Mitochondrial biogenesis in the metabolic syndrome and cardiovascular disease

The metabolic syndrome is a constellation of metabolic disorders including obesity, hypertension, and insulin resistance, components which are risk factors for the development of diabetes, hypertension, cardiovascular, and renal disease. Pathophysiological abnormalities that contribute to the development of the metabolic syndrome include impaired mitochondrial oxidative phosphorylation and mitochondrial biogenesis, dampened insulin metabolic signaling, endothelial dysfunction, and associated myocardial functional abnormalities. Recent evidence suggests that impaired myocardial mitochondrial biogenesis, fatty acid metabolism, and antioxidant defense mechanisms lead to diminished cardiac substrate flexibility, decreased cardiac energetic efficiency, and diastolic dysfunction. In addition, enhanced activation of the renin–angiotensin–aldosterone system and associated increases in oxidative stress can lead to mitochondrial apoptosis and degradation, altered bioenergetics, and accumulation of lipids in the heart. In addition to impairments in metabolic signaling and oxidative stress, genetic and environmental factors, aging, and hyperglycemia all contribute to reduced mitochondrial biogenesis and mitochondrial dysfunction. These mitochondrial abnormalities can predispose a metabolic cardiomyopathy characterized by diastolic dysfunction. Mitochondrial dysfunction and resulting lipid accumulation in skeletal muscle, liver, and pancreas also impede insulin metabolic signaling and glucose metabolism, ultimately leading to a further increase in mitochondrial dysfunction. Interventions to improve mitochondrial function have been shown to correct insulin metabolic signaling and other metabolic and cardiovascular abnormalities. This review explores mechanisms of mitochondrial dysfunction with a focus on impaired oxidative phosphorylation and mitochondrial biogenesis in the pathophysiology of metabolic heart disease.     

Impact of short-term high-fat feeding on glucose and insulin metabolism in young healthy men

A high-fat, high-calorie diet is associated with obesity and type 2 diabetes. However, the relative contribution of metabolic defects to the development of hyperglycaemia and type 2 diabetes is controversial. Accumulation of excess fat in muscle and adipose tissue in insulin resistance and type 2 diabetes may be linked with defective mitochondrial oxidative phosphorylation. The aim of the current study was to investigate acute effects of short-term fat overfeeding on glucose and insulin metabolism in young men. We studied the effects of 5 days' high-fat (60% energy) overfeeding (+50%) versus a control diet on hepatic and peripheral insulin action by a hyperinsulinaemic euglycaemic clamp, muscle mitochondrial function by ³¹P magnetic resonance spectroscopy, and gene expression by qrt-PCR and microarray in 26 young men. Hepatic glucose production and fasting glucose levels increased significantly in response to overfeeding. However, peripheral insulin action, muscle mitochondrial function, and general and specific oxidative phosphorylation gene expression were unaffected by high-fat feeding. Insulin secretion increased appropriately to compensate for hepatic, and not for peripheral, insulin resistance. High-fat feeding increased fasting levels of plasma adiponectin, leptin and gastric inhibitory peptide (GIP). High-fat overfeeding increases fasting glucose levels due to increased hepatic glucose production. The increased insulin secretion may compensate for hepatic insulin resistance possibly mediated by elevated GIP secretion. Increased insulin secretion precedes the development of peripheral insulin resistance, mitochondrial dysfunction and obesity in response to overfeeding, suggesting a role for insulin per se as well GIP, in the development of peripheral insulin resistance and obesity.     

