scholarly journals Roles of Mitochondrial Sirtuins in Mitochondrial Function, Redox Homeostasis, Insulin Resistance and Type 2 Diabetes

2020 ◽  
Vol 21 (15) ◽  
pp. 5266 ◽  
Author(s):  
Chih-Hao Wang ◽  
Yau-Huei Wei
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Mitochondrial Function ◽  
Oxidative Metabolism ◽  
Antioxidant Defense ◽  
Tricarboxylic Acid Cycle ◽  
Redox Homeostasis ◽  
Metabolic Adaptation ◽  
Pyrimidine Nucleotide

Mitochondria are the metabolic hubs that process a number of reactions including tricarboxylic acid cycle, β-oxidation of fatty acids and part of the urea cycle and pyrimidine nucleotide biosynthesis. Mitochondrial dysfunction impairs redox homeostasis and metabolic adaptation, leading to aging and metabolic disorders like insulin resistance and type 2 diabetes. SIRT3, SIRT4 and SIRT5 belong to the sirtuin family proteins and are located at mitochondria and also known as mitochondrial sirtuins. They catalyze NAD+-dependent deacylation (deacetylation, demalonylation and desuccinylation) and ADP-ribosylation and modulate the function of mitochondrial targets to regulate the metabolic status in mammalian cells. Emerging evidence has revealed that mitochondrial sirtuins coordinate the regulation of gene expression and activities of a wide spectrum of enzymes to orchestrate oxidative metabolism and stress responses. Mitochondrial sirtuins act in synergistic or antagonistic manners to promote respiratory function, antioxidant defense, insulin response and adipogenesis to protect individuals from aging and aging-related metabolic abnormalities. In this review, we focus on the molecular mechanisms by which mitochondrial sirtuins regulate oxidative metabolism and antioxidant defense and discuss the roles of their deficiency in the impairment of mitochondrial function and pathogenesis of insulin resistance and type 2 diabetes.

scholarly journals Mitochondrial Function in Skeletal Muscle Is Normal and Unrelated to Insulin Action in Young Men Born with Low Birth Weight

2008 ◽  
Vol 93 (10) ◽  
pp. 3885-3892 ◽  
Author(s):  
Charlotte Brøns ◽  
Christine B. Jensen ◽  
Heidi Storgaard ◽  
Amra Alibegovic ◽  
Stine Jacobsen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Birth Weight ◽  
Low Birth Weight ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Young Men ◽  
Hepatic Insulin Resistance

Objective: Low birth weight (LBW) is an independent risk factor of insulin resistance and type 2 diabetes. Recent studies suggest that mitochondrial dysfunction and impaired expression of genes involved in oxidative phosphorylation (OXPHOS) may play a key role in the pathogenesis of insulin resistance in aging and type 2 diabetes. The aim of this study was to determine whether LBW in humans is associated with mitochondrial dysfunction in skeletal muscle. Methods: Mitochondrial capacity for ATP synthesis was assessed by 31phosphorus magnetic resonance spectroscopy in forearm and leg muscles in 20 young, lean men with LBW and 26 matched controls. On a separate day, a hyperinsulinemic euglycemic clamp with excision of muscle biopsies and dual-energy x-ray absorptiometry scanning was performed. Muscle gene expression of selected OXPHOS genes was determined by quantitative real-time PCR. Results: The LBW subjects displayed a variety of metabolic and prediabetic abnormalities, including elevated fasting blood glucose and plasma insulin levels, reduced insulin-stimulated glycolytic flux, and hepatic insulin resistance. Nevertheless, in vivo mitochondrial function was normal in LBW subjects, as was the expression of OXPHOS genes. Conclusions: These data support and expand previous findings of abnormal glucose metabolism in young men with LBW. In addition, we found that the young, healthy men with LBW exhibited hepatic insulin resistance. However, the study does not support the hypothesis that muscle mitochondrial dysfunction per se is the underlying key metabolic defect that explains or precedes whole body insulin resistance in LBW subjects at risk for developing type 2 diabetes.

scholarly journals HEPATIC SOD1 GENE EXPRESSION CHANGES IN THE NAFLD PATHOGENESIS IN OBESITY

