Abstract
Cells damaged by mechanical or infectious injury release proinflammatory mitochondrial DNA (mtDNA) fragments into the circulation. We evaluated the relation between plasma levels of mtDNA fragments in obese type 2 diabetes mellitus (T2DM) patients and measures of chronic inflammation and insulin resistance. In 10 obese T2DM patients and 12 healthy control (HC) subjects, we measured levels of plasma cell-free mtDNA with quantitative real-time polymerase chain reaction, and mtDNA damage in skeletal muscle with quantitative alkaline Southern blot. Also, markers of systemic inflammation and oxidative stress in skeletal muscle were measured. Plasma levels of mtDNA fragments, mtDNA damage in skeletal muscle and plasma tumor necrosis factor α levels were greater in obese T2DM patients than HC subjects. Also, the abundance of plasma mtDNA fragments in obese T2DM patients levels positively correlated with insulin resistance. To the best of our knowledge, this is the first published evidence that elevated level of plasma mtDNA fragments is associated with mtDNA damage and oxidative stress in skeletal muscle and correlates with insulin resistance in obese T2DM patients. Plasma mtDNA may be a useful biomarker for predicting and monitoring insulin resistance in obese patients.
Highlights
Insulin resistance in obese patients and the associated disease cluster of type 2 diabetes mellitus (T2DM), hyperlipidemia, and hypertension are major global health problems
In support of the concept that oxidative mitochondrial DNA (mtDNA) damage contributes to T2DM, we previously showed that damage to mtDNA increases mitochondrial oxidative stress and insulin resistance in skeletal muscle cell [10,11]
Plasma levels of the Cox1, NADH dehydrogenase subunit 4 (ND4), and displacement loop (D-loop) fragments from mtDNA regions were significantly greater in obese T2DM patients compared to healthy control (HC) subjects (Table 3)
Summary
Insulin resistance in obese patients and the associated disease cluster of type 2 diabetes mellitus (T2DM), hyperlipidemia, and hypertension are major global health problems. Obesity is associated with chronic, low-grade inflammation, known as metabolic inflammation or metaflammation [1], which is considered a pivotal point in the initiation and progression of insulin resistance and T2DM. Mitochondrial dysfunction induced by oxidative stress contributes to obesity-related insulin resistance [2,3,4], but the relationship between mitochondrial dysfunction and the pathogenesis of insulin resistance is unknown. Damage to mitochondrial DNA (mtDNA) may disrupt transcription of proteins encoded by mtDNA that are essential for energy metabolism, initiate apoptotic cell death, and alter mitochondrial redox signaling. Circulating mitochondrial DNA in diabetes and obesity and analysis, decision to publish, or preparation of the manuscript
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