scholarly journals Targeting Mitochondria in Diabetes

2021 ◽  
Vol 22 (12) ◽  
pp. 6642
Author(s):  
Nina Krako Jakovljevic ◽  
Kasja Pavlovic ◽  
Aleksandra Jotic ◽  
Katarina Lalic ◽  
Milica Stoiljkovic ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Mitochondrial Function ◽  
Whole Body ◽  
Noncommunicable Diseases ◽  
Pharmacological Interventions ◽  
Cellular Energy ◽  
Cellular Energy Metabolism ◽  
Data Comparison ◽  
Selection Of

Type 2 diabetes (T2D), one of the most prevalent noncommunicable diseases, is often preceded by insulin resistance (IR), which underlies the inability of tissues to respond to insulin and leads to disturbed metabolic homeostasis. Mitochondria, as a central player in the cellular energy metabolism, are involved in the mechanisms of IR and T2D. Mitochondrial function is affected by insulin resistance in different tissues, among which skeletal muscle and liver have the highest impact on whole-body glucose homeostasis. This review focuses on human studies that assess mitochondrial function in liver, muscle and blood cells in the context of T2D. Furthermore, different interventions targeting mitochondria in IR and T2D are listed, with a selection of studies using respirometry as a measure of mitochondrial function, for better data comparison. Altogether, mitochondrial respiratory capacity appears to be a metabolic indicator since it decreases as the disease progresses but increases after lifestyle (exercise) and pharmacological interventions, together with the improvement in metabolic health. Finally, novel therapeutics developed to target mitochondria have potential for a more integrative therapeutic approach, treating both causative and secondary defects of diabetes.

scholarly journals Mitochondrial Dysfunction, Insulin Resistance, and Potential Genetic Implications

Endocrinology ◽  
2020 ◽  
Vol 161 (4) ◽  
Author(s):  
Panjamaporn Sangwung ◽  
Kitt Falk Petersen ◽  
Gerald I Shulman ◽  
Joshua W Knowles
Keyword(s):  
Insulin Resistance ◽  
Mitochondrial Function ◽  
Ex Vivo ◽  
Critical Role ◽  
Whole Body ◽  
Genetic Studies ◽  
Cellular Energy

Abstract Insulin resistance (IR) is fundamental to the development of type 2 diabetes (T2D) and is present in most prediabetic (preDM) individuals. Insulin resistance has both heritable and environmental determinants centered on energy storage and metabolism. Recent insights from human genetic studies, coupled with comprehensive in vivo and ex vivo metabolic studies in humans and rodents, have highlighted the critical role of reduced mitochondrial function as a predisposing condition for ectopic lipid deposition and IR. These studies support the hypothesis that reduced mitochondrial function, particularly in insulin-responsive tissues such as skeletal muscle, white adipose tissue, and the liver, is inextricably linked to tissue and whole body IR through the effects on cellular energy balance. Here we discuss these findings as well as address potential mechanisms that serve as the nexus between mitochondrial malfunction and IR.

scholarly journals Can resveratrol help to maintain metabolic health?

2014 ◽  
Vol 73 (2) ◽  
pp. 271-277 ◽  
Author(s):  
Patrick Schrauwen ◽  
Silvie Timmers
Keyword(s):  
Type 2 Diabetes ◽  
Mitochondrial Function ◽  
Therapeutic Strategy ◽  
Metabolic Diseases ◽  
Human Subjects ◽  
Metabolic Health ◽  
Sirtuin 1 ◽  
Cellular Energy ◽  
Cellular Energy Metabolism

The number of people suffering from metabolic diseases is dramatically increasing worldwide. This stresses the need for new therapeutic strategies to combat this growing epidemic of metabolic diseases. A reduced mitochondrial function is one of the characteristics of metabolic diseases and therefore a target for intervention. Here we review the evidence that mitochondrial function may act as a target to treat and prevent type 2 diabetes mellitus, and, if so, whether these effects are due to reduction in skeletal muscle fat accumulation. We describe how exercise may affect these parameters and can be beneficial for type 2 diabetes. We next focus on alternative ways to improve mitochondrial function in a non-exercise manner. Thus, in 2003, resveratrol (3,5,4′-trihydroxystilbene) was discovered to be a small molecule activator of sirtuin 1, an important molecular target regulating cellular energy metabolism and mitochondrial homoeostasis. Rodent studies have clearly demonstrated the potential of resveratrol to improve various metabolic health parameters. Here we review data in human subjects that is available on the effects of resveratrol on metabolism and mitochondrial function and discuss how resveratrol may serve as a new therapeutic strategy to preserve metabolic health. We also discuss whether the effects of resveratrol are similar to the effects of exercise training and therefore if resveratrol can be considered as an exercise mimetic.

