Glucose regulation of ß-cell stress in type 2 diabetes.

In type 2 diabetes, the ß-cell is exposed to chronic hyperglycaemia, which increases its metabolic activity, with excess generation of reactive oxygen species (ROS) as a consequence. ROS accumulation induces both oxidative and endoplasmic reticulum (ER) stress, which may lead to ß-cell dysfunction and apoptosis. Recent data suggest that oxidative and ER stress are interconnected, although the mechanisms involved in nutrient regulation of the different stress pathways are dissimilar. Several components of the oxidative and ER stress machineries have important roles in the physiological response to glucose and are thus necessary for normal ß-cell function. Glucose stimulates signalling pathways that provide crucial messages for ß-cell adaptation to metabolic stress; however, the same pathways may eventually lead to apoptosis. Dynamic, temporally fluctuating activation of stress signalling is probably required for the maintenance of ß-cell survival, whereas its persistent activation results in ß-cell dysfunction and apoptosis. Thus, stress signalling is a 'double-edged sword' that may promote adaptation or apoptosis according to the balance between the divergent outputs of the various pathways. Developing new strategies for ß-cell protection based on inhibition of oxidative and/or ER stress requires comprehensive understanding of the switch from ß-cell adaptation to ß-cell apoptosis under conditions of metabolic stress, such as occurs under hyperglycaemic conditions.

Insulin counteracts glucotoxic effects by suppressing thioredoxin-interacting protein production in INS-1E beta cells and in Psammomys obesus pancreatic islets.

AIMS/HYPOTHESIS: In type 2 diabetes, glucose toxicity leads to beta cell apoptosis with decreased beta cell mass as a consequence. Thioredoxin-interacting protein (TXNIP) is a critical mediator of glucose-induced beta cell apoptosis. Since hyperglycaemia leads to elevated serum insulin, we hypothesised that insulin is involved in the regulation of TXNIP protein levels in beta cells. METHODS: We studied the production of TXNIP in INS-1E beta cells and in islets of Psammomys obesus, an animal model of type 2 diabetes, in response to glucose and different modulators of insulin secretion. RESULTS: TXNIP production was markedly augmented in islets from diabetic P. obesus and in beta cells exposed to high glucose concentration. In contrast, adding insulin to the culture medium or stimulating insulin secretion with different secretagogues suppressed TXNIP. Inhibition of glucose and fatty acid-stimulated insulin secretion with diazoxide increased TXNIP production in beta cells. Nitric oxide (NO), a repressor of TXNIP, enhanced insulin signal transduction, whereas inhibition of NO synthase abolished its activation, suggesting that TXNIP inhibition by NO is mediated by stimulation of insulin signalling. Treatment of beta cells chronically exposed to high glucose with insulin reduced beta cell apoptosis. Txnip knockdown mimicking the effect of insulin prevented glucose-induced beta cell apoptosis. CONCLUSIONS/INTERPRETATION: Insulin is a potent repressor of TXNIP, operating a negative feedback loop that restrains the stimulation of TXNIP by chronic hyperglycaemia. Repression of TXNIP by insulin is probably an important compensatory mechanism protecting beta cells from oxidative damage and apoptosis in type 2 diabetes.

Mutations in the familial Mediterranean fever gene of patients with IgA nephropathy and other forms of glomerulonephritis.

Glomerulonephritis, particularly IgA nephropathy (IgAN), seems to be more common in familial Mediterranean fever (FMF), an inherited disease caused by mutations in the MEditerranean FeVer gene (MEFV). The present study is aimed to determine, in populations not suffering from FMF, whether carriage of MEFV mutations may modify or precipitate IgAN and other forms of primary glomerulonephritis (PGN). Forty patients with biopsy proven IgAN and 40 with PGN were surveyed for the presence of the three most common MEFV mutations (M694V, V726A and E148Q), using polymerase chain reaction amplification and restriction enzyme analysis. The rate of MEFV mutations in the patients was related to the expected carrier rate in the general population of the same ethnic extraction. The effect of mutation carriage on the disease course was determined in the IgAN patient group. The frequency of MEFV mutations in IgAN or PGN was comparable to that found in ethnically adjusted general population (p = 0.1 and 0.5, respectively). Carriage of mutated MEFV was not associated with the course and severity of the disease or findings in kidney biopsy and urine analysis. In a population, mostly of Jewish extraction, MEFV mutations do not seem to predispose to the development of IgAN and other forms of PGN or affect the phenotype.