2021 ◽  
Vol 23 (4) ◽  
pp. 761-766
Author(s):  
A. A. Komar ◽  
D. A. Shunkina (Skuratovsvkaia) ◽  
M. A. Vulf ◽  
H. Q. Vu ◽  
N. M. Todosenko ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Type 2 Diabetes ◽  
Copy Number ◽  
Tricarboxylic Acid Cycle ◽  
Reactive Oxygen ◽  
Metabolic Adaptation ◽  
Control Group ◽  
Obese Patients ◽  
Oxygen Species

Steatosis in the liver in obesity increases the work of mitochondria to utilize excess lipids. An overload of β-oxidation of fatty acids, the tricarboxylic acid cycle, and oxidative phosphorylation leads to a decrease in ATP and an increase in the formation of reactive oxygen species. Normally, mitochondria can efficiently remove elevated levels of reactive oxygen species using the cell's antioxidant system and metabolic adaptation to altered conditions. This study aimed to investigate the role of hepatic SOD expression in the pathogenesis of NAFLD in obesity. It was found that the level of SOD1 expression in the liver in obese patients with and without type 2 diabetes with a BMI > 40 kg/m2 was lower than in healthy donors. The copy number of mitochondrial DNA (mtDNA) in the liver in all obese patients was more than two times lower than in the control group. In the liver of obese patients without type 2 diabetes, the SOD1 protein level and the mtDNA copy number were interrelated and negatively correlated with the area of fatty inclusions. Thus, in obese patients, a decrease in antioxidant defense in the liver leads to the vulnerability of mitochondria, which, in turn, contributes to the progression of steatosis and insulin resistance.

scholarly journals A review of the putative causal mechanisms associated with lower macular pigment in diabetes mellitus

2019 ◽  
Vol 32 (2) ◽  
pp. 247-264 ◽  
Author(s):  
Grainne Scanlon ◽  
James Loughman ◽  
Donal Farrell ◽  
Daniel McCartney
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Redox Homeostasis ◽  
Redox Status ◽  
Macular Pigment ◽  
Healthy Controls ◽  
Retinal Tissue ◽  
Causal Mechanisms

AbstractMacular pigment (MP) confers potent antioxidant and anti-inflammatory effects at the macula, and may therefore protect retinal tissue from the oxidative stress and inflammation associated with ocular disease and ageing. There is a body of evidence implicating oxidative damage and inflammation as underlying pathological processes in diabetic retinopathy. MP has therefore become a focus of research in diabetes, with recent evidence suggesting that individuals with diabetes, particularly type 2 diabetes, have lower MP relative to healthy controls. The present review explores the currently available evidence to illuminate the metabolic perturbations that may possibly be involved in MP’s depletion. Metabolic co-morbidities commonly associated with type 2 diabetes, such as overweight/obesity, dyslipidaemia, hyperglycaemia and insulin resistance, may have related and independent relationships with MP. Increased adiposity and dyslipidaemia may adversely affect MP by compromising the availability, transport and assimilation of these dietary carotenoids in the retina. Furthermore, carotenoid intake may be compromised by the dietary deficiencies characteristic of type 2 diabetes, thereby further compromising redox homeostasis. Candidate causal mechanisms to explain the lower MP levels reported in diabetes include increased oxidative stress, inflammation, hyperglycaemia, insulin resistance, overweight/obesity and dyslipidaemia; factors that may negatively affect redox status, and the availability, transport and stabilisation of carotenoids in the retina. Further study in diabetic populations is warranted to fully elucidate these relationships.

scholarly journals Exercise Induction of Key Transcriptional Regulators of Metabolic Adaptation in Muscle Is Preserved in Type 2 Diabetes

2019 ◽  
Vol 104 (10) ◽  
pp. 4909-4920 ◽  
Author(s):  
Rugivan Sabaratnam ◽  
Andreas J Pedersen ◽  
Tilde V Eskildsen ◽  
Jonas M Kristensen ◽  
Jørgen F P Wojtaszewski ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Transcription Factors ◽  
Acute Exercise ◽  
Transcriptional Regulators ◽  
Metabolic Adaptation ◽  
Response To Exercise ◽  
Adaptation To Exercise

