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1.  Changes in Post-prandial Glucose and Pancreatic Hormones, and Steady-State Insulin and Free Fatty Acids after Gastric Bypass Surgery 
Changes in the multiple mechanisms that regulate glucose metabolism after gastric bypass (RYGB) are still being unveiled.
To compare the changes of glucose and pancreatic hormones [C-peptide, glucagon and pancreatic polypeptide (PP)] during a meal test (MTT) and steady-state insulin and free fatty acid (FFA) concentrations during euglycemic–hyperinsulinemic clamp 14 days and 6 months after RYGB in morbidly obese non-diabetic patients.
Academic Medical Center, United States.
Two groups were studied at baseline and at 14 days: RYGB followed by caloric restriction (RYGB, n=12) or equivalent caloric restriction alone (Diet, n=10), to control for energy intake and weight loss. The RYGB group was studied again at 6 months, to assess the changes after substantial weight loss. During MTT we determined the early and overall changes in glucose and pancreatic hormone concentrations, and during the clamp we assessed steady-state insulin and FFA concentrations.
After 14 days, RYGB subjects had enhanced post-prandial glucose, C-peptide and glucagon responses and decreased post-prandial PP concentrations. Steady-state insulin concentrations were decreased at 14 days only in RYGB subjects, and FFA increased in both groups. Six months after RYGB and substantial weight loss, the decrease in insulin concentrations during clamp persisted, and there were further changes in post-prandial glucose and glucagon responses. FFA concentrations during clamp were significantly lower at 6 months, relative to pre-surgical values.
RYGB produces, in morbidly obese non-diabetic patients, early changes in post-meal glucose, C-peptide, glucagon and PP responses, and appears to enhance insulin clearance early after RYGB and improve insulin sensitivity in adipose tissue at 6 months post-surgery. The early changes cannot be explained by caloric restriction alone.
PMCID: PMC3896512  PMID: 24209879
Gastric bypass; gut hormones; incretins; insulin resistance; free fatty acids; insulin clearance; hyperinsulinemic euglycemic clamp; bariatric surgery; C-peptide; glucagon; glucose; type 2 diabetes
2.  Cutis Verticis Gyrata in Men Affected by HIV-Related Lipodystrophy 
We report the occurrence of cutis verticis gyrata (CVG), a disfiguring dermatological condition, in four patients with HIV-related lipodystrophy (HIVLD). These four patients had abnormal metabolic and hormonal lab values which we compare with metabolic and hormonal perturbations cited in previous HIVLD cohorts. In addition, we describe the sole use of poly-L-lactic acid as a potential treatment for decreasing the appearance of CVG-associated ridges.
PMCID: PMC3789479  PMID: 24159328
3.  Assessing the Association between Leptin and Bone Mineral Density in HIV-Infected Men 
AIDS Research and Treatment  2012;2012:103072.
HIV-infected individuals are at risk for decreased bone mineral density (BMD). The known risk factors for bone loss do not fully explain the increased risk in this population. There is emerging evidence that leptin, a hormone secreted by adipocytes, plays an important role in bone metabolism. Several studies have assessed the relationship between leptin and bone density in healthy adults, but there are few such studies in HIV-infected individuals. Furthermore, HIV infected individuals on antiretroviral therapy are at increased risk for altered fat distribution, which may impact the relationship between leptin and BMD. In a cross-sectional analysis of data in 107 HIV-infected men, we determined whether serum leptin levels were associated with whole-body BMD and bone mineral content measured by dual-energy X-ray absorptiometry (DEXA), after adjusting for confounders including body fat distribution. We found an inverse association between leptin and bone density in those with peripheral lipoatrophy, defined objectively as <3 kg appendicular fat by DEXA, but no such relationship was seen in those with >3 kg appendicular fat. This result suggests that fat distribution may modify the relationship between leptin and bone density.
PMCID: PMC3433112  PMID: 22966425
4.  Boosting-Dose Ritonavir Does Not Alter Peripheral Insulin Sensitivity in Healthy, HIVSeronegative Volunteers 
Some HIV protease inhibitors (PI), including full dose ritonavir (800 mg) and ritonavir-boosted lopinavir, acutely induce insulin resistance in the absence of HIV infection and changes in body composition. Boosting-dose ritonavir (100 to 200 mg) is the most commonly prescribed PI, yet its effects on glucose metabolism have not been described in the absence of another PI.
