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Biomedical subjects

K E Yarasheski

Publications and source records attributed to K E Yarasheski.

At least 19 recordsLinked to original sources
PubMed2005

Alterations in liver, muscle, and adipose tissue insulin sensitivity in men with HIV infection and dyslipidemia.

Dyslipidemia is common in patients with HIV infection. In this study, a two-stage euglycemic hyperinsulinemic clamp, with infusion of stable isotopically labeled tracers, was used to evaluate insulin action in skeletal muscle, liver, and adipose tissue in HIV-infected men with dyslipidemia (HIV-DL; plasma triglyceride >250 mg/dl and HDL <45 mg/dl; n=12), HIV-infected men without dyslipidemia (HIV w/o DL; n=12), and healthy men (n=6). Basal rates of glucose production (glucose R(a)), glucose disposal (glucose R(d)), and lipolysis (palmitate R(a)) were similar between groups. The relative suppression of glucose R(a) (63+/- 4, 77+/- 2, and 78+/- 3%, P=0.008) and palmitate R(a) (49+/-4, 63+/-3, and 68+/-3%, P=0.005) during ow-dose insulin infusion (plasma insulin approximately 30 microU/ml), and the relative stimulation of glucose R(d) (214+/-21, 390+/-25, and 393+/-46%, P=0.001) during high-dose insulin infusion (plasma insulin approximately 75 microU/ml) were lower in HIV-DL than in HIV w/o DL and healthy volunteers, respectively. Suppression of basal glucose R(a) correlated with plasma adiponectin (r=0.44, P=0.02) and inversely with plasma IL-6 (r=-0.49, P<0.001). Stimulation of glucose R(d) correlated directly with adiponectin (r=0.48, P<0.01) and inversely with IL-6 (r=-0.49, P=0.02). We conclude that dyslipidemia in HIV-infected men is indicative of multiorgan insulin resistance, and circulating adipokines may be important in the pathogenesis of impaired insulin action.

Adiponectin↗
PubMed2004

CO2 production during acute infection in malnourished Malawian children.

OBJECTIVE: This study tested the hypotheses that the rate of CO2 production is less in marasmic children with acute infection when compared to well-nourished children, but greater when compared to uninfected marasmic children. DESIGN: A descriptive comparison of children aged 12-60 months who had their rates of CO2 production measured using a stable isotope tracer dilution method while receiving feedings. Body mass index (BMI) was the best measure of lean body mass available in this study. SETTING: Queen Elizabeth Central Hospital, Blantyre, Malawi. SUBJECTS: A total of 56 children were studied, 28 with marasmus and acute infection, 16 with marasmus, and 12 well nourished with acute infection. Those with acute infection had malaria, pneumonia, or sepsis. RESULTS: Well-nourished children with acute infection produced more CO2 than marasmic children (344+/-60 vs 225+/-65 mmol CO2/h, mean+/-s.d., P<0.001; 24.2+/-4.6 vs 18.4+/-5.4 mmol CO2/BMI h, P=0.001). However, the rate of CO2 production in marasmic children with acute infection was not greater than in uninfected marasmic children (225+/-65 vs 228+/-61 mmol CO2/h). The observed rate of CO2 production was greater than that which could be produced from the dietary intake alone (29.6 vs. 25.8 mmol CO2/kg h). CONCLUSIONS: Marasmic children do not increase energy expenditure in response to acute infection, as well-nourished children do. Dietary energy provided to marasmic children should be at least 420 kJ/kg day.

Body Mass Index↗
PubMed2004

Protein quantity, not protein quality, accelerates whole-body leucine kinetics and the acute-phase response during acute infection in marasmic Malawian children.

The present study compared leucine kinetics and acute-phase-protein concentrations in three groups of marasmic, acutely infected Malawian children fed one of three isoenergetic diets. These were: an enhanced-protein-quality diet (egg-white+tryptophan, providing 1.2 g protein/kg per d; n 14); an increased-protein-content diet (egg-white+tryptophan, providing 1.8 g protein/kg per d; n 14); a standard-protein diet (1.2 g milk protein/kg per d; n 25). The hypotheses tested were that children receiving a diet with more protein would have greater rates of non-oxidative leucine disposal and that children receiving an isonitrogenous diet with a higher protein quality would have lower rates of leucine oxidation. The children were studied after 24 h of therapy using standard [(13)C]leucine stable-isotope tracer techniques. The children receiving the higher-protein-content diet had greater leucine kinetic rates than those receiving the standard-protein-content diet; non-oxidative leucine disposal was 170 (sd 52) v. 122 (sd 30) mumol leucine/kg per h (P<0.01). Leucine oxidation was less in the children receiving the enhanced-protein-quality diet than in those receiving the standard-protein-quality diet; 34 (sd 12) v. 45 (sd 13) mumol leucine/kg per h (P<0.05). The children receiving the high-protein-content diet increased their serum concentration for five of six acute-phase proteins 24 h after starting therapy, while those receiving the standard-protein-content diet did not. These data suggest that there was greater whole-body protein synthesis, and a more vigorous acute-phase response associated with the higher-protein-content diet. The clinical benefits associated with a higher protein intake in marasmic, acutely infected children need further study.

