A small molecule MST1/2 inhibitor accelerates murine liver regeneration with improved survival in models of steatohepatitis.

Dysfunctional liver regeneration following surgical resection remains a major cause of postoperative mortality and has no therapeutic options. Without targeted therapies, the current treatment paradigm relies on supportive therapy until homeostasis can be achieved. Pharmacologic acceleration of regeneration represents an alternative therapeutic avenue. Therefore, we aimed to generate a small molecule inhibitor that could accelerate liver regeneration with an emphasis on diseased models, which represent a significant portion of patients who require surgical resection and are often not studied. Utilizing a clinically approved small molecule inhibitor as a parent compound, standard medicinal chemistry approaches were utilized to generate a small molecule inhibitor targeting serine/threonine kinase 4/3 (MST1/2) with reduced off-target effects. This compound, mCLC846, was then applied to preclinical models of murine partial hepatectomy, which included models of diet-induced metabolic dysfunction-associated steatohepatitis (MASH). mCLC846 demonstrated on target inhibition of MST1/2 and reduced epidermal growth factor receptor inhibition. The inhibitory effects resulted in restored pancreatic beta-cell function and survival under diabetogenic conditions. Liver-specific cell-line exposure resulted in Yes-associated protein activation. Oral delivery of mCLC846 perioperatively resulted in accelerated murine liver regeneration and improved survival in diet-induced MASH models. Bulk transcriptional analysis of regenerating liver remnants suggested that mCLC846 enhanced the normal regenerative pathways and induced them following liver resection. Overall, pharmacological acceleration of liver regeneration with mCLC846 was feasible, had an acceptable therapeutic index, and provided a survival benefit in models of diet-induced MASH.

A small molecule UPR modulator for diabetes identified by high throughput screening.

Unfolded protein response (UPR) is a stress response that is specific to the endoplasmic reticulum (ER). UPR is activated upon accumulation of unfolded (or misfolded) proteins in the ER's lumen to restore protein folding capacity by increasing the synthesis of chaperones. In addition, UPR also enhances degradation of unfolded proteins and reduces global protein synthesis to alleviate additional accumulation of unfolded proteins in the ER. Herein, we describe a cell-based ultra-high throughput screening (uHTS) campaign that identifies a small molecule that can modulate UPR and ER stress in cellular and in vivo disease models. Using asialoglycoprotein receptor 1 (ASGR) fused with Cypridina luciferase (CLuc) as reporter assay for folding capacity, we have screened a million small molecule library and identified APC655 as a potent activator of protein folding, that appears to act by promoting chaperone expression. Furthermore, APC655 improved pancreatic ß cell viability and insulin secretion under ER stress conditions induced by thapsigargin or cytokines. APC655 was also effective in preserving ß cell function and decreasing lipid accumulation in the liver of the leptin-deficient (ob/ob) mouse model. These results demonstrate a successful uHTS campaign that identified a modulator of UPR, which can provide a novel candidate for potential therapeutic development for a host of metabolic diseases.

Neratinib protects pancreatic beta cells in diabetes.

The loss of functional insulin-producing ß-cells is a hallmark of diabetes. Mammalian sterile 20-like kinase 1 (MST1) is a key regulator of pancreatic ß-cell death and dysfunction; its deficiency restores functional ß-cells and normoglycemia. The identification of MST1 inhibitors represents a promising approach for a ß-cell-protective diabetes therapy. Here, we identify neratinib, an FDA-approved drug targeting HER2/EGFR dual kinases, as a potent MST1 inhibitor, which improves ß-cell survival under multiple diabetogenic conditions in human islets and INS-1E cells. In a pre-clinical study, neratinib attenuates hyperglycemia and improves ß-cell function, survival and ß-cell mass in type 1 (streptozotocin) and type 2 (obese Leprdb/db) diabetic mouse models. In summary, neratinib is a previously unrecognized inhibitor of MST1 and represents a potential ß-cell-protective drug with proof-of-concept in vitro in human islets and in vivo in rodent models of both type 1 and type 2 diabetes.