Abstract Context Type 2 diabetes (T2D) is characterized by insulin resistance in skeletal muscle. Regular exercise improves insulin sensitivity, mitochondrial function, and energy metabolism. Thus, an impaired response to exercise may contribute to insulin resistance. Objective We hypothesized that key transcriptional regulators of metabolic adaptation to exercise show an attenuated response in skeletal muscle in T2D. Design and Patients Skeletal muscle biopsies were obtained from 13 patients with T2D and 14 age- and weight-matched controls before, immediately after 1 hour acute exercise (70% maximal pulmonary oxygen uptake), and 3 hours into recovery to examine mRNA expression of key transcription factors and downstream targets and activity of key upstream kinases underlying the metabolic adaptation to exercise. Results Acute exercise increased gene expression of the nuclear hormone receptor 4A (NR4A) subfamily (∼4- to 36-fold) and other key transcription factors, including ATF3, EGR1, JUNB, SIK1, PPARA, and PPARG (∼1.5- to 12-fold), but with no differences between groups. The expression of NR4A1 (approximately eightfold) and NR4A3 (∼75-fold) was further increased 3 hours into recovery, whereas most muscle transcripts sustained elevated or returned to basal levels, again with no differences between groups. Muscle expression of HKII and SLC2A4 and hexokinase II protein content were reduced in patients with T2D. The phosphorylation of p38 MAPK, Erk1/2, Ca2+/calmodulin-dependent kinase II, and cAMP-responsive element-binding protein was equally increased in response to exercise and/or recovery in both groups. Conclusion Acute exercise elicits a pronounced and overall similar increase in expression of key transcription factors and activation of key upstream kinases involved in muscle metabolic adaptation to exercise in patients with T2D and weight-matched controls.

Mitochondrial oxidative function and type 2 diabetes

2006 ◽  
Vol 31 (6) ◽  
pp. 675-683 ◽  
Author(s):  
Rasmus Rabøl ◽  
Robert Boushel ◽  
Flemming Dela
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Electron Transport ◽  
Mitochondrial Function ◽  
Oxidative Enzymes ◽  
Mitochondrial Content ◽  
Atp Production ◽  
Oxidative Function

The cause of insulin resistance and type 2 diabetes is unknown. The major part of insulin-mediated glucose disposal takes place in the skeletal muscle, and increased amounts of intramyocellular lipid has been associated with insulin resistance and linked to decreased activity of mitochondrial oxidative phosphorylation. This review will cover the present knowledge and literature on the topics of the activity of oxidative enzymes and the electron transport chain (ETC) in skeletal muscle of patients with type 2 diabetes. Different methods of studying mitochondrial function are described, including biochemical measurements of oxidative enzyme and electron transport activity, isolation of mitochondria for measurements of respiration, and ATP production and indirect measurements of ATP production using nuclear magnetic resonance (NMR) - spectroscopy. Biochemical markers of mitochondrial content are also discussed. Several studies show reduced activity of oxidative enzymes in skeletal muscle of type 2 diabetics. The reductions are independent of muscle fiber type, and are accompanied by visual evidence of damaged mitochondria. In most studies, the reduced oxidative enzyme activity is explained by decreases in mitochondrial content; thus, evidence of a functional impairment in mitochondria in type 2 diabetes is not convincing. These impairments in oxidative function and mitochondrial morphology could reflect the sedentary lifestyle of the diabetic subjects, and the influence of physical activity on oxidative activity and mitochondrial function is discussed. The studies on insulin-resistant offspring of type 2 diabetic parents have provided important insights in the earliest metabolic defects in type 2 diabetes. These defects include reductions in basal ATP production and an attenuated response to insulin stimulation. The decreased basal ATP production does not affect overall lipid or glucose oxidation, and no studies linking changes in oxidative activity and insulin sensitivity in type 2 diabetes have been published. It is concluded that evidence of a functional impairment in mitochondria in type 2 diabetes is not convincing, and that intervention studies describing the correlation between changes in insulin resistance and mitochondrial function in type 2 diabetes are lacking. Specific effects of regular physical training and muscular work on mitochondrial function and plasticity in type 2 diabetes remain an important area of research.

scholarly journals Sphingolipids as a Culprit of Mitochondrial Dysfunction in Insulin Resistance and Type 2 Diabetes