Acute Disease↗
PubMed2003

Alterations in lipid kinetics in men with HIV-dyslipidemia.

Hypertriglyceridemia is common in individuals with human immunodeficiency (HIV) infection, but the mechanisms responsible for increased plasma triglyceride (TG) concentrations are not clear. We evaluated fatty acid and VLDL-TG kinetics during basal conditions and during a glucose infusion that resulted in typical postprandial plasma glucose and insulin concentrations in six men with HIV-dyslipidemia [body mass index (BMI): 28 +/- 2 kg/m2] and six healthy men (BMI: 26 +/- 2 kg/m2). VLDL-TG secretion and palmitate rate of appearance (Ra) in plasma were measured by using stable-isotope-labeled tracer techniques. Basal palmitate Ra and VLDL-TG secretion rates were greater (P < 0.01 for both) in men with HIV-dyslipidemia (1.04 +/- 0.07 micromol palmitate x kg-1 x min-1 and 5.7 +/- 0.6 micromol VLDL-TG x l plasma-1 x min-1) than in healthy men (0.67 +/- 0.08 micromol palmitate. kg-1 x min-1 and 3.0 +/- 0.5 micromol VLDL-TG x l plasma-1 x min-1). Basal VLDL-TG plasma clearance was lower in men with HIV-dyslipidemia (13 +/- 1 ml/min) than in healthy men (19 +/- 2 ml/min; P < 0.05). Glucose infusion decreased palmitate Ra (by approximately 50%) and the VLDL-TG secretion rate (by approximately 30%) in both groups, but the VLDL-TG secretion rate remained higher (P < 0.05) in subjects with HIV-dyslipidemia. These findings demonstrate that increased secretion of VLDL-TG and decreased plasma VLDL-TG clearance, during both fasting and fed conditions, contribute to hypertriglyceridemia in men with HIV-dyslipidemia. Although it is likely that increased free fatty acid release from adipose tissue contributes to the increase in basal VLDL-TG concentration, other factors must be involved, because insulin-induced suppression of lipolysis and systemic fatty acid availability did not normalize the VLDL-TG secretion rate.

Adult↗
PubMed2002

Serum myostatin-immunoreactive protein is increased in 60-92 year old women and men with muscle wasting.

BACKGROUND: Myostatin is a recently discovered member of the TGF-b superfamily of genes. It is expressed in skeletal muscle and believed to suppress muscle growth. Myostatin-null mice develop skeletal muscles that are 2-3x larger than wild type mice. Serum and intramuscular concentrations of myostatin-immunoreactive protein are increased in AIDS-muscle wasting and are inversely related with fat-free mass (FFM). OBJECTIVE: We hypothesized that increased expression of the myostatin gene is associated with the reduction in FFM and muscle mass typical of advancing age. DESIGN: A cross-sectional comparison of serum myostatin-immunoreactive protein levels, FFM and skeletal muscle mass in 19-35 yr old men and women (young), healthy 60-75 yr old men and women (middle-aged), and physically frail 76-92 yr old women. RESULTS: Muscle mass declined with advancing age in both men and women. Serum myostatin-immunoreactive protein levels were the highest in the 76-92 yr old women (P<0.05). Middle-aged men and women had higher serum myostatin levels than young men and women (P<0.05). FFM and muscle mass, corrected for height, were inversely correlated with serum myostatin-immunoreactive protein concentrations. CONCLUSIONS: These findings suggest that serum myostatin may be a biomarker of age-associated sarcopenia. They are consistent with the hypothesis that the human myostatin gene product is a suppressor of skeletal muscle growth in advancing age.

Journal Article↗
PubMed2002

Managing sarcopenia with progressive resistance exercise training.

