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Diabetes affects over 29 million people in the United States, and 1 in 4 of those affected are unaware that they have diabetes.[1] Type 1 diabetes is usually diagnosed in younger people and occurs when the body cannot produce enough insulin. Type 1 DiabetesType 2 DiabetesDefinition Beta cells in pancreas are being attacked by body's own cells and therefore can't produce insulin to take sugar out of the blood stream. Diet related insulin release is so large and frequent that receptor cells have become less sensitive to the insulin. Until recently, the only type of diabetes that was common in children was Type 1 diabetes, most children who have Type 2 diabetes have a family history of diabetes, are overweight, and are not very physically active. When the body doesn't produce or process enough insulin, it causes an excess of blood glucose (sugar).
The most common diabetes, type 2, is known as adult-onset or non-insulin dependent diabetes.
Because people with type 1 diabetes can’t produce enough or any insulin, they are required to take insulin every day. The pancreas produces and secretes insulin, a hormone that helps the body turn food into energy.
With low levels of insulin, the blood glucose (sugar) level rises or declines beyond normal range; fluctuating levels are especially common in type 2 diabetes.
People are more likely to get diabetes if they smoke, have high blood pressure or cholesterol, or, in women, if they had gestational diabetes or gave birth to a baby who weighed more than 9 pounds. Symptoms of Type 1 diabetes include increased thirst and urination, constant hunger, weight loss, blurred vision and extreme tiredness. Type 1 diabetics are required to take regular insulin injections to move sugar from the bloodstream. Type 2 diabetics can use diet, weight management, expercise, and—in many cases—medication as the treatment.
There is some scientific evidence that Type 2 diabetes can be reversed with a strict dietary regimen. A study published in May 2014 found that from 2001 to 2009, prevalence of type 1 diabetes increased 21%, and type 2 diabetes increased 30% among children and adolescents in the U.S. One month later, in June 2014, the CDC released the latest statistics on diabetes and pre-diabetes. Without weight loss and physical activity, 15 to 30% of those with pre-diabetes will develop diabetes within 5 years.
Being overweight and leading a sedentary lifestyle are the biggest risk factors for diabetes. Science, Technology and Medicine open access publisher.Publish, read and share novel research.
Mitochondrial Metabolism and Insulin ActionNigel Turner1, 2[1] Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, Australia[2] Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia1. When the body's level of glucose is too high, that becomes the chronic condition known as diabetes. This is called type 1 diabetes, which usually develops in children and teens; however, type 1 can develop at any time in a person's life. This is called type 2 diabetes, and it is the most common form of diabetes, mainly affecting overweight adults over the age of 40 who have a family history of type 2 diabetes. Insulin also helps store nutrients as excess energy that the body can make use of at a later time. The disease is usually diagnosed in children and young adults, although it can technically strike at any age.
Higher-risk ethnic groups include African Americans, Latinos and Hispanics, Native Americans, Alaskan Natives, Asians, and those with Pacific Islander American heritage. A free diabetes risk test is provided by and only takes a few minutes to complete. Occasionally, especially later in life, a person with type 2 may be placed on insulin to better control blood sugar. Specifically, this "Newcastle diet" recommends reducing calorific intake to 800 calories for 8 weeks. They are also at increased risk for serious health problems like blindness, kidney failure, heart disease, and loss of toes, feet, or legs. Adults who lose weight and engage in even moderate physical activity can significantly increase their chances of preventing or delaying the onset of diabetes. Prevention of prediabetes progression to type 2 diabetes with the use of natural products appears to a cost-effective solution. During the oxidative metabolism of glucose and fatty acids, reducing equivalents (NADH or FADH2) are generated from glycolysis, the TCA cycle and ?-oxidation. IntroductionThe major disease epidemics of modern society are not those of contagion, but are the result of lifestyle imposed upon our genetic pre-disposition.
Glucose comes from foods such as breads, cereals, pasta, rice, potatoes, fruits, and some vegetables. These cells are called beta cells, and they make insulin, a hormone that prompts cells to absorb glucose. In type 2 diabetes, insulin production is too low or the cells have become resistant to the hormone, essentially ignoring it. While some type 2 diabetics manage to avoid needing insulin for decades or even their whole lifetime, type 2 diabetes is a progressive disease, meaning it worsens over time in most individuals. When a person eats, insulin releases blood glucose to the body's cells, where it becomes an energy source for making proteins, sugars, and fat.
Scientists do not know yet exactly what causes type 1 diabetes but suspect the disease involves a combination of genetic, environmental, and autoimmune factors. Symptoms include unexpected weight loss, blurred vision, feeling tired or sick more frequently, more frequent urination (especially at night).
Researchers who studied this diet found that Type 2 diabetes is caused by fat clogging up the pancreas, preventing it from producing sufficient insulin to control blood sugar level. It’s also very important for people with type 1 and 2 to keep in close contact with a diabetes specialist (endocrinologist). Binding of insulin to the insulin receptor initiates a signaling cascade that involves multiple phosphorylation events (green circles) and leads to alterations in glucose and lipid metabolism.2.
When NADH and FADH2 are oxidized to NAD+ or FAD, electrons pass along the mitochondrial respiratory chain while protons are pumped into the intermembrane space through complex I, III and IV. Unrestricted access to calorie-dense food, along with a reduction in physical activity, has resulted in a rapid rise in metabolic disorders. This means that insulin levels can be low, high, or normal, and may even fluctuate if a diabetic is not careful with treatment. Because of this, type 2 diabetics may require insulin and other medications later in life or if they do not carefully manage their diets and exercise.
Between meals, insulin regulates the body's use of these stored proteins, sugars, and fats. These specialists work with other professionals (diabetes nurse educators, dietitian educators, etc.) to give patients the best care possible. The daily 800-calorie diet comprises either three 200g liquid food supplements of soups and shakes, and 200g of non-starchy vegetables or the tastier 800g equivalent of calorie-shy meals you measure out yourself, plus 2-3 liters of water.
