My academic research group focused on the pathogenesis and treatments for metabolic, anthropomorphic, and cardiovascular syndromes associated with HIV-infection, advanced age, and cachectic conditions. We utilized interdisciplinary resources and translational approaches to address patient and disease-oriented issues. In my current position, we develop liquid chromatography-tandem mass spectrometry and in vivo stable isotope labeling methods to detect, characterize, and quantify proteins, peptides and other biomolecules that can serve as predictive and pathogenic biomarkers for neurodegenerative disorders. Phone: 3146331882 Address: C2N Diagnostics 4340 Duncan Avenue St.Louis, MO 63110
Type 2 diabetes is characterized by impaired glucose tolerance (IGT) and insulin resistance with ... more Type 2 diabetes is characterized by impaired glucose tolerance (IGT) and insulin resistance with respect to glucose metabolism but not amino acid metabolism. We examined whether whole-body leucine and protein metabolism are dysregulated in HIV-infected individuals with IGT. Glucose and leucine kinetics were measured under fasting insulin conditions and during euglycemic hyperinsulinemia using primed-constant infusions of 2 H 2-glucose and 13 C-leucine in 10 HIV-seronegative control subjects, 16 HIV؉ subjects with normal glucose tolerance, and 21 HIV؉IGT subjects. Glucose disposal rate during hyperinsulinemia was lower in HIV؉IGT than the other two groups. Absolute plasma leucine levels and rate of appearance (whole-body proteolysis) were higher in HIV؉IGT at all insulin levels but declined in response to hyperinsulinemia in parallel to those in the other two groups. HIV؉IGT had greater visceral adiposity, fasting serum interleukin (IL)-8 and free fatty acid levels, and higher lipid oxidation rates during the clamp than the other two groups. These findings implicate several factors in the insulin signaling pathway, which may be further dysregulated in HIV؉IGT, and support the notion that insulin signaling pathways for glucose and leucine metabolism may be disrupted by increased proinflammatory adipocytokines (IL-8) and increased lipid oxidation. Increased proteolysis may provide amino acids for gluconeogenesis, exacerbating hyperglycemia in HIV.
Objective: To test the hypothesis that HIV infection impairs the beneficial effects of weight los... more Objective: To test the hypothesis that HIV infection impairs the beneficial effects of weight loss on insulin sensitivity, adipose tissue inflammation, and endoplasmic reticulum (ER) stress. Methods: A prospective clinical trial evaluated the effects of moderate diet-induced weight loss on body composition, metabolic function, and adipose tissue biology in women with obesity who were HIV-seronegative (HIV-) or HIV-positive (HIV+). Body composition, multiorgan insulin sensitivity (assessed by using a two-stage hyperinsulinemic-euglycemic clamp procedure with stable isotopically labeled tracer infusions), and adipose tissue expression of markers of inflammation, autophagy, and ER stress were evaluated in 8 HIV- and 20 HIV+ women with obesity before and after diet-induced weight loss of 6% to 8%. Results: Although weight loss was not different between groups (7.5%), the decrease in fat-free mass was greater in HIV+ than HIV- subjects (24.4 ± 0.7% vs. 21.7 ± 1.0%, P < 0.05). Weight loss improved insulin sensitivity in adipose tissue (suppression of palmitate rate of appearance [Ra]), liver (suppression of glucose Ra), and muscle (glucose disposal) similarly in both groups. Weight loss did not affect adipose tissue expression of markers of inflammation or ER stress in either group. Conclusions: Moderate diet-induced weight loss improves multiorgan insulin sensitivity in HIV+ women to the same extent as women who are HIV-. However, weight loss causes a greater decline in fat-free mass in HIV+ than HIV- women.
Trehalose is a naturally occurring disaccharide that has gained attention for its ability to indu... more Trehalose is a naturally occurring disaccharide that has gained attention for its ability to induce cellular autophagy and mitigate diseases related to pathological protein aggregation. Despite decades of ubiquitous use as a nutraceutical, preservative, and humectant, its mechanism of action remains elusive. We showed that trehalose inhibited members of the SLC2A (also known as GLUT) family of glucose transporters. Trehalose-mediated inhibition of glucose transport induced AMPK (adenosine 5&amp;amp;amp;amp;amp;amp;amp;amp;#39;-monophosphate-activated protein kinase)-dependent autophagy and regression of hepatic steatosis in vivo and a reduction in the accumulation of lipid droplets in primary murine hepatocyte cultures. Our data indicated that trehalose triggers beneficial cellular autophagy by inhibiting glucose transport.
Medicine and Science in Sports and Exercise, Sep 1, 2001
PURPOSE: To determine whether eating a breakfast cereal with a moderate glycemic index could alte... more 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.