Type 2 diabetes mellitus and skeletal muscle metabolic function

Type 2 diabetic patients are characterized by a decreased fat oxidative capacity and high levels of circulating free fatty acids (FFAs). The latter is known to cause insulin resistance, in particularly in skeletal muscle, by reducing insulin stimulated glucose uptake, most likely via accumulation of lipid inside the muscle cell. A reduced skeletal muscle oxidative capacity can exaggerate this. Furthermore, type 2 diabetes is associated with impaired metabolic flexibility, i.e. an impaired switching from fatty acid to glucose oxidation in response to insulin. Thus, a reduced fat oxidative capacity and metabolic inflexibility are important components of skeletal muscle insulin resistance. The cause of these derangements in skeletal muscle of type 2 diabetic patients remains to be elucidated. An impaired mitochondrial function is a likely candidate. Evidence from both in vivo and ex vivo studies supports the idea that an impaired skeletal muscle mitochondrial function is related to the development of insulin resistance and type 2 diabetes mellitus. A decreased mitochondrial oxidative capacity in skeletal muscle was revealed in diabetic patients, using in vivo 31-Phosphorus Magnetic Resonance Spectroscopy (31P-MRS). However, quantification of mitochondrial function using ex vivo high-resolution respirometry revealed opposite results. Future (human) studies should challenge this concept of impaired mitochondrial function underlying metabolic defects and prove if mitochondria are truly functional impaired in insulin resistance, or low in number, and whether it represents the primary starting point of pathogenesis of insulin resistance, or is just an other feature of the insulin resistant state.     

The diabetic phenotype is preserved in myotubes established from type 2 diabetic subjects: a critical appraisal

Cultured human myotubes offer a unique model to distinguish between primary and environmental factors in the aetiology of insulin resistance in human skeletal muscle. The objective of this review was to summarize our and other group studies on insulin resistance in human myotubes established from lean, obese and type 2 diabetes (T2D) subjects. Overall, studies of human myotubes established from lean, obese and T2D subjects clearly show that part of the diabetic phenotype observed in vivo is preserved in diabetic myotubes. Diabetic myotubes express a primary coordinated impairment of lipid oxidation, oxidative phosphorylation (OXPHOS) and insulin‐stimulated glucose metabolism. Currently, both the responsible molecular mechanisms as well as the extent to which these alterations depend on genetic and/or epigenetic alterations have yet to be identified. Based on the data, it is hypothesized that the impaired insulin‐mediated glucose metabolism, impaired OXPHOS and reduced lipid oxidation observed in diabetic myotubes are caused by the reduced peroxisome proliferator‐activated receptor gamma coactivator‐1α (PGC1α) expression.     

Mitochondrial function--role in insulin resistance and lipid metabolism

Risk factors for the development of type 2 diabetes mellitus, including weight gain, lack of physical exercise and increasing age, are associated with an impaired mitochondrial function. Clinical studies could demonstrate a reduced mitochondrial activity in non-diabetic but insulin-resistant offsprings of type 2 diabetics. A key enzyme in the regulation of cellular energy supply and thus also in glucose and lipid metabolism is AMP-activated proteinkinase (AMPK). Pharmacological substances, which stimulate AMPK-activity ameliorate insulin resistance induced by free fatty acids. Various therapeutical interventions for the improvement of insulin sensitivity, including weight loss, physical exercise, as well as metformin and glitazones, increase AMPK activity.     

Monogenic syndromes of abnormal glucose homeostasis: clinical review and relevance to the understanding of the pathology of insulin resistance and beta cell failure

Type 2 diabetes mellitus is caused by a combination of insulin resistance and beta cell failure. The polygenic nature of type 2 diabetes has made it difficult to study. Although many candidate genes for this condition have been suggested, in most cases association studies have been equivocal. Monogenic forms of diabetes have now been studied extensively, and the genetic basis of many of these syndromes has been elucidated, leading to greater understanding of the functions of the genes involved. Common variations in the genes causing monogenic disorders have been associated with susceptibility to type 2 diabetes in several populations and explain some of the linkage seen in genome-wide scans. Monogenic disorders are also helpful in understanding both normal and disordered glucose and insulin metabolism. Three main areas of defect contribute to diabetes: defects in insulin signalling leading to insulin resistance; defects of insulin secretion leading to hypoinsulinaemia; and apoptosis leading to decreased beta cell mass. These three pathological pathways are reviewed, focusing on rare genetic syndromes which have diabetes as a prominent feature. Apoptosis seems to be a final common pathway in both type 1 and type 2 diabetes. Study of rare forms of diabetes may help ion determining new therapeutic targets to preserve or increase beta cell mass and function.     

Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus

To identify early metabolic abnormalities in non-insulin-dependent diabetes mellitus (NIDDM), we measured sensitivity to insulin and insulin secretion in 26 first-degree relatives of patients with NIDDM and compared these subjects both with 14 healthy control subjects with no family history of NIDDM and with 19 patients with NIDDM. The euglycemic insulin-clamp technique, indirect calorimetry, and infusion of [3-3H]glucose were used to assess insulin sensitivity. Total-body glucose metabolism was impaired in the first-degree relatives as compared with the controls (P less than 0.01). The defect in glucose metabolism was almost completely accounted for by a defect in nonoxidative glucose metabolism (primarily the storage of glucose as glycogen). The relatives with normal rates of metabolism (mean +/- SEM, 1.81 +/- 0.27 mg per kilogram of body weight per minute) and impaired rates (1.40 +/- 0.22 mg per kilogram per minute) in oral glucose-tolerance tests had the same degree of impairment in glucose storage as compared with healthy control subjects (3.76 +/- 0.55 mg per kilogram per minute; P less than 0.01 for both comparisons). During hyperglycemic clamping, first-phase insulin secretion was lacking in patients with NIDDM (P less than 0.01) and severely impaired in their relatives with impaired glucose tolerance (P less than 0.05) as compared with control subjects; insulin secretion was normal in the relatives with normal glucose tolerance. We conclude that impaired glucose metabolism is common in the first-degree relatives of patients with NIDDM, despite their normal results on oral glucose-tolerance tests. Both insulin resistance and impaired insulin secretion are necessary for the development of impaired glucose tolerance in these subjects.     

Mining for mitochondrial mechanisms: Linking known syndromes to mitochondrial function

Mitochondrial disorders (MDs) are caused by defects in 1 or multiple complexes of the oxidative phosphorylation (OXPHOS) machinery. MDs are associated with a broad range of clinical signs and symptoms, and have considerable clinical overlap with other neuromuscular syndromes. This overlap might be due to involvement of mitochondrial pathways in some of these non‐mitochondrial syndromes. Here, we give an overview of around 25 non‐mitochondrial syndromes, diagnosed in patients who were initially suspected to have a MD on the basis of clinical and biochemical parameters. In addition, we highlight the mitochondrial connections of 6 of these non‐mitochondrial syndromes (eg, Rett syndrome and Dravet syndrome) diagnosed in multiple patients. Further research to unravel the interplay between these genes and mitochondria may help to increase knowledge on these syndromes. Additionally, it may open new avenues for research on pathways interacting with mitochondrial function in order to find new targets for therapeutics to treat MDs. The data presented in this review underline the importance of careful assessment of clinical, genetic, and biochemical data in all patients suspected of a neuromuscular syndrome, and highlights the importance of the role of clinical geneticists, physicians, and clinical biochemists in recognizing the possible mitochondrial connection of non‐mitochondrial syndromes.     

Hyperinsulinemia and insulin resistance in Wrn null mice fed a diabetogenic diet

Werner syndrome (WS) is an autosomal recessive progeroid syndrome caused by mutations in the Werner (Wrn) gene. WS patients have increased incidence of a number of chronic conditions including insulin resistance and type 2 diabetes. Since ingestion of foods that are high in fat and sugar is associated with increased incidence of diabetes, we examined if Wrn mutations might affect metabolic response to a diabetogenic diet. Four-month-old mice with a null mutation for the Wrn gene were fed a diet consisting of 36% fat (lard), 33% table sugar, and 20% protein plus balanced vitamins and minerals. Wrn null mice had significantly increased body weights, increased serum insulin levels, impaired glucose tolerance, and insulin resistance during 4 months of eating the diabetogenic diet. Diffuse fatty infiltration of the liver and pancreatic islet hyperplasia was characteristic morphological features. These observations suggest that Wrn null mice have impaired glucose homeostasis and fat metabolism, and may be a useful model to investigate metabolic conditions associated with aging.     

