available still induce hypoglycemia and/or weight gain as major side effects, worsening glycemic control. In this respect, the inorganic salt sodium tungstate (Na₂WO₄) has been proven to offer a good antidiabetic alternative in different animal models of diabetes, reducing body weight and normalizing glycemia without causing hypoglycemic episodes. The mechanisms of action mediating the potent antidiabetic actions but also the spectrum of undesirable effects of Na₂WO₄ are still poorly understood. In fact, along with its beneficial effects, Na₂WO₄ has been consistently reported to be toxic and even carcinogenic. Given that Na₂WO₄ is accumulated in the kidneys for elimination, here, we discuss a possible association between long-term Na₂WO₄ treatment and a higher risk of renal carcinogenesis in diabetic individuals.     

Increasing incidence of Type 1 diabetes – role for genes?

Background  

The incidence of Type 1 diabetes (T1DM) is increasing fast in many populations. The reasons for this are not known, although an increase in the penetrance of the diabetes-associated alleles, through changes in the environment, might be the most plausible mechanism. After the introduction of insulin treatment in 1930s, an increase in the pool of genetically susceptible individuals has been suggested to contribute to the increase in the incidence of Type 1 diabetes.     

Setting research priorities for Type 1 diabetes

Diabet. Med. 29, 1321-1326 (2012) ABSTRACT: Aims Research priorities are often set by academic researchers or the pharmaceutical industry. The interests of patients, carers and clinicians may therefore be overlooked and research questions that matter may be neglected. The aims of this study were to collect uncertainties about the treatment of Type?1 diabetes from patients, carers and health professionals, and to collate and prioritize these uncertainties to develop a top 10 list of research priorities, using a structured priority-setting partnership of patients, carers, health professionals and diabetes organizations, as described by the James Lind Alliance. Methods A partnership of interested organizations was set up, and from this a steering committee of 10 individuals was formed. An online and paper survey was used to identify uncertainties. These were collated, and the steering group carried out an interim priority-setting exercise with partner organizations. This group of uncertainties was then voted on to give a smaller list that went forward to the final priority-setting workshop. At this meeting, a final list of the top 10 research priorities was agreed. Results An initial 1141 uncertainties were described. These were reduced to 88 indicative questions, 47 of which went out for voting. Twenty-four were then taken forward to a final priority-setting workshop. This workshop resulted in a list of top 10 research priorities in Type?1 diabetes. Conclusion We have shown that it is possible using the James Lind Alliance process to develop an agreed top 10 list of research priorities for Type?1 diabetes from health professionals, patients and carers.     

Identification of kinectin as a novel Beh?et's disease autoantigen

There has been some evidence that Beh?et's disease (BD) has a significant autoimmune component but the molecular identity of putative autoantigens has not been well characterized. In the initial analysis of the autoantibody profile in 39 Chinese BD patients, autoantibodies to cellular proteins were uncovered in 23% as determined by immunoblotting. We have now identified one of the major autoantibody specificities using expression cloning. Serum from a BD patient was used as a probe to immunoscreen a λZAP expression cDNA library. Candidate autoantigen cDNAs were characterized by direct nucleotide sequencing and their expressed products were examined for reactivity to the entire panel of BD sera using immunoprecipitation. Reactivity was also examined with normal control sera and disease control sera from patients with lupus and Sj?gren's syndrome. Six independent candidate clones were isolated from the cDNA library screen and were identified as overlapping partial human kinectin cDNAs. The finding that kinectin was an autoantigen was verified in 9 out of 39 (23%) BD patient sera by immunoprecipitation of the in vitro translation products. Sera from controls showed no reactivity. The significance of kinectin as a participant in autoimmune pathogenesis in BD and the potential use of autoantibody to kinectin in serodiagnostics are discussed.     

Type 2 diabetes – An autoinflammatory disease driven by metabolic stress

Type 2 diabetes has traditionally been viewed as a metabolic disorder characterised by chronic high glucose levels, insulin resistance, and declining insulin secretion from the pancreas. Modern lifestyle, with abundant nutrient supply and reduced physical activity, has resulted in dramatic increases in the rates of obesity-associated disease conditions, including diabetes. The associated excess of nutrients induces a state of systemic low-grade chronic inflammation that results from production and secretion of inflammatory mediators from the expanded pool of activated adipocytes. Here, we review the mechanisms by which obesity induces adipose tissue dysregulation, detailing the roles of adipose tissue secreted factors and their action upon other cells and tissues central to glucose homeostasis and type 2 diabetes. Furthermore, given the emerging importance of adipokines, cytokines and chemokines in disease progression, we suggest that type 2 diabetes should now be viewed as an autoinflammatory disease, albeit one that is driven by metabolic dysregulation.     

