Role of mitochondrial dysfunction in insulin resistance

Abstract

Insulin resistance is characteristic of obesity, type 2 diabetes, and components of the cardiometabolic syndrome, including hypertension and dyslipidemia, that collectively contribute to a substantial risk for cardiovascular disease. Metabolic actions of insulin in classic insulin target tissues (eg, skeletal muscle, fat, and liver), as well as actions in nonclassic targets (eg, cardiovascular tissue), help to explain why insulin resistance and metabolic dysregulation are central in the pathogenesis of the cardiometabolic syndrome and cardiovascular disease. Glucose and lipid metabolism are largely dependent on mitochondria to generate energy in cells. Thereby, when nutrient oxidation is inefficient, the ratio of ATP production/oxygen consumption is low, leading to an increased production of superoxide anions. Reactive oxygen species formation may have maladaptive consequences that increase the rate of mutagenesis and stimulate proinflammatory processes. In addition to reactive oxygen species formation, genetic factors, aging, and reduced mitochondrial biogenesis all contribute to mitochondrial dysfunction. These factors also contribute to insulin resistance in classic and nonclassic insulin target tissues. Insulin resistance emanating from mitochondrial dysfunction may contribute to metabolic and cardiovascular abnormalities and subsequent increases in cardiovascular disease. Furthermore, interventions that improve mitochondrial function also improve insulin resistance. Collectively, these observations suggest that mitochondrial dysfunction may be a central cause of insulin resistance and associated complications. In this review, we discuss mechanisms of mitochondrial dysfunction related to the pathophysiology of insulin resistance in classic insulin-responsive tissue, as well as cardiovascular tissue.

Figure 1

Mitochondrial abnormality in the liver of transgenic Ren2 male rat at 12 weeks of age. A, The normal hepatic mitochondrial morphology in the Sprague–Dawley control male rat model at 12 weeks of age. B, Mitochondrial abnormality in morphology in the 12-week-old transgenic Ren2 male rat model of hypertension and insulin resistance. Note the swollen and decreased matrix density by transmission electronic microscopy. Magnification, ×25 000.

Figure 2

Mitochondrial biogenesis in the transgenic Ren2 male rat at 10 weeks of age. A, The longitudinal normal myocardial mitochondrial morphology in the Sprague–Dawley control male rat model at 10 weeks of age. Note the orderly and linearly arranged sarcomeres (closed arrows) and subsarcolemmal (sarcoplasmic reticulum) mitochondria (open arrows). Normal intercalated disc (arrowheads). Magnification, ×10 000. Bar=500 nm. B, Mitochondrial biogenesis in the 10-week-old transgenic Ren2 untreated control (Ren2C) rats, which display insulin resistance and abnormalities in both systolic and diastolic cardiac functions. Note the biogenesis of increased myocardial interdigitating mitochondria. Also note the loss of the orderly and linearly arranged sarcomeres. Magnification, ×10 000. Bar=500 nm.

Figure 3

Mitochondrial respiratory chain and nutrient metabolism. Reducing agents (NADH or FADH₂) are generated from glycolysis and Krebs cycle of glucose metabolism and β-oxidation of fatty acids. While NADH or FADH₂ are oxidized to NAD⁺ or FAD, the electrons are carried to complex I (NADH–ubiquinone reductase), complex II (succinated ubiquinone reductase), complex III (ubiquinone–cytochrome c reductase), complex IV (cytochrome oxidase), and finally to O₂, which produces H₂O. Oxidation of NADH or FADH2 generates protons that are pumped to intermembrane space through complex I, III, and IV. The pumped protons increase electrochemical gradient across the membrane. This proton gradient is the driving force for F0F1-ATPase (ATP synthase) to produce ATP, which is used as an energy source in the body. On the other hand, the pumped protons can be leaked to matrix of mitochondria by UCP, which reduces proton gradient and in turn generates heat. Producing ATP or heat is controlled by energy needs in the body. ANT indicates adenine nucleotide translocator.

Figure 4

Mechanism of mitochondrial dysfunction. Excess intake of nutrients, including overloaded FFAs or hyperglycemia conditions, increases ROS production and reduces mitochondrial biogenesis, causing mitochondrial dysfunction. Mitochondrial dysfunction leads to decreased β-oxidation and ATP production and increased ROS production, resulting in insulin resistance, diabetes, and cardiovascular disease.

Figure 5

Insulin signaling pathway. The metabolic PI3K branch of insulin signaling pathway and tissue-specific actions of insulin are shown. PI3K branch of insulin signaling pathway plays a major role in gluconeogenesis in the liver, enhances NO production in the endothelium and heart, and glucose uptake in skeletal muscle, adipose tissue, and heart.

Figure 6

Proposed molecular mechanism for insulin resistance caused by mitochondrial dysfunction. FFAs activate inflammatory signaling and reduce ATP production that contributes to mitochondrial dysfunction and accumulation of LCFA-CoA and DG. Accumulation of lipid metabolite activates PKCs (β, δ, and θ). ROS produced by NADPH oxidase by angiotensin II causes mitochondrial dysfunction. Conversely, mitochondrial dysfunction increases ROS production, which causes activation of serine/threonine kinases, including IKKβ, JNK, and PKCs, which increases serine phosphorylation of IRS proteins and subsequently results in insulin resistance. Increased serine phosphorylation of IRS-1/2 leads to decreased activity of insulin downstream signaling pathways, including PI3K, Akt, and PKCζ, which culminates in decreased glucose uptake, increased glucose production, and reduced vasodilation and insulin secretion. The reduced insulin responsiveness (insulin resistance) causes diabetes and cardiovascular diseases. PDK-1 indicates 3′-phosphoinositide-dependent protein kinase 1.

Figure 7

Improvement of mitochondrial function by pharmacological intervention, exercise, and calorie restriction can improve insulin sensitivity, which leads to normal metabolism and cardiovascular function.