Molecular Events Linking Oxidative Stress and Inflammation to Insulin Resistance and ß-Cell Dysfunction

The prevalence of diabetes mellitus (DM) is increasing worldwide, a consequence of the alarming rise in obesity and metabolic syndrome (MetS). Oxidative stress and inflammation are key physiological and pathological events linking obesity, insulin resistance, and the progression of type 2 DM (T2DM). Unresolved inflammation alongside a “glucolipotoxic” environment of the pancreatic islets, in insulin resistant pathologies, enhances the infiltration of immune cells which through secretory activity cause dysfunction of insulin-secreting β-cells and ultimately cell death. Recent molecular investigations have revealed that mechanisms responsible for insulin resistance associated with T2DM are detected in conditions such as obesity and MetS, including impaired insulin receptor (IR) signalling in insulin responsive tissues, oxidative stress, and endoplasmic reticulum (ER) stress. The aim of the present review is to describe the evidence linking oxidative stress and inflammation with impairment of insulin secretion and action, which result in the progression of T2DM and other conditions associated with metabolic dysregulation

Novel dehydroepiandrosterone troche supplementation improves the serum androgen profile of women undergoing in vitro fertilization

Dehydroepiandrosterone (DHEA) is the most abundant steroid hormone in the circulation and has potent multifunctional activity. Epidemiological evidence suggests that levels of serum DHEA decrease with advancing age, and this has been associated with onset or progression of various age-related ailments, including cognitive decline and dementia, cardiovascular disease, and obesity. Consequently, these findings have sparked intense research interest in DHEA supplementation as an “antiaging” therapy. Currently, DHEA is being used by 25% of in vitro fertilization (IVF) clinicians as an adjuvant in assisted reproductive programs, yet the therapeutic benefit of DHEA is unclear. Here, we examined the use of novel DHEA-containing oral troches in patients undertaking IVF and investigated the impact of these troches on their serum androgen profile. This retrospective study determined the androgen profile of 31 IVF patients before (baseline) and after DHEA supplementation (with DHEA). Baseline serum measurements of testosterone (total and free), DHEA sulfate (DHEAS), sex hormone-binding globulin (SHBG), and androstenedione were made before and after supplementation. Each patient received DHEA troches containing 25 mg of micronized DHEA, and troches were administered sublingually twice daily for a period of no greater than 4 months. Adjuvant treatment with DHEA boosted the serum concentration of a number of androgen-related analytes, including total and free testosterone, androstenedione, and DHEAS, while serum SHBG remained unchanged. Supplementation also significantly increased the free-androgen index in IVF patients. Interestingly, the increase in serum analyte concentration following DHEA supplementation was found to be dependent on body mass index (BMI), but not individual age.Patients with the lowest BMI (30.0 kg/m2) tended to have lower androgen responses following DHEA supplementation, but these were not statistically different from the corresponding baseline level. This method of DHEA administration results in a similar enhancement of testosterone, DHEAS, and androstenedione levels in comparison with other methods of administration. Furthermore, we showed that BMI significantly influences DHEA uptake and metabolism, and that BMI should be carefully considered during dosage calculation to ensure a significant and robust androgen-profile boost

The chaperone balance hypothesis: The importance of the extracellular to intracellular HSP70 ratio to inflammation-driven type 2 diabetes, the effect of exercise, and the implications for clinical management

Recent evidence shows divergence between the concentrations of extracellular 70 kDa heat shock protein [eHSP70] and its intracellular concentrations [iHSP70] in people with type 2 diabetes (T2DM). A vital aspect regarding HSP70 physiology is its versatility to induce antagonistic actions, depending on the location of the protein. For example, iHSP70 exerts a powerful anti-inflammatory effect, while eHSP70 activates proinflammatory pathways. Increased eHSP70 is associated with inflammatory and oxidative stress conditions, whereas decreased iHSP70 levels are related to insulin resistance in skeletal muscle. Serum eHSP70 concentrations are positively correlated with markers of inflammation, such as C-reactive protein, monocyte count, and TNF-a, while strategies to enhance iHSP70 (e.g., heat treatment, chemical HSP70 inducers or coinducers, and physical exercise) are capable of reducing the inflammatory profile and the insulin resistance state. Here, we present recent findings suggesting that imbalances in the HSP70 status, described by the [eHSP70]/[iHSP70] ratio, may be determinant to trigger a chronic proinflammatory state that leads to insulin resistance and T2DM development. This led us to hypothesize that changes in this ratio value could be used as a biomarker for the management of the inflammatory response in insulin resistance and diabetes

Obesity: A Biobehavioral Point of View

Excerpt: If you ask an overweight person, “Why are you fat?’, you will, almost invariably, get the answer, “Because 1 eat too much.” You will get this answer in spite of the fact that of thirteen studies, six find no significant differences in the caloric intake of obese versus nonobese subjects, five report that the obese eat significantly less than the nonobese, and only two report that they eat significantly more

Metabolic fate of glutamine in lymphocytes, macrophages and neutrophils

Eric Newsholmes laboratory was the first to show glutamine utilization by lymphocytes and macrophages. Recently, we have found that neutrophils also utilize glutamine. This amino acid has been shown to play a role in lymphocyte proliferation, cytokine production by lymphocytes and macrophages and phagocytosis and superoxide production by macrophages and neutrophils. Knowledge of the metabolic fate of glutamine in these cells is important for the understanding of the role and function of this amino acid in the maintenance of the proliferative, phagocytic and secretory capacities of these cells. Glutamine and glucose are poorly oxidized by these cells and might produce important precursors for DNA, RNA, protein and lipid synthesis. The high rate of glutamine utilization and its importance in such cells have raised the question as to the source of this glutamine, which, according to current evidence, appears to be muscle

Leucine-glycine and carnosine dipeptides prevent diabetes induced by multiple low-dose streptozotocin in experimental model of adult mice

Aims/Introduction Peptides are considered as quasi‐hormones and effective molecules for regulation of the cells function and metabolic disorders prevention. Di‐ and tripeptides with the ability to gastrointestinal absorption have been proposed to prevent diabetes progression. Materials and Methods Small peptides with different sequences of specific amino acids were synthesized based on a solid phase peptide synthesis (SPPS) protocol as well as carnosine (A) and glutathione (B) were examined for the prevention of diabetes induced by multiple low‐dose of streptozotocin (MLDS) in mice. Results The peptides A, Leu‐Gly (D) and Pro‐Pro (F) exhibited a preventive effects on blood glucose elevation and impairment of the signaling and performance of beta cells. The beta cells function assessed by immunofluorescence and blood glucose level in mice exposed to diabetes treated by the peptides A and D was similar to the normal mice. The peptide D prevented from body weight loss caused by diabetes induction. The use of D and A peptides dramatically prevents the incidence of disruption in beta cells signaling by maintaining the natural balance of intracellular Akt‐2 and cAMP. Conclusions The results proved that peptide D (Leu‐Gly) named Hannaneh inhibits the body weight loss caused by diabetes induction. The Hannaneh and carnosine dipeptides with preservation of normal beta cell signalling and anti DPP‐4 activity were prevented from increasing the blood glucose in mice at risk of diabetes. These dipeptides may be regarded as the pharmaceutical agents for the prevention of diabetes