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Interventions in Obesity & Diabetes

Revisiting Caloric Restriction as Therapeutic Strategy for Metabolic Syndrome, T2DM and Obesity

  • Open or Close Vinod Nikhra*

    Department of Medicine, India

    *Corresponding author: Vinod Nikhra, Chief Medical Officer and Consultant, Department of Medicine, New Delhi, India

Submission: August 20, 2018; Published: November 21, 2018

DOI: 10.31031/IOD.2018.02.000538

ISSN : 2578-0263
Volume2 Issue3


Overnutrition and adiposity: Overnutrition contributes to chronic energy surplus leading to adiposity, insulin resistance (IR), metabolic syndrome (MetS) and obesity with its fallouts including increased oxidative stress, altered glucose, fat and protein metabolism, and altered skeletal muscle mitochondrial function.

Redox balance and thioredoxin system: The cellular redox balance is regulated by activity of several antioxidant systems including thioredoxin (TXN) system. Thioredoxin interacting protein (TXNIP) modulating the activity of TXN, is a key player in regulation of glucose homeostasis and lipid metabolism. The overexpression of TXNIP in T2DM, MetS and obese subjects is associated with metabolic abnormalities including apoptosis of β-cells, decreased insulin sensitivity and energy expenditure. The reduced oxidative capacity of skeletal muscle leads to accumulation of intramyocellular triglyceride (IMTG) and affects mitochondrial function. TXNIP influences metabolic regulation mainly through insulin release from β-cells, glucose production from liver and glucose uptake in peripheral tissues. In addition, it acts as a nutrient sensor in discrete regions of brain.

Effects of CR on metabolic homeostasis: Caloric restriction (CR) is a potentially effective therapeutic strategy to improve adiposity and insulin sensitivity and action at tissue level. CR associated weight loss decreases IMTG and improves mitochondrial function in skeletal myocytes. The decrease in adipose mass, oxidative stress and inflammation lead to downregulation of TXNIP, eliminating its inhibitory effect on glycolysis, glucose transporters, insulin receptors and receptor substrate, insulin-stimulated Akt activation and phosphatidylinositol 3-kinase (PI3K).

Conclusion: Novel additives to polypharmacy: To endorse CR is of immense value, as it consistently leads to improved cardiometabolic outcomes and exerts beneficial effects on every organ system. Yet, CR is difficult to implement in practice for multiple reasons including dietary adherence and perceived decrease in QOL. Still, the focus on CR is important within a specific disease context to clearly delineate underlying mechanisms and exploit the research to achieve therapeutic goals. TXNIP is a potential therapeutic target. Certain anti-diabetic agents like metformin, GLP-1 agonists and CRMs like resveratrol have been shown to inhibit TXNIP expression. Verapamil a calcium channel blocker, tranilast a tryptophan metabolite and allopurinol reduce TXNIP levels in vivo and in vitro studies. Certain calcium channel blockers by lowering TXNIP levels protect β-cells from apoptosis. On a cautious note, the loss of TXNIP may have serious consequences as TXNIP expression is required for maintaining normal fasting glycaemia and TXNIP being a tumour suppressor, its loss is associated with increased incidence of cancer.

Keywords: Caloric restriction; Caloric restriction mimetics; Insulin resistance; Metabolic syndrome; Type 2 diabetes mellitus; Obesity; Redox balance; Thioredoxin (TNX); Thioredoxin interacting protein (TXNIP)

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