Mitochondrial dysfunction as a central event for mechanisms underlying insulin resistance: the roles of long chain fatty acids

Abstract

Insulin resistance is characterized by hyperglycaemia, dyslipidaemia and oxidative stress prior to the development of type 2 diabetes mellitus. To date, a number of mechanisms have been proposed to link these syndromes together, but it remains unclear what the unifying condition that triggered these events in the progression of this metabolic disease. There have been a steady accumulation of data in numerous experimental studies showing the strong correlations between mitochondrial dysfunction, oxidative stress and insulin resistance. In addition, a growing number of studies suggest that the raised plasma free fatty acid level induced insulin resistance with the significant alteration of oxidative metabolism in various target tissues such as skeletal muscle, liver and adipose tissue. In this review, we herein propose the idea of long chain fatty acid-induced mitochondrial dysfunctions as one of the key events in the pathophysiological development of insulin resistance and type 2 diabetes. The accumulation of reactive oxygen species, lipotoxicity, inflammation-induced endoplasmic reticulum stress and alterations of mitochondrial gene subset expressions are the most detrimental that lead to the developments of aberrant intracellular insulin signalling activity in a number of peripheral tissues, thereby leading to insulin resistance and type 2 diabetes.

Celastrol: A Spectrum of Treatment Opportunities in Chronic Diseases

“…The exact mechanism underlying type 2 diabetes is still unclear despite the implication of processes such as mitochondrial dysfunction and inflammation (174). In an in vitro model of insulin resistance on 3T3-L1 adipocytes with mitochondrial dysfunction, it has been revealed that celastrol markedly improves metabolic functions with a reduction in ROS production and an increase in mitochondrial membrane potential via NF-kB pathway inhibition (1).…”

Liver biopsy in type 2 diabetes mellitus: Steatohepatitis represents the sole feature of liver damage

“…Liver steatosis is frequently reported in patients affect by obesity or type 2 diabetes mellitus (T2DM) [3]. The main pathophysiological mechanisms underlying liver steatosis are, at intracellular level, mitochondrial alterations that are also involved in insulin resistance (IR) [4]. These alterations represent the pathophysiological link to the clinical manifestations (hypertension and dyslipidemia) of metabolic syndrome (MS) [5].…”

Viability of primary cultured podocytes is associated with extracellular high glucose-dependent autophagy downregulation

“…Insulin resistance is characterized by a suppressed insulin-stimulated glucose uptake by the cells, resulting from the impairment of intracellular insulin signaling pathways and disability to increase the amount of glucose transporters (GLUTs) in the cell membrane [6]. Defective insulin responsiveness occurs as a consequence of genetic susceptibility and effects of extracellular agents [7], among which the excess of free fatty acids, chronic hyperglycemia and hyperinsulinemia are currently of particular research interest [8, 9]. …”