In this randomized, double-blind, cross-over study, a single dose of ritonavir 200 mg or placebo was given to healthy HIV-seronegative volunteers before assessment of insulin sensitivity by euglycemic hyperinsulinemic clamp.
Boosting dose ritonavir had no effect on insulin-mediated glucose disposal (M/I, placebo: 8.59±0.83 vs. ritonavir: 8.51±0.64 mg/kg per min per μU/mL insulin, p=0.89).
A single boosting dose of ritonavir does not alter insulin sensitivity, suggesting lopinavir is likely responsible for the induction of insulin resistance demonstrated in prior short-term studies of lopinavir/ritonavir. There is a dose-dependent effect of ritonavir on insulin sensitivity.
PMCID: PMC3164483  PMID: 20595906
HIV protease inhibitors; insulin resistance; ritonavir; lopinavir; glucose
5.  Single-Dose Lopinavir-Ritonavir Acutely Inhibits Insulin-Mediated Glucose Disposal in Healthy Volunteers 
Previously, we found that 4 weeks of treatment with lopinavir-ritonavir did not decrease insulin sensitivity but did increase adiponectin levels. In the present study, a single dose of lopinavir-ritonavir decreases insulin sensitivity but does not alter adiponectin levels. Insulin resistance from protease inhibitors may decrease with prolonged use; an increase in adiponectin levels may mediate this effect.
PMCID: PMC3205942  PMID: 16886163
6.  The Effects of Low-Dose Growth Hormone in HIV-Infected Men with Fat Accumulation: A Pilot Study 
Pharmacologic doses of growth hormone (GH) reduce HIV-associated fat accumulation but may worsen glucose metabolism. We investigated the effects of a low dose of GH (1 mg per day) in HIV-infected men with fat accumulation and found that such treatment reduced total fat and increased lean body mass without significant changes in glucose tolerance or insulin sensitivity. Visceral adipose tissue (VAT) levels did not change significantly for the group as a whole, although a reduction in the VAT level was seen in patients with a greater VAT level at baseline.
PMCID: PMC3170406  PMID: 15356790
7.  Effects of ritonavir and amprenavir on insulin sensitivity in healthy volunteers 
AIDS (London, England)  2007;21(16):2183-2190.
Some HIV protease inhibitors (PIs) have been shown to induce insulin resistance in vitro but the degree to which specific PIs affect insulin sensitivity in humans is less well understood.
In two separate double-blind, randomized, cross-over studies, we assessed the effects of a single dose of ritonavir (800 mg) and amprenavir (1200 mg) on insulin sensitivity (euglycemic hyperglycemic clamp) in healthy normal volunteers.
Ritonavir decreased insulin sensitivity (−15%; P=0.008 versus placebo) and non-oxidative glucose disposal (−30%; P=0.0004), whereas neither were affected by amprenavir administration.
Compared to previously performed studies of identical design using single doses of indinavir and lopinavir/ritonavir, a hierarchy of insulin resistance was observed with the greatest effect seen with indinavir followed by ritonavir and lopinavir/ritonavir, with little effect of amprenavir.
PMCID: PMC3167072  PMID: 18090045
amprenavir; diabetes; HIV protease inhibitors; indinavir; insulin resistance; lopinavir/ritonavir; ritonavir
8.  Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: A randomized, placebo-controlled study 
AIDS (London, England)  2002;16(5):F1-F8.
Therapy with HIV protease inhibitors (PI) causes insulin resistance even in the absence of HIV infection, hyperlipidemia or changes in body composition. The mechanism of the effects on insulin action is unknown. In vitro studies suggest that PI selectively and rapidly inhibit the activity of the insulin-responsive glucose transporter GLUT-4. We hypothesized that a single dose of the PI indinavir resulting in therapeutic plasma concentrations would acutely decrease insulin-stimulated glucose disposal in healthy human volunteers.
Randomized, double-blind, cross-over study comparing the effect of 1200 mg of orally administered indinavir and placebo on insulin-stimulated glucose disposal during a 180-min euglycemic, hyperinsulinemic clamp. Six healthy HIV-seronegative adult male volunteers were studied twice with 7 to 10 days between studies.
