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Fatty Acid Synthase Inhibitor TVB-2640 Reduces Hepatic de Novo Lipogenesis in Males With Metabolic Abnormalities.
Syed-Abdul, MM, Parks, EJ, Gaballah, AH, Bingham, K, Hammoud, GM, Kemble, G, Buckley, D, McCulloch, W, Manrique-Acevedo, C
Hepatology (Baltimore, Md.). 2020;(1):103-118
Abstract
BACKGROUND AND AIMS Elevated hepatic de novo lipogenesis (DNL) is a key distinguishing characteristic of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis. In rodent models of NAFLD, treatment with a surrogate of TVB-2640, a pharmacological fatty acid synthase inhibitor, has been shown to reduce hepatic fat and other biomarkers of DNL. The purpose of this phase I clinical study was to test the effect of the TVB-2640 in obese men with certain metabolic abnormalities that put them at risk for NAFLD. APPROACH AND RESULTS Twelve subjects (mean ± SEM, 42 ± 2 years, body mass index 37.4 ± 1.2 kg/m2 , glucose 103 ± 2 mg/dL, triacylglycerols 196 ± 27 mg/dL, and elevated liver enzymes) underwent 10 days of treatment with TVB-2640 at doses ranging from 50-150 mg/day. Food intake was controlled throughout the study. Hepatic DNL was measured before and after an oral fructose/glucose bolus using isotopic labeling with 1-13 C1 -acetate intravenous infusion, followed by measurement of labeled very low-density lipoprotein palmitate via gas chromatography mass spectometry. Substrate oxidation was measured by indirect calorimetry. Across the range of doses, fasting DNL was reduced by up to 90% (P = 0.003). Increasing plasma concentrations of TVB-2640 were associated with progressive reductions in the percent of fructose-stimulated peak fractional DNL (R2 = -0.749, P = 0.0003) and absolute DNL area under the curve 6 hours following fructose/glucose bolus (R2 = -0.554, P = 0.005). For all subjects combined, alanine aminotransferase was reduced by 15.8 ± 8.4% (P = 0.05). Substrate oxidation was unchanged, and safety monitoring revealed that the drug was well tolerated, without an increase in plasma triglycerides. Alopecia occurred in 2 subjects (reversed after stopping the drug), but otherwise no changes were observed in fasting glucose, insulin, ketones, and renal function. CONCLUSION These data support the therapeutic potential of a fatty acid synthase inhibitor, TVB-2640 in particular, in patients with NAFLD and nonalcoholic steatohepatitis.
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Outcomes of mitochondrial derived diseases: a single-center experience.
Erdol, S, Saglam, H
Journal of pediatric endocrinology & metabolism : JPEM. 2018;(4):399-405
Abstract
BACKGROUND The purpose of this study is to help elucidate which part of the mitochondria is causing a problem through anamnesis, physical examination, and routine biochemical tests in the event of a suspected mitochondrial disease case. METHODS The data were obtained retrospectively from the medical records of 75 cases; the mitochondrial-derived disease (MDD) cases were observed in our center from 2011 to 2017. RESULTS The most commonly observed MDDs were oxidative phosphorylation disorders at 44%, followed by fatty acid oxidation disorder at 40%, pyruvate metabolism disorder at 12%, and ketone metabolism disorder at 4%, respectively. The most common clinical presentation at the time of referral to the hospital was metabolic acidosis (20%), and the most common symptom was respiratory distress (24%). There were abnormal findings in 84.3% of the cases subjected to cranial magnetic resonance imaging (MRI), with the most common being hyperintensity in the bilateral basal ganglia (49.0%). CONCLUSIONS Anamnesis, physical examination, and simple laboratory data could provide some important clues in assessing MDD. Blood gas should definitely be measured in cases with respiratory symptoms, particularly if they have a history of consanguineous marriage or a sibling suffering from a similar disease. If metabolic acidosis exists in the blood gas, MDDs should absolutely be included in the differential diagnosis. Furthermore, ophthalmic and cardiac assessment and cranial MRI will also reveal significant data for diagnosing MDDs.