A novel inhibitor of inducible NOS dimerization protects against cytokine-induced rat beta cell dysfunction.

BACKGROUND AND PURPOSE: Beta cell apoptosis is a major feature of type 1 diabetes, and pro-inflammatory cytokines are key drivers of the deterioration of beta cell mass through induction of apoptosis. Mitochondrial stress plays a critical role in mediating apoptosis by releasing cytochrome C into the cytoplasm, directly activating caspase-9 and its downstream signalling cascade. We aimed to identify new compounds that protect beta cells from cytokine-induced activation of the intrinsic (mitochondrial) pathway of apoptosis. EXPERIMENTAL APPROACH: Diabetogenic media, composed of IL-1ß, IFN-γ and high glucose, were used to induce mitochondrial stress in rat insulin-producing INS1E cells, and a high-content image-based screen of small molecule modulators of Casp9 pathway was performed. KEY RESULTS: A novel small molecule, ATV399, was identified from a high-content image-based screen for compounds that inhibit cleaved caspase-9 activation and subsequent beta cell apoptosis induced by a combination of IL-1ß, IFN-γ and high glucose, which together mimic the pathogenic diabetic milieu. Through medicinal chemistry optimization, potency was markedly improved (6-30 fold), with reduced inhibitory effects on CYP3A4. Improved analogues, such as CAT639, improved beta cell viability and insulin secretion in cytokine-treated rat insulin-producing INS1E cells and primary dispersed islet cells. Mechanistically, CAT639 reduced the production of NO by allosterically inhibiting dimerization of inducible NOS (iNOS) without affecting its mRNA levels. CONCLUSION AND IMPLICATIONS: Taken together, these studies demonstrate a successful phenotypic screening campaign resulting in identification of an inhibitor of iNOS dimerization that protects beta cell viability and function through modulation of mitochondrial stress induced by cytokines.

Development and validation of the Somali WHOQOL-BREF among refugees living in the USA.

PURPOSE: This study is the first translation and validation of the WHOQOL-BREF for general use in Somali refugee populations. METHODS: A community sample of 303 Somali refugees living in the USA responded to the WHOQOL-BREF following translation, adaptation, and validation guidelines established by the World Health Organization. Psychometric properties of the quality of life instrument were assessed including tests of the four-domain factor structure using multiple regression and principal component analysis. RESULTS: Principal component analysis demonstrated an acceptable fit between PCA components and original WHOQOL-BREF domains. Four components had eigenvalues greater than one and explained 63.4% of the observed variance. Most scale items loaded like the original WHOQOL-BREF domains, with the notable difference among four items of physical health that loaded more strongly under the environment domain. Construct validity of the scale was confirmed by higher intercorrelations of each WHOQOL-BREF item with its intended domain (all r (2) > 0.50) than with other domains. Multiple regression analyses of the domain scores on overall quality of life (Q1) and health satisfaction (Q2) explained half of the observed variance in each measure. Item correlations showed good internal consistency (0.65 ≥ Cronbach's alpha ≤ 0.82). CONCLUSIONS: Validation of this first Somali version of the WHOQOL-BREF provides further evidence that this instrument can be a valid measure for cross-cultural comparative studies of quality of life. Policies that address health disparities can be more broadly evaluated if quality of life is systematically measured in the community. This is particularly important for evaluating policy impact and implications for refugee populations.

The likelihood of khat chewing serving as a neglected and reverse 'gateway' to tobacco use among UK adult male khat chewers: a cross sectional study.