When the sucrase and glucoamylase activities of GO2KA1 and control mice were evaluated using enzymatic assay, we observed that GO2KA1 significantly inhibited sucrase in all 3 parts of the intestine, while glucoamylase activity was significantly reduced only in the middle and lower part. The pumped protons generate an electrochemical gradient across the inner mitochondrial membrane, which is used as the driving force for ATP synthase (complex V) to produce ATP. After the 8 weeks of "starvation", calorific intake can be increased but only to a maximum of two-thirds of the pre-diagnosis level. When the sucrase-isomaltase (SI) complex expression on mRNA level was evaluated, we observed that GO2KA1 had minimal inhibitory effect on the upper part, more pronounced inhibitory effect on the middle part, while the highest inhibition was observed on the lower part. T2D rarely occurs in isolation and is frequently associated with a number of comorbidities, including obesity, dyslipidemia, cardiovascular disease, and inflammation, collectively referred to as the metabolic syndrome. Insulin resistance causes an over-release of fatty acids, a negative condition frequently seen in obesity-related diabetes.
A central aspect of the disorders comprising the metabolic syndrome is insulin resistance; defined as an impaired ability for insulin to regulate fuel metabolism in target tissues. With respect to glucose homeostasis the main insulin-responsive tissues involved are skeletal muscle, liver and adipose tissue.
Under normal physiological conditions, insulin is released into the circulation from the beta cells in the islets of Langerhans in the pancreas in response to the ingestion of a meal.
Type 2 diabetes accounts for about 90% to 95% of all diagnosed cases of diabetes in adults [1]. Upon binding to its receptor, insulin stimulates a well-described signaling cascade [1] involving the phosphorylation, docking and translocation of a series of signaling molecules, ultimately leading to alterations in specific endpoints of glucose and lipid metabolism (Figure 1):In skeletal muscle, insulin promotes the translocation of the glucose transporter GLUT4 to the plasma membrane to increase glucose uptake and also stimulates glycogen synthesis. Pre-diabetes is a condition in which individuals have blood glucose levels higher than normal but not high enough to be classified as diabetes [2]. The major hepatic actions of insulin are the promotion of glycogen and lipid synthesis and the suppression of gluconeogenesis. At least 347 million people worldwide have diabetes and this figure is likely to double by 2030 [3].
In adipose tissue, insulin stimulates GLUT4-mediated glucose uptake and lipid synthesis, and additionally represses lipolysis, leading to net lipid accumulation.
In United States, in 2010, 25.8 million people (10% of American adults) had diabetes and by 2050 this figure is expected to jump to 33%, or one-third of all American adults [1]. Binding of insulin to the insulin receptor initiates a signaling cascade that involves multiple phosphorylation events (green circles) and leads to alterations in glucose and lipid metabolism.In the insulin resistant state, the effect of insulin on the above pathways is compromised, leading to insufficient uptake of glucose into tissues and an impaired suppression of hepatic glucose output. To overcome the diminished effectiveness of insulin, the pancreatic beta cells secrete more insulin. I±-Glucosidase inhibitors, such as acarbose and voglibose, are the only oral anti-diabetes agent approved for the treatment of pre-diabetes [5]. The ensuing hyperinsulinemia can adequately compensate for the insulin resistance in most of the population, however in genetically susceptible individuals, the beta cells ultimately fail in the face of the increased workload and this leads to elevated blood glucose levels and T2D. Briefly, lower doses of acarbose have shown to have beneficial effect towards pre-diabetes management by delaying the absorption of carbohydrates from the gut [6].
Thus insulin resistance can be considered a very early and important player in the pathogenesis of T2D.At the molecular level, the precise mechanisms responsible for insulin resistance are not fully elucidated. Studies have reported overactivation of stress-related and inflammatory pathways in tissues of insulin resistant humans and rodents. Digestion of dietary carbohydrates in the distal small intestine begins with hydrolysis, which is carried out by a group of hydrolytic enzymes that includes pancreatic I±-amylase and intestinal I±-glucosidases [9]. For example, ER stress was shown by the Hotamisligil lab to be present in the liver of obese mice and subsequent studies using chaperones that reduce ER stress revealed improvements in metabolic homeostatsis [2,3]. Inhibition of I±-glucosidase suppresses postprandial hyperglycemia by slowing down the catabolism of dietary carbohydrates [6, 10]. Oxidative stress has also been implicated in the development of insulin resistance, with studies showing elevated reactive oxygen species generation in insulin resistant cell models, rodents and humans [4-6].
Recent studies showed that phenolic phytochemicals from botanical sources are natural inhibitors of I±-amylase and I±-glucosidase [11a€“14] and thus can be potentially used to manage pre-diabetes progression to type 2 diabetes.Chitosan is a natural product commercially obtained by the deacetylation of chitin.
Finally, inflammation in adipose tissue and liver (and to some extent muscle) has been reported in obese, insulin-resistant humans and rodents [7,8].
Low molecular weight chitosan oligosaccharide results from the enzymatic digestion of chitosan and has been shown to have many health beneficial biological activities including antitumor [15, 16], immunoenhancing [17], anti-hypertension [18] and anti-diabetic [19, 20]. While the above factors are often described as causative players in the development of insulin resistance, it still remains unresolved whether they are the primary factors leading to diminished insulin action, or if they arise as a consequence of insulin resistance.One factor that is one of the earliest defects associated with insulin resistance and T2D is lipid accumulation in non-adipose tissues [9-13].
Under conditions of excess nutrient supply, fatty acids and their metabolites inappropriately spillover into tissues such as skeletal muscle, liver and the heart, precipitating defects in insulin action.