ABSTRACT Fibrates, activators of the nuclear receptor PPARalpha, improve dyslipidemia, but their ... more ABSTRACT Fibrates, activators of the nuclear receptor PPARalpha, improve dyslipidemia, but their effects on insulin resistance and vascular disease are unresolved. To test the hypothesis that PPARalpha activation improves insulin resistance and vascular function, we determined the effects of fenofibrate in healthy adults with insulin resistance induced by short-term glucocorticoid administration. Eighteen normal-weight subjects were studied in four stages: at baseline, after 21 days of fenofibrate (160 mg/day) alone, after 3 days of dexamethasone (8 mg/day) added to fenofibrate, and after 3 days of dexamethasone added to placebo (dexamethasone alone). Dexamethasone alone caused hyperinsulinemia, increased glucose, decreased glucose disposal, and reduced insulin-induced suppression of hepatic glucose production as determined by hyperinsulinemic euglycemic clamp and increased systolic blood pressure as determined by ambulatory monitoring, features associated with an insulin-resistant state. Fenofibrate improved fasting LDL and total cholesterol in the setting of dexamethasone treatment but had no significant effect on levels of insulin or glucose, insulin-stimulated glucose disposal, or insulin suppression of glucose production during clamps, or ambulatory monitored blood pressure. In the absence of dexamethasone, fenofibrate lowered fasting triglycerides and cholesterol but unexpectedly increased systolic blood pressure by ambulatory monitoring. These data suggest that PPARalpha activation in humans does not correct insulin resistance induced by glucocorticoids and may adversely affect blood pressure.
The Journal of Nutrition Health and Aging, Feb 1, 2002
Advancing age appears to alter the chemical and physical properties of skeletal muscle proteins. ... more 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.
American Journal of Physiology Endocrinology and Metabolism, Jul 1, 1999
Abstract Muscle atrophy (sarcopenia) in the elderly is associated with a reduced rate of muscle p... more Abstract Muscle atrophy (sarcopenia) in the elderly is associated with a reduced rate of muscle protein synthesis. The purpose of this study was to determine if weight-lifting exercise increases the rate of muscle protein synthesis in physically frail 76-to 92-yr-old ...
It has been shown that muscle protein synthetic rate (MPS) is elevated in humans by 50% at 4 hrs ... more It has been shown that muscle protein synthetic rate (MPS) is elevated in humans by 50% at 4 hrs following a bout of heavy resistance training, and by 109% at 24 hrs following training. This study further examined the time course for elevated muscle protein synthesis by examining its rate at 36 hrs following a training session. Six healthy young men performed 12 sets of 6- to 12-RM elbow flexion exercises with one arm while the opposite arm served as a control. MPS was calculated from the in vivo rate of incorporation of L-[1,2-13C2] leucine into biceps brachii of both arms using the primed constant infusion technique over 11 hrs. At an average time of 36 hrs postexercise, MPS in the exercised arm had returned to within 14% of the control arm value, the difference being nonsignificant. It is concluded that following a bout of heavy resistance training, MPS increases rapidly, is more than double at 24 hrs, and thereafter declines rapidly so that at 36 hrs it has almost returned to baseline.
Type 2 diabetes is characterized by impaired glucose tolerance (IGT) and insulin resistance with ... more Type 2 diabetes is characterized by impaired glucose tolerance (IGT) and insulin resistance with respect to glucose metabolism but not amino acid metabolism. We examined whether whole-body leucine and protein metabolism are dysregulated in HIV-infected individuals with IGT. Glucose and leucine kinetics were measured under fasting insulin conditions and during euglycemic hyperinsulinemia using primed-constant infusions of 2 H 2-glucose and 13 C-leucine in 10 HIV-seronegative control subjects, 16 HIV؉ subjects with normal glucose tolerance, and 21 HIV؉IGT subjects. Glucose disposal rate during hyperinsulinemia was lower in HIV؉IGT than the other two groups. Absolute plasma leucine levels and rate of appearance (whole-body proteolysis) were higher in HIV؉IGT at all insulin levels but declined in response to hyperinsulinemia in parallel to those in the other two groups. HIV؉IGT had greater visceral adiposity, fasting serum interleukin (IL)-8 and free fatty acid levels, and higher lipid oxidation rates during the clamp than the other two groups. These findings implicate several factors in the insulin signaling pathway, which may be further dysregulated in HIV؉IGT, and support the notion that insulin signaling pathways for glucose and leucine metabolism may be disrupted by increased proinflammatory adipocytokines (IL-8) and increased lipid oxidation. Increased proteolysis may provide amino acids for gluconeogenesis, exacerbating hyperglycemia in HIV.