BACKGROUND: Chewing khat leaves is often accompanied by tobacco use. We assessed aspects of tobacco use and explored factors associated with tobacco use patterns (frequency of use per week) among khat chewers who used tobacco only when chewing khat ("simultaneous tobacco and khat users", STKU). METHODS: A sample of 204 male khat chewers was recruited during random visits to khat outlets. Data collected included socio-demographic items, tobacco use and khat chewing behaviours. Both psychological and physical dependence on khat were assessed using the Severity of Psychological Dependence on Khat (SDS-Khat) Scale, the Diagnostic Statistical Manual IV (DSM-IV) and adapted items from the Fagerström Test for Nicotine Dependence (chewing even when ill, and difficulty in abstaining from khat chewing for an entire week). Descriptive statistics and non-parametric analyses were conducted. RESULTS: Of the 204 khat chewers, 35% were khat chewers only, 20% were STKU, and the remainder were daily cigarette smokers. The mean age of STKU was 38.12 (±14.05) years. Fifty seven percent of STKU smoked tobacco and chewed khat for two days per week and 43% smoked and chewed more frequently (three to six days: 33%, daily: 10%). Three quarters (74%) were former daily tobacco users. Khat chewing initiated tobacco smoking among 45% of STKU and 71% reported attempts to quit tobacco smoking during khat chew. Among STKU, smoking tobacco for more than two days per week was significantly associated (p < 0.05) with psychological dependence (increased levels of SDS-Khat), physical dependence (increased levels of DSM-IV symptoms, chewing even when ill, difficulty in abstaining from chewing for an entire week and self-reported health conditions) and behavioural factors (e.g. amount of khat chewed in typical khat session). CONCLUSIONS: Khat chewing may promote different patterns of tobacco smoking, initiate and sustain tobacco smoking, and trigger tobacco cessation relapses among STKU. Increased frequency of tobacco smoking among STKU was linked to psycho-physical and behavioural factors. Further investigation within large and representative samples of both sexes of STKU in different contexts should be considered for health research and policy development. Khat chewing should be considered when designing tobacco prevention uptake, cessation interventions and relapse prevention programmes.

Colostrum avoidance, prelacteal feeding and late breast-feeding initiation in rural Northern Ethiopia.

OBJECTIVE: To identify specific cultural and behavioural factors that might be influenced to increase colostrum feeding in a rural village in Northern Ethiopia to improve infant health. DESIGN: Background interviews were conducted with six community health workers and two traditional birth attendants. A semi-structured tape-recorded interview was conducted with twenty mothers, most with children under the age of 5 years. Variables were: parental age and education; mother's ethnicity; number of live births and children's age; breast-feeding from birth through to weaning; availability and use of formula; and descriptions of colostrum v. other stages of breast milk. Participant interviews were conducted in Amharic and translated into English. SETTING: Kossoye, a rural Amhara village with high prevalence rates of stunting: inappropriate neonatal feeding is thought to be a factor. SUBJECTS: Women (20-60 years of age) reporting at least one live birth (range: 1-8, mean: ∼4). RESULTS: Colostrum (inger) and breast milk (yetut wotet) were seen as different substances. Colostrum was said to cause abdominal problems, but discarding a portion was sufficient to mitigate this effect. Almost all (nineteen of twenty) women breast-fed and twelve (63 %) reported ritual prelacteal feeding. A majority (fifteen of nineteen, 79 %) reported discarding colostrum and breast-feeding within 24 h of birth. Prelacteal feeding emerged as an additional factor to be targeted through educational intervention. CONCLUSIONS: To maximize neonatal health and growth, we recommend culturally tailored education delivered by community health advocates and traditional health practitioners that promotes immediate colostrum feeding and discourages prelacteal feeding.

Significant associations of age, menopausal status and lifestyle factors with visceral adiposity in African-American and European-American women.

