Type 2 diabetes metabolic pathways poster,type 2 diabetes diet app,gc ms derivatization,management of type 2 diabetes mellitus pdf - Reviews


Tufts OCW material is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported License. Science, Technology and Medicine open access publisher.Publish, read and share novel research. Age is an Important Risk Factor For Type 2 Diabetes Mellitus and Cardiovascular DiseasesKetut Suastika1, Pande Dwipayana1, Made Siswadi Semadi1 and RA Tuty Kuswardhani2[1] Division of Endocrinology and Metabolism, Internal Medicine, Faculty of Medicine, Udayana University, Sanglah Hospital, Denpasar, Indonesia[2] Division of Geriatrics; Department of Internal Medicine, Faculty of Medicine, Udayana University, Sanglah Hospital, Denpasar, Indonesia1. Akbaraly TN, Kivimaki M, Ancelin ML, Barberger-Gateau P, Mura T, Tzourio C, Touchon J, Ritchie K, Berr C.
Hayashi T, Kawashima S, Itoh H, Yamada N, Sone H, Watanabe H, Hattori Y, Ohrui T, Yokote K, Nomura H, Umegaki H, Iguchi A; Japan CDM Group. Holvoet P, Kritchevsky SB, Tracy RP, Mertens A, Rubin SM, Butler J, Goodpaster B, Harris TB.
Kirwan JP, Khrisnan RK, Weaver JA, Del Aguila LF, Evans WJ.Human aging is associated with altered TNF-a production during hyperglycemia and hyperinsulinemia. Minamino T, Orimo M, Shimizu I, Kunieda T, Yokoyama M, Ito T, Nojima A, Nabetani A, Oike Y, Matsubara H, Ishikawa F, Komuro I. Poehlman ET, Berke EM, MI Joseph JR, Gardner AW, Ades PA, Katzan-Rook SR, Goran MI.Influence of aerobic capacity, body composition, and thyroid hormone on age-related decline in resting metabolic rate. December 8, 2014 by arpan Leave a Comment Management of hyperglycaemia is still a challenge in patients with type 2 diabetes mellitus despite an increase in the pharmacological options. SGLT2 inhibitors are the new armour in the hands of the physicians for the treatment of type 2 diabetes.
Most glucose filtered through the glomeruli is reabsorbed in the proximal renal tubule, mediated by SGLT-1 (10%) and SGLT-2 (90%). There are only a few clinical trials comparing SGLT-2 inhibitors and DPP4 inhibitors available.The DPP-4 inhibitor that is used in all the trials is sitagliptin 100mg.
Canagliflozin has showed non inferiority when compared with sitagliptin and subsequent analysis showed superiority with greater reductions in body weight, FPG, and blood pressure over the period of 52 weeks. Empagliflozin also showed similar or greater reductions in HbA1C with clinically relevant reductions in weight and systolic blood pressure. Since the clinical trials comparing SGLT-2 inhibitors with DPP-4 inhibitors are for short term, conclusions about long term safety of the drugs are difficult to make. Therefore, at present it is difficult to choose between the two classes of drugs for the control of hyperglycaemia considering the advantages and disadvantages of each drug. Similar or greater reductions in HbA1C with clinically relevant reductions in weight and systolic blood pressure.
The fascinating miniature world of the mitochondria—its precious role in our healthy cells and how mitochondria gone bad can lead to cancer. In the first article in this series there is a list of differences between normal cells and cancer cells. Normal cells use the sophisticated process of respiration to efficiently turn any kind of nutrient (fat, carbohydrate, or protein) into high amounts of energy. Now, normal cells sometimes have to resort to fermentation if they are temporarily experiencing an oxygen shortage (a cool example is deep-diving animals).
Cancer cells are bizarre in that they use fermentation even when there’s plenty of oxygen around. One way these things can cause problems for mitochondria is by generating reactive oxygen species (ROS), which damage respiration. It just so happens that some of the genes most strongly linked to cancer (“oncogenes”) are those that code for mitochondrial proteins.
Malignant cancer cells have been shown to have substantially lower respiration rates compared to normal cells.
Mitochondria evolved a process called the retrograde response, which helps them deal with temporary stress or damage. A variety of genes spring into action—genes that code for proteins required to run fermentation instead of respiration. Genes like p53, APE-1 and SMC4.  These genes code for DNA repair proteins and are associated with respiration.
Remember from the first article how transplanting (mutant) DNA from cancer cells into healthy cells only caused cancer in 2 out of 24 cases at best?