More specifically, while elevated triglycerides are frequently reported in tissues of insulin resistant humans and rodents, the accumulation of metabolically active long chain acyl-CoAs (LCACoAs) and other cytosolic lipid metabolites, such as ceramides and diacylglycerol (DAG), are considered to be more directly linked with insulin resistance [9,10]. In support of this, the above lipid metabolites can activate many pathways and factors (e.g.
Under conditions of elevated lipid availability, enhanced uptake of fat into tissues contributes to greater lipid deposition [14,15]. Recently, the effect of degree of chitosan hydrolysis on type 2 diabetes prevention via inhibition of carbohydrate hydrolysis enzymes was evaluated [21].
Any impairment in the utilization (oxidation) of lipids would also be predicted to increase partitioning of lipids into storage pools. Indeed, over the last decade a popular theory has emerged suggesting that defects in mitochondrial oxidative metabolism, particularly in skeletal muscle, lead to obesity and lipid accumulation and thus may play an important role in the pathogenesis of insulin resistance and T2D [16]. Mitochondrial structure and functionThe mitochondrion is the key site for energy production in cells, providing a platform for the oxidation of fuel substrates to produce ATP.
During the oxidative metabolism of nutrients (primarily glucose and fatty acids under normal circumstances), reducing equivalents (NADH or FADH2) are generated from glycolysis, the TCA cycle and ?-oxidation. Corn starch, casein, vitamin mix, mineral mix, calcium phosphate and sodium chloride were purchased from Raon Bio (Yonginsi, Korea). Are mitochondria good therapeutic targets for the treatment of insulin resistance and T2D?7.1. When NADH and FADH2 are oxidized to NAD+ or FAD, electrons pass along the mitochondrial electron transport chain coupled to the pumping of protons into the intermembrane space through complex I, III and IV.
Total cholesterol and total glyceride kits were purchased from Stanbio laboratory (Boerne, USA). The pumped protons generate an electrochemical gradient across the inner mitochondrial membrane, which is used as the driving force for the ATP synthase (complex V) to produce ATP. All rats were adapted to a meal-feeding schedule of free access to Pico 5053 diet (Oriental Bio.
Mitochondrial biogenesisMitochondrial function within a given tissues is regulated at a number of different levels, including the number or density of mitochondria. The experimental protocols were approved by the Institutional Animal Care and Use Committee (IACUC) of the Hannam University (Approval number: HNU2012-0003).
The biogenesis of new mitochondria involves a coordinated interaction between the nuclear and mitochondrial genomes [17].

The mitochondrial genome encodes for 13 protein subunits of the mitochondrial respiratory complexes, as well tRNAs and rRNAs necessary for the translation of the mitochondrial-encoded proteins. The nuclear genome therefore encodes the vast majority of mitochondrial proteins and also encodes the transcription factor responsible for controlling mitochondrial transcription, namely TFAM.
The small intestine was cut transversely into three segments (upper, middle, and lower part) of roughly equal length. Proteins encoded by the nucleus are translated in the cytosol and imported into the appropriate mitochondrial compartments via a suite of import complexes [18].
Thus it is obvious that mitochondrial biogenesis is an extremely complex process, reliant upon the exquisite orchestration of separate genomes and multiple cellular processes. Furthermore the concentration of HbA1c was measured using Nycocard reader (Anyang, Korea).Preparation of crude enzyme extractsThe small intestine was cut transversely into three segments (upper, middle, and lower part) of roughly equal length.
The master regulators of the mitochondrial biogenic program are the peroxisome proliferator-activated receptor gamma (PPAR?) coactivator (PGC-1) family of transcriptional coactivators. The PGC-1 proteins are promiscuous coactivators that interact with and promote transcriptional activity in the key transcription factors (described below) that regulate the expression of genes involved in mitochondrial substrate oxidation, fibre-type determination, mitochondrial biogenesis and mitochondrial function [17,19].
The PGC-1 proteins do not bind directly to DNA, but instead recruit a wide array of chromatin-remodelling cofactors to transcriptional complexes. PGC-1? was the first described member of this family, initially identified in a screen for activators of PPAR? in brown adipocytes [20].
Sucrase and Glucoamylase activities were assayed by modifying a method developed by Dahlqvist [22]. The other members of the family, PGC-1? and PRC were identified based on sequence homology to PGC-1? [21,22].
Overexpression and knockout studies for PGC-1 proteins have provided clear evidence that these coactivator proteins induce increases in mitochondrial oxidative capacity and promote a switch to a more oxidative fibre type in muscle [23-27].
PGC-1? appears to be the most responsive member of this family, with PGC-1? proposed to be important in the regulation of basal mitochondrial content [28]. The lysed cells were then subjected to electrophoresis using sodium dodecylsulfatea€“polyacrylamide gel electrophoresis (SDSa€“PAGE) and transferred to nitrocellulose membranes.
Environmental stimuli such as exercise, fasting and cold exposure can induce a rapid increase in PGC-1? expression and activity [19]. The membranes were reacted with primary antibodies for 3A h and then incubated with the appropriate goat peroxide-conjugated secondary antibodies for 1A h at room temperature. The activity of PGC-1? is regulated by a number of post-translational mechanisms including acetylation and phosphorylation.
The relative level of PGC-1? acetylation is determined by the balance between the activity of the acetyltransferase GCN5 and the NAD+ dependent deacetylase SIRT1 [30,31]. With respect to phosphorylation, the energy sensing kinase AMPK has been shown to directly phosphorylate PGC-1? and alter its transcriptional activity [32]. Thus in responsive to specific stimuli, changes in the concentrations of key molecules within the intracellular milieu (e.g.
We observed that fasting glucose levels were significantly reduced with GO2KA1 treatment to levels similar to acarbose (TableA 2).
NAD+, adenine nucleotides) results in stimulation of upstream regulators of PGC-1? activity and initiaition of the mitochondrial biogenic cascade.