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Are heterozygous carriers for hereditary fructose intolerance predisposed to metabolic disturbances when exposed to fructose?
Debray, FG, Damjanovic, K, Rosset, R, Mittaz-Crettol, L, Roux, C, Braissant, O, Barbey, F, Bonafé, L, De Bandt, JP, Tappy, L, et al
The American journal of clinical nutrition. 2018;(2):292-299
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Abstract
BACKGROUND High fructose intake causes hepatic insulin resistance and increases postprandial blood glucose, lactate, triglyceride, and uric acid concentrations. Uric acid may contribute to insulin resistance and dyslipidemia in the general population. In patients with hereditary fructose intolerance, fructose consumption is associated with acute hypoglycemia, renal tubular acidosis, and hyperuricemia. OBJECTIVE We investigated whether asymptomatic carriers for hereditary fructose intolerance (HFI) would have a higher sensitivity to adverse effects of fructose than would the general population. DESIGN Eight subjects heterozygous for HFI (hHFI; 4 men, 4 women) and 8 control subjects received a low-fructose diet for 7 d and on the eighth day ingested a test meal, calculated to provide 25% of the basal energy requirement, containing 13C-labeled fructose (0.35 g/kg), glucose (0.35 g/kg), protein (0.21 g/kg), and lipid (0.22 g/kg). Glucose rate of appearance (GRa, calculated with [6,6-2H2]glucose), fructose, net carbohydrate, and lipid oxidation, and plasma triglyceride, uric acid, and lactate concentrations were monitored over 6 h postprandially. RESULTS Postprandial GRa, fructose, net carbohydrate, and lipid oxidation, and plasma lactate and triglyceride concentrations were not significantly different between the 2 groups. Postprandial plasma uric acid increased by 7.2% compared with fasting values in hHFI subjects (P < 0.01), but not in control subjects (-1.1%, ns). CONCLUSIONS Heterozygous carriers of hereditary fructose intolerance had no significant alteration of postprandial fructose metabolism compared with control subjects. They did, however, show a postprandial increase in plasma uric acid concentration that was not observed in control subjects in responses to ingestion of a modest amount of fructose. This trial was registered at the US Clinical Trials Registry as NCT02979106.
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One-year outcomes of an intense workplace cardio-metabolic risk reduction program among high-risk employees: The My Unlimited Potential.
Rouseff, M, Aneni, EC, Guzman, H, Das, S, Brown, D, Osondu, CU, Spatz, E, Shaffer, B, Santiago-Charles, J, Ochoa, T, et al
Obesity (Silver Spring, Md.). 2016;(1):71-8
Abstract
OBJECTIVE This study details 6- and 12-month cardio-metabolic outcomes of an intense 12-week workplace lifestyle intervention program, the My Unlimited Potential (MyUP), conducted in a large healthcare organization. METHODS This study was conducted among 230 employees of Baptist Health South Florida with high cardiovascular disease (CVD) risk. Employees were considered at high risk and eligible for the study if they had two or more of the following cardio-metabolic risk factors: total cholesterol ≥ 200 mg/dl, systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg, hemoglobin A1C (HbA1c) ≥ 6.5%, body mass index (BMI) ≥ 30 kg/m(2) . RESULTS At the end of 12 weeks, there was significant reduction in the mean BMI, SBP and DBP, serum lipids, and HbA1c among persons with diabetes. At 1 year, there was significant decline in the mean BMI, SBP and DBP, HbA1c, and high-sensitivity C-reactive protein, and in the prevalence of poor BP control, BMI ≥ 35 kg/m(2) , and abnormal HbA1c among all persons and those with diabetes. CONCLUSIONS This intensive 12-week lifestyle change program was successful at improving cardio-metabolic risk factors at 1 year. This study provides a template for other workplace programs aimed at improving CVD risk in high-risk employees.