The correction of anemia in severe resistant heart failure with erythropoietin and intravenous iron prevents the progression of both the heart and the renal failure and markedly reduces hospitalization.

Both Congestive Heart Failure (CHF) and Chronic Renal Failure (CRF) are increasing steadily in the community. We propose that there is a vicious circle established whereby CHF and CRF both cause anemia and the anemia then worsens both the CHF and CRF causing more anemia and so on. We call this the Cardio Renal Anemia (CRA) syndrome. By the combination of active treatment of the CHF and control of the anemia with subcutaneous erythropoietin and intravenous iron, the progression of both the CHF and the CRF can be slowed or stopped in most cases, the quality of life improved and the need for recurrent hospitalization reduced. This will involve cooperation between internists, cardiologists, and nephrologists to allow early and maximal therapy of both the CHF and the anemia.

Sweet's syndrome in association with Crohn's disease: report of a case and review of the literature.

A 41-year-old woman developed a skin rash as part of Sweet's syndrome concurrent with the first episode of Crohn's disease of the colon. Sweet's syndrome, acute febrile neutrophilic dermatosis, may be associated with inflammatory, infectious, or neoplastic diseases. Its association with Crohn's disease is very rare, and when reported it has been mainly associated with Crohn's colitis. This association has been described in various stages of the disease. Sweet's syndrome may be considered one of the extraintestinal manifestations of Crohn's disease. Early diagnosis of this dermatosis may be important because of the prompt response to treatment with corticosteroids. The value of metronidazole should be considered because this medication may enhance response to treatment.

Aggressive therapy of congestive heart failure and associated chronic renal failure with medications and correction of anemia stops or slows the progression of both diseases.

The prevalence of congestive heart failure (CHF) is increasing rapidly in the community. We and others have shown that the prevalence and severity of both anemia and chronic renal failure (CRF) increase steadily with increasing severity of CHF. We have also shown that CHF patients may be resistant to standard drug therapy for CHF as long as the associated anemia is not corrected, and that correction of the anemia with subcutaneous erythropoietin and intravenous iron sucrose (Venofer: Vifor International, St. Gallen, Switzerland) may improve both the CHF and CRF and markedly reduce hospitalizations without causing side effects. We report here our experience with correcting anemia in this manner in 126 cases of anemic-resistant CHF patients. As in our previous studies, correction of the anemia improved both CHF and CRF, and reduced hospitalizations. Our studies suggest that correction of even mild anemia in CHF may be an important addition to the treatment of patients with the combination of CHF and CRF.

Meta-analyses comparing theory of mind abilities of individuals with autism, individuals with mental retardation, and normally developing individuals.

A deficit in theory of mind (ToM) abilities has been described as the core deficit in autism. The authors performed 3 meta-analyses, comparing ToM abilities of individuals with autism, individuals with mental retardation (MR), and normally developing individuals. Results indicated that individuals with autism and MR have impaired ToM abilities. The etiology associated with MR (i.e., Down syndrome, undifferentiated etiology) was found to be an important moderator variable. Chronological age (CA) and verbal mental age (VMA) of the normally developing children and CA, VMA, and performance mental age of individuals with MR, and type of matching between the groups were also found to be moderator variables. Discussion focuses on the implication of the findings and emphasizes the need to consider the specific etiology of comparison groups when studying abilities and impairments of individuals with autism and MR.

Stochastic comparison of processes generated by random interruptions of monotone functions and related results.

Many stochastic processes considered in applied probability models, and, in particular, in reliability theory, are processes of the following form: Shocks occur according to some point process, and each shock causes the process to have a random jump. Between shocks the process increases or decreases in some deterministic fashion. In this paper we study processes for which the rate of increase or decrease between shocks depends only on the height of the process. For such processes we find conditions under which the processes can be stochastically compared. We also study 'hybrid' processes in which periods of increase and periods of decrease alternate. A further result yields a stochastic comparison of processes that start with a random jump, rather than processes in which there is at the beginning some random delay time before the first jump.