Nuclear transcription factors involved in mitochondrial biogenesisPGC-1 proteins orchestrate the mitochondrial biogenic program by promoting transcriptional activity through a variety of transcription factors.
Nuclear transcription factors bind to specific sequences in gene promoter regions to regulate transcription of a subset of specific genes. Nuclear Respiratory Factor 1 (NRF-1)NRF-1 plays a crucial role in coordinating nuclear and mitochondrial gene expression. It induces the expression of TFAM, as well as other components of the mitochondrial transcriptional machinery (e.g.
NRF-1 also promotes the expression of mitochondrial import proteins that are involved in transporting nuclear-encoded proteins into mitochondria. Forced overexpression of NRF-1 in skeletal muscle in mice, results in increased expression of a subset of mitochondrial proteins, but no net increase in mitochondrial oxidative capacity [36]. The target genes of NRF-2 include all respiratory complex IV subunits, TFAM and a range of other proteins involved in mitochondrial transcription and replication [38].
Consistent with the findings in NRF-1 knockout animals, NRF-2 deletion also causes a lethal phenotype, underlying the crucial importance of this transcription factor [39]. Our observations suggest that sucrase activity is significantly reduced in throughout the small intestine (FigureA 3).
Estrogen-Related Receptors (ERR)The estrogen related receptor family contains 3 members, ERR?, ERR?, ERR?. ERRs regulate the expression of a wide array of genes involved in substrate uptake, the TCA cycle, fatty acid oxidation (FAO), oxidative phosphorylation and mitochondrial fusion [40,41]. ERR? knockout mice only display a mild phenotype [42], however deletion of the other two isoforms results in a lethal phenotype [43,44].
Peroxisome-Proliferator Activated Receptors (PPAR)Similar to the ERR family, PPARs nuclear receptors that exist as 3 separate isoforms PPAR?, PPAR?, PPAR?.
The expression of PPARs varies markedly across different tissues, with PPAR? being highly expressed in liver, PPAR? in skeletal muscle and PPAR? in adipose tissue [45]. PPARs are activated by long-chain polyunsaturated fatty acids and a range of lipid derivatives, and several mitochondrial genes, particularly those involved in fatty acid oxidation, are amongst their gene targets [46,47]. We observed that acarbose significantly reduced SI expression in all three intestinal parts (FigureA 5).
Yin Yang 1 (YY1)A range of mitochondrial genes are also regulated by the transcription factor YY1. Puigserver’s group have shown that the regulation of mitochondrial oxidative function by mTOR is regulated through YY1 [48] and recently it has been shown that mitochondrial function and morphology are abnormal in mice with muscle-specific YY1 knockout, highlighting an important role for this transcription factor in regulating mitochondrial function [49]. We observed that in the upper part SI expression was slightly up-regulated (FigureA 5), when compared to control. In the middle part, the expression was significantly reduced, compared to control and it was in the same levels with the acarbose treated group (FigureA 5). MitophagyIn addition to the biogenesis of new organelles, mitochondrial content is also partly determined by the rate of degradation. Indeed, mitochondrial autophagy (or mitophagy) is now recognized as a key quality control process regulating mitochondrial homeostasis [50]. Autophagy is a conserved cellular event in which damaged organelles and proteins are degraded in a two-step process, that first involves the formation of a double membrane structure called the ‘autophagosome’, followed by the fusion of the autophagosome with lysosomes and the subsequent degradation of the enveloped contents.
Mitophagy can be inititiated by a number of events that signal stress within mitochondria, such as opening of the permeability transition pore or fragmentation of mitochondria [51,52]. Prevention of the progression of pre-diabetes to type 2 diabetes using natural products is an appealing strategy to control the incidence of diet-linked hyperglycaemia.
From a physiological perspective, mitophagy plays important roles in several developmental processes, such as red blood cell maturation and the removal of paternal mitochondria following fertilization of the oocyte [53-55]. Intrinsic factors regulating mitochondrial functionWhile the number of mitochondria is obviously an important determinant of the oxidative capacity of different tissues, variations in the intrinsic properties of mitochondria are also critical. Mitochondria from different sites in the body can have different capacities for the same process. For example, mitochondria from red slow-twitch and white fast-twitch muscle display very different rates of fatty acid oxidation [57]. This difference is in line with the functional requirements of these muscles, and is likely related to the differences in protein expression of key enzymes in this pathway [58]. In addition to differential expression of proteins within specific pathways, another emerging factor that may influence mitochondrial oxidative capacity is post-translational modifications of mitochondrial enzymes. Our observations suggest that GO2KA1 administration resulted in reduced sucrase and glucoamylase activities (FiguresA 3 and 4). Following translation, many different facets of protein function (activity, subcellular localization, protein-protein interactions) can be altered by the addition of functional groups to specific residues in the protein. It is well-documented that acarbose binds with high affinity and specificity to I±-glucosidases found in the brush border of the small intestine [5, 9, 23]. The most well-described PTM is likely phosphorylation, and proteomics screens have revealed widespread phosphorylation of mitochondrial proteins [59]. However, when acarbose is used at lower doses for prevention of pre-diabetes progression to type 2 diabetes, the resulting effect is milder inhibition of glucosidases throughout the small intestine to eventually retard glucose uptake [5].
The activity of specific mitochondrial proteins, such as uncoupling protein 3, has been shown to be directly regulated by phosphorylation [60]. Other recent work has shown that perhaps the most abundant PTM in mitochondria is lysine acetylation.
Acetylation involves the transfer of an acetyl group from acetyl-CoA to a lysine residue in specific proteins. The major side effect of acarbose administration is flatulence and diarrhoea resulting from the excessive inhibition of starch breakdown. This inhibition of pancreatic I±-amylase by acarbose may induce major adverse effects such as abdominal distention, flatulence, meteorism, and diarrhea a consequence of undigested carbohydrates entering the colon where they are used as nutrients for bacterial growth [24, 25].