BACKGROUND: Elevated visceral adiposity is strongly predictive of cardiometabolic disease, but, due to the high cost of biomedical imaging, assessment of factors contributing to normal variation in visceral (VAT) and subcutaneous (SAT) adipose tissue partitioning in large cohorts of healthy individuals are few, particularly in ethnic and racial minority populations. OBJECTIVE: To describe age, menopausal status, smoking and physical activity differences in VAT and abdominal subcutaneous adipose tissue (ASAT) mass in African-American (AA) and European-American (EA) women. METHODS: Magnetic resonance imaging measures of VAT and ASAT mass and VAT% (VAT/VAT+ASAT, %) were obtained from a cross-sectional sample of 617 EA and 111 AA non-diabetic women aged 18-80 years. Multivariate linear regression was used to test independent effects of the covariates. RESULTS: VAT and VAT% were higher in EA than AA women (p < 0.01). Differences in VAT, ASAT and VAT% across age groups began in early adulthood in both ethnic groups, but the association of age with VAT% was stronger in EA women (p for interaction = 0.03). Current smokers had higher VAT and VAT% (p < 0.01) and lower TBF than non-smokers. Frequent participation in sports activities was associated with ∼30% lower VAT in older (>55 years) as well as younger ( < 40 years) women (p < 0.0001). CONCLUSION: Greater allocation of abdominal adipose tissue into the visceral compartment occurs in EA than AA women and in older than younger women. Avoidance of cigarette smoking and frequent participation in sports activities may partially counteract this deleterious phenomenon of ageing.

Symptom prevalence of ADHD in a community residential substance abuse treatment program.

OBJECTIVE: ADHD is a common comorbid condition with substance use disorder. This study seeks to examine the discrepancy in the prevalence rate between those previously diagnosed with ADHD and those diagnosed while in treatment. It is hypothesized that clients with ADHD would have earlier unsuccessful terminations from treatment than non-ADHD clients and that the ADHD Self-Report Scale (ASRS Version 1.1) would be a reliable predictor. METHOD: Participants (N = 87) are admitted to a publicly funded 28-day residential treatment program. All participants are screened with the ASRS and participate in a clinical assessment evaluation. RESULTS: A significant difference is found between the clinical record rate of 3.44% and the 43.68% rate found during treatment. The ASRS significantly predicts ADHD. CONCLUSIONS: The use of the ASRS is recommended and should be incorporated into standard intake assessment protocols. Careful diagnostic interviews are urged to determine if clients in residential treatment have ADHD.

Cardiac rehabilitation for women: a systematic review.

PURPOSE: Current cardiac rehabilitation (CR) evidence was systematically evaluated to identify program components that may yield improvements in physiological and psychosocial outcomes in women. METHODS: A search was conducted in the electronic databases: MEDLINE, Embase, CINAHL, Scopus, Sport Discus and Cochrane Library. Search terms included women, heart disease, exercise therapy, and cardiac rehabilitation. A systematic elimination process was used with specific inclusion/exclusion criteria. Included articles were independently evaluated by four reviewers for level of evidence and internal validity. Specific recommendations were made based on trends in the literature and strength of supporting evidence. RESULTS: Thirty-seven articles were included with a combined sample of 3,807 subjects. Ten studies included an analysis of physiological effects of exercise. Aerobic, resistance, and combined exercise interventions all yield physiological benefits. CR yielded favourable health-related quality of life outcomes and women benefited from psychosocial support in both formal and informal environments. CONCLUSIONS: The following recommendations are based on the review: 1) For patients with good cardiac function, community/home-based programs are as effective as supervised programs (Level II, B); 2) resistance training should be included as an adjunct to aerobic training (Level I, A); 3) programs need to address the specific educational needs of women (Level I, A) and a stronger emphasis needs to be placed on social support (Level II, B).

Visceral adiposity and its anatomical distribution as predictors of the metabolic syndrome and cardiometabolic risk factor levels.

