Antidiabetic Actions of Endogenous and Exogenous GLP-1 in Type 1 Diabetic Patients With and Without Residual β-Cell Function

OBJECTIVE—To investigate the effect of exogenous as well as endogenous glucagon-like peptide 1 (GLP-1) on postprandial glucose excursions and to characterize the secretion of incretin hormones in type 1 diabetic patients with and without residual b-cell function. RESEARCH DESIGN AND METHODS—Eight type 1 diabetic patients with (T1D+), eight without (T1D2) residual b-cell func-tion, and eight healthy matched control subjects were studied during a mixed meal with concomitant infusion of GLP-1 (1.2 pmol/kg/min), saline, or exendin 9-39 (300 pmol/kg/min). Before the meal, half dose of usual fast-acting insulin was injected. Plasma glucose (PG), glucagon, C-peptide, total GLP-1, intact glucose-dependent insulinotropic polypeptide (GIP), free fatty acids, triglycerides, and gastric emptying rate (GE) by plasma acetaminophen were measured

Element-specific probe of quantum criticality in CeCoIn5\mathrm{CeCoIn_{5}}

Employing the elemental sensitivity of x-ray absorption spectroscopy (XAS) and x-ray magnetic circular dichroism (XMCD), we study the valence and magnetic order in the heavy fermion superconductor CeCoIn$_5$. We probe spin population of the f-electrons in Ce and d-electrons in Co as a function of temperature (down to 0.1 K) and magnetic field (up to 6 T). From the XAS we find a pronounced contribution of Ce$^{4+}$ component at low temperature and a clear temperature dependence of the Ce valence below 5 K, suggesting enhanced valence fluctuations, an indication for the presence of a nearby quantum critical point (QCP). We observe no significant corresponding change with magnetic field. The XMCD displays a weak signal for Ce becoming clear only at 6 T. This splitting of the Kramers doublet ground state of Ce$^{3+}$ is significantly smaller than expected for independent but screened ions, indicating strong antiferromagnetic pair interactions. The unconventional character of superconductivity in CeCoIn$_5$ is evident in the extremely large specific heat step at the superconducting transition.Comment: 5 pages, 5 figures. Supplementary information (4 pages, 5 figures

Genetic and other factors determining mannose-binding lectin levels in American Indians: the Strong Heart Study

<p>Abstract</p> <p>Background</p> <p>Mannose-binding lectin (MBL) forms an integral part of the innate immune system. Persistent, subclinical infections and chronic inflammatory states are hypothesized to contribute to the pathogenesis of atherosclerosis. MBL gene (<it>MBL2</it>) variants with between 12 to 25% allele frequency in Caucasian and other populations, result in markedly reduced expression of functional protein. Prospective epidemiologic studies, including a nested, case-control study from the present population, have demonstrated the ability of <it>MBL2 </it>genotypes to predict complications of atherosclerosis,. The genetic control of <it>MBL2 </it>expression is complex and genetic background effects in specific populations are largely unknown.</p> <p>Methods</p> <p>The Strong Heart Study is a longitudinal, cohort study of cardiovascular disease among American Indians. A subset of individuals genotyped for the above mentioned case-control study were selected for analysis of circulating MBL levels by double sandwich ELISA method. Mean MBL levels were compared between genotypic groups and multivariate regression was used to determine other independent factors influencing <it>MBL2 </it>expression.</p> <p>Results</p> <p>Our results confirm the effects of variant structural (B, C, and D) and promoter (H and Y) alleles that have been seen in other populations. In addition, MBL levels were found to be positively associated with male gender and hemoglobin A1c levels, but inversely related to triglyceride levels. Correlation was not found between MBL and other markers of inflammation.</p> <p>Conclusion</p> <p>New data is presented concerning the effects of known genetic variants on MBL levels in an American Indian population, as well as the relationship of <it>MBL2 </it>expression to clinical and environmental factors, including inflammatory markers.</p

Pharmacokinetic Properties of Liraglutide as Adjunct to Insulin in Subjects with Type 1 Diabetes Mellitus.

BACKGROUND: The pharmacokinetic properties of liraglutide, a glucagon-like peptide-1 receptor agonist approved for the treatment of type 2 diabetes mellitus (T2D), have been established in healthy individuals and subjects with T2D. Liraglutide has been under investigation as adjunct treatment to insulin in type 1 diabetes mellitus (T1D). This single-center, double-blind, placebo-controlled, crossover, clinical pharmacology trial is the first to analyze the pharmacokinetic properties of liraglutide as add-on to insulin in T1D. METHODS: Subjects (18-64 years; body mass index 20.0-28.0 kg/m(2); glycated hemoglobin ≤9.5 %) were randomized 1:1:1 to 0.6, 1.2, or 1.8 mg liraglutide/placebo. Each group underwent two 4-week treatment periods (liraglutide then placebo or placebo then liraglutide) separated by a 2- to 3-week washout. Both trial drugs were administered subcutaneously, once daily, as adjunct to insulin. A stepwise hypoglycemic clamp was performed at the end of each treatment period (data reported previously). Pharmacokinetic endpoints were derived from liraglutide concentration-time curves after the final dose and exposure was compared with data from previous trials in healthy volunteers and subjects with T2D. RESULTS: The pharmacokinetic properties of liraglutide in T1D were comparable with those observed in healthy volunteers and subjects with T2D. Area under the steady-state concentration-time curve (AUC) and maximum plasma concentration data were consistent with dose proportionality of liraglutide. Comparison of dose-normalized liraglutide AUC suggested that exposure in T1D, when administered with insulin, is comparable with that observed in T2D. CONCLUSIONS: Liraglutide, administered as adjunct to insulin in subjects with T1D, shows comparable pharmacokinetics to those in subjects with T2D. ClinicalTrials.gov Identifier: NCT01536665

Effects of an Infectious Fungus, Batrachochytrium dendrobatidis, on Amphibian Predator-Prey Interactions

The effects of parasites and pathogens on host behaviors may be particularly important in predator-prey contexts, since few animal behaviors are more crucial for ensuring immediate survival than the avoidance of lethal predators in nature. We examined the effects of an emerging fungal pathogen of amphibians, Batrachochytrium dendrobatidis, on anti-predator behaviors of tadpoles of four frog species. We also investigated whether amphibian predators consumed infected prey, and whether B. dendrobatidis caused differences in predation rates among prey in laboratory feeding trials. We found differences in anti-predator behaviors among larvae of four amphibian species, and show that infected tadpoles of one species (Anaxyrus boreas) were more active and sought refuge more frequently when exposed to predator chemical cues. Salamander predators consumed infected and uninfected tadpoles of three other prey species at similar rates in feeding trials, and predation risk among prey was unaffected by B. dendrobatidis. Collectively, our results show that even sub-lethal exposure to B. dendrobatidis can alter fundamental anti-predator behaviors in some amphibian prey species, and suggest the unexplored possibility that indiscriminate predation between infected and uninfected prey (i.e., non-selective predation) could increase the prevalence of this widely distributed pathogen in amphibian populations. Because one of the most prominent types of predators in many amphibian systems is salamanders, and because salamanders are susceptible to B. dendrobatidis, our work suggests the importance of considering host susceptibility and behavioral changes that could arise from infection in both predators and prey