The differences in cecum weight and volume among the control, acarbose, and GO2KA1 groups are shown in TableA 2. Mitochondrial dynamicsMitochondria are not static organelles, but exist largely as a reticular network. Acarbose administration resulted in a 3-fold increase in the weight and volume of the cecum compared with the control and GO2KA1, which is consistent with a previous study [24, 25]. Mitochondria are constantly engaged in the process of fusion and fission, providing morphological plasticity to allow adjustments in response to the prevailing cellular stresses and metabolic requirements [65].
Mitochondrial fusion is mediated by the mammalian GTPases mitofusin 1 and mitofusin 2, as well as optic atrophy protein 1 (Opa1).
Fusion occurs in a two-step process, which initially involves fusion of the outer membrane (mediated by mitofusins), followed by subsequent fusion of the inner membrane (driven by Opa1) [66,67]. Here we show in an animal model that the mechanism involves inhibition of carbohydrate hydrolysis enzymes. Fission is regulated by another GTPase, dynamin-related protein 1 (Drp1), which resides in the cytosol and is recruited to the mitochondrial surface to engage other key components of the fission machinery (e.g. One of the authors is a member of Kunpoong Bio, the company that produces the low molecular weight chitosan oligosaccharide. The fusion process is thought to allow two mitochondria to functionally complement each other through the exchange and repartitioning of their respective components (e.g. Fission on the other hand is important both in the separation of the organelle into daughter cells during cell division and also in isolating and targeting damaged mitochondria for degradation.
Kunpoong bio played no role in the design and interpretation of the results.Authorsa€™ contributionsJGK, SHJ and KSH conducted the animal experiment and analyzed the data. Collectively the balance of fusion and fission allows mitochondria to form a spectrum of shapes from small individual units to elongated interconnected networks.In muscle cells, the mitochondrial network is arranged into two discrete, but interconnected pools – the subsarcolemmal (SS) pool near the cell surface, and the intermyofibrillar (IMF) pool in the interior of the cell between myofibres [70-72]. These two pools of mitochondria have been reported to display some differences in their metabolic characteristics, with SS mitochondria appearing to be more responsive to increase their oxidative capacity following an exercise stimuli than IMF mitochondria [57,73]. Despite the differences between mitochondrial pools, it has been proposed that the arrangement of mitochondria may important for efficient mitochondrial function; SS mitochondria have greater access to oxygen and metabolic substrates, and the proton gradient generated through substrate oxidation in the SS pool may potentially contribute fuel ATP synthesis in the IMF pool, where energy demands are highest during contraction [71].
Mitochondrial dysfunction in muscle and its association with insulin resistanceAs detailed above, mitochondria represent complex organelles and perturbations in any aspect of mitochondrial regulation and function, could impact on metabolic homeostasis. The mitochondrial theory of insulin resistance has developed over the last 10-15 years and is based on the notion that defective mitochondrial metabolism will result in inadequate substrate oxidation, leading to a buildup of lipid metabolites and the subsequent development of insulin resistance. Support for this theory comes from many studies in humans and rodents, which have largely examined skeletal muscle and are reviewed below.In the late 1990’s and early part of last decade, several groups published studies showing that muscle from obese and insulin resistant subjects displayed reduced oxidative enzyme activity [74-76]. Some of these studies also examined lipid oxidation either in muscle homogenates, or by making RQ measurements across the leg, and it was shown that fatty acid oxidation was also decreased in obese, insulin resistant subjects compared to age-matched controls, potentially suggesting that defects in mitochondrial metabolism may be involved in the development of obesity and insulin resistance [74,75]. A year later, two influential microarray studies were published, reporting a coordinated downregulation of genes involved in mitochondrial biogenesis and oxidative phosphorylation in subjects with T2D and non-diabetic individuals with a family history (FH+) of T2D [78,79]. These microarray studies were considered particularly important, as they documented a reduction in the master regulator of mitochondrial biogenesis, PGC-1?, and thus they provided a mechanism for the reduced oxidative gene expression. They were also important, as they showed that abnormal mitochondrial gene expression could be observed in insulin resistant relatives of patients with T2D and thus may be a pathogenic factor in the ‘pre-diabetic’ state.
Numerous approaches have been employed, including measurements of parameters in frozen muscle samples (e.g.
All these assays provide some indication of mitochondrial function, however they may not always correlate with each other and this needs to be considered when interpreting studies in this area.
The level of mtDNA was also shown to be lower in both obese, insulin resistant subjects and obese subjects with T2D [85,86]. The activity of specific enzymes involved in oxidative pathways have been reported to be lower in various insulin-resistant populations [81,86,88,89] and additionally electron microscopy studies have reported reduced mitochondrial size and density in insulin-resistant muscle [77,80,86]. Interestingly, in the studies reporting mitochondrial deficiencies, there has been disparate results regarding which population of mitochondria may underlie the functional defects. Differences in mitochondrial function may not only be present within different intramuscular populations, but also between different muscles across the body. Rabol and colleagues used high resolution respirometry to measure mitochondrial function in saponin-permeabilised fibres from m. This impairment in insulin action was associated with a 40% reduction in ATP synthesis capacity, and a pronounced accumulation of intramuscular fat.
The same group published a paper the following year in which they studied lean insulin-resistant offspring of patients with T2D using the same methods. The insulin-resistant offspring displayed a 60% reduction in insulin-stimulated glucose uptake into muscle and this was again associated with increased intramyocellular lipid and reduced basal mitochondrial ATP synthesis capacity [93]. In several other studies, patients with T2D have been shown to have reduced ATP synthesis capacity or phosphocreatine recovery rates, indicative of reduced mitochondrial function in these populations [96-99]. A further interesting case report using MRS showed that a MELAS patient with mtDNA mutations, displayed insulin resistance in muscle association with reduced baseline and insulin-stimulated ATP synthesis capacity [100].A number of investigations have sought to determine if there is an intrinsic difference in the functional capacity per mitochondrion that may underlie the reductions in mitochondrial function reported with MRS.
