Dipeptidyl peptidase IV (DPP IV) and related molecules in type 2 diabetes

Dipeptidyl peptidase IV (DPP IV) is a widely distributed physiological enzyme that can be found solubilized in blood, or membrane-anchored in tissues. DPP IV and related dipeptidase enzymes cleave a wide range of physiological peptides and have been associated with several disease processes including Crohn's disease, chronic liver disease, osteoporosis, multiple sclerosis, eating disorders, rheumatoid arthritis, cancer, and of direct relevance to this review, type 2 diabetes. Here, we place particular emphasis on two peptide substrates of DPP IV with insulin-releasing and antidiabetic actions namely, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The rationale for inhibiting DPP IV activity in type 2 diabetes is that it decreases peptide cleavage and thereby enhances endogenous incretin hormone activity. A multitude of novel DPP IV inhibitor compounds have now been developed and tested. Here we examine the information available on DPP IV and related enzymes, review recent preclinical and clinical data for DPP IV inhibitors, and assess their clinical significance.

A Hybrid Evolutionary Approach to the Nurse Rostering Problem

Nurse rostering is a difficult search problem with many constraints. In the literature, a number of approaches have been investigated including penalty function methods to tackle these constraints within genetic algorithm frameworks. In this paper, we investigate an extension of a previously proposed stochastic ranking method, which has demonstrated superior performance to other constraint handling techniques when tested against a set of constrained optimisation benchmark problems. An initial experiment on nurse rostering problems demonstrates that the stochastic ranking method is better in finding feasible solutions but fails to obtain good results with regard to the objective function. To improve the performance of the algorithm, we hybridise it with a recently proposed simulated annealing hyper-heuristic within a local search and genetic algorithm framework. The hybrid algorithm shows significant improvement over both the genetic algorithm with stochastic ranking and the simulated annealing hyper-heuristic alone. The hybrid algorithm also considerably outperforms the methods in the literature which have the previously best known results.

Molecular detection of exercise-induced free radicals following ascorbate prophylaxis in type 1 diabetes mellitus: a randomised controlled trial

Aims/hypothesis: Patients with type 1 diabetes mellitus are more susceptible than healthy individuals to exercise-induced oxidative stress and vascular endothelial dysfunction, which has important implications for the progression of disease. Thus, in the present study, we designed a randomised double-blind, placebo-controlled trial to test the original hypothesis that oral prophylaxis with vitamin C attenuates rest and exercise-induced free radical-mediated lipid peroxidation in type 1 diabetes mellitus. Methods: All data were collected from hospitalised diabetic patients. The electron paramagnetic resonance spectroscopic detection of spin-trapped a-phenyl-tert-butylnitrone (PBN) adducts was combined with the use of supporting markers of lipid peroxidation and non-enzymatic antioxidants to assess exercise-induced oxidative stress in male patients with type 1 diabetes (HbA1c 7.9±1%, n=12) and healthy controls (HbA1c 4.6±0.5%, n=14). Following participant randomisation using numbers in a sealed envelope, venous blood samples were obtained at rest, after a maximal exercise challenge and before and 2 h after oral ingestion of 1 g ascorbate or placebo. Participants and lead investigators were blinded to the administration of either placebo or ascorbate treatments. Primary outcome was the difference in changes in free radicals following ascorbate ingestion. Resuts: Six diabetic patients and seven healthy control participants were randomised to each of the placebo and ascorbate groups. Diabetic patients (n=12) exhibited an elevated concentration of PBN adducts (p<0.05 vs healthy, n=14), which were confirmed as secondary, lipid-derived oxygen-centred alkoxyl (RO•) radicals (a nitrogen=1.37 mT and aßhydrogen=0.18 mT). Lipid hydroperoxides were also selectively elevated and associated with a depression of retinol and lycopene (p<0.05 vs healthy). Vitamin C supplementation increased plasma vitamin C concentration to a similar degree in both groups (p<0.05 vs pre-supplementation) and attenuated the exercise-induced oxidative stress response (p<0.05 vs healthy). There were no selective treatment differences between groups in the primary outcome variable. Conclusions/ interpretation: These findings are the first to suggest that oral vitamin C supplementation provides an effective prophylaxis against exercise-induced free radical-mediated lipid peroxidation in human diabetic blood.

Maternal age at birth and childhood type 1 diabetes: a pooled analysis of 30 observational studies

OBJECTIVE - The aim if the study was to investigate whether children born to older mothers have an increased risk of type 1 diabetes by performing a pooled analysis of previous studies using individual patient data to adjust for recognized confounders.
RESEARCH DESIGN AND METHODS - Relevant studies published before June 2009 were identified from MEDLINE, Web of Science, and EMBASE. Authors of studies were contacted and asked to provide individual patient data or conduct prespecified analyses. Risk estimates of type 1 diabetes by maternal age were calculated for each study, before and after adjustment for potential confounders. Meta-analysis techniques were used to derive combined odds ratios and to investigate heterogeneity among studies.
RESULTS - Data were available for 5 cohort and 25 case-control studies, including 14,724 cases of type 1 diabetes. Overall, there was, on average, a 5% (95% CI 2-9) increase in childhood type 1 diabetes odds per 5-year increase in maternal age (P = 0.006), but there was heterogeneity among studies (heterogeneity I 2 = 70%). In studies with a low risk of bias, there was a more marked increase in diabetes odds of 10% per 5-year increase in maternal age. Adjustments for potential confounders little altered these estimates. CONCLUSIONS - There was evidence of a weak but significant linear increase in the risk of childhood type 1 diabetes across the range of maternal ages, but the magnitude of association varied between studies. A very small percentage of the increase in the incidence of childhood type 1 diabetes in recent years could be explained by increases in maternal age.