一氧化氦与脂肪细胞能量代谢

脂肪组织在维持机体的能量代谢平衡和糖、脂代谢稳态中起着重要作用。脂肪细胞合成、释放的一氧化氮(n itric oxide,NO)通过影响线粒体生物合成、脂肪细胞分化以及脂肪分解等,参与能量代谢的调节。NO生成异常可导致能量代谢紊乱甚至肥胖和胰岛素抵抗,后者是冠心病、高血压、2型糖尿病及高脂血症等多种疾病共同的病理基础。深入研究NO对脂肪细胞能量代谢的调控及其机制,可为探讨上述疾病的发生机理和防治措施提供新的思路。     

Mitochondrial dysfunction and organic aciduria in five patients carrying mutations in the Ras-MAPK pathway

Various syndromes of the Ras-mitogen-activated protein kinase (MAPK) pathway, including the Noonan, Cardio-Facio-Cutaneous, LEOPARD and Costello syndromes, share the common features of craniofacial dysmorphisms, heart defect and short stature. In a subgroup of patients, severe muscle hypotonia, central nervous system involvement and failure to thrive occur as well. In this study we report on five children diagnosed initially with classic metabolic and clinical symptoms of an oxidative phosphorylation disorder. Later in the course of the disease, the children presented with characteristic features of Ras-MAPK pathway-related syndromes, leading to the reevaluation of the initial diagnosis. In the five patients, in addition to the oxidative phosphorylation disorder, disease-causing mutations were detected in the Ras-MAPK pathway. Three of the patients also carried a second, mitochondrial genetic alteration, which was asymptomatically present in their healthy relatives. Did we miss the correct diagnosis in the first place or is mitochondrial dysfunction directly related to Ras-MAPK pathway defects? The Ras-MAPK pathway is known to have various targets, including proteins in the mitochondrial membrane influencing mitochondrial morphology and dynamics. Prospective screening of 18 patients with various Ras-MAPK pathway defects detected biochemical signs of disturbed oxidative phosphorylation in three additional children. We concluded that only a specific, metabolically vulnerable sub-population of patients with Ras-MAPK pathway mutations presents with mitochondrial dysfunction and a more severe, early-onset disease. We postulate that patients with Ras-MAPK mutations have an increased susceptibility, but a second metabolic hit is needed to cause the clinical manifestation of mitochondrial dysfunction.     

Physiological and pathophysiological regulation of regional adipose tissue in the development of insulin resistance and type 2 diabetes

Aim: To survey the latest state of knowledge concerning the regulation of regional adipocytes and their role in the development of insulin resistance and type 2 diabetes. Methods: Data from the English‐language literature on regional adipocytes, including abdominal, intramyocellular, intrahepatic and intra‐islet fat as well as the adipokines and their relations to insulin resistance and type 2 diabetes, were reviewed. Results: It is not the total amount of fat but the fat that resides within skeletal muscle cell (intramyocellular fat), hepatocytes and intra‐abdominally (visceral fat), via systemic and local secretion of several adipokines, that influences insulin resistance. Among the adipokines that relate to insulin resistance, adiponectin and leptin appear to have clinical relevance to human insulin resistance and others may also contribute, but their role is still inconclusive. The intra‐islet fat also adversely affects β‐cell function and number (β‐cell apoptosis), eventually leading to deterioration of glucose tolerance. The abnormal location of fat observed in patients with type 2 diabetes and their relatives is conceivably partly the results of the genetically determined, impaired mitochondrial fatty acid oxidative capacity. Restriction or elimination of the fat load by weight control, regular exercise and thiazolidinediones has been shown to improve insulin resistance and β‐cell function and to delay the development of type 2 diabetes. Conclusion: These data support the plausibility of an essential role of regional adipose tissue in the development of insulin resistance and type 2 diabetes.     

