Reciprocal relationships between abnormal metabolic parameters and endothelial dysfunction

PURPOSE OF REVIEW: Endothelial dysfunction plays a crucial role in the pathogenesis of atherosclerosis and related cardiovascular diseases. Glucotoxicity, lipotoxicity, and inflammation all independently contribute to development of both endothelial dysfunction and insulin resistance. We review pathophysiological mechanisms underlying reciprocal relationships between endothelial dysfunction and insulin resistance and recent insights from therapeutic interventions to improve both metabolic and vascular function. RECENT FINDINGS: Shared causal factors such as glucotoxicity, lipotoxicity, and inflammation interact at multiple levels creating reciprocal relationships between insulin resistance and endothelial dysfunction that help to explain frequent clustering of metabolic and cardiovascular disorders. Metabolic abnormalities implicated in the development of insulin resistance, including hyperglycemia, elevated levels of free fatty acids, accumulation of advanced glycation end products, dyslipidemias, and decreased levels of adiponectin, also contribute importantly to endothelial dysfunction. Diet, exercise, cardiovascular drugs, and insulin sensitizers simultaneously improve endothelium-dependent vascular function, reduce inflammation, and improve insulin sensitivity by both distinct and interrelated mechanisms. SUMMARY: Pathophysiological mechanisms underlying reciprocal relationships between endothelial dysfunction and insulin resistance contribute to clustering of metabolic and cardiovascular diseases represented by the metabolic syndrome. Therapeutic interventions that target endothelial dysfunction or insulin resistance often simultaneously improve both metabolic and vascular function.     

SIRT1 attenuates high glucose-induced insulin resistance via reducing mitochondrial dysfunction in skeletal muscle cells

Insulin resistance is often characterized as the most critical factor contributing to the development of type 2 diabetes mellitus (T2DM). Sustained high glucose is an important extracellular environment that induces insulin resistance. Acquired insulin resistance is associated with reduced insulin-stimulated mitochondrial activity as a result of increased mitochondrial dysfunction. Silent information regulator 1 (SIRT1) is one member of the SIRT2 (Sir2)-like family of proteins involved in glucose homeostasis and insulin secretion in mammals. Although SIRT1 has a therapeutic effect on metabolic deterioration in insulin resistance, it is still not clear how SIRT1 is involved in the development of insulin resistance. Here, we demonstrate that pcDNA3.1 vector-mediated overexpression of SIRT1 attenuates insulin resistance in the high glucose-induced insulin-resistant skeleton muscle cells. These beneficial effects were associated with ameliorated mitochondrial dysfunction. Further studies have demonstrated that SIRT1 restores mitochondrial complex I activity leading to decreased oxidative stress and mitochondrial dysfunction. Furthermore, SIRT1 significantly elevated the level of another SIRT which is named SIRT3, and SIRT3 siRNA-suppressed SIRT1-induced mitochondria complex activity increments. Taken together, these results showed that SIRT1 improves insulin sensitivity via the amelioration of mitochondrial dysfunction, and this is achieved through the SIRT1–SIRT3–mitochondrial complex I pathway.     

Medical management of metabolic dysfunction in PCOS

Polycystic ovary syndrome (PCOS) is associated with metabolic derangements including insulin resistance, dyslipidemia, systemic inflammation and endothelial dysfunction. There is a growing need to develop pharmacologic interventions to improve metabolic function in women with PCOS. Medications that have been tested in patients with PCOS include metformin, thiazolidinediones, acarbose, naltrexone, orlistat, vitamin D and statins. Metformin decreases hepatic gluconeogenesis and free fatty acid oxidation while increasing peripheral glucose uptake. Early studies in PCOS suggested that metformin indirectly reduces insulin level, dyslipidemia and systemic inflammation; however, recent placebo-controlled trials failed to demonstrate significant metabolic benefit. Thiazolidinediones act primarily by increasing peripheral glucose uptake. Most studies in PCOS have demonstrated that thiazolidinediones reduce insulin resistance; however, effects on dyslipidemia were disappointing. Use of thiazolidinediones is associated with weight gain and major complications. Acarbose reduces digestion of polysaccharides. Studies in PCOS yielded inconsistent effects of acarbose on insulin sensitivity and no significant improvement of dyslipidemia. Naltrexone reduces appetite and modulates insulin release; its use in PCOS may reduce hyperinsulinemia. Orlistat decreases absorption of dietary fats; studies in PCOS suggest beneficial effects on insulin sensitivity. Vitamin D may improve insulin sensitivity but mixed results on lipid profile in PCOS have been reported. Statins are competitive inhibitors of the key enzyme regulating the mevalonate pathway; their effects are related to reduced cholesterol production as well as anti-inflammatory and anti-oxidant properties. In women with PCOS, statins reduce hyperandrogenism, improve lipid profile and reduce systemic inflammation while the effects on insulin sensitivity are variable. Use of statins is contraindicated in pregnancy.     

Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver

The manner in which insulin resistance impinges on hepatic mitochondrial function is complex. Although liver insulin resistance is associated with respiratory dysfunction, the effect on fat oxidation remains controversial, and biosynthetic pathways that traverse mitochondria are actually increased. The tricarboxylic acid (TCA) cycle is the site of terminal fat oxidation, chief source of electrons for respiration, and a metabolic progenitor of gluconeogenesis. Therefore, we tested whether insulin resistance promotes hepatic TCA cycle flux in mice progressing to insulin resistance and fatty liver on a high-fat diet (HFD) for 32 weeks using standard biomolecular and in vivo (2)H/(13)C tracer methods. Relative mitochondrial content increased, but respiratory efficiency declined by 32 weeks of HFD. Fasting ketogenesis became unresponsive to feeding or insulin clamp, indicating blunted but constitutively active mitochondrial β-oxidation. Impaired insulin signaling was marked by elevated in vivo gluconeogenesis and anaplerotic and oxidative TCA cycle flux. The induction of TCA cycle function corresponded to the development of mitochondrial respiratory dysfunction, hepatic oxidative stress, and inflammation. Thus, the hepatic TCA cycle appears to enable mitochondrial dysfunction during insulin resistance by increasing electron deposition into an inefficient respiratory chain prone to reactive oxygen species production and by providing mitochondria-derived substrate for elevated gluconeogenesis.     

Mitochondrial fission contributes to mitochondrial dysfunction and insulin resistance in skeletal muscle

Mitochondrial dysfunction in skeletal muscle has been implicated in the development of insulin resistance and type 2 diabetes. Considering the importance of mitochondrial dynamics in mitochondrial and cellular functions, we hypothesized that obesity and excess energy intake shift the balance of mitochondrial dynamics, further contributing to mitochondrial dysfunction and metabolic deterioration in skeletal muscle. First, we revealed that excess palmitate (PA), but not hyperglycemia, hyperinsulinemia, or elevated tumor necrosis factor alpha, induced mitochondrial fragmentation and increased mitochondrion-associated Drp1 and Fis1 in differentiated C2C12 muscle cells. This fragmentation was associated with increased oxidative stress, mitochondrial depolarization, loss of ATP production, and reduced insulin-stimulated glucose uptake. Both genetic and pharmacological inhibition of Drp1 attenuated PA-induced mitochondrial fragmentation, mitochondrial depolarization, and insulin resistance in C2C12 cells. Furthermore, we found smaller and shorter mitochondria and increased mitochondrial fission machinery in the skeletal muscle of mice with genetic obesity and those with diet-induced obesity. Inhibition of mitochondrial fission improved the muscle insulin signaling and systemic insulin sensitivity of obese mice. Our findings indicated that aberrant mitochondrial fission is causally associated with mitochondrial dysfunction and insulin resistance in skeletal muscle. Thus, disruption of mitochondrial dynamics may underlie the pathogenesis of muscle insulin resistance in obesity and type 2 diabetes.     

