Author: Graf, Anastasia V ; I. Bunik, Victoria ; Ksenofontov, Alexander L ; Graf, Anastasia V. ; Artiukhov, Artem V. ; Artiukhov, Artem V ; Ksenofontov, Alexander L. ; Solovjeva, Olga N. ; I Bunik, Victoria ; Solovjeva, Olga N

The risk of developing diabetes and cardiometabolic disorders is associated with increased levels of alpha-aminoadipic acid and disturbances in the metabolism of branched-chain amino acids. The side effects of the widely used antidiabetic drug metformin include impaired degradation of branched-chain amino acids and inhibition of intracellular thiamin transport. These effects may be interconnected, as thiamine deficiency impairs the functioning of thiamine diphosphate (ThDP)-dependent dehydrogenases of 2-oxo acids involved in amino acids degradation, while diabetes is often associated with perturbed thiamine status. In this work, we investigate the action of metformin in rats with impaired thiamine availability. The reduction in the thiamine influx is induced by simultaneous administration of the thiamine transporters inhibitors metformin and amprolium. After 24 days of combined metformin/amprolium administration, no significant changes in the total brain levels of ThDP or activities of ThDP-dependent enzymes of central metabolism are observed, but the affinities of transketolase and 2-oxoglutarate dehydrogenase to ThDP increase. The treatment also significantly elevates the brain levels of free amino acids and ammonia, reduces the antioxidant defense, and alters the sympathetic/parasympathetic regulation, which is evident from changes in the ECG and behavioral parameters. Strong positive correlations between brain ThDP levels and contents of ammonia, glutathione disulfide, alpha-aminoadipate, glycine, citrulline, and ethanolamine are observed in the metformin/amprolium-treated rats, but not in the control animals. Analysis of the obtained data points to a switch in the metabolic impact of ThDP from the antioxidant and nitrogen-sparing in the control rats to the pro-oxidant and hyperammonemic in the metformin/amprolium-treated rats. As a result, metformin administration along with the amprolium-reduced thiamine supply significantly perturb the metabolism of amino acids in the rat brain, altering behavioral and ECG parameters.

01 Jan 2023·Frontiers in endocrinology

Association of alpha-aminoadipic acid with cardiometabolic risk factors in healthy and high-risk individuals.

Article

Author: Calcutt, M Wade ; Gabriel, Curtis L ; Desine, Stacy ; Wang, Chuan ; Carr, John Jeffrey ; Linton, MacRae F ; Smith, Holly M ; Antonetti, Olivia R ; Doran, Amanda C ; Koethe, John R ; Ferguson, Jane F ; Silver, Heidi J ; Brown, Jonathan D ; Terry, James G ; Nair, Sangeeta

IntroductionPlasma levels of the metabolite alpha-aminoadipic acid (2-AAA) have been associated with risk of type 2 diabetes (T2D) and atherosclerosis. However, little is known about the relationship of 2-AAA to other cardiometabolic risk markers in pre-disease states, or in the setting of comorbid disease.MethodsWe measured circulating 2-AAA using two methods in 1) a sample of 261 healthy individuals (2-AAA Study), and 2) in a sample of 134 persons comprising 110 individuals with treated HIV, with or without T2D, a population at high risk of metabolic disease and cardiovascular events despite suppression of circulating virus, and 24 individuals with T2D without HIV (HATIM Study). We examined associations between plasma 2-AAA and markers of cardiometabolic health within each cohort.Results and discussionWe observed differences in 2-AAA by sex and race in both cohorts, with higher levels observed in men compared with women, and in Asian compared with Black or white individuals (P<0.05). There was no significant difference in 2-AAA by HIV status within individuals with T2D in the HATIM Study. We confirmed associations between 2-AAA and dyslipidemia in both cohorts, where high 2-AAA associated with low HDL cholesterol (P<0.001) and high triglycerides (P<0.05). As expected, within the cohort of people with HIV, 2-AAA was higher in the setting of T2D compared to pre-diabetes or normoglycemia (P<0.001). 2-AAA was positively associated with body mass index (BMI) in the 2-AAA Study, and with waist circumference and measures of visceral fat volume in HATIM (all P<0.05). Further, 2-AAA associated with increased liver fat in persons with HIV (P<0.001). Our study confirms 2-AAA as a marker of cardiometabolic risk in both healthy individuals and those at high cardiometabolic risk, reveals relationships with adiposity and hepatic steatosis, and highlights important differences by sex and race. Further studies are warranted to establish molecular mechanisms linking 2-AAA to disease in other high-risk populations.

01 Dec 2016·Nutrition & MetabolismQ3 · MEDICINE

Serum metabolic biomarkers distinguish metabolically healthy peripherally obese from unhealthy centrally obese individuals

Q3 · MEDICINE

ArticleOA

Author: Gao, Xiang ; Wang, Yongbo ; Randell, Edward ; Sun, Guang ; Gulliver, Wayne ; Cahill, Farrell ; Pedram, Pardis ; Zhai, Guangju ; Zhang, Weidong

BACKGROUNDMetabolic abnormalities are more associated with central obesity than peripheral obesity, but the underlying mechanisms are largely unknown. The present study was to identify serum metabolic biomarkers which distinguish metabolically unhealthy centrally obese (MUCO) from metabolically healthy peripherally obese (MHPO) individuals.METHODSA two-stage case-control study design was employed. In the discovery stage, 20 individuals (10 MHPO and 10 MUCO) were included and in the following validation stage, 79 individuals (20 normal weight (NW), 30 MHPO, 29 MUCO) were utilized. Study groups were matched for age, sex, physical activity and total dietary calorie intake with MHPO and MUCO additionally matched for BMI. Metabolic abnormality was defined as: 1) HOMA-IR > 4.27 (90(th) percentile), 2) high-density lipoprotein cholesterol < 1.03 mmol/L in men and < 1.30 mmol/L in women, 3) fasting blood glucose ≥ 5.6 mmol/L, and 4) waist circumference > 102 cm in men and > 88 cm in women. MUCO individuals had all of these abnormalities whereas MHPO and NW individuals had none of them. A targeted metabolomics approach was performed on fasting serum samples, which can simultaneously identify and quantify 186 metabolites.RESULTSIn the discovery stage, serum leucine, isoleucine, tyrosine, valine, phenylalanine, alpha-aminoadipic acid, methioninesulfoxide and propionylcarnitine were found to be significantly higher in MUCO, compared with MHPO group after multiple testing adjustment. Significant changes of five metabolites (leucine, isoleucine, valine, alpha-aminoadipic acid, propionylcarnitine) were confirmed in the validation stage.CONCLUSIONSSignificantly higher levels of serum leucine, isoleucine, valine, alpha-aminoadipic acid, propionylcarnitine are characteristic of metabolically unhealthy centrally obese patients. The finding provides novel insights into the pathogenesis of metabolic abnormalities in obesity.

100 Deals associated with Alpha-tocopheroloxyacetic acid (Veana Therapeutics)

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Phase 1	US	Veana Therapeutics, Inc.	07 Apr 2020
Carcinoma	Phase 1	US	Providence Health & Services	-
Lymphoma	Phase 1	US	Veana Therapeutics, Inc.	-
Lymphoma	Phase 1	US	Providence Health & Services	-
Sarcoma	Phase 1	US	Veana Therapeutics, Inc.	-
Sarcoma	Phase 1	US	Providence Health & Services	-
Carcinoma	Discovery	US	Veana Therapeutics, Inc.	-

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