There were no significant differences in baseline fasting body weight, or plasma glucose, insulin, lipid and lipoprotein levels between placebo- and indinavir-treated subjects. During steady-state (t60–180 min) insulin reached comparable levels (394 ± 13 versus 390 ± 11 pmol/l) and glucose was clamped at approximately 4.4 mmol/l under both conditions. The average maximum concentration of indinavir was 9.4 ± 2.2 μM and the 2-h area under the curve was 13.5 ± 3.1 μM · h. Insulin-stimulated glucose disposal per unit of insulin (M/I) decreased in all subjects from 14.1 ± 1.2 to 9.2 ± 0.8 mg/kg · min per μUI/ml (95% confidence interval for change, 3.7–6.1; P < 0.001) on indinavir (average decrease, 34.1 ± 9.2%). The non-oxidative component of total glucose disposal (storage) decreased from 3.9 ± 1.8 to 1.9 ± 0.9 mg/kg · min (P < 0.01). Free fatty acid levels were not significantly different at baseline and were suppressed equally with insulin administration during both studies.
A single dose of indinavir acutely decreases total and non-oxidative insulin-stimulated glucose disposal during a euglycemic, hyperinsulinemic clamp. Our data are compatible with the hypothesis that an acute effect of indinavir on glucose disposal in humans is mediated by a direct blockade of GLUT-4 transporters.
PMCID: PMC3166537  PMID: 11964551
HIV protease inhibitors; indinavir; insulin resistance; glucose transport; metabolic complications; diabetes; lipodystrophy; HIV; AIDS
9.  Metabolic effects of indinavir in healthy HIV-seronegative men 
AIDS (London, England)  2001;15(7):F11-F18.
Therapy with HIV protease inhibitors (PI) has been associated with hyperglycemia, hyperlipidemia and changes in body composition. It is unclear whether these adverse effects are drug related, involve an interaction with the host response to HIV or reflect changes in body composition.
Indinavir 800 mg twice daily was given to 10 HIV-seronegative healthy men to distinguish direct metabolic effects of a PI from those related to HIV infection. Fasting glucose and insulin, lipid and lipoprotein profiles, oral glucose tolerance (OGTT), insulin sensitivity by hyperinsulinemic euglycemic clamp, and body composition were measured prior to and after 4 weeks of indinavir therapy.
Fasting glucose (4.9 ± 0.1 versus 5.2 ± 0.2 mmol/l; P = 0.05) insulin concentrations (61.7 ± 12.2 versus 83.9 ± 12.2 pmol/l; P < 0.05), insulin : glucose ratio (12.6 ± 1.7 versus 15.9 ± 1.9 pmol/mmol; P < 0.05) and insulin resistance index by homeostasis model assessment (1.9 ± 0.3 versus 2.8 ± 0.5; P < 0.05) all increased significantly. During OGTT, 2 h glucose (5.1 ± 0.4 versus 6.5 ± 0.6 mmol/l; P < 0.05) and insulin levels (223.1 ± 48.8 versus 390.3 ± 108.8 pmol/l; P =0.05) also increased significantly. Insulin-mediated glucose disposal decreased significantly (10.4 ± 1.4 versus 8.6 ± 1.2 mg/kg · min per µU/ml insulin; 95% confidence interval 0.6–3.0; P < 0.01). There was no significant change in lipoprotein, triglycerides or free fatty acid levels. There was a small loss of total body fat (15.8 ± 1.4 versus 15.2 ± 1.4 kg; P = 0.01) by X-ray absorptiometry without significant changes in weight, waist : hip ratio, and visceral or subcutaneous adipose tissue by computed tomography.
In the absence of HIV infection, treatment with indinavir for 4 weeks causes insulin resistance independent of increases in visceral adipose tissue or lipid and lipoprotein levels.
PMCID: PMC3164882  PMID: 11399973
HIV protease inhibitors; indinavir; insulin resistance; body composition; cholesterol; triglycerides; diabetes; lipodystrophy; HIV; AIDS
10.  The metabolic effects of lopinavir/ritonavir in HIV-negative men 
AIDS (London, England)  2004;18(4):641-649.
Therapy with HIV protease inhibitors (PI) has been shown to worsen glucose and lipid metabolism, but whether these changes are caused by direct drug effects, changes in disease status, or body composition is unclear. Therefore, we tested the effects of the PI combination lopinavir and ritonavir on glucose and lipid metabolism in HIV-negative subjects.
A dose of 400 mg lopinavir/100 mg ritonavir was given twice a day to 10 HIV-negative men. Fasting glucose and insulin, lipid and lipoprotein profiles, oral glucose tolerance, insulin sensitivity by euglycemic hyperinsulinemic clamp, and body composition were determined before and after lopinavir/ritonavir treatment for 4 weeks.
