Metabolic and Energy Imbalance in Dysglycemia-Based Chronic Disease

Kalra, Sanjay; Unnikrishnan, Ambika Gopalakrishnan; Baruah, Manash P; Sahay, Rakesh; Bantwal, Ganapathi

doi:10.2147/dmso.s286888

Cited by 20 publications

(24 citation statements)

References 172 publications

(88 reference statements)

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“…It has been reported that both acute and chronic disorders can cause or exacerbate undernutrition [ 4 ]. One of the factors contributing to the development of hypertension and dyslipidemia is excessive energy intake [ 45 ]. Therefore, these were negatively related to undernutrition.…”

Section: Discussionmentioning

confidence: 99%

Eating Slowly Is Associated with Undernutrition among Community-Dwelling Adult Men and Older Adult Women

Nakamura

Takashima

et al. 2021

Nutrients

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The double burden of malnutrition refers to the co-occurrence of overweight and obesity and undernutrition. Eating quickly has been linked to overweight and obesity. However, no study has examined the association between eating speed and undernutrition. This retrospective, cross-sectional study analyzed data from 3529 community-dwelling residents. Eating speed was divided into three categories: fast, medium, and slow. Undernutrition was defined as body mass index (BMI) of <18.5 kg/m2 in adults aged < 70 years (adults) and as <20 kg/m2 in adults aged ≥ 70 years (older adults), in accordance with the Global Leadership Initiative on Malnutrition criteria for Asians. Multivariable logistic regression analysis was used to examine the association between eating speed and undernutrition. Among adult men, compared with eating quickly, eating slowly was associated with elevated prevalence of undernutrition (odds ratio (OR) 9.68, 95% confidence interval (CI) 2.32–40.51, p = 0.001). Among older adult women, the prevalence of undernutrition in the slow-eating group was higher than that in the fast-eating group (OR 3.82, 95% Cl 1.51–9.69, p = 0.005). Eating slowly is independently associated with the prevalence of undernutrition among community-dwelling adult men and older adult women in Japan.

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Section: Discussionmentioning

confidence: 99%

Eating Slowly Is Associated with Undernutrition among Community-Dwelling Adult Men and Older Adult Women

Nakamura

Takashima

et al. 2021

Nutrients

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“…The underpinnings of metabolic inflexibility manifesting as reduced skeletal muscle glucose disposal rate, impaired suppression of hepatic gluconeogenesis, and adipose tissue lipolysis due to insulin resistance and the beginning of a slightly compromised pancreatic beta-cell reserve were seen in the population in this study. 3 A consequence of insulin resistance is also upregulation of the pro-hypertensive pathways. Consistent with the mechanism of action of TRC150094, a first-in-class mitochondrial modulator, showed an improvement in insulin resistance and associated reduction in fasting and post-prandial glucose, atherogenic lipid fractions, and blood pressure in subjects treated for 24 weeks.…”

Section: Discussionmentioning

confidence: 99%

“… 2 Further, evidence suggests that the derangement of metabolic flexibility, ie, inability to respond/adapt to conditional changes in metabolic demand is a common thread linking IR to metabolic drivers of CMBCD. 3 …”

Section: Introductionmentioning

confidence: 99%

TRC150094, a Novel Mitochondrial Modulator, Reduces Cardio-Metabolic Risk as an Add-On Treatment: a Phase-2, 24-Week, Multi-Center, Randomized, Double-Blind, Clinical Trial

Joshi¹,

Gj²,

Ghosh³

et al. 2022

DMSO

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Background TRC150094, a novel mitochondrial modulator, reduces insulin resistance and is expected to improve the trinity of dysglycemia, dyslipidemia, and hypertension. In this multi-dose phase-2 study, we evaluated the safety and efficacy of TRC150094 in diabetic subjects with dyslipidemia receiving standard of care. Methods A randomized, multicenter, double-blind, placebo-controlled, parallel-group, Phase 2 study was conducted in 225 subjects from July 2013 to August 2015. The key inclusion criteria were body mass index of 23–35 kg/m 2 , age between 30 and 65 years, fasting glucose of ≥126 or glycated hemoglobin (HbA1c) of ≥6.4% stabilized on treatment with ≤2 oral hypoglycemic agents, apolipoprotein-B (apo-B) ≥100 mg/dL, serum triglyceride (TG) ≥150 mg/dL, systolic blood pressure (SBP) ≥130 mmHg, and diastolic blood pressure (DBP) ≥85 mmHg with/without antihypertensive treatment. The subjects were randomly assigned to one of three TRC150094 doses (25, 50, or 75 mg) or placebo for 24 weeks. The outcomes assessed included fasting plasma glucose (FPG), insulin, mean arterial blood pressure (MAP), and apoB. In addition, safety and tolerability were assessed. Results A reduction for dose up to 50 mg was noted for FPG in the range of 13.9 to 21.7 mg/dL (p < 0.05 for TRC150094 25 and 50 mg), fasting insulin reduction in the range 2.7 to 6.0 mU/L (all doses, p > 0.05), and improved HOMA-IR (−2.0 to −2.5) (all doses, p > 0.05) compared to placebo after 24 weeks of treatment. Furthermore, a significant reduction in MAP in the range 3.1 to 4.2 mmHg (p < 0.05 for TRC150094 25 and 75 mg) was noted. In addition, TRC150094 treatment was weight neutral, had a favorable effect on lowering atherogenic lipid fractions, including non-HDL cholesterol (−6.8 mg/dL at 50 mg dose). Adverse events were mild to moderate in nature and not dose-related. One adverse event not related to treatment led to the discontinuation of the study. Overall, TRC150094 was safe and well tolerated for up to 24 weeks. Conclusion In this study, TRC150094 treatment in the dose range of 25 to 50 mg showed improvement in various components of CMBCD, ie, dysglycemia, dyslipidemia, and hypertension. Trial Registration This study was registered in the Clinical Trial Registry of India. Trial registration number: CTRI/2013/03/003444. Date of registration: 4th March 2013.