Advancing age appears to alter the chemical and physical properties of skeletal muscle proteins. Alterations include: reduced contractile, mitochondrial, and enzyme protein synthesis rates, altered expression and post-translational modifications to muscle proteins, reduced maximum voluntary muscle strength, reduced muscle strength per unit muscle mass and muscle power. These age-associated impairments in muscle protein quantity and quality contribute to physical disability and frailty, a loss of independent function, the risk of falling and fractures, and contribute to escalating health care costs. Progressive resistance exercise training is a potent, non-pharmacologic, effective therapy that opposes the impairments in muscle protein quantity and quality in middle age and physically frail adults. In the absence of contraindications to exercise, muscle proteins adapt to an exercise training stimulus despite the depredation of age. The proposed pathogenesis for some of these impairments is briefly reviewed. Evidence that supports the use of progressive resistance exercise training to restore muscle quality and quantity in elderly adults is reviewed.

Journal Article↗
PubMed2001

Bone mineral density response to estrogen replacement in frail elderly women: a randomized controlled trial.

CONTEXT: Although hormone replacement therapy (HRT) is an established approach for osteoporosis prevention, little is known about the osteoprotective effects of HRT in frail elderly women. OBJECTIVE: To determine whether HRT increases bone mineral density (BMD) in frail elderly women. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled trial conducted in a US university-based research center from September 1995 to August 2000. PARTICIPANTS: Sixty-seven women aged 75 years or older with mild-to-moderate physical frailty. INTERVENTION: Participants were randomly assigned to receive conjugated estrogens, 0.625 mg/d, plus trimonthly medroxyprogesterone acetate, 5 mg/d for 13 days (n = 45), or matching placebo (n = 22), for 9 months. MAIN OUTCOME MEASURES: The primary outcome measure was 9-month change in BMD of the lumbar spine and hip, measured by dual-energy x-ray absorptiometry. Secondary outcomes were changes in markers of bone turnover. RESULTS: Based on intention-to-treat analyses, HRT resulted in significantly larger increases in BMD of the lumbar spine than placebo (mean change, 4.3% vs 0.4%; between-group difference, 3.9%; 95% confidence interval [CI], 3.5%-4.3%) and total hip (mean change, 1.7% vs -0.1%; between-group difference, 1.8%; 95% CI, 1.5%-2.1%). Compared with placebo, HRT resulted in significant decreases in serum bone-specific alkaline phosphatase levels (mean change, -24% vs 6%; between-group difference, -30%; 95% CI, -26% to -33%) and urine N-telopeptide levels (mean change, -48% vs 4%; between-group difference, -52%; 95% CI, -47% to -55%). CONCLUSIONS: In physically frail elderly women, 9 months of HRT significantly increased BMD compared with placebo in clinically important skeletal regions. Further studies are needed to determine whether these osteogenic effects of HRT in elderly women are associated with a reduction in osteoporotic fractures.

Absorptiometry, Photon↗
PubMed2001

Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication.

The recently discovered aging-dependent large accumulation of point mutations in the human fibroblast mtDNA control region raised the question of their occurrence in postmitotic tissues. In the present work, analysis of biopsied or autopsied human skeletal muscle revealed the absence or only minimal presence of those mutations. By contrast, surprisingly, most of 26 individuals 53 to 92 years old, without a known history of neuromuscular disease, exhibited at mtDNA replication control sites in muscle an accumulation of two new point mutations, i.e., A189G and T408A, which were absent or marginally present in 19 individuals younger than 34 years. These two mutations were not found in fibroblasts from 22 subjects 64 to 101 years of age (T408A), or were present only in three subjects in very low amounts (A189G). Furthermore, in several older individuals exhibiting an accumulation in muscle of one or both of these mutations, they were nearly absent in other tissues, whereas the most frequent fibroblast-specific mutation (T414G) was present in skin, but not in muscle. Among eight additional individuals exhibiting partial denervation of their biopsied muscle, four subjects >80 years old had accumulated the two muscle-specific point mutations, which were, conversely, present at only very low levels in four subjects < or =40 years old. The striking tissue specificity of the muscle mtDNA mutations detected here and their mapping at critical sites for mtDNA replication strongly point to the involvement of a specific mutagenic machinery and to the functional relevance of these mutations.

Adult↗
PubMed2001

Inhibition of sorbitol dehydrogenase exacerbates autonomic neuropathy in rats with streptozotocin-induced diabetes.