BACKGROUND: Despite the recognition that central obesity plays a critical role in chronic disease, few large-scale imaging studies have documented human variation in abdominal adipose tissue patterning. OBJECTIVE: We aimed to compare the associations between abdominal subcutaneous adipose tissue (ASAT) and visceral abdominal tissue (VAT), which were measured at different locations across the abdomen, and the presence of the metabolic syndrome (MS; National Cholesterol Education Program Adult Treatment Panel III definition) and individual cardiometabolic risk factors. DESIGN: This study included 713 non-Hispanic whites aged 18-86 y, in whom VAT and ASAT were assessed by using multiple-image magnetic resonance imaging. The anatomical position of the magnetic resonance image containing the maximum VAT area for each subject was used as a measure of VAT patterning. Multivariate linear and logistic regression analyses were used to examine the relation of VAT, ASAT, and VAT patterning to cardiometabolic risk. RESULTS: VAT mass was a stronger predictor of the MS than was ASAT mass, but ASAT mass (and other measures of subcutaneous adiposity) had signification interactions with VAT mass, whereby elevated ASAT reduced the probability of MS among men with high VAT (P = 0.0008). There was variation across image locations in the association of VAT area with the MS in men, and magnetic resonance images located 4-8 cm above L4-L5 provided the strongest correlations between VAT area and cardiometabolic risk factors. Subjects whose maximum VAT area was higher in the abdomen had higher LDL-cholesterol concentrations (R(2) = 0.07, P < 0.0001), independent of age and adiposity. CONCLUSION: Further studies are needed to confirm the effects of VAT patterning on cardiometabolic risk.

Sex differences in young adulthood metabolic syndrome and physical activity: the Fels longitudinal study.

OBJECTIVE: To evaluate the effects of habitual physical activity (PA) on the metabolic syndrome (MS) in young adult men and women. RESEARCH METHODS AND PROCEDURES: Cross-sectional PA data were utilized from 249 women and 237 men, aged 18-40 years in the Fels Longitudinal Study. MS components--abdominal circumference (AC), triglycerides (TG), HDL, blood pressure (BP), and fasting glucose (FG)--were dichotomized according to the National Cholesterol Education Program's Adult Treatment Panel III revised criteria. Leisure, sport, work, and total PA scores were calculated using the Baecke Questionnaire of Habitual Physical Activity. Multiple logistic regression modeling assessed the effects of PA, age, smoking, and BMI on MS status. RESULTS: 26.9% of men and 19.3% of women had MS. For men, MS risk was reduced with increases in both total PA [OR = 0.65 (95% CI: 0.47, 0.90)] and sport PA [OR = 0.40 (95% CI: 0.23, 0.70)]. AC, TG, and HDL values also improved with total and sport PA. Among women, the risk for MS was marginally reduced by total PA [OR = 0.72 (95% CI: 0.50, 1.02)] and HDL levels were increased by both total PA [OR = 0.79 (95% CI: 0.63, 0.98)] and sport PA [OR = 0.54 (95% CI: 0.35, 0.84)]. DISCUSSION: Increased total and sport PA reduces risk for the MS in young men, though not as clearly in young women.

New saliva DNA collection method compared to buccal cell collection techniques for epidemiological studies.

Epidemiological studies may require noninvasive methods for off-site DNA collection. We compared the DNA yield and quality obtained using a whole-saliva collection device (Oragene DNA collection kit) to those from three established noninvasive methods (cytobrush, foam swab, and oral rinse). Each method was tested on 17 adult volunteers from our center, using a random crossover collection design and analyzed using repeated-measures statistics. DNA yield and quality were assessed via gel electrophoresis, spectophotometry, and polymerase chain reaction (PCR) amplification rate. The whole-saliva method provided a significantly greater DNA yield (mean +/- SD = 154.9 +/- 103.05 microg, median = 181.88) than the other methods (oral rinse = 54.74 +/- 41.72 microg, 36.56; swab = 11.44 +/- 7.39 microg, 10.72; cytobrush = 12.66 +/- 6.19, 13.22 microg) (all pairwise P < 0.05). Oral-rinse and whole-saliva samples provided the best DNA quality, whereas cytobrush and swab samples provided poorer quality DNA, as shown by lower OD(260)/OD(280) and OD(260)/OD(230) ratios. We conclude that both a 10-ml oral-rinse sample and 2-ml whole-saliva sample provide sufficient DNA quantity and better quality DNA for genetic epidemiological studies than do the commonly used buccal swab and brush techniques.