Metabolic syndrome and mitochondrial function: molecular replacement and antioxidant supplements to prevent membrane peroxidation and restore mitochondrial function

Metabolic syndrome consists of a cluster of metabolic conditions, such as hypertriglyceridemia, hyper-low-density lipoproteins, hypo-high-density lipoproteins, insulin resistance, abnormal glucose tolerance and hypertension, that-in combination with genetic susceptibility and abdominal obesity-are risk factors for type 2 diabetes, vascular inflammation, atherosclerosis, and renal, liver and heart disease. One of the defects in metabolic syndrome and its associated diseases is excess cellular oxidative stress (mediated by reactive oxygen and nitrogen species, ROS/RNS) and oxidative damage to mitochondrial components, resulting in reduced efficiency of the electron transport chain. Recent evidence indicates that reduced mitochondrial function caused by ROS/RNS membrane oxidation is related to fatigue, a common complaint of MS patients. Lipid replacement therapy (LRT) administered as a nutritional supplement with antioxidants can prevent excess oxidative membrane damage, restore mitochondrial and other cellular membrane functions and reduce fatigue. Recent clinical trials have shown the benefit of LRT plus antioxidants in restoring mitochondrial electron transport function and reducing moderate to severe chronic fatigue. Thus LRT plus antioxidant supplements should be considered for metabolic syndrome patients who suffer to various degrees from fatigue.     

Obesity accelerates cognitive decline by aggravating mitochondrial dysfunction,insulin resistance and synaptic dysfunction under estrogen-deprived conditions

Chronic consumption of a high-fat diet (HF) causes peripheral insulin resistance, brain insulin resistance, brain mitochondrial dysfunction and cognitive impairment. Estrogen deprivation has also been found to impair cognition. However, the combined effect of both conditions on the brain is unclear. We hypothesized that estrogen deprivation causes brain insulin resistance, brain mitochondrial dysfunction, hippocampal synaptic dysfunction and cognitive impairment, and that consumption of a HF accelerates these impairments in an estrogen-deprived condition. Seventy-two female rats were divided into sham (S) and ovariectomized (O) groups. Rats in each group were further divided into two subgroups to be fed with either a normal diet (ND) or HF for 4, 8 and 12 weeks. At the end of each period, the Morris water maze test was carried out, after which the blood and brain were collected for metabolic and brain function analysis. Obesity, peripheral insulin resistance, increased brain oxidative stress and hippocampal synaptic dysfunction were observed at the eighth week in the NDO, HFS and HFO rats. However, these impairments were worse in the HFO rats. Interestingly, brain insulin resistance, brain mitochondrial dysfunction and cognitive impairment developed earlier (week eight) in the HFO rats, whereas these conditions were observed later at week 12 in the NDO and HFS rats. Either estrogen deprivation or HF appears to cause peripheral insulin resistance, increased brain oxidative stress, hippocampal synaptic dysfunction, brain mitochondrial dysfunction and brain insulin resistance, which together can lead to cognitive impairment. A HF accelerates and aggravates these deleterious effects under estrogen-deprived conditions.     

Insulin resistance and the metabolism of branched-chain amino acids in humans

Peripheral resistance to insulin action is the major mechanism causing the metabolic syndrome and eventually type 2 diabetes mellitus. The metabolic derangement associated with insulin resistance is extensive and not restricted to carbohydrates. The branched-chain amino acids (BCAAs) are particularly responsive to the inhibitory insulin action on amino acid release by skeletal muscle and their metabolism is profoundly altered in conditions featuring insulin resistance, insulin deficiency, or both. Obesity, the metabolic syndrome and diabetes mellitus display a gradual increase in the plasma concentration of BCAAs, from the obesity-related low-grade insulin-resistant state to the severe deficiency of insulin action in diabetes ketoacidosis. Obesity-associated hyperinsulinemia succeeds in maintaining near-normal or slightly elevated plasma concentration of BCAAs, despite the insulin-resistant state. The low circulating levels of insulin and/or the deeper insulin resistance occurring in diabetes mellitus are associated with more marked elevation in the plasma concentration of BCAAs. In diabetes ketoacidosis, the increase in plasma BCAAs is striking, returning to normal when adequate metabolic control is achieved. The metabolism of BCAAs is also disturbed in other situations typically featuring insulin resistance, including kidney and liver dysfunction. However, notwithstanding the insulin-resistant state, the plasma level of BCAAs in these conditions is lower than in healthy subjects, suggesting that these organs are involved in maintaining BCAAs blood concentration. The pathogenesis of the decreased BCAAs plasma level in kidney and liver dysfunction is unclear, but a decreased afflux of these amino acids into the blood stream has been observed.     