We have developed an animal model of diabetic autonomic neuropathy that is characterized by neuroaxonal dystrophy (NAD) involving ileal mesenteric nerves and prevertebral sympathetic superior mesenteric ganglia (SMG) in chronic streptozotocin (STZ)-diabetic rats. Studies with the sorbitol dehydrogenase inhibitor SDI-158, which interrupts the conversion of sorbitol to fructose (and reactions dependent on the second step of the sorbitol pathway), have shown a dramatically increased frequency of NAD in ileal mesenteric nerves and SMG of SDI-treated versus untreated diabetics. Although lesions developed prematurely and in greater numbers in SDI-treated diabetics, their distinctive ultrastructural appearance was identical to that previously reported in long-term untreated diabetics. An SDI effect was first demonstrated in the SMG of rats that were diabetic for as little as 5 wk and was maintained for at least 7.5 months. As in untreated diabetic rats, rats treated with SDI i) showed involvement of lengthy ileal, but not shorter, jejunal mesenteric nerves; ii) demonstrated NAD in paravascular mesenteric nerves distributed to myenteric ganglia while sparing adjacent perivascular axons ramifying within the vascular adventitia; and, iii) failed to develop NAD in the superior cervical ganglia (SCG). After only 2 months of SDI-treatment, tyrosine hydroxylase immunolocalization demonstrated marked dilatation of postganglionic noradrenergic axons in paravascular ileal mesenteric nerves and within the gut wall versus those innervating extramural mesenteric vasculature. The effect of SDI on diabetic NAD in SMG was completely prevented by concomitant administration of the aldose reductase inhibitor Sorbinil. Treatment of diabetic rats with Sorbinil also prevented NAD in diabetic rats not treated with SDI. These findings indicate that sorbitol pathway-linked metabolic imbalances play a critical role in the development of NAD in this model of diabetic sympathetic autonomic neuropathy.

Animals↗
PubMed2001

Resistance exercise decreases skeletal muscle tumor necrosis factor alpha in frail elderly humans.

Skeletal muscle protein and function decline with advancing age but the underlying pathophysiology is poorly understood. To test the hypothesis that the catabolic cytokine tumor necrosis factor alpha (TNF-alpha) contributes to this process, we studied the effects of aging and resistance exercise on TNF-alpha expression in human muscle. Using in situ hybridization, TNF-alpha message was localized to myocytes in sections of skeletal muscle from elderly humans. Both TNF-alpha mRNA and protein levels were elevated in skeletal muscle from frail elderly (81+/-1 year) as compared to healthy young (23+/-1 year) men and women. To determine whether resistance exercise affects TNF-alpha expression, frail elderly men and women were randomly assigned to a training group or to a nonexercising control group. Muscle biopsies were performed before and after 3 months. Muscle TNF-alpha mRNA and protein levels decreased in the exercise group but did not change in the control group. Muscle protein synthesis rate in the exercise group was inversely related to levels of TNF-alpha protein. These data suggest that TNF-alpha contributes to age-associated muscle wasting and that resistance exercise may attenuate this process by suppressing skeletal muscle TNF-alpha expression.

Adult↗
PubMed2001

Exercise treatment for HIV-associated metabolic and anthropomorphic complications.

Infection with the human immunodeficiency virus (HIV) has been associated with several alterations in body composition and metabolism. We propose that resistance and aerobic exercise training programs are effective nonpharmacologic treatments for managing these HIV-related complications and for improving quality of life.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Effects of a moderate glycemic meal on exercise duration and substrate utilization.

PURPOSE: To determine whether eating a breakfast cereal with a moderate glycemic index could alter substrate utilization and improve exercise duration. METHODS: Six active women (age, 24 +/- 2 yr; weight, 62.2 +/- 2.6 kg; VO(2peak), 46.6 +/- 3.8 mL x kg(-1) x min(-1)) ate 75 g of available carbohydrate in the form of regular whole grain rolled oats (RO) mixed with 300 mL of water or water alone (CON). The trials were performed in random order and the meal or water was ingested 45 min before performing cycling exercise to exhaustion (60% of VO(2peak)). Blood samples were drawn for glucose, glucose kinetics, free fatty acids (FFA), glycerol, insulin, epinephrine (EPI), and norepinephrine (NE) determination. A muscle biopsy was obtained from the vastus lateralis muscle before the trial and immediately after exercise for glycogen determination. Glucose kinetics (Ra) were determined using a [6,6-(2)H] glucose tracer. RESULTS: Compared with CON, plasma FFA and glycerol levels were suppressed (P < 0.05) during the first 120 min of exercise for the RO trial. Respiratory exchange ratios (RER) were also higher (P < 0.05) for the first 120 min of exercise for the RO trial. At exhaustion, glucose, insulin, FFA, glycerol, EPI, NE, RER, and muscle glycogen were not different between trials. Glucose Ra was greater (P < 0.05) during the RO trial compared with CON (2.36 +/- 0.22 and 1.92 +/- 0.27 mg x kg(-1) x min(-1), respectively). Exercise duration was 5% longer during RO, but the mean times were not significantly different (253.6 +/- 6 and 242.0 +/- 15 min, respectively). CONCLUSIONS: Increased hepatic glucose output before fatigue provides some evidence of glucose sparing after the breakfast cereal trial. However, exercise duration was not significantly altered, possibly because of the sustained suppression of lipid metabolism and increased carbohydrate utilization throughout much of the exercise period.