On lopinavir/ritonavir, there was an increase in fasting triglyceride (0.89 ± 0.15 versus 1.63 ± 0.36 mmol/l; P =0.007), free fatty acid (FFA; 0.33 ± 0.04 versus 0.43 ± 0.06 mmol/l; P =0.001), and VLDL cholesterol (15.1 ± 2.6 versus 20 ± 3.3 mg/dl; P =0.05) levels. There were no changes in fasting LDL, HDL, IDL, lipoprotein (a), or total cholesterol levels. Fasting glucose, insulin, and insulin-mediated glucose disposal were unchanged, but on a 2 h oral glucose tolerance test glucose and insulin increased. There were no changes in weight, body fat, or abdominal adipose tissue by computed tomography.
Treatment with 4 weeks of lopinavir/ritonavir in HIV-negative men causes an increase in triglyceride levels, VLDL cholesterol, and FFA levels. Lopinavir/ritonavir leads to a deterioration in glucose tolerance at 2 h, but there is no significant change in insulin-mediated glucose disposal rate by euglycemic hyperinsulinemic clamp.
PMCID: PMC3166345  PMID: 15090769
HIV protease inhibitors; ritonavir; insulin resistance; body composition; cholesterol; triglycerides; lipodystrophy; HIV
11.  The Acute Effects of HIV Protease Inhibitors on Insulin Suppression of Glucose Production in Healthy HIV-negative Men 
The effects of different HIV protease inhibitors (PIs) on peripheral insulin resistance have been described, but less is known about their effects on insulin suppression of endogenous glucose production (EGP).
We tested the acute effects of three PIs, indinavir, ritonavir and amprenavir, on EGP quantified by stable isotope techniques during the hyperinsulinemic, euglycemic clamp in three similar placebo-controlled protocols.
EGP was higher with indinavir in the hyperinsulinemic state than with placebo (4.1±1.3 vs. 2.2±0.8 µg/kg*min, p=0.04). A trend towards higher EGP was seen with ritonavir (3.6±0.3 vs. 3.0±0.5 µg/kg*min, p=0.08). There was no evidence that amprenavir blunted insulin suppression of EGP compared to placebo (2.9±0.04 vs. 3.2±0.7 µg/kg*min, p=0.63).
Some PIs can acutely blunt the ability of insulin to suppress EGP, but, as with insulin resistance, the effects of PIs on EGP are drug-specific, not class-specific.
PMCID: PMC3164488  PMID: 19680131
12.  Insulin Resistance in Non-Obese Subjects Is Associated with Activation of the JNK Pathway and Impaired Insulin Signaling in Skeletal Muscle 
PLoS ONE  2011;6(5):e19878.
The pathogenesis of insulin resistance in the absence of obesity is unknown. In obesity, multiple stress kinases have been identified that impair the insulin signaling pathway via serine phosphorylation of key second messenger proteins. These stress kinases are activated through various mechanisms related to lipid oversupply locally in insulin target tissues and in various adipose depots.
Methodology/Principal Findings
To explore whether specific stress kinases that have been implicated in the insulin resistance of obesity are potentially contributing to insulin resistance in non-obese individuals, twenty healthy, non-obese, normoglycemic subjects identified as insulin sensitive or resistant were studied. Vastus lateralis muscle biopsies obtained during euglycemic, hyperinsulinemic clamp were evaluated for insulin signaling and for activation of stress kinase pathways. Total and regional adipose stores and intramyocellular lipids (IMCL) were assessed by DXA, MRI and 1H-MRS. In muscle of resistant subjects, phosphorylation of JNK was increased (1.36±0.23 vs. 0.78±0.10 OD units, P<0.05), while there was no evidence for activation of p38 MAPK or IKKβ. IRS-1 serine phosphorylation was increased (1.30±0.09 vs. 0.22±0.03 OD units, P<0.005) while insulin-stimulated tyrosine phosphorylation decreased (10.97±0.95 vs. 0.89±0.50 OD units, P<0.005). IMCL levels were twice as high in insulin resistant subjects (3.26±0.48 vs. 1.58±0.35% H2O peak, P<0.05), who also displayed increased total fat and abdominal fat when compared to insulin sensitive controls.