Liver mitochondria and insulin resistance

With a steadily increasing prevalence, insulin resistance (IR) is a major public health issue. This syndrome is defined as a set of metabolic dysfunctions associated with, or contributing to, a range of serious health problems. These disorders include type 2 diabetes, metabolic syndrome, obesity, and non-alcoholic steatohepatitis (NASH). According to the literature in the field, several cell types like β-cell, myocyte, hepatocyte and/or adipocyte, as well as related complex signaling environment involved in peripheral insulin sensitivity are believed to be central in this pathology. Because of the central role of the liver in the whole-body energy homeostasis, liver insulin sensitivity and its potential relationship with mitochondrial oxidative phosphorylation appear to be crucial. The following short review highlights how liver mitochondria could be implicated in IR and should therefore be considered as a specific therapeutic target in the future.     

Mitochondrial dysfunction and lipotoxicity

Mitochondrial dysfunction in skeletal muscle has been suggested to underlie the development of insulin resistance and type 2 diabetes mellitus. Reduced mitochondrial capacity will contribute to the accumulation of lipid intermediates, desensitizing insulin signaling and leading to insulin resistance. Why mitochondrial function is reduced in the (pre-)diabetic state is, however, so far unknown. Although it is tempting to suggest that skeletal muscle insulin resistance may result from an inherited or acquired reduction in mitochondrial function in the pre-diabetic state, it cannot be excluded that mitochondrial dysfunction may in fact be the consequence of the insulin-resistant/diabetic state. Lipotoxicity, the deleterious effects of accumulating fatty acids in skeletal muscle cells, may lie at the basis of mitochondrial dysfunction: next to producing energy, mitochondria are also the major source of reactive oxygen species (ROS). Fatty acids accumulating in the vicinity of mitochondria are vulnerable to ROS-induced lipid peroxidation. Subsequently, these lipid peroxides could have lipotoxic effects on mtDNA, RNA and proteins of the mitochondrial machinery, leading to mitochondrial dysfunction. Indeed, increased lipid peroxidation has been reported in insulin resistant skeletal muscle and the mitochondrial uncoupling protein-3, which has been suggested to prevent lipid-induced mitochondrial damage, is reduced in subjects with an impaired glucose tolerance and in type 2 diabetic patients. These findings support the hypothesis that fat accumulation in skeletal muscle may precede the reduction in mitochondrial function that is observed in type 2 diabetes mellitus.     

Impact of high dietary lipid intake and related metabolic disorders on the abundance and acyl composition of the unique mitochondrial phospholipid,cardiolipin

Excessive dietary lipid intake, coupled with lack of exercise, are the major causes of the development and progression of metabolic syndrome features e. g. obesity, hepatic steatosis, insulin resistance, type 2 diabetes and cardiovascular diseases. These metabolic diseases are associated with both structural and functional alterations of mitochondria. Cardiolipin (CL) is a unique phospholipid that is almost exclusively localized in the mitochondrial inner membrane. Cardiolipin is at the heart of mitochondrial metabolism playing a key role in several processes of mitochondrial bioenergetics as well as in mitochondrial membrane stability and dynamics, and in many of the mitochondrial-dependent steps of apoptosis. Indeed, alterations to CL content and acyl chain profile have been associated with mitochondrial dysfunction in multiple tissues in Barth syndrome and in many other physio-pathological conditions. After a brief overview of the biological roles of CL, we highlight the consequences of lipid overload-related nutritional manipulations as well as related metabolic disorders on both CL content and its fatty acid composition in the major metabolic tissues, the heart, muscle and liver. The goal of this review is to fill a void in the CL literature concerning the effects of CL abundance and form that arise following high lipid supplementation and the related metabolic disorders.     

Chicoric acid mitigates impaired insulin sensitivity by improving mitochondrial function

Mitochondrial dysfunction is associated with insulin resistance. Although chicoric acid (CA) is known to have beneficial effects on insulin sensitivity, the involvement of mitochondrial function has not been elucidated yet. Here, we investigated the effect of CA on insulin resistance and mitochondrial dysfunction. In palmitate-induced insulin-resistant C2C12 myotubes, CA improved impaired glucose uptake and insulin signaling pathways, along with enhanced mitochondrial membrane potential and oxygen consumption. CA treatment in diet-induced obese mice ameliorated glucose tolerance and increased insulin sensitivity. CA treatment also recovered the dysregulated expression of glucose metabolism-related genes in the high-fat-fed mice. CA significantly increased the mitochondrial DNA content, citrate synthase, and ATP content, as well as the expression of genes related to mitochondrial biogenesis and oxidative phosphorylation in the liver and skeletal muscle in high-fat- fed obese mice. These findings suggested that CA attenuates insulin resistance and promotes insulin sensitivity by enhancing mitochondrial function.     