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Effects of rapid or slow weight loss on body composition and metabolic risk factors in obese postmenopausal women. A pilot study.
Sénéchal, M, Arguin, H, Bouchard, DR, Carpentier, AC, Ardilouze, JL, Dionne, IJ, Brochu, M
Appetite. 2012;(3):831-4
Abstract
To compare the effect of rapid or slow weight loss (WL) on body composition and metabolic risk factors following a caloric restriction. Ten obese, postmenopausal women were matched for total body WL. Dependent variables were: body composition, lipid profile and blood pressure. Both groups decreased obesity measures (all P≤0.05) while lean body mass decreased in the rapid WL group (P≤0.05). Significant improvements in fasting triglyceride level and diastolic blood pressure were observed only in the slow WL group. A slower WL seems to be more beneficial to improve body composition as well as metabolic risk factors in postmenopausal women.
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Beneficial effect of the insulin sensitizer (HSP inducer) BGP-15 on olanzapine-induced metabolic disorders.
Literáti-Nagy, B, Péterfai, E, Kulcsár, E, Literáti-Nagy, Z, Buday, B, Tory, K, Mandl, J, Sümegi, B, Fleming, A, Roth, J, et al
Brain research bulletin. 2010;(6):340-4
Abstract
Olanzapine is a widely used atypical antipsychotic, with well known metabolic side effects such as weight gain, insulin resistance and blood glucose abnormalities. It has been previously shown in a phase II clinical trial that BGP-15, an amidoxim derivative has insulin-sensitizing effects. The aim of this study was to investigate the efficacy of BGP-15 for the treatment of olanzapine-induced metabolic side effects, in healthy volunteers. Thirty-seven (37) subjects (ages 18-55 years) with normal glucose metabolism were randomly assigned to 17 days of once-daily treatment with 400mg of BGP-15 or placebo and 5mg of olanzapine for 3 days followed by 10mg for 14 days. Total body and muscle tissue glucose utilization was determined by hyperinsulinemic-euglycemic clamp technique. As expected the 17-day olanzapine treatment provoked insulin resistance and body weight gain (p<0.05) in both groups. Administration of BGP-15 significantly reduced olanzapine-induced insulin resistance. The protective effect of BGP-15 on insulin stimulated glucose utilization had the highest magnitude in the values calculated for the muscle tissue (p=0.002). In healthy individuals BGP-15 was safe and well tolerated during the whole study period. It is suggested that BGP-15 can be a successful insulin sensitizer agent to prevent side effects of olanzapine treatment.
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Verapamil SR and trandolapril combination therapy is safe and effective in hypertensive patients with metabolic disorders.
Aksöyek, S, Ozer, N, Aytemir, K, Kes, S, ,
International journal of clinical practice. 2001;(1):5-9
Abstract
Verapamil SR (180 mg) plus trandolapril (2 mg) is a potent antihypertensive combination but the efficacy and safety of this treatment has not been studied fully in hypertensive patients with metabolic disorders. We enrolled 298 patients with mild to moderate hypertension who had at least one of the following disorders: diabetes mellitus, hypercholesterolaemia or mild renal failure. The sitting systolic pressure and diastolic blood pressures were significantly decreased after 12 weeks of treatment. Blood pressure was inadequately controlled in only 24 patients (8.8%). Progressive decreases in blood glucose, total cholesterol, low-density lipoprotein and triglyceride levels were observed during the study. There was no significant change in blood urea nitrogen, creatinine and transaminase levels (p > 0.05). There was a significant decrease in microalbuminuria levels. There was no significant change in glycosylated haemoglobin levels in diabetic patients. Verapamil SR plus trandolapril is an effective drug combination in the treatment of hypertension. It may be used safely in patients with diabetes mellitus, hyperlipidaemia and mild renal failure.