Age-related degeneration of corpus callosum in the 90+ years measured with stereology

The present study is aimed to assess age-related structural changes in corpus callosum with stereology in 21 postmortem human brains without neuropathology, of age 65-75 (Group A, n = 7), 80-85 (Group B, n = 7), and 94-105 (Group C, n = 7) years. Cross-sectional area, fiber number and density decrease in Group B compared with Group A, then remain unchanged in Group C. Mean fiber diameter increases with age. Cross-sectional area shows strong positive correlation to fiber numbers and negative correlation to mean fiber thickness. With age, modest but significant change in fiber size including a decrease in the percentage of 1-2-μm fibers and an increase in 2-3-μm fibers was observed. Fiber density shows a steeper decline with age in the anterior compared with posterior segments. Neurodegeneration is an ongoing process where the anterior corpus callosum is more susceptible to age-related degeneration. Corpus callosum cross-sectional area atrophy is mostly related to decline in fiber number and density rather than demyelination, with preferential disruption of small caliber fibers.     

Effects of lipopolysaccharide infusion on arterial levels and transcerebral exchange kinetics of glutamate and glycine in healthy humans

An imbalance between glutamate and glycine signalling may contribute to sepsis‐associated encephalopathy by causing neuronal excitotoxicity. In this study, we therefore investigated the transcerebral exchange kinetics of glutamate and glycine in a human‐experimental model of systemic inflammation. Cerebral blood flow (CBF) and arterial to jugular venous concentration differences of glutamate and glycine were determined before and after a 4‐h intravenous infusion of Escherichia coli lipopolysaccharide (LPS, total dose of 0.3 ng/kg) in 12 healthy volunteers. The global cerebral net exchange was calculated by multiplying CBF with the arterial to jugular venous differences. LPS induced a systemic inflammatory response with fever, neutrocytosis, and elevated arterial levels of tumour necrosis factor‐α. This was associated with a decrease in the arterial levels of both glutamate and glycine; however, their transcerebral exchange kinetics were unaffected. Inflammation‐induced alterations of the circulating levels of glutamate and glycine, do not affect the global transcerebral exchange kinetics of these amino acids in healthy humans.     

No difference in self reported health among coalminers in two different shift schedules at Spitsbergen, Norway, a two years follow-up

This study was performed among coal miners in the remote location Svea, Spitsbergen. The shift schedule used to be 7 d on and 7 d off. The aim of this study was to investigate possible changes in health after a voluntary implementation of a new shift schedule, with periods of 14 d on and 14 d off, for 74 percent of the workers in 2007. A questionnaire was distributed to all employees before and two times after the new shift schedule, comprising questions on type of work, shift schedule, pain, sleep, stress and coping. Ninety nine percent of the employees responded; 274 in 2006, 307 in 2007 and 312 in 2008. Work neither in the 14/14 shift nor 7/7 shift was related to any change in the health after these two years. The coping index for workers in the 14/14 shift improved.     

Medium-chain and long-chain fatty acids have different postabsorptive fates in Atlantic salmon

An increasingly larger proportion of the oils used in diets for farmed fish are plant derived and rapeseed oil is most commonly used. Despite high dietary lipid levels and a marked change in lipid composition, the transport and metabolic fate of absorbed fatty acids is not fully understood in teleost fish. The main purpose of this study was to trace the postabsorptive metabolic fate of 2 fatty acids of different chain length: oleic acid [(3)H-18:1(n-9)], constituting 70% of fatty acids in rapeseed oil, and the medium-chain decanoic acid [(14)C-10:0], which does not require carrier molecules for membrane passage. The fatty acids and their metabolites were traced in portal and peripheral blood, liver, heart, skeletal muscle, and visceral adipose tissue at time intervals from 3 to 48 h after feeding. The portal vein was the primary transport route for both 10:0 and 18:1(n-9) from the intestine to the liver the first 6 h after feed intake. From 12 to 48 h, the peripheral route became increasingly more important. The study also indicates a possible direct transport route of fatty acids from the intestine to the surrounding viscera. Our data demonstrate that whereas 18:1(n-9) is primarily deposited as TG in skeletal muscle and visceral adipose tissue, 10:0 is used by the heart and skeletal muscle as a source for rapid energy production.     

AMP-activated protein kinase (AMPK) beta1beta2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise

AMP-activated protein kinase (AMPK) β1 or β2 subunits are required for assembling of AMPK heterotrimers and are important for regulating enzyme activity and cellular localization. In skeletal muscle, α2β2γ3-containing heterotrimers predominate. However, compensatory up-regulation and redundancy of AMPK subunits in whole-body AMPK α2, β2, and γ3 null mice has made it difficult to determine the physiological importance of AMPK in regulating muscle metabolism, because these models have normal mitochondrial content, contraction-stimulated glucose uptake, and insulin sensitivity. In the current study, we generated mice lacking both AMPK β1 and β2 isoforms in skeletal muscle (β1β2M-KO). β1β2M-KO mice are physically inactive and have a drastically impaired capacity for treadmill running that is associated with reductions in skeletal muscle mitochondrial content but not a fiber-type switch. Interestingly, young β1β2M-KO mice fed a control chow diet are not obese or insulin resistant but do have impaired contraction-stimulated glucose uptake. These data demonstrate an obligatory role for skeletal muscle AMPK in maintaining mitochondrial capacity and contraction-stimulated glucose uptake, findings that were not apparent in mice with single mutations or deletions in muscle α, β, or γ subunits.     