Metabolic stress in insulin's target cells leads to ROS accumulation - a hypothetical common pathway causing insulin resistance

The metabolic syndrome is a cluster of cardiovascular risk factors, and visceral adiposity is a central component that is also strongly associated with insulin resistance. Both visceral obesity and insulin resistance are important risk factors for the development of type 2 diabetes. It is likely that adipose tissue, particularly in the intra-abdominal depot, is part of a complex interplay involving several tissues and that dysregulated hormonal, metabolic and neural signalling within and between organs can trigger development of metabolic disease. One attractive hypothesis is that many factors leading to insulin resistance are mediated via the generation of abnormal amounts of reactive oxygen species (ROS). There is much evidence supporting that detrimental effects of glucose, fatty acids, hormones and cytokines leading to insulin resistance can be exerted via such a common pathway. This review paper mainly focuses on metabolic and other 'stress' factors that affect insulin's target cells, in particular adipocytes, and it will highlight oxidative stress as a potential unifying mechanism by which these stress factors promote insulin resistance and the development and progression of type 2 diabetes.     

Effects of excess dietary iron and fat on glucose and lipid metabolism

PurposeDiets rich in fat and energy are associated with metabolic syndrome (MS). Increased body iron stores have been recognized as a feature of MS. High-fat diets (HFs), excess iron loading and MS are closely associated, but the mechanism linking them has not been clearly defined. We investigated the interaction between dietary fat and dietary Fe in the context of glucose and lipid metabolism in the body.MethodsC57BL6/J mice were divided into four groups and fed the modified AIN-93G low-fat diet (LF) and HF with adequate or excess Fe for 7 weeks. The Fe contents were increased by adding carbonyl iron (2% of diet weight) (LF+Fe and HF+Fe).ResultsHigh iron levels increased blood glucose levels but decreased high-density lipoprotein cholesterol levels. The HF group showed increases in plasma levels of glucose and insulin and insulin resistance. HF+Fe mice showed greater changes. Representative indices of iron status, such hepatic and plasma Fe levels, were not altered further by the HF. However, both the HF and excess iron loading changed the hepatic expression of hepcidin and ferroportin. The LF+Fe, HF and HF+Fe groups showed greater hepatic fat accumulation compared with the LF group. These changes were paralleled by alterations in the levels of enzymes related to hepatic gluconeogenesis and lipid synthesis, which could be due to increases in mitochondrial dysfunction and oxidative stress.ConclusionsHigh-fat diets and iron overload are associated with insulin resistance, modified hepatic lipid and iron metabolism and increased mitochondrial dysfunction and oxidative stress.     

SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome

Acetylation is increasingly recognized as an important metabolic regulatory posttranslational protein modification, yet the metabolic consequence of mitochondrial protein hyperacetylation is unknown. We find that high-fat diet (HFD) feeding induces hepatic mitochondrial protein hyperacetylation in mice and downregulation of the major mitochondrial protein deacetylase SIRT3. Mice lacking SIRT3 (SIRT3KO) placed on a HFD show accelerated obesity, insulin resistance, hyperlipidemia, and steatohepatitis compared to wild-type (WT) mice. The lipogenic enzyme stearoyl-CoA desaturase 1 is highly induced in SIRT3KO mice, and its deletion rescues both WT and SIRT3KO mice from HFD-induced hepatic steatosis and insulin resistance. We further identify a single nucleotide polymorphism in the human SIRT3 gene that is suggestive of a genetic association with the metabolic syndrome. This polymorphism encodes a point mutation in the SIRT3 protein, which reduces its overall enzymatic efficiency. Our findings show that loss of SIRT3 and dysregulation of mitochondrial protein acetylation contribute to the metabolic syndrome.     