Anatomical patterning of visceral adipose tissue: race, sex, and age variation.

OBJECTIVE: We tested sex, race, and age differences in the patterning of visceral adipose tissue (VAT) and subcutaneous adipose tissue. RESEARCH METHODS AND PROCEDURES: Contiguous 1-cm-thick magnetic resonance (MR) images of the abdomen were collected from 820 African-American and white adults. Repeated-measures ANOVA was used to examine the effects of image location, sex, race, and age (>or=50 vs. <50 years) on adipose tissue areas. Maximum VAT area was identified for each subject from the raw data. RESULTS: Compared to women, men had greater total VAT volume (p < 0.0001), and their maximum VAT area occurred higher in the abdomen (p < 0.0001). Among white men, maximim VAT area most frequently occurred 5 to 10 cm above L4-L5, whereas in the other groups, maximim VAT area most frequently occurred 1 to 4 cm above L4-L5 (p < 0.0001). African-American men had greater total VAT volume than African-American women (p < 0.01), but this sex difference was only significant using single images cranial to L4-L5 + 2 cm. Age-related increases in VAT tended to be greatest 5 to 10 cm above L4-L5 in men and near L4-L5 in women. DISCUSSION: A single MR image 5 to 10 cm above L4-L5 may allow more accurate conclusions than the L4-L5 image regarding group differences in visceral adiposity.

The belated autopsy and identification of an eighteenth century naval hero--the saga of John Paul Jones.

John Paul Jones, the "Father of the American Navy," is known for the battletime assertion that he had "not yet begun to fight." His central role in a triumph of scientific forensic identification more than a century after his death is less known. John Paul Jones died in 1792 and was buried in Paris, France. The location of his grave was lost over time and a search for his corpse began in 1899. Remains matching his physical characteristics and circumstance of burial were discovered in 1905 and returned to the United States for a hero's burial. Some questioned the identification at the time and the major source of identifying information has since been shown to contain false information. The published forensic literature fails to address existing critiques of the identification. We provide a substantive analysis and conclude that the available evidence supports the identification of the unknown remains as those of John Paul Jones.

Effective use of thiazolidinediones for the treatment of glucocorticoid-induced diabetes.

We evaluated the efficacy of a thiazolidinedione in the treatment of diabetes induced by glucocorticoids. We examined the effectiveness of troglitazone in seven patients with long-standing steroid-induced diabetes. Five of the seven subjects were treated with insulin alone, one was treated with both insulin and oral therapy and one was treated with oral therapy alone. The mean insulin dose in six of the seven subjects was 0.66+/-0.09 units/kg per day. Diabetes status was assessed by measuring serum fructosamine, HgbA1c, oral glucose and meal tolerance tests (OGTT and MTT) at baseline and after treatment for 5-8 weeks with troglitazone 400 mg/day. Troglitazone caused a significant decrease in fructosamine (274+/-32 vs. 217+/-22 mmol/l; P<0.01) and HgbA1C (7.8+/-0.4 vs. 7.2+/-0.4%; P<0.01) as well as decrements in the areas under the OGTT 2,308+/-156 vs. 1,937+/-127 mmol/l; P<0.05) and MTT glucose curves (4694+/-449 vs. 4057+/-437 mmol/l; P<0.05). In addition, the area under the insulin curve for the oral glucose tolerance test showed a significant increase from 27,438+/-4,488 to 41,946+/-6,048 pmol/l (P<0.05). Total and LDL cholesterol were also significantly decreased (6.4+/-0.9 vs. 5.0+/-0.6 mmol/l and 3.8+/-0.7 vs. 2.7+/-0.4 mmol/l, respectively, P<0.05). Fasting leptin values decreased by 23% despite an increase in body weight. Troglitazone is effective in the treatment of glucocorticoid-induced diabetes as manifested by lower measures of glycemia, HgbA1c, and post-prandial glucose values, while the doses of other diabetes medications remained unchanged or were reduced. The insulin-sensitizing drug also produced a marked increase in endogenous insulin secretion in response to glucose, lower total and LDL cholesterol, and decreased fasting leptin despite weight gain. Thiazolidinediones may improve diabetes-related parameters by antagonizing pathways of glucocorticoid-induced insulin resistance and by reversing adverse effects of glucocorticoids on beta cell function.