Adult↗
PubMed2001

Effects of resistance training on the rate of muscle protein synthesis in frail elderly people.

Advancing age is associated with a reduction in skeletal muscle protein, muscle strength, muscle quality, and chemical modifications that may impair protein function. Sarcopenia has been coupled with physical disability, frailty, and a loss of independent function. Using stable isotope tracer methodologies and mass spectrometric detection, we observed: (a) 76-92-year-old physically frail and 62-74-year-old middle-age adults have lower mixed muscle protein synthetic rates than 20-32-year-old men and women; (b) 2 weeks and 3 months of weightlifting exercise increased the synthetic rate of myosin heavy chain (MHC) and mixed muscle proteins to a similar magnitude in frail, middle-age, and young women and men; (c) Serum myostatin-immunoreactive protein levels were elevated in physically frail women and were inversely correlated with lean mass. This suggests that the protein synthetic machinery adapts rapidly to increased contractile activity and that the adaptive response(s) are maintained even in frail elders.

Adaptation, Physiological↗
PubMed2001

Testosterone dose-response relationships in healthy young men.

Testosterone increases muscle mass and strength and regulates other physiological processes, but we do not know whether testosterone effects are dose dependent and whether dose requirements for maintaining various androgen-dependent processes are similar. To determine the effects of graded doses of testosterone on body composition, muscle size, strength, power, sexual and cognitive functions, prostate-specific antigen (PSA), plasma lipids, hemoglobin, and insulin-like growth factor I (IGF-I) levels, 61 eugonadal men, 18-35 yr, were randomized to one of five groups to receive monthly injections of a long-acting gonadotropin-releasing hormone (GnRH) agonist, to suppress endogenous testosterone secretion, and weekly injections of 25, 50, 125, 300, or 600 mg of testosterone enanthate for 20 wk. Energy and protein intakes were standardized. The administration of the GnRH agonist plus graded doses of testosterone resulted in mean nadir testosterone concentrations of 253, 306, 542, 1,345, and 2,370 ng/dl at the 25-, 50-, 125-, 300-, and 600-mg doses, respectively. Fat-free mass increased dose dependently in men receiving 125, 300, or 600 mg of testosterone weekly (change +3.4, 5.2, and 7.9 kg, respectively). The changes in fat-free mass were highly dependent on testosterone dose (P = 0.0001) and correlated with log testosterone concentrations (r = 0.73, P = 0.0001). Changes in leg press strength, leg power, thigh and quadriceps muscle volumes, hemoglobin, and IGF-I were positively correlated with testosterone concentrations, whereas changes in fat mass and plasma high-density lipoprotein (HDL) cholesterol were negatively correlated. Sexual function, visual-spatial cognition and mood, and PSA levels did not change significantly at any dose. We conclude that changes in circulating testosterone concentrations, induced by GnRH agonist and testosterone administration, are associated with testosterone dose- and concentration-dependent changes in fat-free mass, muscle size, strength and power, fat mass, hemoglobin, HDL cholesterol, and IGF-I levels, in conformity with a single linear dose-response relationship. However, different androgen-dependent processes have different testosterone dose-response relationships.

Adult↗
PubMed2001

Resistance exercise training reduces hypertriglyceridemia in HIV-infected men treated with antiviral therapy.

