Himalaya Livline | Vol 6 | No. 5 | Sep–Dec 2023 | 3 Summary • The linear link between metabolic syndrome and hepatic steatosis, fibrosis, and cirrhosis suggests a close connection between glycemic levels and NAFLD. • NAFLD elicits a cascade of events that involves impairment of insulin sensitivity and glucose homeostasis and elevation in the levels of liver enzymes. • The pathogenesis of fatty liver can be triggered by increased levels of free fatty acids, de novo lipogenesis, decreased free fatty acid oxidation, and hepatic triglyceride secretion. • Hyperinsulinemia, a response to systemic IR by the body, leads to an increase in hepatic de novo lipogenesis. • Lipotoxicity impairs insulin signaling, induces oxidative damage, and promotes inflammation and fibrosis. The following are a few ways the pathogenesis of NAFLD is associated with elevated levels of HbA1c: Glucose permeability HbA1c is influenced by the lifespan and glucose permeability of erythrocytes. Thus, transmembrane glucose gradient (rather than the rate of glucose transport) correlates with the HbA1c level. Therefore, elevated HbA1c level in NAFLD can be related to the increased intracellular glucose levels in patients with NAFLD.2 Hyperglycemic episodes HbA1c is generally produced in direct proportions to the duration and episodes of high blood glucose concentrations. Hyperglycemic episodes, in addition to the production of advanced glycation end products such as HbA1c, also affect lipid metabolism and result in increased synthesis of triacylglycerols (TAGs). These TAGs tend to deposit in various tissues of the body, including the liver. TAG deposition in the liver parenchyma leads to fatty liver. Thus, HbA1c can be strongly linked to fat deposition in the liver and can be considered a causative factor of NAFLD.5 Oxidative stress The erythrocyte fragility that influences the lifespan of erythrocytes is positively correlated with elevated HbA1c levels. Immoderate hemolysis enhances oxidative stress. In response to oxidative stress, changes in erythrocyte morphology and reduction in membrane fluidity can occur, which can be easily captured by the liver macrophages.2 It is well-understood that overeating and consumption of energy-dense, nutritionally imbalanced, and appetite-dysregulating foods; stress; and sleep deprivation are the leading causes of metabolic derangement and IR. These perturbations eventually trigger the pathogenic spectrum of NAFLD. Lifestyle interventions such as caloric restrictions and consumption of a balanced diet, regular physical activity, and maintaining a healthy weight are proven beneficial in alleviating hepatic steatosis and liver fibrosis in patients with NAFLD.6 References 1. Chen C, et al. Biosci Rep. 2020; 40(1):BSR20193996. 2. Ma H, et al. BMC Gastroenterol. 2013;13:3. 3. Zupo R, et al. J Clin Med. 2021;10(8):1695. 4. Chen Z, et al. Lipids Health Dis. 2017;16:203. 5. Masroor M, Haque Z. J Clin Transl Hepatol. 2021;9(1):15–21. 6. Chao HW, et al. Int J Mol Sci. 2019;20(2):298. A recent study confirms that diabetic, nondiabetic, obese, and lean individuals with glycated hemoglobin > 5.7% are 4 times more prone to developing fatty liver disease.5 Insulin Resistance and Glycated Hemoglobin
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