Fusing tumor cytoplasm (mitochondria) with normal cells (with healthy DNA in their nuclei) and then injecting these hybrid cells into animals produces tumors in 97% of animals. Fusing normal cytoplasm (mitochondria) with tumor nuclei (with mutant DNA inside) reduces the rate and extent of tumor formation. If you pre-treat normal cytoplasm (mitochondria) with radiation, it loses its ability to rescue tumor cells from cancerous behavior (because radiation damages mitochondria). Transferring healthy mitochondria into cells with damaged mitochondria reduces cancerous behavior. Billions of years ago, before plants took hold on our planet, earth’s atmosphere had very little oxygen, and so living creatures used fermentation to generate energy. Many cells will simply die if their mitochondria are damaged, but if the damage is not too sudden or too severe, some cells will be able to adapt and survive by switching back to fermentation to make energy. Mitochondria are so good at producing energy that their arrival on the evolutionary scene is thought to be largely responsible for the increase in complexity of living things. Any number of environmental hazards can damage mitochondria—these are the same kinds of things we typically think of as damaging our DNA and causing cancer. Even though there’s plenty of oxygen around, damaged mitochondria have no choice but to resort to fermentation, which, if you’ll remember, is primitive, wasteful, and dirty. Tripping Over the Truth: The Return of the Metabolic Theory of Cancer Illuminates a New and Hopeful Path to a Cure  by Travis Christofferson. Sign up to be notified of my latest posts!Signup now and receive an email once I publish new content. Nutrition Savvy MomsSmart moms know how important fruits and veggies are for growing and developing kids.
Children are constantly told that eating a healthy breakfast may help with weight control and academic performance. Previous studies have shown an association between skipping breakfast and obesity in young people. A new investigation found that young people who ate a healthy breakfast every day were less likely to develop type 2 diabetes than those who skipped breakfast. Wife to one man and mother of three boys; I'm a big believer in second chances, the semi-colon, and "bless your heart. Frequency of metabolic syndrome (MS), impaired fasting glycemia (IFG), and diabetes mellitus (DM) in the younger-aged and elderly. IntroductionA field study by World Health Organization (WHO), World Bank and Harvard University in 1990 found a changing pattern of diseases caused by unhealthy lifestyle changes that may eventually lead to metabolic syndrome, type 2 diabetes mellitus, coronary arterial diseases, depression, and traffic accidents (Kinsella and Phillips, 2005). Low HDL cholesterol is associated with the risk of stroke in elderly diabetic individuals: changes in the risk for atherosclerotic diseases at various ages.
The metabolic syndrome, circulating oxidized LDL, and risk of myocardial infarction in well-functioning elderly people in the health, aging, and body composition cohort. High liporotein (a) level promotes both coronary atherosclerosis and myocardial infarction: a path analysis using a large number of autosy cases. Although metformin is the first drug to be started for the treatment of type 2 diabetes mellitus, some patients may not tolerate it and the many patients do not get adequate control with metformin alone and an additional drug will become necessary.
Although DPP4 inhibitors have lesser risk of hypoglycaemia and weight gain, they are expensive. Two SGLT2 inhibitors dapagliflozin and canagliflizon are already available in the market and the third one empagliflozin is expected to commercialise in the near future. The glycosuria induced by glomeruli has been linked with various metabolic responses in type 2 diabetes mellitus patients including increased total glucose removal, improved beta cell function, and shift in glucose utilisation from glucose to lipid.
The adverse effects reported were slightly increased incidence of genital infections and benign urinary infections. And also there is not much data available on the durability of glycaemic control with SGLT-2 inhibitors. More prospective, long term, randomized control trials may help us to choose between the two drugs in the future. Garcia-Roves2, 3[1] Diabetes and Obesity Laboratory, August Pi i Sunyer Biomedical Research Center (IDIBAPS),, Spain[2] Diabetes and Obesity Laboratory, August Pi i Sunyer Biomedical Research Center (IDIBAPS),, Spain[3] Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Barcelona,, Spain1. But I left out one key difference because it would have been confusing to mention it too early. This process requires oxygen and breaks food down completely into harmless carbon dioxide and water.  Cancer cells use a primitive process called “fermentation” to inefficiently turn either glucose (primarily from carbohydrates) or the amino acid glutamine (from protein) into small quantities of energy.
But no cell in its right mind would ever choose to use fermentation when there’s enough oxygen around.
This is called the Warburg Effect, which is considered the “metabolic signature” of cancer cells. You can think of ROS as unstable molecular pinballs, wreaking havoc with molecules around them, causing random damage wherever they strike.
In one study of human metastatic rectal cancer, the cancerous cells had respiration rates 70% lower than the surrounding normal cells. It is called a retrograde (backwards) response because under normal circumstances, the DNA inside the nucleus calls the shots and sends orders out to the mitochondria in the cytoplasm. These same genes also happen to be known in the cancer world as “tumor suppressor genes” (genes that prevent cancer).
When something serious goes wrong within a cell, it is the mitochondrion’s job to make sure the cell bows out gracefully, for the sake of the organism.
Proper calcium flow is critical to normal cell division because the mitotic spindle, which is the structure that helps chromosomes separate properly, is calcium-dependent.
Organisms were very simple, without sophisticated controls to help them decide when to reproduce; they just reproduced as fast as they possibly could.