Coeliac disease in Type 1 diabetes from 1990 to 2009: higher incidence in young children after longer diabetes duration

Diabet. Med. 29, e286-e289 (2012) ABSTRACT: Aims To determine the incidence of coeliac disease in young people with Type?1 diabetes and to examine the effect of age at diabetes onset and disease duration. Methods This was a clinic-based observational cohort study of 4379 people aged ≤?18?years (49% male) between 1990 and 2009 from Sydney, Australia. Screening for coeliac disease was performed at diagnosis and 1-2?yearly using anti-endomysial and/or anti-tissue transglutaminase immunoglobulin?A (IgA) antibodies. Coeliac disease was diagnosed by small bowel biopsy based on Marsh score ≥?III. Results Coeliac disease was confirmed by biopsy in 185; of these, 61 (33%) were endomysial or tissue transglutaminase IgA antibody-positive at diabetes diagnosis. Mean age at diabetes onset was 6.6?±?4.0 vs. 8.4?±?4.1?years in those without coeliac disease (P?相似文献   

Can primary hyperaldosteronism be considered as a specific form of diabetes mellitus?

Aldosterone-producing adenoma (aldosteronoma)--the most frequent form of primary hyperaldosteronism (PH)--is considered a specific form of diabetes mellitus (DM). In a previous study we demonstrated insulin resistance in patients with PH. We have therefore undertaken a study to evaluate the incidence of abnormalities of glucose metabolism in patients with PH (36 subjects) compared to control subjects with essential hypertension (EH) (21 patients). The following parameters were measured in all studied subjects: office blood pressure (by mercury sphygmomanometer in the sitting position), body mass index (BMI), plasma potassium, plasma glucose and insulin levels during oral glucose tolerance test (OGTT) (0, 60, 120 min), plasma renin activity and plasma aldosterone. Although patients with PH tended to have higher stimulated plasma glucose levels after 60 and 120 min compared to EH, these differences did not attain statistical significance. Patients with EH tended to have higher insulin levels at each measured interval, but due to a high variability these differences were again not significant. There were no significant differences between PH and EH in the proportion of diabetics (20% vs. 14%) or patients with impaired glucose tolerance (18% vs. 10%). In conclusion, we have found the absence of significant differences in the frequency of diabetes mellitus, impaired glucose tolerance and insulin resistance in patients with EH and PH. Our data thus do not support the idea of primary hyperaldosteronism as a specific type of diabetes mellitus. Furthermore, our results indicate that glucose metabolic characteristics in essential hypertension and primary hyperaldosteronism tend to be similar. The definitive conclusion with respect to the possible causal relationship between DM and PH, however, can be obtained only on larger groups of subjects, in particular after the evaluation of the effect of surgical/pharmacological treatment of primary hyperaldosteronism.     

B cells as a therapeutic target for IFN-β in relapsing-remitting multiple sclerosis

IFN-β-1b is a first-line immunomodulatory therapy for relapsing-remitting multiple sclerosis (RR MS). However, its effects on B cells have not been characterized. In vitro studies of B cells derived from RR MS patients revealed that IFN-β-1b decreases B cells' stimulatory capacity, as detected by inhibition of the Ag-specific T cell proliferative response upon Ag presentation by IFN-β-1b-treated B cells. Our study has identified that IFN-β-1b inhibited B cells' stimulatory capacity in RR MS patients and healthy controls through the suppression of CD40 and CD80 expression, whereas the MHC class I and II expression was not changed. IFN-β-1b in vitro treatment inhibited B cell secretion of IL-1β and IL-23 and induced IL-12 and IL-27. Supernatants transferred from IFN-β-1b-treated B cells inhibited Th17 cell differentiation, as they suppressed gene expression of the retinoic acid-related orphan nuclear hormone receptor C and IL-17A and secretion of IL-17A. In addition, IFN-β-1b induced B cells' IL-10 secretion, which may mediate their regulatory effect. Studies of B cells derived from RR MS patients treated with recombinant s.c. injected IFN-β-1b revealed that they induced a significantly lower proliferative response in allogenic MLR than the B cells from untreated patients. Further confirming the IFN-β-1b in vitro-induced changes in B cell cytokine secretion, B cells derived from the IFN-β-1b-treated patients secreted significantly lower levels of IL-1β and IL-23 and higher levels of IL-12 and IL-27 in comparison with the B cells derived from untreated patients. We conclude that IFN-β-1b exerts its therapeutic effects in part by targeting B cells' functions that contribute to the autoimmune pathogenesis of RR MS.     

Type II diabetes of early onset: a distinct clinical and genetic syndrome?

The inheritance of non-insulin-dependent (type II) diabetes was studied by a continuous infusion of glucose test in all available first degree relatives of 48 diabetic probands of various ages and with differing severity of disease. In an initial study of 38 type II diabetic subjects and their first degree relatives six islet cell antibody negative patients with early onset disease (aged 25-40 at diagnosis) were found to have a particularly high familial prevalence of diabetes or glucose intolerance. Nine of 10 parents available for study either had type II diabetes or were glucose intolerant. A high prevalence of diabetes or glucose intolerance was also found in their siblings (11/16;69%). In a second study of the families of a further 10 young diabetic probands (presenting age 25-40) whose islet cell antibody state was unknown a similar high prevalence of diabetes or glucose intolerance was found among parents of the five islet cell antibody negative probands (8/9; 89%) but not among parents of the five islet cell antibody positive probands (3/8;38%). Islet cell antibody negative diabetics with early onset type II disease may have inherited a diabetogenic gene or genes from both parents. They commonly need insulin to maintain adequate glycaemic control and may develop severe diabetic complications. Early onset type II diabetes may represent a syndrome in which characteristic pedigrees, clinical severity, and absence of islet autoimmunity make it distinct from either type I diabetes, maturity onset diabetes of the young, or late onset type II diabetes.     