Niacin plus simvastatin reduces coronary stenosis progression among patients with metabolic syndrome despite a modest increase in insulin resistance: A subgroup analysis of the HDL-Atherosclerosis treatment study

BackgroundMetabolic syndrome, insulin resistance, and diabetes are associated with an increased risk of cardiovascular disease. Niacin is known to increase insulin resistance and have adverse effects on blood glucose levels, but to have beneficial effects on plasma lipids and lipoproteins. We, therefore, aimed to determine whether intensive lipid therapy with a niacin-containing regimen would have a beneficial effect on cardiovascular disease, despite an expected increase in plasma glucose and insulin resistance in subjects with the metabolic syndrome, insulin resistance, or abnormal fasting plasma glucose levels.MethodsThe effect of 3 years’ treatment with niacin plus simvastatin (N+S) on both angiographic and clinical outcomes was analyzed in the 160 subjects with coronary artery disease and low levels of high-density lipoproteins (HDL) from the HDL-Atherosclerosis Treatment Study. A subgroup analysis was performed on the basis of: (1) the presence or absence of the metabolic syndrome, (2) higher or lower insulin resistance, and (3) the presence or absence of impaired fasting glucose or diabetes (dysglycemia). Individuals classified as having the metabolic syndrome, increased insulin resistance or dysglycemia would be expected to have increased cardiovascular risk.ResultsN+S reduced the change in mean proximal percent stenosis (Δ%S) compared to placebo (PL) in subjects with the metabolic syndrome (Δ%Sprox 0.3 vs 3.0, P = 0.003) and in the more insulin-resistant group of subjects (Δ%Sprox 0.5 vs 2.7, P = 0.001), while subjects with dysglycemia (impaired fasting glucose or diabetes) showed a lesser benefit (Δ%Sprox 1 vs 3.2, P = 0.13). These changes occurred despite increased in-treatment fasting glucose levels (3%), fasting insulin (19%) and decreased insulin sensitivity (−10%). Overall primary clinical events were reduced by 60% with N+S compared to PL (P = 0.02). A similar reduction of the rate of primary events was seen in patients with metabolic syndrome, insulin resistance, and, to a lesser extent, in patients with dysglycemia in the N+S group compared to PL.ConclusionsThese data indicate that, in coronary artery disease patients with low HDL, treating the atherogenic dyslipidemia with a combination of N+S leads to substantial benefits in terms of stenosis progression and clinical events, independently of whether the patient has the metabolic syndrome or is insulin-resistant. During a 3-year period, the beneficial effect of niacin in combination with simvastatin appears to offset the modest adverse effect of niacin on glucose metabolism and insulin resistance in at higher-risk patients, as long as careful attention is paid to glycemic control.     

Thiamine-dependent processes and treatment strategies in neurodegeneration

Reductions in brain glucose metabolism and increased oxidative stress invariably occur in Alzheimer's disease (AD) and thiamine (vitamin B1) deficiency. Both conditions cause irreversible cognitive impairment; their behavioral consequences overlap but are not identical. Thiamine-dependent processes are critical in glucose metabolism, and recent studies implicate thiamine in oxidative stress, protein processing, peroxisomal function, and gene expression. The activities of thiamine-dependent enzymes are characteristically diminished in AD, and the reductions in autopsy AD brain correlate highly with the extent of dementia in the preagonal state. Abnormalities in thiamine-dependent processes can be plausibly linked to the pathology of AD. Seemingly paradoxical properties of thiamine-dependent processes may underlie their relation to the pathophysiology of AD: Reduction of thiamine-dependent processes increase oxidative stress. Thiamine can act as a free radical scavenger. Thiamine-dependent mitochondrial dehydrogenase complexes produce oxygen free radicals and are sensitive to oxidative stress. Genetic disorders of thiamine metabolism that lead to neurological disease can be treated with large doses of thiamine. Although thiamine itself has not shown dramatic benefits in AD patients, the available data is scanty. Adding thiamine or more absorbable forms of thiamine to tested treatments for the abnormality in glucose metabolism in AD may increase their efficacy.     

