Body composition is the main determinant for the difference in type 2 diabetes pathophysiology between Japanese and Caucasians.

OBJECTIVE This cross-sectional clinical study compared the pathophysiology of type 2 diabetes in Japanese and Caucasians and investigated the role of demographic, genetic, and lifestyle-related risk factors for insulin resistance and β-cell response. RESEARCH DESIGN AND METHODS A total of 120 Japanese and 150 Caucasians were enrolled to obtain comparable distributions of high/low BMI values across glucose tolerance states (normal glucose tolerance, impaired glucose tolerance, and type 2 diabetes), which were assessed by oral glucose tolerance tests. BMI in the two cohorts was distributed around the two regional cutoff values for obesity.

Single cell measurements of vacuolar rupture caused by intracellular pathogens.

Shigella flexneri are pathogenic bacteria that invade host cells entering into an endocytic vacuole. Subsequently, the rupture of this membrane-enclosed compartment allows bacteria to move within the cytosol, proliferate and further invade neighboring cells. Mycobacterium tuberculosis is phagocytosed by immune cells, and has recently been shown to rupture phagosomal membrane in macrophages.

Transgenic mice with astrocyte-targeted production of interleukin-6 are resistant to high-fat diet-induced increases in body weight and body fat.

Interleukin-6 (IL-6) is a major cytokine involved in both normal physiological brain functions and underlying significant neuropathology. IL-6 has been suggested to play a role in the control of body weight but the results are somewhat controversial. In this study we have challenged transgenic mice with astrocyte-targeted IL-6 expression (GFAP-IL6 mice) with a high-fat diet (55% kcal from fat) versus a control diet (10%).

Interleukin-6 markedly decreases skeletal muscle protein turnover and increases nonmuscle amino acid utilization in healthy individuals.

Context: IL-6 is a key modulator of immune function and suggested to be involved in skeletal muscle wasting as seen in sepsis.

Objective: Our objective was to determine the role of IL-6 in human in vivo systemic and skeletal muscle amino acid metabolism and protein turnover.

Subjects And Methods: There were 12 healthy men infused for 3 h with saline (saline, n = 6) or recombinant human IL (rhIL)-6 (n = 6).

Nitric oxide production is a proximal signaling event controlling exercise-induced mRNA expression in human skeletal muscle.

Previous studies have described the magnitude and time course by which several genes are regulated within exercising skeletal muscle. These include interleukin-6 (IL-6), interleukin-8 (IL-8), heme oxygenase-1 (HO-1), and heat shock protein-72 (HSP72), which are involved in secondary signaling and preservation of intracellular environment. However, the primary signaling mechanisms coupling contraction to transcription are unknown.

Differential regulation of IL-6 and TNF-alpha via calcineurin in human skeletal muscle cells.

Interleukin-6 increases in skeletal muscle during exercise, and evidence points to Ca2+ as an initiator of IL-6 production. However, the signalling pathway whereby this occurs is unknown. One candidate for Ca2+ -mediated IL-6 induction is calcineurin, an activator of NF-AT.

Interleukin-6 regulation of AMP-activated protein kinase. Potential role in the systemic response to exercise and prevention of the metabolic syndrome.

Interleukin (IL)-6 is a pleiotropic hormone that has both proinflammatory and anti-inflammatory actions. AMP-activated protein kinase (AMPK) is a fuel-sensing enzyme that among its other actions responds to decreases in cellular energy state by enhancing processes that generate ATP and inhibiting others that consume ATP but are not acutely necessary for survival. IL-6 is synthesized and released from skeletal muscle in large amounts during exercise, and in rodents, the resultant increase in its concentration correlates temporally with increases in AMPK activity in multiple tissues.

Visfatin mRNA expression in human subcutaneous adipose tissue is regulated by exercise.

Visfatin [pre-beta-cell colony-enhancing factor (PBEF)] is a novel adipokine that is produced by adipose tissue, skeletal muscle, and liver and has insulin-mimetic actions. Regular exercise enhances insulin sensitivity. In the present study, we therefore examined visfatin mRNA expression in abdominal subcutaneous adipose tissue and skeletal muscle biopsies obtained from healthy young men at time points 0, 3, 4.