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“…The CMBCD model positions insulin resistance, prediabetes, T2DM, and related complications along a continuous spectrum. Further evidence suggests that the phenomenon of derangement of metabolic flexibility or metabolic inflexibility is a common thread linking insulin resistance to CMBCD, including dysglycemia, hypertension, and/or dyslipidemia, progressing to micro-and macro-vascular complications, such as atherosclerotic vascular disease (Sergi et al, 2019;Kalra et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…A previous study has reported the possible contribution of mitochondrial dysfunction to the pathological state (Camara et al, 2010). Therefore, targeting mitochondria may represent a valuable therapeutic tool for improving insulin resistance and reducing the cardiovascular risk in subjects with T2DM, dyslipidemia, and hypertension (Kalra et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Safety, Tolerability, and Pharmacokinetics of a Novel Mitochondrial Modulator, TRC150094, in Overweight and Obese Subjects: A Randomized Phase-I Clinical Trial

et al. 2021

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TRC150094, a novel mitochondrial modulator, can restore metabolic flexibility by improving insulin resistance in preclinical studies. This study primarily aims to evaluate the safety, tolerability, and pharmacokinetics (PK) of oral TRC150094 after conducting two double-blind, randomized, Phase-I studies, single ascending dose (SAD) and multiple ascending dose (MAD), with n = 46, in overweight/obese adult and elderly subjects. In addition, the effect of TRC150094 on pharmacodynamic (PD) efficacy markers was evaluated. PK assessments, including maximum concentration (Cmax), area under the plasma concentration (AUC), time to Cmax (Tmax), and elimination half-life (t½), were assessed at pre-specified time points. PD assessments included apolipoprotein B (ApoB), triglycerides, hepatic fat by magnetic resonance spectroscopy (MRS) and cardiopulmonary exercise testing (CPET) parameters. TRC150094 was rapidly absorbed, and the AUC of TRC150094 increased in a dose-dependent manner across all doses in non-elderly and elderly cohorts. Cmax was more than the dose-proportional for all doses in all cohorts. Tmax ranged from 0.25 to 4 h, and t½ ranged from 15 to 18 h, making TRC150094 suitable for once-daily dosing. Food did not interfere with the overall absorption of the drug. The metabolites of TRC150094 were glucuronide and sulfate conjugates, and 20% of the drug was excreted unchanged in the urine. TRC150094 at 50 mg showed an improving trend in triglycerides. A significant reduction in Apo B was observed after 50 mg dose (−2.34 vs. 13.24%, p = 0.008), which was, however, not the case after 150 mg (8.78 vs. 13.24%, p = 0.1221). Other parameters such as hepatic fat and insulin sensitivity indices (HOMA-IR, MATSUDA Index derived from OGTT) showed an improving trend for the dose of 50 mg. In terms of safety, all the AEs reported were mild to moderate in severity. None of the adverse events was considered definitely or probably related to treatment, and there were no abnormal laboratory findings. In conclusion, the PK of TRC150094 was linear with no clinically significant food effect. TRC150094 and its metabolites suggest a lesser likelihood of drug-drug interactions. Overall, TRC150094 ensured safety and exhibited suitability for all subjects.Clinical Trial Registration: EUDRA CT: 2009-014941-10 (SAD) and CTR-India registration: CTRI/2009/091/000601 (MAD)

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Metabolic and Energy Imbalance in Dysglycemia-Based Chronic Disease

Cited by 20 publications

References 172 publications

Eating Slowly Is Associated with Undernutrition among Community-Dwelling Adult Men and Older Adult Women

Eating Slowly Is Associated with Undernutrition among Community-Dwelling Adult Men and Older Adult Women

TRC150094, a Novel Mitochondrial Modulator, Reduces Cardio-Metabolic Risk as an Add-On Treatment: a Phase-2, 24-Week, Multi-Center, Randomized, Double-Blind, Clinical Trial

Safety, Tolerability, and Pharmacokinetics of a Novel Mitochondrial Modulator, TRC150094, in Overweight and Obese Subjects: A Randomized Phase-I Clinical Trial

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