These studies therefore only see marked differences when mitochondrial capacity is expressed per unit mass of skeletal muscle and thus indicate that in vivo mitochondrial defects observed with MRS may be more strongly related to reductions in mitochondrial number, than to substantial intrinsic mitochondrial defects. Another study from this group also observed similar differences in intrinsic mitochondrial function in T2D patients compared to BMI-matched controls [96].

One limitation of the aforementioned studies is that they only provide static measurements of different populations at a given time and are unable to delineate whether the observed defects in mitochondrial metabolism are primary drivers of insulin resistance or arise as a consequence of decreases in insulin action.
In this regard, intervention studies in rodents and humans have provided some experimental evidence that manipulations which result in declines in insulin action, are also associated with mitochondrial dysfunction. For example, infusion of fatty acids into humans for 6–48h to mimic the effects of chronic lipid overload resulted in a robust induction of whole-body insulin resistance and reduced insulin-stimulated ATP synthesis rates and expression of mRNA encoding PGC1? and other mitochondrial genes in muscle [104-106]. In healthy male subjects, high-fat feeding for 3 days was sufficient to reduce mRNA levels of PGC1?, PGC-1? and several other mitochondrial genes in skeletal muscle [107]. Similarly, genetic, or high-fat diet-induced obesity and insulin resistance in rodents has been reported by several groups to reduce mitochondrial gene expression, protein expression and mitochondrial respiration in skeletal muscle [107-111]. Providing additional evidence of a link between mitochondrial dysfunction and insulin resistance is the fact that antiretroviral therapy used to suppress human immunodeficiency virus infection causes insulin resistance in association with mtDNA copy number [112].
Collectively, the above studies illustrate that there are many instances where defects in mitochondrial metabolism and impairments in insulin action occur in conjunction with each other in skeletal muscle. LiverThe liver plays a major role in regulating glucose homeostasis, producing glucose during the fasting state and storing glucose after the ingestion of a meal. Hepatic insulin resistance causes impaired glycogen synthesis and reduced suppression of endogenous glucose and is closely correlated with excess accumulation of lipid in liver. Chronic elevation of liver lipid content is referred to as non-alcoholic liver disease (NAFLD) and this condition progresses to non-alcoholic steatohepatitis (NASH) when inflammatory and fibrotic processes become involved.
A range of different parameters have been studied in rodents and humans with respect to liver mitochondrial metabolism. The collective findings indicate that the liver appears to be able to adapt to an excess of lipid by upregulating fatty acid oxidative capacity and TCA cycle activity, but this is not always coupled to a concomitant increase in electron transport chain activity, and as a consequence reactive oxygen species are produced (see [113] for an excellent review on the topic).
White adipose tissueWhite adipose tissue (WAT) serves a principal role as the most important energy store in the body. However it has become increasingly clear over the last decade that WAT is also an active endocrine organ, releasing adipokines that influence whole-body energy homeostasis and insulin action. Mitochondrial content in WAT is low compared to other tissues, however the diversity of mitochondrial proteins in WAT has been shown to be greater than in muscle and heart [117].
Intact mitochondrial metabolism is critical for maintaining normal WAT functions, such as the appropriate synthesis and secretion of adipokines and cycling reactions involved in lipid synthesis [118].WAT mitochondrial content has been reported to be reduced in insulin-resistant humans and rodents. In women with T2D, electron transport chain genes were shown to be downregulated in visceral WAT independently of obesity and perhaps as a consequence of TNFalpha-induced inflammation [119]. In obese humans, mtDNA copy number was reported to be lower than in control subjects and was directly correlated with basal and insulin-stimulated lipogenesis [120]. In rodent models of genetic or dietary-induced obesity and insulin resistance, there are reductions in mtDNA copy number, mitochondrial density and mitochondrial OXPHOS activity [121-123]. Administration of thiazolidinediones promotes mitochondrial biogenesis in WAT in animals and humans, in conjunction with improved whole-body insulin sensitivity [46,123], suggesting that specific changes in WAT mitochondrial metabolism in obesity and T2D, may be imparting whole-body metabolic consequences. Indeed, recent work has shown adipose-restricted alterations in mitochondrial activity can have profound effects on global glucose and lipid homeostasis [124,125]. Brown adipose tissueUnlike WAT, the principal function of brown adipose tissue (BAT) is energy dissipation, rather than energy storage.
BAT has a high mitochondrial density per gram of tissue, and the unique presence of uncoupling protein 1 (UCP1) allows brown adipocytes to couple the oxidation of lipids, not to ATP synthesis, but to heat generation via proton leak across the mitochondrial inner membrane. Interest in brown adipose tissue has recently soared on the back of 3 important papers published in 2009 that unequivocally demonstrated the presence of functional BAT in humans [126-128].
HeartLike skeletal muscle, translocation of GLUT4 in response to insulin occurs in myocardium. This process is blunted in insulin-resistant humans and animals in association with other abnormalities in fuel metabolism ([132-134]. With respect to mitochondrial metabolism, genetic and diet-induced obesity and type 2 diabetes in rodents is associated impaired mitochondrial function [135-137].
Insulin resistanceInsulin is a potent anabolic hormone and it has been proposed that mitochondrial dysfunction may emerge secondary to insulin resistance.
Insulin infusion in humans leads to increases in mitochondrial gene expression, higher oxidative enzyme activity and elevated ATP synthesis in muscle [143,144].