Effect of exercise, training, and glycogen availability on IL-6 receptor expression in human skeletal muscle.

The cytokine interleukin-6 (IL-6) exerts it actions via the IL-6 receptor (IL-6R) in conjunction with the ubiquitously expressed gp130 receptor. IL-6 is tightly regulated in response to exercise, being affected by factors such as exercise intensity and duration, as well as energy availability. Although the IL-6 response to exercise has been extensively studied, little is known about the regulation of the IL-6R response.

Interleukin-6 receptor expression in contracting human skeletal muscle: regulating role of IL-6.

Contracting muscle fibers produce and release IL-6, and plasma levels of this cytokine are markedly elevated in response to physical exercise. We recently showed autocrine regulation of IL-6 in human skeletal muscle in vivo and hypothesized that this may involve up-regulation of the IL-6 receptor. Therefore, we investigated IL-6 receptor regulation in response to exercise and IL-6 infusion in humans.

Effects of cidofovir on cell death and replication of feline herpesvirus-1 in cultured feline corneal epithelial cells.

Objective: To assess the effect of cidofovir on viability of feline corneal epithelial (FCE) cells, replication of feline herpesvirus (FHV)-1, and virus-induced cytopathic changes.

Sample Population: Healthy eyes from 14 recently euthanatized cats.

Procedure: Cidofovir at concentrations ranging from 0.

Effects of interferon-alpha on cytopathic changes and titers for feline herpesvirus-1 in primary cultures of feline corneal epithelial cells.

Objective: To assess the effect of interferon (IFN)-alpha on viability of feline corneal epithelial cells, replication of feline herpesvirus (FHV)-1, and virus-induced cytopathic changes.

Sample Population: Healthy eyes from 10 recently euthanatized cats.

Procedure: 4 replicate primary cultures of feline corneal epithelial cells were grown after the addition of 10(2) to 10(6) IU of IFN-alpha/mL.

Culture of feline corneal epithelial cells and infection with feline herpesvirus-1 as an investigative tool.

Objective: To isolate and characterize pure cultures of feline corneal epithelial cells and to assess the extent and nature of feline herpesvirus (FHV)-1 infection in these cells.

Sample Population: Healthy eyes from 23 recently euthanatized cats.

Procedure: Stroma and epithelium of the rostral portion of the cornea were surgically isolated, and epithelial cells were detached from the stroma by enzymatic incubation.

TNF-alpha, but not IL-6, stimulates plasminogen activator inhibitor-1 expression in human subcutaneous adipose tissue.

Plasminogen activator inhibitor-1 (PAI-1) is produced by adipose tissue, and elevated PAI-1 levels in plasma are a risk factor in the metabolic syndrome. We investigated the regulatory effects of TNF-alpha and IL-6 on PAI-1 gene induction in human adipose tissue. Twenty healthy men underwent a 3-h infusion of either recombinant human TNF-alpha (n = 8), recombinant human IL-6 (n = 6), or vehicle (n = 6).

Leptin gene expression and systemic levels in healthy men: effect of exercise, carbohydrate, interleukin-6, and epinephrine.

Leptin, an adipose tissue-derived cytokine, is correlated with adipose mass as obese persons have increased levels of leptin that decrease with weight loss. Previous studies demonstrate that high-energy-expenditure exercise decreases circulating leptin levels, whereas low-energy-expenditure exercise has no effect. We aimed to test the hypothesis that acute exercise reduced leptin mRNA levels in human adipose tissue and that this effect would be ameliorated by carbohydrate supplementation.

Exercise-induced metallothionein expression in human skeletal muscle fibres.