2021 ◽  
Vol 12 ◽  
Author(s):  
Kamila Roszczyc-Owsiejczuk ◽  
Piotr Zabielski
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Protein Kinase ◽  
Mitochondrial Dysfunction ◽  
Signaling Pathway ◽  
Mitochondrial Function ◽  
Insulin Signaling ◽  
Skeletal Muscles ◽  
Insulin Signaling Pathway

Insulin resistance is defined as a complex pathological condition of abnormal cellular and metabolic response to insulin. Obesity and consumption of high-fat diet lead to ectopic accumulation of bioactive lipids in insulin-sensitive tissues. Intracellular lipid accumulation is regarded as one of the major factors in the induction of insulin resistance and type 2 diabetes (T2D). A significant number of studies have described the involvement of ceramides and other sphingolipids in the inhibition of insulin-signaling pathway in both skeletal muscles and the liver. Adverse effects of sphingolipid accumulation have recently been linked to the activation of protein kinase Cζ (PKCζ) and protein phosphatase 2A (PP2A), which, in turn, negatively affect phosphorylation of serine/threonine kinase Akt [also known as protein kinase B (PKB)], leading to decreased glucose uptake in skeletal muscles as well as increased gluconeogenesis and glycogenolysis in the liver. Sphingolipids, in addition to their direct impact on the insulin signaling pathway, may be responsible for other negative aspects of diabetes, namely mitochondrial dysfunction and deficiency. Mitochondrial health, which is characterized by appropriate mitochondrial quantity, oxidative capacity, controlled oxidative stress, undisturbed respiratory chain function, adenosine triphosphate (ATP) production and mitochondrial proliferation through fission and fusion, is impaired in the skeletal muscles and liver of T2D subjects. Recent findings suggest that impaired mitochondrial function may play a key role in the development of insulin resistance. Mitochondria stay in contact with the endoplasmic reticulum (ER), Golgi membranes and mitochondria-associated membranes (MAM) that are the main places of sphingolipid synthesis. Moreover, mitochondria are capable of synthesizing ceramide though ceramide synthase (CerS) activity. Recently, ceramides have been demonstrated to negatively affect mitochondrial respiratory chain function and fission/fusion activity, which is also a hallmark of T2D. Despite a significant correlation between sphingolipids, mitochondrial dysfunction, insulin resistance and T2D, this subject has not received much attention compared to the direct effect of sphingolipids on the insulin signaling pathway. In this review, we focus on the current state of scientific knowledge regarding the involvement of sphingolipids in the induction of insulin resistance by inhibiting mitochondrial function.

scholarly journals Quantification of Mitochondrial Oxidative Phosphorylation in Metabolic Disease: Application to Type 2 Diabetes

2019 ◽  
Vol 20 (21) ◽  
pp. 5271 ◽  
Author(s):  
Matthew T. Lewis ◽  
Jonathan D. Kasper ◽  
Jason N. Bazil ◽  
Jefferson C. Frisbee ◽  
Robert W. Wiseman
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Oxidative Phosphorylation ◽  
Glucose Uptake ◽  
Mitochondrial Function ◽  
Health Concern ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Increased Risk

Type 2 diabetes (T2D) is a growing health concern with nearly 400 million affected worldwide as of 2014. T2D presents with hyperglycemia and insulin resistance resulting in increased risk for blindness, renal failure, nerve damage, and premature death. Skeletal muscle is a major site for insulin resistance and is responsible for up to 80% of glucose uptake during euglycemic hyperglycemic clamps. Glucose uptake in skeletal muscle is driven by mitochondrial oxidative phosphorylation and for this reason mitochondrial dysfunction has been implicated in T2D. In this review we integrate mitochondrial function with physiologic function to present a broader understanding of mitochondrial functional status in T2D utilizing studies from both human and rodent models. Quantification of mitochondrial function is explained both in vitro and in vivo highlighting the use of proper controls and the complications imposed by obesity and sedentary lifestyle. This review suggests that skeletal muscle mitochondria are not necessarily dysfunctional but limited oxygen supply to working muscle creates this misperception. Finally, we propose changes in experimental design to address this question unequivocally. If mitochondrial function is not impaired it suggests that therapeutic interventions and drug development must move away from the organelle and toward the cardiovascular system.