Comparison of Gd-DTPA and Gd-BOPTA for studying renal perfusion and filtration

Purpose:

To measure the systematic error in perfusion and filtration parameters derived from magnetic resonance (MR) renography caused by protein binding of MR contrast agents.

Materials and Methods:

Eight healthy Danish Landrace pigs were examined with dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI). In four pigs a bolus of gadopentetate‐dimeglumine (Gd‐DTPA; no protein binding) was injected, followed by gadobenate‐dimeglumine (Gd‐BOPTA; 10% protein binding). The order was reversed in the other four pigs. A two‐compartment filtration model was generalized to allow for protein binding and fitted to whole‐cortex region of interest (ROI) curves. Single‐kidney plasma flow and volume, tubular flow (or GFR), and tubular transit time of both agents were compared.

Results:

The data show a strong systematic underestimation (P < 0.001) in GFR by Gd‐BOPTA (33 ± 7.2%), and no significant differences (P > 0.05) in plasma flow (2.2 ± 18%), plasma volume (?1.7 ± 7.8%) and tubular transit time (3.1 ± 7.2%). The order of injection had no significant effect.

Conclusion:

Theory and experiments agree that perfusion parameters of both agents are comparable, whereas GFR is underestimated with Gd‐BOPTA due to the dependence of relaxivity on protein content. Hence, GFR cannot be measured with protein‐bound contrast agents, but the proposed dual‐agent protocol may produce new functional indices measuring protein filtration. J. Magn. Reson. Imaging 2011;. © 2011 Wiley‐Liss, Inc.

     

Lipid-induced insulin resistance affects women less than men and is not accompanied by inflammation or impaired proximal insulin signaling

OBJECTIVE

We have previously shown that overnight fasted women have higher insulin-stimulated whole body and leg glucose uptake despite a higher intramyocellular triacylglycerol concentration than men. Women also express higher muscle mRNA levels of proteins related to lipid metabolism than men. We therefore hypothesized that women would be less prone to lipid-induced insulin resistance.

RESEARCH DESIGN AND METHODS

Insulin sensitivity of whole-body and leg glucose disposal was studied in 16 young well-matched healthy men and women infused with intralipid or saline for 7 h. Muscle biopsies were obtained before and during a euglycemic-hyperinsulinemic clamp (1.42 mU · kg⁻¹ · min⁻¹).

RESULTS

Intralipid infusion reduced whole-body glucose infusion rate by 26% in women and 38% in men (P < 0.05), and insulin-stimulated leg glucose uptake was reduced significantly less in women (45%) than men (60%) after intralipid infusion. Hepatic glucose production was decreased during the clamp similarly in women and men irrespective of intralipid infusion. Intralipid did not impair insulin or AMPK signaling in muscle and subcutaneous fat, did not cause accumulation of muscle lipid intermediates, and did not impair insulin-stimulated glycogen synthase activity in muscle or increase plasma concentrations of inflammatory cytokines. In vitro glucose transport in giant sarcolemmal vesicles was not decreased by acute exposure to fatty acids. Leg lactate release was increased and respiratory exchange ratio was decreased by intralipid.

CONCLUSIONS

Intralipid infusion causes less insulin resistance of muscle glucose uptake in women than in men. This insulin resistance is not due to decreased canonical insulin signaling, accumulation of lipid intermediates, inflammation, or direct inhibition of GLUT activity. Rather, a higher leg lactate release and lower glucose oxidation with intralipid infusion may suggest a metabolic feedback regulation of glucose metabolism.Whole-body insulin resistance plays a major role in the pathogenesis of type 2 diabetes and has generally been related to high plasma concentrations of lipids. Intralipid infusion increases plasma lipid concentrations and has been used as a model to investigate lipid-induced insulin resistance in rodents (1,2) and humans (3–5). The studies uniformly demonstrate that intralipid infusion reduces whole-body insulin sensitivity markedly within 3–4 h. Various mechanisms have been suggested to explain this phenomenon, including lipid-induced interaction with proximal insulin-signaling capacity, accumulation of lipid intermediates, and inflammation (5). The classic lipid-induced inhibition of the insulin-signaling pathway has, however, been challenged in recent studies where insulin receptor substrate (IRS)-1 tyrosine phosphorylation, IRS-1–associated phosphatidylinositol (PI) 3-kinase activity, Akt, and AS160 phosphorylation were unaltered after 2- to 6-h intralipid infusion in rats (1) and in lean (6) and obese (7) men.Only one of the human studies included women and, in that study, a matching of sexes with respect to important matching criteria (i.e., aerobic fitness levels) was not performed (8). In a rodent study, 2 h of intralipid infusion reduced insulin-stimulated whole-body glucose uptake in male rats but not in females rats (9) and, in accordance, phosphorylation of IRS-1 and PI 3-kinase activity was reduced only in male rats (9). We have previously reported that women have greater insulin-stimulated whole-body and leg glucose uptake than matched men despite higher intramyocellular triacylglycerol (IMTG) concentration (10). Also, women have higher muscle mRNA levels of several proteins involved in muscle lipid metabolism including fatty acid translocase/CD36 (FAT/CD36), membrane-bound fatty acid–binding protein (FABPpm), cytosolic fatty acid–binding protein (FABPc), lipoprotein lipase (11), and a higher percentage of myosin heavy chain type 1 muscle fibers (10,12,13). Therefore, the aims of this study were 1) to test the hypothesis that women are less prone to intralipid-induced insulin resistance on a whole-body level and in skeletal muscle than men and 2) to investigate the molecular mechanisms responsible for the intralipid-induced decrease in insulin sensitivity.