Exercise induces free oxygen radicals that cause oxidative stress, and metallothioneins (MTs) are increased in states of oxidative stress and possess anti-apoptotic effects. We therefore studied expression of the antioxidant factors metallothionein I and II (MT-I + II) in muscle biopsies obtained in response to 3 h of bicycle exercise performed by healthy men and in resting controls. Both MT-I + II proteins and MT-II mRNA expression increased significantly in both type I and II muscle fibres after exercise.

Does the aging skeletal muscle maintain its endocrine function?

Contracting skeletal muscles produce and release the cytokine interleukin (IL)-6 and this release is augmented by the presence of low muscle glycogen. Since muscle metabolism in elderly subjects relies on glycogen more than younger subjects, it is possible that aging is associated with an altered production of muscle-derived IL-6 during exercise. To test the relation between aging and muscle-derived IL-6, seven healthy elderly males, mean age 70+/-1 (SEM) yr and six healthy young males, mean age 26+/-2 (SEM) yr performed three hours of dynamic knee-extensor exercise at 50% of maximal work load (Wmax).

Glucose ingestion attenuates the exercise-induced increase in circulating heat shock protein 72 and heat shock protein 60 in humans.

Heat shock protein (Hsp) 72 is a cytosolic stress protein that is highly inducible by several factors including exercise. Hsp60 is primarily mitochondrial in cellular location, plays a key role in the intracellular protein translocation and cytoprotection, is increased in skeletal muscle by exercise, and is found in the peripheral circulation of healthy humans. Glucose deprivation increases Hsp72 in cultured cells, whereas reduced glycogen availability elevates Hsp72 in contracting human skeletal muscle.

Exercise induces interleukin-8 expression in human skeletal muscle.

Skeletal muscle has been recognized as an endocrine organ, and muscle cell cultures express several cytokines with potential hormonal effects. Interleukin-8 (IL-8), a chemokine, which induces angiogenesis, is expressed in working muscles; however, the cell source of origin has not been identified. We aimed to elucidate if IL-8 protein is: (1) expressed in contracting muscle fibres and (2) whether there is a release of IL-8 from exercising muscle.

Exercise normalises overexpression of TNF-alpha in knockout mice.

TNF-alpha is linked with insulin resistance, as greater amounts of TNF are detected in muscle and adipose tissue in glycemically challenged people and TNF-alpha inhibits insulin receptor signalling. However, what modulates this overexpression of TNF-alpha is currently unknown. We examined the effect of 1 h exercise on overexpression of the TNF-alpha gene in TNF receptor 1 and 2 knockout mice.

Metabolic and hormonal interactions between muscle and adipose tissue.

From the perspective of a muscle physiologist, adipose tissue has long been perceived predominantly as a fuel reservoir that provides muscle and other tissues with NEFA when exogenous nutrients are insufficient for their energy needs. Recently, studies have established that adipose tissue is also an endocrine organ. Among the hormones it releases are adiponectin and leptin, both of which can activate AMP-activated protein kinase and increase fatty acid oxidation in skeletal muscle and probably other tissues.

AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise.

Following exercise, AMP-activated protein kinase (AMPK) activity is increased several fold in rat liver and adipose tissue as well as muscle; however, the mechanism by which this occurs is not known. Interleukin-6 (IL-6) is released from muscle in large amounts during and after sustained physical activity resulting in up to 100-fold increases in its plasma concentration, from 1-2 ng/ml to 50-100 ng/ml. We report here that incubation with IL-6 (30-120 ng/ml) increases the phosphorylation of AMPK (an indicator of its activation) and that of its target molecule, acetyl CoA carboxylase (ACC), in both extensor digitorum longus muscle and cultured F422a adipocytes.

Epinephrine infusion increases adipose interleukin-6 gene expression and systemic levels in humans.

Exercise increases IL-6 mRNA in subcutaneous adipose tissue; however, the immediate signal for the IL-6 induction is unknown. We, therefore, explored the possible role of epinephrine in the induction of IL-6 in adipose tissue. Subcutaneous adipose tissue biopsies and blood samples were obtained from eight healthy men (mean age 27 yr, mean height 184 cm, mean weight 83 kg) in response to epinephrine infusion or in response to saline infusion.