Gestational diabetes: a non-entity?

Screening for gestational diabetes is commonly recommended despite the absence of a common definition of gestational diabetes. Furthermore, there is no consensus about management or treatment. Those who recommend screening do so largely on the basis of fetal morbidity, which seems to be predominantly "macrosomia"--another term without an agreed definition. The implications of macrosomia in terms of actual morbidity are also not clear. R J Jarrett reviews the history of the subject and concludes that gestational diabetes is simply impaired glucose tolerance temporally associated with pregnancy. Its main importance is as a predictor of subsequent non-insulin dependent diabetes, but it fails the major tests for a condition suitable for a screening programme.     

Is Alzheimer's disease a systemic disease?

Although Alzheimer's disease (AD) is the most common neurodegenerative disease, the etiology of AD is not well understood. In some cases, genetic factors explain AD risk, but a high percentage of late-onset AD is unexplained. The fact that AD is associated with a number of physical and systemic manifestations suggests that AD is a multifactorial disease that affects both the CNS and periphery. Interestingly, a common feature of many systemic processes linked to AD is involvement in energy metabolism. The goals of this review are to 1) explore the evidence that peripheral processes contribute to AD risk, 2) explore ways that AD modulates whole-body changes, and 3) discuss the role of genetics, mitochondria, and vascular mechanisms as underlying factors that could mediate both central and peripheral manifestations of AD. Despite efforts to strictly define AD as a homogeneous CNS disease, there may be no single etiologic pathway leading to the syndrome of AD dementia. Rather, the neurodegenerative process may involve some degree of baseline genetic risk that is modified by external risk factors. Continued research into the diverse but related processes linked to AD risk is necessary for successful development of disease-modifying therapies.     

Type 2 diabetes caused by reductive redox potential?

<正>Reactive oxygen species arise(ROS)in the mitochondria as byproducts of respiration and oxidase activity and have important roles in many physiological and pathophysiological conditions.The current literature indicate that excessive levels of ROS can cause oxidative stress and that lots of evidences link ROS and oxidative stress to the pathogenesis of type 2 diabetes mellitus(T2DM)and development of complications.Several studies have shown elevated extraand intracellular glucose concentrations result in oxidative stress both in animal models of diabetes and in diabetic patients[1].And ROS can contribute to the development and progression of diabetes and related complications by directly damaging DNA,proteins,and lipids or indirectly activating a number of cellular stress-sensitive pathways to induce damage to tissues such as isletβcells[2].     

Can plants serve as a vector for prions causing chronic wasting disease?

Prions, the causative agent of chronic wasting disease (CWD) enter the environment through shedding of bodily fluids and carcass decay, posing a disease risk as a result of their environmental persistence. Plants have the ability to take up large organic particles, including whole proteins, and microbes. This study used wheat (Triticum aestivum L.) to investigate the uptake of infectious CWD prions into roots and their transport into aerial tissues. The roots of intact wheat plants were exposed to infectious prions (PrP^TSE) for 24 h in three replicate studies with PrP^TSE in protein extracts being detected by western blot, IDEXX and Bio-Rad diagnostic tests. Recombinant prion protein (PrP^C) bound to roots, but was not detected in the stem or leaves. Protease-digested CWD prions (PrP^TSE) in elk brain homogenate interacted with root tissue, but were not detected in the stem. This suggests wheat was unable to transport sufficient PrP^TSE from the roots to the stem to be detectable by the methods employed. Undigested PrP^TSE did not associate with roots. The present study suggests that if prions are transported from the roots to the stems it is at levels that are below those that are detectable by western blot, IDEXX or Bio-Rad diagnostic kits.     

Pregnancy as a harm?

Michigan's Appellate Court ruled in 2004 that a pregnancy that resulted from a rape should be considered a bodily injury for sentencing purposes. Interestingly, all three possible outcomes of a pregnancy-abortion, miscarriage, or childbirth-are considered to bring with them significant and substantial physical, psychological, and emotional changes. While the immediate impact of the ruling in People v. Cathey affected only the guilty individual, there are larger implications for this ruling beyond just sentencing guidelines. The ruling can be considered a step forward in prosecuting rapists, but possibly at the expense of reimagining the female body. This article considers the Cathey ruling itself, the potential benefits and consequences of this understanding on feminist discourse, and, crucially, the impact of this decision on abortion discussions. The central question that emerges is, can we both consider pregnancy a harm and believe that this harm is not always wrong-making?