Troglitazone antagonizes metabolic effects of glucocorticoids in humans: effects on glucose tolerance, insulin sensitivity, suppression of free fatty acids, and leptin.

Glucocorticoids induce insulin resistance in humans, whereas thiazolidinediones enhance insulin sensitivity. Although the effects of glucocorticoids and thiazolidinediones have been assessed in isolation, interaction between these drugs, which both act as ligands for nuclear receptors, has been less well studied. Therefore, we examined the metabolic effects of dexamethasone and troglitazone, alone and in combination, for the first time in humans. A total of 10 healthy individuals with normal glucose tolerance (age 40 +/- 11 years, BMI 31 +/- 6.1 kg/m(2)) were sequentially studied at baseline, after 4 days of dexamethasone (4 mg/day), after 4-6 weeks on troglitazone alone (400 mg/day), and again after 4 days of dexamethasone added to troglitazone. Key metabolic variables included glucose tolerance assessed by blood glucose and insulin responses to an oral glucose tolerance test (OGTT), insulin sensitivity evaluated via hyperinsulinemic-euglycemic clamp, free fatty acids (FFAs) and FFA suppressibility by insulin during the clamp study, and fasting serum leptin. Dexamethasone drastically impaired glucose tolerance, with fasting and 2-h OGTT insulin values increasing by 2.3-fold (P < 0.001) and 4.4-fold (P < 0.001) over baseline values, respectively. The glucocorticoid also induced a profound state of insulin resistance, with a 34% reduction in maximal glucose disposal rates (GDRs; P < 0.001). Troglitazone alone increased GDRs by 20% over baseline (P = 0.007) and completely prevented the deleterious effects of dexamethasone on glucose tolerance and insulin sensitivity, as illustrated by a return of OGTT glucose and insulin values and maximal GDR to near-baseline levels. Insulin-mediated FFA suppressibility (FFA decline at 30 min during clamp/FFA at time 0) was also markedly reduced by dexamethasone (P = 0.002). Troglitazone had no effect per se, but it was able to normalize FFA suppressibility in subjects coadministered dexamethasone. Futhermore, the magnitudes of response of FFA suppressibility and GDR to dexamethasone were proportionate. The same was true for the reversal of dexamethasone-induced insulin resistance by troglitazone, but not in response to troglitazone alone. Leptin levels were increased 2.2-fold above baseline by dexamethasone. Again, troglitazone had no effect per se but blocked the dexamethasone-induced increase in leptin. Subjects experienced a 1.7-kg weight gain while taking troglitazone but no other untoward effects. We conclude that in healthy humans, thiazolidinediones antagonize the action of dexamethasone with respect to multiple metabolic effects. Specifically, troglitazone reverses both glucocorticoid-induced insulin resistance and impairment of glucose tolerance, prevents dexamethasone from impairing the antilipolytic action of insulin, and blocks the increase in leptin levels induced by dexamethasone. Even though changes in FFA suppressibility were correlated with dexamethasone-induced insulin resistance and its reversal by troglitazone, a cause-and-effect relationship cannot be established. However, the data suggest that glucocorticoids and thiazolidinediones exert fundamentally antagonistic effects on human metabolism in both adipose and muscle tissues. By preventing or reversing insulin resistance, troglitazone may prove to be a valuable therapeutic agent in the difficult clinical task of controlling diabetes in patients receiving glucocorticoids.