Objective: To test the hypothesis that HIV infection impairs the beneficial effects of weight los... more Objective: To test the hypothesis that HIV infection impairs the beneficial effects of weight loss on insulin sensitivity, adipose tissue inflammation, and endoplasmic reticulum (ER) stress. Methods: A prospective clinical trial evaluated the effects of moderate diet-induced weight loss on body composition, metabolic function, and adipose tissue biology in women with obesity who were HIV-seronegative (HIV-) or HIV-positive (HIV+). Body composition, multiorgan insulin sensitivity (assessed by using a two-stage hyperinsulinemic-euglycemic clamp procedure with stable isotopically labeled tracer infusions), and adipose tissue expression of markers of inflammation, autophagy, and ER stress were evaluated in 8 HIV- and 20 HIV+ women with obesity before and after diet-induced weight loss of 6% to 8%. Results: Although weight loss was not different between groups (7.5%), the decrease in fat-free mass was greater in HIV+ than HIV- subjects (24.4 ± 0.7% vs. 21.7 ± 1.0%, P < 0.05). Weight loss improved insulin sensitivity in adipose tissue (suppression of palmitate rate of appearance [Ra]), liver (suppression of glucose Ra), and muscle (glucose disposal) similarly in both groups. Weight loss did not affect adipose tissue expression of markers of inflammation or ER stress in either group. Conclusions: Moderate diet-induced weight loss improves multiorgan insulin sensitivity in HIV+ women to the same extent as women who are HIV-. However, weight loss causes a greater decline in fat-free mass in HIV+ than HIV- women.
Trehalose is a naturally occurring disaccharide that has gained attention for its ability to indu... more Trehalose is a naturally occurring disaccharide that has gained attention for its ability to induce cellular autophagy and mitigate diseases related to pathological protein aggregation. Despite decades of ubiquitous use as a nutraceutical, preservative, and humectant, its mechanism of action remains elusive. We showed that trehalose inhibited members of the SLC2A (also known as GLUT) family of glucose transporters. Trehalose-mediated inhibition of glucose transport induced AMPK (adenosine 5&amp;amp;amp;amp;amp;amp;amp;amp;#39;-monophosphate-activated protein kinase)-dependent autophagy and regression of hepatic steatosis in vivo and a reduction in the accumulation of lipid droplets in primary murine hepatocyte cultures. Our data indicated that trehalose triggers beneficial cellular autophagy by inhibiting glucose transport.
Medicine and Science in Sports and Exercise, Sep 1, 2001
PURPOSE: To determine whether eating a breakfast cereal with a moderate glycemic index could alte... more 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.
ABSTRACT Fibrates, activators of the nuclear receptor PPARalpha, improve dyslipidemia, but their ... more ABSTRACT Fibrates, activators of the nuclear receptor PPARalpha, improve dyslipidemia, but their effects on insulin resistance and vascular disease are unresolved. To test the hypothesis that PPARalpha activation improves insulin resistance and vascular function, we determined the effects of fenofibrate in healthy adults with insulin resistance induced by short-term glucocorticoid administration. Eighteen normal-weight subjects were studied in four stages: at baseline, after 21 days of fenofibrate (160 mg/day) alone, after 3 days of dexamethasone (8 mg/day) added to fenofibrate, and after 3 days of dexamethasone added to placebo (dexamethasone alone). Dexamethasone alone caused hyperinsulinemia, increased glucose, decreased glucose disposal, and reduced insulin-induced suppression of hepatic glucose production as determined by hyperinsulinemic euglycemic clamp and increased systolic blood pressure as determined by ambulatory monitoring, features associated with an insulin-resistant state. Fenofibrate improved fasting LDL and total cholesterol in the setting of dexamethasone treatment but had no significant effect on levels of insulin or glucose, insulin-stimulated glucose disposal, or insulin suppression of glucose production during clamps, or ambulatory monitored blood pressure. In the absence of dexamethasone, fenofibrate lowered fasting triglycerides and cholesterol but unexpectedly increased systolic blood pressure by ambulatory monitoring. These data suggest that PPARalpha activation in humans does not correct insulin resistance induced by glucocorticoids and may adversely affect blood pressure.
The Journal of Nutrition Health and Aging, Feb 1, 2002
Advancing age appears to alter the chemical and physical properties of skeletal muscle proteins. ... more 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.
American Journal of Physiology Endocrinology and Metabolism, Jul 1, 1999
Abstract Muscle atrophy (sarcopenia) in the elderly is associated with a reduced rate of muscle p... more Abstract Muscle atrophy (sarcopenia) in the elderly is associated with a reduced rate of muscle protein synthesis. The purpose of this study was to determine if weight-lifting exercise increases the rate of muscle protein synthesis in physically frail 76-to 92-yr-old ...
It has been shown that muscle protein synthetic rate (MPS) is elevated in humans by 50% at 4 hrs ... more It has been shown that muscle protein synthetic rate (MPS) is elevated in humans by 50% at 4 hrs following a bout of heavy resistance training, and by 109% at 24 hrs following training. This study further examined the time course for elevated muscle protein synthesis by examining its rate at 36 hrs following a training session. Six healthy young men performed 12 sets of 6- to 12-RM elbow flexion exercises with one arm while the opposite arm served as a control. MPS was calculated from the in vivo rate of incorporation of L-[1,2-13C2] leucine into biceps brachii of both arms using the primed constant infusion technique over 11 hrs. At an average time of 36 hrs postexercise, MPS in the exercised arm had returned to within 14% of the control arm value, the difference being nonsignificant. It is concluded that following a bout of heavy resistance training, MPS increases rapidly, is more than double at 24 hrs, and thereafter declines rapidly so that at 36 hrs it has almost returned to baseline.
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Papers by Kevin E Yarasheski, PhD