This response is attenuated in insulin-resistant T2D individuals, supporting a direct role for insulin resistance leading to mitochondrial dysfunction [143]. Further evidence for this notion comes from a study by Karakelides et al, who showed that acute insulin removal from subjects with type 1 diabetes, caused reductions in mitochondrial ATP production and in mitochondrial gene expression in skeletal muscle [145]. Additionally a recent study in patients with congenital defects in insulin signal transduction, reported that mitochondrial function (assessed by phosphocreatine recovery rates) in muscle was reduced in this population [146]. Finally a recent study that induced insulin resistance by prolonged fasting, also reported defects in mitochondrial function [147]. Overall these studies indicate that insulin can directly regulate mitochondrial biogenesis and metabolism, and therefore it is plausible that some of the mitochondrial defects observed in insulin-resistant subjects, could be a consequence of the insulin resistance itself. Altered mitochondrial dynamics Any perturbation in the dynamics of the mitochondrial network could potentially contribute to the pathogenesis of insulin resistance in skeletal muscle.
The complex process of mitochondrial fission and fusion has been described above and alterations in key proteins mediating these dynamic events have been reported in insulin resistant and obese states.
The expression of mitofusin 2 (MFN2), which appears to have additional pleitropic effects in cells beyond the maintenance of the mitochondrial network [148-152], is reduced in the skeletal muscle of obese insulin-resistant humans, type 2 diabetic humans and diabetic Zucker rats [149,153] and correlates with the capacity for glucose oxidation [154]. Recent work has also shown that mice deficient in the mitochondrial protease OMA1, display obesity and altered metabolic homeostasis, due to altered processing of the inner membrane fusion protein OPA1 and disruptions in mitochondrial morphology and fuel metabolism [156]. It has also been reported that abnormalitieis in mitochondrial fission events may play a role lipid-induced insulin resistance.
In C2C12 muscle cells, palmitic acid (but not other long-chain fatty acids) was shown to induce mitochondrial fragmentation in conjunction with insulin resistance and this effect could be blocked by genetic or pharmacological inhibition of Drp1 [157].
Reduced physical activityPhysical inactivity has recently been reported to be as big a risk factor for non-communicable diseases as smoking, stressing the importance of exercise in metabolic health [158].
Exercise is one of the major stimuli for mitochondrial biogenesis and chronic inactivity results in decreases in mitochondrial number in muscle [159]. A number of studies have shown that obesity and other metabolic disorders are characterised by decreased physical activity levels and elevations in sedentary behaviour [160-162].
Given these differences, it is likely that some of the mitochondrial defects reported in overweight or obese insulin-resistant subjects may be explained, in part, by low levels of physical activity.
Genetic and epigenetic factorsThere is evidence in the literature that the metabolic phenotype of skeletal muscle may be strongly influenced by genetic programming.
For example, despite being cultured under similar conditions for several weeks, studies have shown that primary human skeletal muscle cells in culture display a similar metabolic phenotype (e.g. PGC-1?, NDUFB6) have been linked with insulin action and T2D, as have mtDNA deletions [165,166]. An emerging area of research is also the regulation of mitochondrial function by epigenetic factors.
Barres et al showed that the promoter of PGC-1a is methylated at non-CpG sites and exposure of primary human myotubes to hyperlipidemia or inflammatory stimuli, promoted PGC-1? hypermethylation. Intriguingly PGC-1? hypermethylation was observed in muscle of T2D patients in conjunction with reduced mitochondrial density [167].
PGC-1? hypermethylation has also been linked with insulin resistance in non-alcoholic fatty liver disease [168]. A number of other studies have also reported that methylation of other mitochondrial genes (e.g. NDUFB6 and ATP50) as well as TFAM, can be regulated by methylation and associated with insulin resistance. One recent study has also shown that methylation of mitochondrial DNA is also correlated with severity of NAFLD [171]. In addition to methylation, acetylation can also influence gene transcription and the potential importance of this epigenetic factor is highlighted by a recent study showing that pharmacological inhibition of HDAC1 in cells and obese animals could promote mitochondrial biogenesis and improve metabolic phenotype [172].
Oxidative stressOxidative stress can be defined as a chronic imbalance between the production of reactive species and the protection against these species by antioxidant defenses, ultimately leading to macromolecular damage. Reactive oxygen species (ROS) are an unavoidable byproduct of metabolic reactions within cells and a major site for ROS production is the mitochondrion [173]. Studies from a number of different groups have shown that in genetic or diet-induced obese rodents, there is increase ROS production [4,5,174,175]. Importantly, most [4,5,175,176], but not all studies [177] show that insulin action is improved by genetic or pharmacological attenuatation of mitochondrial ROS production, indicating an especially important role for generation of reactive species in this organelle. Since mitochondria are particularly susceptible to oxidative attack [178,179], it is possible that overactive ROS generation in response to obesity or high dietary lipid supply, may lead to defects in mitochondrial function.
Post-translational regulation of mitochondrial functionAs noted above, there is an emerging appreciation for the fact that specific mitochondrial enzymes and pathways may be regulated by post-translational modifications. Several groups have shown that mitochondrial acetylation is increased in tissues of diet-induced obese mice [180,181]. SIRT3 is a key regulator of mitochondrial acetylation and the expression of this deacetylase enzyme is markedly reduced in a number of different experimental models of insulin resistance and diabetes [181-183]. SIRT3 KO mice display insulin resistance in muscle [182] and these mice also exhibit an accelerated development of the metabolic syndrome when challenged with long-term high fat diet, in association with pronounced hyperacetylation of liver mitochondria [181].
Interestingly, in addition to showing that SIRT3 KO mice have a compromised phenotype, Hirschey et al have also shown that a point mutation in SIRT3 that results in reduced activity of this protein, is associated with the development of metabolic syndrome in humans [181]. The above studies suggest that altered acetylation of mitochondrial proteins may associate with insulin resistance and impaired mitochondrial function, and while further study in this field is required, there is some evidence that other mitochondrial PTMs may also be altered in insulin resistance and T2D [184,185].6. Mitochondrial dysfunction is not always linked with insulin resistanceDespite the frequent association of mitochondrial dysfunction and insulin resistance, evidence of a cause-and-effect relationship between the two is still lacking.
