The Mammalian target of rapamycin pathway regulates nutrient-sensitive glucose uptake in man

The nutrient-sensitive kinase mammalian target of rapamycin (mTOR) and its downstream target S6 kinase (S6K) are involved in amino acid-induced insulin resistance. Whether the mTOR/S6K pathway directly modulates glucose metabolism in humans is unknown. We studied 11 healthy men (29 years old, BMI 23 kg/m(2)) twice in random order after oral administration of 6 mg rapamycin, a specific mTOR inhibitor, or placebo. An amino acid mixture was infused to activate mTOR, and somatostatin-insulin-glucose clamps created conditions of low peripheral hyperinsulinemia (approximately 100 pmol/l, 0-180 min) and prandial-like peripheral hyperinsulinemia (approximately 450 pmol/l, 180-360 min). Glucose turnover was assessed using d-[6,6-(2)H(2)]glucose infusion (n = 8). Skeletal muscle biopsies were performed at baseline and during prandial-like peripheral hyperinsulinemia (n = 3). At low peripheral hyperinsulinemia, whole-body glucose uptake was not affected by rapamycin. During prandial-like peripheral hyperinsulinemia, rapamycin increased glucose uptake compared with placebo by 17% (R(d 300-360 min), 75 +/- 5 vs. 64 +/- 5 micromol x kg(-1) x min(-1), P = 0.0008). Rapamycin affected endogenous glucose production neither at baseline nor during low or prandial-like peripheral hyperinsulinemia. Combined hyperaminoacidemia and prandial-like hyperinsulinemia increased S6K phosphorylation and inhibitory insulin receptor substrate-1 (IRS-1) phosphorylation at Ser312 and Ser636 in the placebo group. Rapamycin partially inhibited this increase in mTOR-mediated S6K phosphorylation and IRS-1 Ser312 and Ser636 phosphorylation. In conclusion, rapamycin stimulates insulin-mediated glucose uptake in man under conditions known to activate the mTOR/S6K pathway.     

Phagocytosis mediates specificity in the immune defence of an invertebrate, the woodlouse Porcellio scaber (Crustacea: Isopoda)

Specificity and memory are the hallmarks of the adaptive immune system of vertebrates. However, phenomena of specificity upon priming of immunity have recently been demonstrated also in invertebrates, which rely exclusively on innate immune defence. It has been suggested that phagocytosis might represent a core candidate for such specificity in invertebrates. We here developed in vitro phagocytosis measurements for different bacteria in the woodlouse Porcellio scaber (Crustacea: Isopoda). After immune priming with heat-killed bacteria, hemocytes showed increased phagocytosis of a previously encountered bacterial strain compared to other bacteria. These data support the role of phagocytosis in invertebrate immunological specificity and suggest a high degree of specificity that even enables to differentiate between strains of the same bacterial species.     

Pain Sensitivity in Sleepy Pain-Free Normals

Study Objective:

Past studies have shown that acute experimental reduction of time in bed in otherwise healthy, non-sleepy people leads to hyperalgesia. We hypothesized that otherwise healthy, sleepy people may also exhibit hyperalgesia relative to their non-sleepy counterparts.

Design:

Between-groups sleep laboratory study.

Setting:

Hospital-based sleep disorders center.

Participants:

Twenty-seven, healthy, normal participants (age 18–35 years) were recruited and categorized into sleepy and non-sleepy groups based on their average sleep latencies on a screening multiple sleep latency test (MSLT).

Interventions:

Both groups were then allowed 8 hours time in bed, following which they underwent pain sensitivity testing (10:30 and 14:30) and sleepiness assessments by the MSLT (10:00, 12:00, 14:00, and 16:00). Pain sensitivity assessments were made by measuring finger withdrawal latencies to a radiant heat source delivering 5 different heat intensities.

Measurements and Results:

This study showed that after only one night of 8 hours time in bed, the sleepy participants continued to be sleepy and exhibited a more rapid finger withdrawal response (i.e., increased pain sensitivity) to radiant heat than non-sleepy participants.

Conclusion:

This suggests that sleepy individuals experience hyperalgesia in response to a painful stimulus when compared with non-sleepy individuals.

Citation:

Chhangani BS; Roehrs TA; Harris EJ; Hyde M; Drake C; Hudgel DW; Roth T. Pain sensitivity in sleepy pain-free normals. SLEEP 2009;32(8):1011-1017.     

Oxidative stress and autophagy in the regulation of lysosome-dependent neuron death

Lysosomes critically regulate the pH-dependent catabolism of extracellular and intracellular macromolecules delivered from the endocytic/heterophagy and autophagy pathways, respectively. The importance of lysosomes to cell survival is underscored not only by their unique ability effectively to degrade metalloproteins and oxidatively damaged macromolecules, but also by the distinct potential for induction of both caspase-dependent and -independent cell death with a compromise in the integrity of lysosome function. Oxidative stress and free radical damage play a principal role in cell death induced by lysosome dysfunction and may be linked to several upstream and downstream stimuli, including alterations in the autophagy degradation pathway, inhibition of lysosome enzyme function, and lysosome membrane damage. Neurons are sensitive to lysosome dysfunction, and the contribution of oxidative stress and free radical damage to lysosome dysfunction may contribute to the etiology of neurodegenerative disease. This review provides a broad overview of lysosome function and explores the contribution of oxidative stress and autophagy to lysosome dysfunction-induced neuron death. Putative signaling pathways that either induce lysosome dysfunction or result from lysosome dysfunction or both, and the role of oxidative stress, free radical damage, and lysosome dysfunction in pediatric lysosomal storage disorders (neuronal ceroid lipofuscinoses or NCL/Batten disease) and in Alzheimer's disease are emphasized.     

Recruitment rates and reasons for community physicians' non-participation in an interdisciplinary intervention study on leg ulceration

Background  

This article describes the challenges a research team experienced recruiting physicians within a randomised controlled trial about leg ulcer care that seeks to foster the cooperation between the medical and nursing professions. Community-based physicians in North Rhine-Westphalia, Germany, were recruited for an interdisciplinary intervention designed to enhance leg ulcer patients' self-care agency. The aim of this article is to investigate the success of different recruitment strategies employed and reasons for physicians' non-participation.