This is the first report demonstrating that insulin resistance in non-obese, normoglycemic subjects is associated with activation of the JNK pathway related to increased IMCL and higher total body and abdominal adipose stores. While JNK activation is consistent with a primary impact of muscle lipid accumulation on metabolic stress, further work is necessary to determine the relative contributions of the various mediators of impaired insulin signaling in this population.
PMCID: PMC3092773  PMID: 21589939
13.  A Genome-wide Association Study of Carotid Atherosclerosis in HIV-infected Men 
AIDS (London, England)  2010;24(4):583-592.
The role of host genetics in the development of subclinical atherosclerosis in the context of HIV infected persons who are being treated with highly active antiretroviral therapy (HAART) is not well understood.
The present genome-wide association study (GWAS) is based on 177 HIV-positive Caucasian males receiving HAART who participated in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) Study. Common and internal carotid intima-media thicknesses (cIMT) measured by B-mode ultrasound were used as a subclinical measure of atherosclerosis. Single nucleotide polymorphisms (SNPs) were assayed using the Illumina HumanCNV370-quad beadchip. Copy Number Variants (CNV) were inferred using a hidden Markov Model (PennCNV). Regression analyses were used to assess the association of common and internal cIMT with individual SNPs and CNVs, adjusting for age, duration of antiretroviral treatment, and principal components to account for potential population stratification.
Two SNPs in tight linkage disequilibrium, rs2229116 (a missense, nonsynonymous polymorphism (IIe to Val)) and rs7177922, located in the Ryanodine receptor (RYR3) gene on chromosome 15 were significantly associated with common cIMT (p-value<1.61×10−7). The RYR gene family has been known to play a role in the etiology of cardiovascular disease and has been shown to be regulated by HIV TAT protein.
These results suggest that in the context of HIV infection and HAART, a functional SNP in a biologically plausible candidate gene, RYR3, is associated with increased common carotid IMT, which is a surrogate for atherosclerosis.
PMCID: PMC3072760  PMID: 20009918
HIV; HAART; atherosclerosis; GWAS; intima-media thickness
14.  Enhanced Uridine Bioavailability Following Administration of a Triacetyluridine-Rich Nutritional Supplement 
PLoS ONE  2011;6(2):e14709.
Uridine is a therapy for hereditary orotic aciduria and is being investigated in other disorders caused by mitochondrial dysfunction, including toxicities resulting from treatment with nucleoside reverse transcriptase inhibitors in HIV. Historically, the use of uridine as a therapeutic agent has been limited by poor bioavailability. A food supplement containing nucleosides, NucleomaxX®, has been reported to raise plasma uridine to supraphysiologic levels.
Methodology/Principal Findings
Single- and multi-dose PK studies following NucleomaxX® were compared to single-dose PK studies of equimolar doses of pure uridine in healthy human volunteers. Product analysis documented that more than 90% of the nucleoside component of NucleomaxX® is in the form of triacetyluridine (TAU). Single and repeated dosing with NucleomaxX® resulted in peak plasma uridine concentrations 1–2 hours later of 150.9±39.3 µM and 161.4±31.5 µM, respectively, levels known to ameliorate mitochondrial toxicity in vitro. Cmax and AUC were four-fold higher after a single dose of NucleomaxX® than after uridine. No adverse effects of either treatment were observed.
NucleomaxX®, containing predominantly TAU, has significantly greater bioavailability than pure uridine in human subjects and may be useful in the management of mitochondrial toxicity.
PMCID: PMC3040752  PMID: 21379380
15.  Can the use of creatine supplementation attenuate muscle loss in cachexia and wasting? 
Purpose of review
Weight loss and low BMI due to an underlying illness have been associated with increased mortality, reduced functional capacity, and diminished quality of life. There is a need for safe, long- term approaches to maintain body weight in patients with cachexia or wasting. The purpose of this review is to highlight the scientific and clinical evidence derived from the recent literature investigating the rationale for and potential medical use of creatine supplementation in patients with cachexia or wasting.
Recent findings
Some studies have demonstrated that supplementation with creatine can increase creatine reserves in skeletal muscle and increase muscle mass and performance in various disease states that affect muscle size and function. The mechanisms underlying these effects are not clear. It has been suggested that creatine supplementation may increase intramuscular phosphocreatine stores and promote more rapid recovery of adenosine triphosphate levels following exercise, thus allowing users to exercise for longer periods or at higher intensity levels. Other hypothesized mechanisms include attenuation of proinflammatory cytokines, stimulation of satellite cell proliferation, and up-regulation of genes that promote protein synthesis and cell repair.