In fact, a substantial literature now exists in both humans and rodents directly challenging the notion that deficiencies in mitochondrial oxidative capacity are an obligate part of the link between lipid accumulation (obesity) and insulin resistance. Human studiesTrenell and colleagues used MRS to determine basal and maximal ATP turnover in muscle of well-controlled T2D patients compared with physical activity-, age- and weight-matched control subjects and observed no difference between the two groups [186]. A similar finding was reported in a separate population where post-exercise phosphocreatine recovery indicated similar mitochondrial function between obese patients in either the early or advanced stages of T2D and normoglycemic controls matched for age, body composition and habitual physical activity levels [187]. A further study from the same group also recently reported similar in vivo mitochondrial function with MRS in prediabetic subjects compared with age, BMI and activity-matched controls, despite the presence of insulin resistance (by HOMA-IR and OGTT) [83]. In young lean men born with low birth-weight, mitochondrial function by MRS and mitochondrial gene expression are intact, despite these subjects displaying several pre-diabetic characteristics [188]. Two groups have also reported measurement of in vitro ATP production capacity and respiratory charactersitics in mitochondria isolated from obese subjects and fail to see any difference compared to controls [189,190]. Studies in different ethnic groups have also provided data contrary to the mitochondrial dysfunction theory of insulin resistance. In this study the authors also went on to stratify the Asian Indian group into those with T2D and those without, and despite the diabetic individuals displaying impaired insulin sensitivity and increased muscle lipid levels, there was no difference in the various markers of mitochondrial oxidative capacity. The studies above provide evidence that at least in those populations, mitochondrial dysfunction does not seem to be present in a number of insulin resistant groups. In line with these examples of a discordant relationship between these two variables, several human intervention studies have also shown that changes in insulin sensitivity can occur without concurrent improvements in mitochondrial function.
For instance, dietary restriction in overweight and obese subjects enhanced insulin sensitivity, without altering mtDNA, cardiolipin content or NADH-oxidase activity [192]. Improved insulin sensitivity was reported in insulin-resistant subjects with a family history of T2D following 7 days of treatment with the anti-lipolytic agent acipimox, yet mitochondrial gene expression in muscle actually declined in these subjects [193].
Treatment of diabetic patients with rosiglitazone improved insulin sensitivity, without altering in vivo mitochondrial function or markers of mitochondrial content [194,195].
Recently Samocha-Bonet also showed that 28 days of high-fat overfeeding was sufficient to induce insulin resistance in health humans, without any detectable defects in various markers of mitochondrial function [6]. Rodent studiesTo complement the studies in humans, a number of investigators have used gene-manipulated mice to more directly test whether specifically targeting mitochondrial metabolism, can induce changes in insulin sensitivity. Mitochondrial oxidative capacity was shown to be compromised in muscle-specific TFAM knockout mice, however these animals exhibited improved glucose clearance during a glucose tolerance test and maintained insulin-stimulated glucose uptake in muscle [197]. TFAM knockout in adipose tissue was recently shown to protect against diet-induced obesity and insulin resistance, despite causing abnormalities in mitochondrial function [125]. Similar findings were reported in mice with liver or muscle-specific deletion of apoptosis-inducing factor.
These animals exhibited a gene expression pattern of mitochondrial oxidative phosphorylation deficiency similar to that observed in human insulin resistance [78,79], however they were lean and insulin-sensitive and did not manifest the usual deleterious effects of a high-fat diet [198]. Due to their key role in mitochondrial biogenesis, muscle-specific knockout of PGC-1? or loss-of-function mutation of PGC-1? produced the expected decline in markers of mitochondrial function yet insulin sensitivity in muscle was preserved or in fact slightly enhanced in these animals compared to wild-type counterparts [26,199]. Two separately generated lines of muscle-specific PGC-1? transgenic mice have shown predictable increases in many mitochondrial parameters, but these animals are insulin resistant, potentially due to excessive fatty acid delivery into muscle [200] or decreased GLUT4 expression [201].
Collectively the above studies clearly demonstrate that targeted manipulation of mitochondrial function, does not produce ‘predictable’ alterations in insulin action. Feeding rats an iron-deficient diet causes a deficiency in mitochondrial electron transport chain enzymes, however this is not associated with the development of insulin resistance [205]. In 2007, our group showed that high-fat feeding in mice induced insulin resistance and was associated with increased expression of a PGC-1? and a number of mitochondrial proteins, elevated oxidative enzyme activity and higher fatty acid oxidation rates [206]. These findings of enhanced mitochondrial oxidative capacity occurring in parallel with the induction of insulin resistance, suggested that diet-induced insulin resistance does not involve mitochondrial dysfunction. At a similar time Garcia-Roves also showed that high-fat feeding with daily heparin injections in rats resulted in mitochondrial biogenesis in skeletal muscle [207] and subsequent work by the same lab the following year confirmed that oversupply of dietary lipid produced insulin resistance, despite an increase in mitochondria in muscle [208]. Since the time of these publications, a number of other groups have shown that diets rich in fat increase mitochondrial biogenesis in muscle, despite the fact that the same diets robustly induce whole-body and muscle-specific insulin resistance [209-211].
One interpretation of these findings is that skeletal muscle is mounting an appropriate response to the increase in caloric load, by upregulating catabolic pathways, however this response is inadequate or mismatched with the elevation in nutrient intake, thus resulting in ectopic lipid accumulation in muscle and insulin resistance. Interestingly we have shown that the upregulation of mitochondrial oxidative capacity is far greater when medium chain fatty acids are substituted for long chain fatty acids in the diet and this is sufficient to prevent the accumulation of myocellular lipid and the development of insulin resistance in muscle [212].

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