The molecular basis for oxidative stress-induced insulin resistance

Reactive oxygen and nitrogen molecules have been typically viewed as the toxic by-products of metabolism. However, accumulating evidence has revealed that reactive species, including hydrogen peroxide, serve as signaling molecules that are involved in the regulation of cellular function. The chronic and/or increased production of these reactive molecules or a reduced capacity for their elimination, termed oxidative stress, can lead to abnormal changes in intracellular signaling and result in chronic inflammation and insulin resistance. Inflammation and oxidative stress have been linked to insulin resistance in vivo. Recent studies have found that this association is not restricted to insulin resistance in type 2 diabetes, but is also evident in obese, nondiabetic individuals, and in those patients with the metabolic syndrome. An increased concentration of reactive molecules triggers the activation of serine/threonine kinase cascades such as c-Jun N-terminal kinase, nuclear factor-kappaB, and others that in turn phosphorylate multiple targets, including the insulin receptor and the insulin receptor substrate (IRS) proteins. Increased serine phosphorylation of IRS reduces its ability to undergo tyrosine phosphorylation and may accelerate the degradation of IRS-1, offering an attractive explanation for the molecular basis of oxidative stress-induced insulin resistance. Consistent with this idea, studies with antioxidants such as vitamin E, alpha-lipoic acid, and N-acetylcysteine indicate a beneficial impact on insulin sensitivity, and offer the possibility for new treatment approaches for insulin resistance.     

Mitochondria and degenerative disorders

In mammalian cells, mitochondria provide energy from aerobic metabolism. They play an important regulatory role in apoptosis, produce and detoxify free radicals, and serve as a cellular calcium buffer. Neurodegenerative disorders involving mitochondria can be divided into those caused by oxidative phosphorylation (OXPHOS) abnormalities either due to mitochondrial DNA (mtDNA) abnormalities, e.g., chronic external ophthalmoplegia, or due to nuclear mutations of OXPHOS proteins, e.g., complex I and II associated with Leigh syndrome. There are diseases caused by nuclear genes encoding non-OXPHOS mitochondrial proteins, such as frataxin in Friedreich ataxia (which is likely to play an important role in mitochondrial-cytosolic iron cycling), paraplegin (possibly a mitochondrial ATP-dependent zinc metalloprotease of the AAA-ATPases in hereditary spastic paraparesis), and possibly Wilson disease protein (an abnormal copper transporting ATP-dependent P-type ATPase associated with Wilson disease). Huntingon disease is an example of diseases with OXPHOS defects associated with mutations of nuclear genes encoding non-mitochondrial proteins such as huntingtin. There are also disorders with evidence of mitochondrial involvement that cannot as yet be assigned. These include Parkinson disease (where a complex I defect is described and free radicals are generated from dopamine metabolism), amyotrophic lateral sclerosis, and Alzheimer disease, where there is evidence to suggest mitochondrial involvement perhaps secondary to other abnormalities.     

A Reappraisal of the Blood Glucose Homeostat which Comprehensively Explains the Type 2 Diabetes Mellitus–Syndrome X Complex

Blood glucose concentrations are unaffected by exercise despite very high rates of glucose flux. The plasma ionised calcium levels are even more tightly controlled after meals and during lactation. This implies 'integral control'. However, pairs of integral counterregulatory controllers (e.g. insulin and glucagon, or calcitonin and parathyroid hormone) cannot operate on the same controlled variable, unless there is some form of mutual inhibition. Flip-flop functional coupling between pancreatic α- and β-cells via gap junctions may provide such a mechanism. Secretion of a common inhibitory chromogranin by the parathyroids and the thyroidal C-cells provides another. Here we describe how the insulin:glucagon flip-flop controller can be complemented by growth hormone, despite both being integral controllers. Homeostatic conflict is prevented by somatostatin-28 secretion from both the hypothalamus and the pancreatic islets. Our synthesis of the information pertaining to the glucose homeostat that has accumulated in the literature predicts that disruption of the flip-flop mechanism by the accumulation of amyloid in the pancreatic islets in type 2 diabetes mellitus will lead to hyperglucagonaemia, hyperinsulinaemia, insulin resistance, glucose intolerance and impaired insulin responsiveness to elevated blood glucose levels. It explains syndrome X (or metabolic syndrome) as incipient type 2 diabetes in which the glucose control system, while impaired, can still maintain blood glucose at the desired level. It also explains why it is characterised by high plasma insulin levels and low plasma growth hormone levels, despite normoglycaemia, and how this leads to central obesity, dyslipidaemia and cardiovascular disease in both syndrome X and type 2 diabetes.