Hypertriglyceridemia, peripheral insulin resistance, and trunk adiposity are metabolic complications recently recognized in people infected with human immunodeficiency virus (HIV) and treated with highly active antiretroviral therapy (HAART). These complications may respond favorably to exercise training. Using a paired design, we determined whether 16 wk of weight-lifting exercise increased muscle mass and strength and decreased fasting serum triglycerides and adipose tissue mass in 18 HIV-infected men. The resistance exercise regimen consisted of three upper and four lower body exercises done for 1-1.5 h/day, 4 days/wk for 64 sessions. Dual-energy X-ray absorptiometry indicated that exercise training increased whole body lean mass 1.4 kg (P = 0.005) but did not reduce adipose tissue mass (P = NS). Axial proton-magnetic resonance imaging indicated that thigh muscle cross-sectional area increased 5-7 cm(2) (P < 0.005). Muscle strength increased 23-38% (P < 0.0001) on all exercises. Fasting serum triglycerides were decreased at the end of training (281-204 mg/dl; P = 0.02). These findings imply that resistance exercise training-induced muscle hypertrophy may promote triglyceride clearance from the circulation of hypertriglyceridemic HIV-infected men treated with antiviral therapy.

Adipose Tissue↗
PubMed2001

Effects of acute creatine monohydrate supplementation on leucine kinetics and mixed-muscle protein synthesis.

Creatine monohydrate (CrM) supplementation during resistance exercise training results in a greater increase in strength and fat-free mass than placebo. Whether this is solely due to an increase in intracellular water or whether there may be alterations in protein turnover is not clear at this point. We examined the effects of CrM supplementation on indexes of protein metabolism in young healthy men (n = 13) and women (n = 14). Subjects were randomly allocated to CrM (20 g/day for 5 days followed by 5 g/day for 3-4 days) or placebo (glucose polymers) and tested before and after the supplementation period under rigorous dietary and exercise controls. Muscle phosphocreatine, creatine, and total creatine were measured before and after supplementation. A primed-continuous intravenous infusion of L-[1-(13)C]leucine and mass spectrometry were used to measure mixed-muscle protein fractional synthetic rate and indexes of whole body leucine metabolism (nonoxidative leucine disposal), leucine oxidation, and plasma leucine rate of appearance. CrM supplementation increased muscle total creatine (+13.1%, P < 0.05) with a trend toward an increase in phosphocreatine (+8.8%, P = 0.09). CrM supplementation did not increase muscle fractional synthetic rate but reduced leucine oxidation (-19.6%) and plasma leucine rate of appearance (-7.5%, P < 0.05) in men, but not in women. CrM did not increase total body mass or fat-free mass. We conclude that short-term CrM supplementation may have anticatabolic actions in some proteins (in men), but CrM does not increase whole body or mixed-muscle protein synthesis.

Adenosine Triphosphate↗
PubMed2001

The HIV protease inhibitor indinavir decreases insulin- and contraction-stimulated glucose transport in skeletal muscle.

In many patients with human immunodeficiency virus (HIV) treated with HIV protease inhibitors, a complication develops that resembles abdominal obesity syndrome, with insulin resistance and glucose intolerance that, in some cases, progresses to diabetes. In this study, we tested the hypothesis that indinavir, an HIV-protease inhibitor, directly induces insulin resistance of glucose transport in skeletal muscle. Rat epitrochlearis muscles were incubated with a maximally effective insulin concentration (12 nmol/l) and 0, 1, 5, 20, or 40 micromol/l indinavir for 4 h. In control muscles, insulin increased 3-O-[(3)H]methyl-D-glucose (3MG) transport from 0.15 +/- 0.03 to 1.10 +/- 0.05 micromol. ml(-)(1). 10 min(-)(1). Incubation of muscles with 5 micromol/l indinavir reduced the insulin-stimulated increase in 3MG transport by 40%, whereas 20 micromol/l indinavir reduced the insulin-stimulated increase in 3MG transport by 58%. Indinavir induced a similar reduction in maximally insulin-stimulated 3MG transport in the soleus muscle. The increase in glucose transport activity induced by stimulating epitrochlearis muscles to contract was also markedly reduced by indinavir. The insulin-stimulated increase in cell-surface GLUT4, assessed using the 2-N-4-(1-azi-2,2,2-trifluoroethyl)benzoyl-1,3-bis-[2-(3)H] (D-mannose-4-yloxy)-2-propylamine exofacial photolabeling technique, was reduced by approximately 70% in the presence of 20 micromol/l indinavir. Insulin stimulation of phosphatidylinositol 3-kinase activity and phosphorylation of protein kinase B were not decreased by indinavir. These results provide evidence that indinavir inhibits the translocation or intrinsic activity of GLUT4 rather than insulin signaling.

Animals↗