Targeting skeletal muscle mitochondria to prevent type 2 diabetes in youth

2015 ◽  
Vol 93 (5) ◽  
pp. 452-465 ◽  
Author(s):  
Joseph W. Gordon ◽  
Vernon W. Dolinsky ◽  
Wajihah Mughal ◽  
Grant R.J. Gordon ◽  
Jonathan McGavock
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Mitochondrial Function ◽  
Vascular Complications ◽  
Whole Body ◽  
Cellular Mechanisms ◽  
Peripheral Insulin Resistance

The prevalence of type 2 diabetes (T2D) has increased dramatically over the past two decades, not only among adults but also among adolescents. T2D is a systemic disorder affecting every organ system and is especially damaging to the cardiovascular system, predisposing individuals to severe cardiac and vascular complications. The precise mechanisms that cause T2D are an area of active research. Most current theories suggest that the process begins with peripheral insulin resistance that precedes failure of the pancreatic β-cells to secrete sufficient insulin to maintain normoglycemia. A growing body of literature has highlighted multiple aspects of mitochondrial function, including oxidative phosphorylation, lipid homeostasis, and mitochondrial quality control in the regulation of peripheral insulin sensitivity. Whether the cellular mechanisms of insulin resistance in adults are comparable to that in adolescents remains unclear. This review will summarize both clinical and basic studies that shed light on how alterations in skeletal muscle mitochondrial function contribute to whole body insulin resistance and will discuss the evidence supporting high-intensity exercise training as a therapy to circumvent skeletal muscle mitochondrial dysfunction to restore insulin sensitivity in both adults and adolescents.

Oxidative stress in skeletal muscle impairs mitochondrial respiration and limits exercise capacity in type 2 diabetic mice

2009 ◽  
Vol 297 (3) ◽  
pp. H1069-H1077 ◽  
Author(s):  
Takashi Yokota ◽  
Shintaro Kinugawa ◽  
Kagami Hirabayashi ◽  
Shouji Matsushima ◽  
Naoki Inoue ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Mitochondrial Dysfunction ◽  
Exercise Capacity ◽  
Mitochondrial Function ◽  
Exercise Intolerance ◽  
Whole Body

Insulin resistance or diabetes is associated with limited exercise capacity, which can be caused by the abnormal energy metabolism in skeletal muscle. Oxidative stress is involved in mitochondrial dysfunction in diabetes. We hypothesized that increased oxidative stress could cause mitochondrial dysfunction in skeletal muscle and make contribution to exercise intolerance in diabetes. C57/BL6J mice were fed on normal diet or high fat diet (HFD) for 8 wk to induce obesity with insulin resistance and diabetes. Treadmill tests with expired gas analysis were performed to determine the exercise capacity and whole body oxygen uptake (V̇o2). The work (vertical distance × body weight) to exhaustion was reduced in the HFD mice by 36%, accompanied by a 16% decrease of peak V̇o2. Mitochondrial ADP-stimulated respiration, electron transport chain complex I and III activities, and mitochondrial content in skeletal muscle were decreased in the HFD mice. Furthermore, superoxide production and NAD(P)H oxidase activity in skeletal muscle were significantly increased in the HFD mice. Intriguingly, the treatment of HFD-fed mice with apocynin [10 mmol/l; an inhibitor of NAD(P)H oxidase activation] improved exercise intolerance and mitochondrial dysfunction in skeletal muscle without affecting glucose metabolism itself. The exercise capacity and mitochondrial function in skeletal muscle were impaired in type 2 diabetes, which might be due to enhanced oxidative stress. Therapies designed to regulate oxidative stress and maintain mitochondrial function could be beneficial to improve the exercise capacity in type 2 diabetes.

scholarly journals Obese Older Type 2 Diabetes Mellitus Patients with Muscle Insulin Resistance Benefit from an Enriched Protein Drink during Combined Lifestyle Intervention: The PROBE Study

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2979 ◽  
Author(s):  
Wilrike J. Pasman ◽  
Robert G. Memelink ◽  
Johan de Vogel-Van den Bosch ◽  
Mark P. V. Begieneman ◽  
Willem J. van den Brink ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Muscle Mass ◽  
Lifestyle Intervention ◽  
Tolerance Test ◽  
Whole Body ◽  
Physiological Data ◽  
Oral Glucose ◽  
Before And After

(1) Background: Recent research showed that subtypes of patients with type 2 diabetes may differ in response to lifestyle interventions based on their organ-specific insulin resistance (IR). (2) Methods: 123 Subjects with type 2 diabetes were randomized into 13-week lifestyle intervention, receiving either an enriched protein drink (protein+) or an isocaloric control drink (control). Before and after the intervention, anthropometrical and physiological data was collected. An oral glucose tolerance test was used to calculate indices representing organ insulin resistance (muscle, liver, and adipose tissue) and β-cell functioning. In 82 study-compliant subjects (per-protocol), we retrospectively examined the intervention effect in patients with muscle IR (MIR, n = 42) and without MIR (no-MIR, n = 40). (3) Results: Only in patients from the MIR subgroup that received protein+ drink, fasting plasma glucose and insulin, whole body, liver and adipose IR, and appendicular skeletal muscle mass improved versus control. Lifestyle intervention improved body weight and fat mass in both subgroups. Furthermore, for the MIR subgroup decreased systolic blood pressure and increased VO2peak and for the no-MIR subgroup, a decreased 2-h glucose concentration was found. (4) Conclusions: Enriched protein drink during combined lifestyle intervention seems to be especially effective on increasing muscle mass and improving insulin resistance in obese older, type 2 diabetes patients with muscle IR.