Mitochondrial dysfunction in metabolic syndrome

Metabolic syndrome is co-occurrence of obesity, insulin resistance, atherogenic dyslipidemia (high triglyceride, low high density lipoprotein cholesterol), and hypertension. It is a global health problem. An estimated 20%–30% of adults of the world have metabolic syndrome. Metabolic syndrome is associated with increased risk of type 2 diabetes mellitus, nonalcoholic fatty liver disease, myocardial infarction, and stroke. Thus, it is a major cause of morbidity and mortality worldwide. However, molecular pathogenesis of metabolic syndrome is not well known. Recently, there has been interest in the role of mitochondria in pathogenesis of metabolic problems such as obesity, metabolic syndrome, and type 2 diabetes mellitus. Mitochondrial dysfunction contributes to the oxidative stress and systemic inflammation seen in metabolic syndrome. Role of mitochondria in the pathogenesis of metabolic syndrome is intriguing but far from completely understood. However, a better understanding will be very rewarding as it may lead to novel approaches to control this major public health problem. This brief review explores pathogenesis of metabolic syndrome from a mitochondrial perspective.     

Mitochondrial dysfunction in diabetes and the regulatory roles of antidiabetic agents on the mitochondrial function

The prevalence of type 2 diabetes mellitus (T2DM) is increasing rapidly with its associated morbidity and mortality. Many pathophysiological pathways such as oxidative stress, inflammatory responses, adipokines, obesity-induced insulin resistance, improper insulin signaling, and beta cell apoptosis are associated with the development of T2DM. There is increasing evidence of the role of mitochondrial dysfunction in the onset of T2DM, particularly in relation to the development of diabetic complications. Here, the role of mitochondrial dysfunction in T2DM is reviewed together with its modulation by antidiabetic therapeutic agents, an effect that may be independent of their hypoglycemic effect.     

多囊卵巢综合征伴胰岛素抵抗的研究进展

多囊卵巢综合征（polycystic ovary syndrome,PCOS）是国内外研究者、医患人员非常关心的育龄期妇女常见的内分泌代谢疾病,其主要表现为闭经、月经量减少、肥胖、不孕、体多毛等。多数伴有胰岛素抵抗（insulin resistance,IR）的发生,胰岛素抵抗（insulin resistance,IR）是指正常水平的胰岛素促进葡萄糖摄取及利用能力下降,机体各组织、器官代偿性分泌胰岛素以维持机体血糖稳定的一种代谢状态。近年来的研究不断证实PCOS患者2型糖尿病、血脂代谢紊乱及代谢综合征（metabolicsyndrome,MS）等并发症的发病率明显增高。运动能够改善2型糖尿病患者胰岛素抵抗的说法已经得到了共识,其分子机制也逐渐分明。PCOS患者胰岛素抵抗的研究目前仍处于进一步探讨阶段,但是经过近几年的努力已经有了新的进展,若在PCOS胰岛素抵抗患者的治疗过程中给予一定的运动干预,相信一定能够有新的突破。本文就PCOS患者胰岛素抵抗研究的机制、诊断及治疗方法的新进展简单做一综述。     

Allyl isothiocyanate ameliorates insulin resistance through the regulation of mitochondrial function

Mitochondrial dysfunction is associated with the pathophysiology of insulin resistance. Allylisothiocyanate (AITC) is found in many cruciferous vegetables and has been reported to possess anticancer activity. However, the effect of AITC on insulin resistance and mitochondrial function has not yet been investigated. Here, we show that AITC increased glucose uptake in insulin-resistant C2C12 myotubes and augmented glucose transporter 4 (GLUT4) translocation in L6-GLUT4myc cells. AITC recovered the impaired insulin signaling evoked by free fatty acid exposure and increased mitochondrial membrane potential and mitochondrial DNA content. AITC also elevated the rate of oxygen consumption in C2C12 cells. Furthermore, mice that were fed a high-fat diet with AITC for 10 weeks had reduced diet-induced obesity and hepatic steatosis. AITC also inhibited the hyperglycemia and hyperinsulinemia induced by the consumption of a high-fat diet. Glucose and insulin tolerance tests indicated that AITC improved both glucose tolerance and insulin sensitivity. In addition, AITC inhibited hepatic gluconeogenesis and ameliorated high fat diet-induced mitochondrial dysfunction. Collectively, these data suggest that the protective effect of AITC on insulin resistance is partly mediated through the modulation of mitochondrial dysfunction.