Creatine is a generally safe, low cost, over-the-counter nutritional supplement that shows potential in improving lean body mass and functionality in patients with wasting diseases. However, placebo-controlled studies have shown variable effects, with improvements in some and not in others. Additional studies with longer follow-up are required to identify the populations that might benefit most from creatine supplementation.
PMCID: PMC2905310  PMID: 19741514
lean body mass; muscle mass; energy metabolism; creatine
16.  Improvement in Peripheral Glucose Uptake After Gastric Bypass Surgery Is Observed Only After Substantial Weight Loss Has Occurred and Correlates with the Magnitude of Weight Lost 
Altered gut and pancreatic hormone secretion may bolster resolution of insulin resistance after Roux-en-Y gastric bypass (RYGB), but the independent effects of weight loss and hormonal secretion on peripheral glucose disposal are unknown.
Two groups of nondiabetic morbidly obese patients were studied: RYGB followed by standardized caloric restriction (RYGB, n = 12) or caloric restriction alone (diet, n = 10). Metabolic evaluations (euglycemic–hyperinsulinemic clamp, meal tolerance test) were done at baseline and 14 days (both groups) and 6 months after RYGB.
At baseline, body composition, fasting insulin, and glucose and peripheral glucose disposal did not differ between groups. At 14 days, excess weight loss (EWL) was similar (RYGB, 12.7% vs. diet, 10.9%; p = 0.12), fasting insulin and glucose decreased to a similar extent, and RYGB subjects had altered postmeal patterns of gut and pancreatic hormone secretion. However, peripheral glucose uptake (M value) was unchanged in both groups. Six months after RYGB, EWL was 49.7%. The changes in fasting glucose and insulin levels and gut hormone secretion persisted. M values improved significantly, and changes in M values correlated with the % EWL (r = 0.68, p = 0.02).
Improvement in peripheral glucose uptake following RYGB was observed only after substantial weight loss had occurred and correlated with the magnitude of weight lost.
PMCID: PMC2793380  PMID: 19838759
Bariatric surgery; Insulin resistance; Obesity; Morbid obesity; Gastric bypass; Weight loss; GLP-1; Insulin; Type 2 diabetes; Diabetes; Calorie restriction; Incretin
17.  Technical Evaluation for In Vivo Abdominal Fat and IMCL Quantification Using MRI and MRSI at 3T 
Magnetic resonance imaging  2007;26(2):188-197.
To develop protocols that measure abdominal fat by MRI and calf muscle lipids by MR spectroscopy (MRS) at 3 Tesla, and to examine the correlation between these parameters and insulin sensitivity.
Materials and Methods
Ten non-diabetic subjects, five insulin-sensitive (IS) and five insulin-resistant (IR), were scanned at 3T. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were segmented semi-automatically from abdominal imaging. Intramyocellular lipids (IMCL) in calf muscles were quantified from single voxel MRS in both soleus and tibialis anterior muscles, and from MR spectroscopic imaging (MRSI), respectively.
The average coefficient of variation (CV) of VAT/(VAT+SAT) was 5.2%. The inter-operator CV was 1.1% and 5.3% for SAT and VAT estimates, respectively. The CV of IMCL was 13.7% in soleus, 11.9% in tibialis anterior, and 2.9% with MRSI. IMCL based on MRSI (3.8% ± 1.2%) was significantly inversely correlated with glucose disposal rate measured by a hyperinsulinemic euglycemic clamp. VAT volume correlated significantly with IMCL. IMCL based on MRSI for IR subjects was significantly greater than that for IS subjects (4.5% ± 0.9% vs. 2.8% ± 0.5%, P = 0.02).
MRI/MRS techniques provide robust, non-invasive measurement for abdominal fat and muscle IMCL that are correlated with insulin action in humans.
PMCID: PMC2713003  PMID: 17683890
magnetic resonance imaging (MRI); magnetic resonance spectroscopy (MRS); abdominal fat; intramyocellular lipids (IMCL); insulin sensitivity
18.  Session V: Development of Appropriate CHD Risk Prediction Models 
Circulation  2008;118(2):e48-e53.