scholarly journals High-fat diet, muscular lipotoxicity and insulin resistance

2007 ◽  
Vol 66 (1) ◽  
pp. 33-41 ◽  
Author(s):  
Patrick Schrauwen
Keyword(s):  
Physical Activity ◽  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Mitochondrial Function ◽  
Dietary Fat ◽  
Plasma Fatty Acid ◽  
Fat Intake ◽  
High Fat

A high dietary fat intake and low physical activity characterize the current Western lifestyle. Dietary fatty acids do not stimulate their own oxidation and a surplus of fat is stored in white adipose tissue, liver, heart and muscle. In these organs intracellular lipids serve as a rapidly-available energy source during, for example, physical activity. However, under conditions of elevated plasma fatty acid levels and high dietary fat intake, conditions implicated in the development of modern diseases such as obesity and type 2 diabetes mellitus, fat accumulation in liver and muscle (intramyocellular lipids; IMCL) is associated with the development of insulin resistance. Recent data suggest that IMCL are specifically harmful when combined with reduced mitochondrial function, both conditions that characterize type 2 diabetes. In the (pre)diabetic state reduced expression of the transcription factor PPARγ co-activator-1α (PGC-1α), which is involved in mitochondrial biogenesis, has been suggested to underlie the reduced mitochondrial function. Importantly, the reduction in PGC-1α may be a result of low physical activity, consumption of high-fat diets and high plasma fatty acid levels. Mitochondrial function can also be impaired as a result of enhanced mitochondrial damage by reactive oxygen species. Fatty acids in the vicinity of mitochondria are particularly prone to lipid peroxidation. In turn, lipid peroxides can induce oxidative damage to mitochondrial RNA, DNA and proteins. The mitochondrial protein uncoupling protein 3, which is induced under high-fat conditions, may serve to protect mitochondria against lipid-induced oxidative damage, but is reduced in the prediabetic state. Thus, muscular lipotoxicity may impair mitochondrial function and may be central to insulin resistance and type 2 diabetes mellitus.

scholarly journals A comparative study of mitochondrial respiration in circulating blood cells and skeletal muscle fibers in women

2019 ◽  
Vol 317 (3) ◽  
pp. E503-E512 ◽  
Author(s):  
Shannon Rose ◽  
Eugenia Carvalho ◽  
Eva C. Diaz ◽  
Matthew Cotter ◽  
Sirish C. Bennuri ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Blood Cells ◽  
Muscle Fibers ◽  
Circulating Cells ◽  
Permeabilized Muscle

Skeletal muscle mitochondrial respiration is thought to be altered in obesity, insulin resistance, and type 2 diabetes; however, the invasive nature of tissue biopsies is an important limiting factor for studying mitochondrial function. Recent findings suggest that bioenergetics profiling of circulating cells may inform on mitochondrial function in other tissues in lieu of biopsies. Thus, we sought to determine whether mitochondrial respiration in circulating cells [peripheral blood mononuclear cells (PBMCs) and platelets] reflects that of skeletal muscle fibers derived from the same subjects. PBMCs, platelets, and skeletal muscle (vastus lateralis) samples were obtained from 32 young (25–35 yr) women of varying body mass indexes. With the use of extracellular flux analysis and high-resolution respirometry, mitochondrial respiration was measured in intact blood cells as well as in permeabilized cells and permeabilized muscle fibers. Respiratory parameters were not correlated between permeabilized muscle fibers and intact PBMCs or platelets. In a subset of samples ( n = 12–13) with permeabilized blood cells available, raw measures of substrate (pyruvate, malate, glutamate, and succinate)-driven respiration did not correlate between permeabilized muscle (per mg tissue) and permeabilized PBMCs (per 106 cells); however, complex I leak and oxidative phosphorylation coupling efficiency correlated between permeabilized platelets and muscle (Spearman’s ρ = 0.64, P = 0.030; Spearman’s ρ = 0.72, P = 0.010, respectively). Our data indicate that bioenergetics phenotypes in circulating cells cannot recapitulate muscle mitochondrial function. Select circulating cell bioenergetics phenotypes may possibly inform on overall metabolic health, but this postulate awaits validation in cohorts spanning a larger range of insulin resistance and type 2 diabetes status.

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