scholarly journals The Carnivore Connection Hypothesis: Revisited

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Jennie C. Brand-Miller ◽  
Hayley J. Griffin ◽  
Stephen Colagiuri
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Selection Pressure ◽  
Glycemic Load ◽  
Dietary Carbohydrate ◽  
Recent Exposure ◽  
Agricultural Revolution ◽  
High Prevalence ◽  
Selection Of

The “Carnivore Connection” hypothesizes that, during human evolution, a scarcity of dietary carbohydrate in diets with low plant : animal subsistence ratios led to insulin resistance providing a survival and reproductive advantage with selection of genes for insulin resistance. The selection pressure was relaxed at the beginning of the Agricultural Revolution when large quantities of cereals first entered human diets. The “Carnivore Connection” explains the high prevalence of intrinsic insulin resistance and type 2 diabetes in populations that transition rapidly from traditional diets with a low-glycemic load, to high-carbohydrate, high-glycemic index diets that characterize modern diets. Selection pressure has been relaxed longest in European populations, explaining a lower prevalence of insulin resistance and type 2 diabetes, despite recent exposure to famine and food scarcity. Increasing obesity and habitual consumption of high-glycemic-load diets worsens insulin resistance and increases the risk of type 2 diabetes in all populations.

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 Insulin Resistance in Osteoarthritis: Similar Mechanisms to Type 2 Diabetes Mellitus

2020 ◽  
Vol 2020 ◽  
pp. 1-16 ◽  
Author(s):  
Elena V Tchetina ◽  
Galina A Markova ◽  
Eugeniya P Sharapova
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
The Body ◽  
Whole Body ◽  
Insulin Resistant ◽  
Resistant State ◽  
Insulin Resistant State

Osteoarthritis (OA) and type 2 diabetes mellitus (T2D) are two of the most widespread chronic diseases. OA and T2D have common epidemiologic traits, are considered heterogenic multifactorial pathologies that develop through the interaction of genetic and environmental factors, and have common risk factors. In addition, both of these diseases often manifest in a single patient. Despite differences in clinical manifestations, both diseases are characterized by disturbances in cellular metabolism and by an insulin-resistant state primarily associated with the production and utilization of energy. However, currently, the primary cause of OA development and progression is not clear. In addition, although OA is manifested as a joint disease, evidence has accumulated that it affects the whole body. As pathological insulin resistance is viewed as a driving force of T2D development, now, we present evidence that the molecular and cellular metabolic disturbances associated with OA are linked to an insulin-resistant state similar to T2D. Moreover, the alterations in cellular energy requirements associated with insulin resistance could affect many metabolic changes in the body that eventually result in pathology and could serve as a unified mechanism that also functions in many metabolic diseases. However, these issues have not been comprehensively described. Therefore, here, we discuss the basic molecular mechanisms underlying the pathological processes associated with the development of insulin resistance; the major inducers, regulators, and metabolic consequences of insulin resistance; and instruments for controlling insulin resistance as a new approach to therapy.

Alterations in cardiac contractile performance and sarcoplasmic reticulum function in sucrose-fed rats is associated with insulin resistance

2006 ◽  
Vol 291 (4) ◽  
pp. C772-C780 ◽  
Author(s):  
Zainisha Vasanji ◽  
Elliott J. F. Cantor ◽  
Danijel Juric ◽  
Mellissa Moyen ◽  
Thomas Netticadan
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Sarcoplasmic Reticulum ◽  
Whole Body ◽  
Dependent Protein Kinase ◽  
Cardiac Contractile ◽  
Type 2 Dm ◽  
Dependent Protein ◽  
Contractile Performance

Diabetes mellitus (DM) causes the development of a specific cardiomyopathy that results from the metabolic derangements present in DM and manifests as cardiac contractile dysfunction. Although myocardial dysfunction in Type 1 DM has been associated with defects in the function and regulation of the sarcoplasmic reticulum (SR), very little is known about SR function in Type 2 DM. Accordingly, this study examined whether abnormalities in cardiac contractile performance and SR function occur in the prestage of Type 2 DM (i.e., during insulin resistance). Sucrose feeding was used to induce whole body insulin resistance, whereas cardiac contractile performance was assessed by echocardiography and SR function was measured by SR calcium (Ca2+) uptake. Sucrose-fed rats exhibited hyperinsulinemia, hyperglycemia, and hyperlipidemia relative to control rats. Serial echocardiographic assessments in the sucrose-fed rats revealed early abnormalities in diastolic function followed by late systolic dysfunction and concurrent alterations in myocardial structure. The hearts of the 10-wk sucrose-fed rats showed depressed SR function demonstrated by a significant reduction in SR Ca2+ uptake. The decline in SR Ca2+ uptake was associated with a significant decrease in the cAMP-dependent protein kinase and Ca2+/calmodulin-dependent protein kinase II-mediated phosphorylation of phospholamban. The results show that abnormalities in cardiac contractile performance and SR function occur at an insulin-resistant stage before the manifestation of overt Type 2 DM.

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