PMCID: PMC2648861  PMID: 18566316
19.  Creatine Fails to Augment the Benefits from Resistance Training in Patients with HIV Infection: A Randomized, Double-Blind, Placebo-Controlled Study 
PLoS ONE  2009;4(2):e4605.
Progressive resistance exercise training (PRT) improves physical functioning in patients with HIV infection. Creatine supplementation can augment the benefits derived from training in athletes and improve muscle function in patients with muscle wasting. The objective of this study was to determine whether creatine supplementation augments the effects of PRT on muscle strength, energetics, and body composition in HIV-infected patients.
Methodology/Principal Findings
This is a randomized, double blind, placebo-controlled, clinical research center-based, outpatient study in San Francisco. 40 HIV–positive men (20 creatine, 20 placebo) enrolled in a 14-week study. Subjects were randomly assigned to receive creatine monohydrate or placebo for 14 weeks. Treatment began with a loading dose of 20 g/day or an equivalent number of placebo capsules for 5 days, followed by maintenance dosing of 4.8 g/day or placebo. Beginning at week 2 and continuing to week 14, all subjects underwent thrice-weekly supervised resistance exercise while continuing on the assigned study medication (with repeated 6-week cycles of loading and maintenance). The main outcome measurements included muscle strength (one repetition maximum), energetics (31P magnetic resonance spectroscopy), composition and size (magnetic resonance imaging), as well as total body composition (dual-energy X-ray absorptiometry). Thirty-three subjects completed the study (17 creatine, 16 placebo). Strength increased in all 8 muscle groups studied following PRT, but this increase was not augmented by creatine supplementation (average increase 44 vs. 42%, difference 2%, 95% CI −9.5% to 13.9%) in creatine and placebo, respectively). There were no differences between groups in changes in muscle energetics. Thigh muscle cross-sectional area increased following resistance exercise, with no additive effect of creatine. Lean body mass (LBM) increased to a significantly greater extent with creatine.
Conclusions / Significance
Resistance exercise improved muscle size, strength and function in HIV-infected men. While creatine supplementation produced a greater increase in LBM, it did not augment the robust increase in strength derived from PRT.
Trial Registration NCT00484627
PMCID: PMC2646129  PMID: 19242554
20.  Time- and exercise-dependent gene regulation in human skeletal muscle 
Genome Biology  2003;4(10):R61.
Skeletal muscle remodeling is a critical component of an organism's response to environmental changes. Exercise causes structural changes in muscle and can induce phase shifts in circadian rhythms, fluctuations in physiology and behavior with a period of around 24 hours that are maintained by a core clock mechanism. Both exercise-induced remodeling and circadian rhythms rely on the transcriptional regulation of key genes.
Skeletal muscle remodeling is a critical component of an organism's response to environmental changes. Exercise causes structural changes in muscle and can induce phase shifts in circadian rhythms, fluctuations in physiology and behavior with a period of around 24 hours that are maintained by a core clock mechanism. Both exercise-induced remodeling and circadian rhythms rely on the transcriptional regulation of key genes.
We used DNA microarrays to determine the effects of resistance exercise (RE) on gene regulation in biopsy samples of human quadriceps muscle obtained 6 and 18 hours after an acute bout of isotonic exercise with one leg. We also profiled diurnal gene regulation at the same time points (2000 and 0800 hours) in the non-exercised leg. Comparison of our results with published circadian gene profiles in mice identified 44 putative genes that were regulated in a circadian fashion. We then used quantitative PCR to validate the circadian expression of selected gene orthologs in mouse skeletal muscle.
The coordinated regulation of the circadian clock genes Cry1, Per2, and Bmal1 6 hours after RE and diurnal genes 18 hours after RE in the exercised leg suggest that RE may directly modulate circadian rhythms in human skeletal muscle.
PMCID: PMC328450  PMID: 14519196
21.  Isolated Hypoaldosteronism 
California Medicine  1973;118(6):33-38.
These discussions are selected from the weekly staff conferences in the Department of Medicine, University of California, San Francisco. Taken from transcriptions, they are prepared by Drs. David W. Martin, Jr., Assistant Professor of Medicine, and Kenneth A. Woeber, Associate Professor of Medicine, under the direction of Dr. Lloyd H. Smith, Jr., Professor of Medicine and Chairman of the Department of Medicine. Requests for reprints should be sent to the Department of Medicine, University of California, San Francisco, San Francisco, Ca. 94122.
PMCID: PMC1454953  PMID: 4709523

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