Mitochondrial damage unlocks an ancient toolkit of pre-existing adaptations that allow cells to survive in low-oxygen environments.
Building and supporting elaborate new creatures with specialized organs and capabilities takes a lot of energy. But hopefully the first article in this series convinced you that damaged DNA is not the primary cause of cancer after all. Ede may not personally respond to comments, however comments shall remain open to encourage community discussion.
Some research has found that children who do not eat the first meal of the day may increase their risk of metabolic syndrome — a cluster of conditions including high blood pressure, high blood sugar, excess body fat around the waist and abnormal cholesterol levels.
I've been on a roller coaster of nutrition research over the past few years because I want to give my boys their best chance to be their best selves. The study also predicted that cerebrovascular diseases would become the most prevalent disease, whereas human HIV infection would sharply increase in the year 2020 (Kinsella and Phillips, 2005). In most of the patients with type 2 diabetes on oral antidiabetic drugs (OADs), the disease progresses and Insulin becomes necessary for the treatment.
SGLT-2 belongs to the family of sodium glucose co-transporters which are located in various tissues including kidney, brain, liver, heart, thyroid and muscle. However, liraglutide is associated with greater weight loss in patients with higher baseline BMI. Introduction“Let food be your medicine and medicine be your food” stated Hippocrates, the father of Western medicine, in 400 B.C. Inside mitochondria are intricately folded membranes studded with special enzymes, fats, and proteins that are used to run elegant chemical reactions.
They can’t rely on their fancy respiration system for energy production because their mitochondria are damaged. This is how cancer cells with all kinds of strange mutations survive; fermentation allows weird cells to live on. Faulty spindles increase the risk of lopsided cell divisions—with one daughter cell getting too many chromosomes and the other daughter cell not getting enough. Mitochondria appeared about 1.5 billion years ago, about a billion years after oxygen became available, and probably already had the ability to switch back and forth between fermentation and respiration, depending on how much oxygen was around. If you’re not constantly pouring energy into a living thing to maintain its form and function, it will gradually succumb to entropy, or chaos. The lifestyle-related and degenerative diseases are significant problems in the old aged population group.The number of elderly population has increased worldwide, and recently it has been increasing sharply in the developing countries. Elliott, Metabolic alterations in middle-aged and elderly obese patients with type 2 diabetes. Selective inhibition of SGLT2 is important because inhibition of SGLT-1 transporter can lead to glucose malabsorption and diarrhea. No interaction between baseline BMI and weight reduction has been observed for dapagliflozin. Controversy about the effects of high fat diet feeding in skeletal muscle oxidative capacity7.2. This statement was based on the belief that food was able to influence disease, a concept that was revived several times in later years by painters, writers, scientists, and philosophers. These chemical reactions are what turn hamburgers into horsepower.  You can see from the picture below that mitochondria (those little orange guys) float around in the outer region of the cell (called the cytoplasm). This will be important later on.] This process does not require oxygen, and only partially breaks down food molecules into lactic acid and ammonia, which are toxic waste products.
Respiration cannot run smoothly unless the all of the delicate interior structures inside mitochondria are nicely intact. For cells, this means regressing…DNA becomes unstable; cells lose their unique shapes, become disorganized, and start reproducing uncontrollably.
The projection of the number of elderly population in Indonesia by the year 2010 is 23,992.
Suastika, Age and homocystein were risk factor for peripheral arterial disease in elderly with type 2 diabetes mellitus.
One such philosopher, Ludwig Feuerbach, famously wrote in his 1863-4 essay “man is what he eats” introducing the idea that if we want to improve the spiritual conditions of people we must first improve their material conditions (Feuerbach, 2003).
Fermentation also takes place inside mitochondria, but the key difference is that fermentation is very simple and doesn’t require the complex inner machinery of the mitochondria. Studies show that mitochondrial damage happens first, and then genetic instability follows. The Indonesian Central Bureau for Statistics (Badan Pusat Statistik) has reported that Indonesia is the world’s fourth in the number of elderly population after China, India, and USA (Komala et al., 2005). However, for years his warnings remained unheeded, at least in Western countries, in contrast to the teachings of Indian and Chinese medicine which for millennia have argued that a living organism has to assume a healthy diet. US Bureau of Census predicted that from 1990 to 2020, the Indonesian elderly population would increase to 41.4%. Like diet, physical activity has been also considered an important starting point for people's health. The predicted increased number of elderly was ascribed to the success of health promotion and improvement of social and economic status (Kinsella and Taeuber, 1993). Hippocrates wrote in his book Regimen "if we could give every individual the right amount of nourishment and exercise, not too little and not too much, we would have found the safest way to health" (Hippocrates, 1955). Chemical bonds consist of positive charges called protons and negative charges called electrons, which hold onto each other tightly.
Metabolic disorders including type 2 diabetes mellitus (T2DM) and cardiovascular diseases are closely related with the aging process.
Nemeth, Histochemical and enzymatic comparison of the gastrocnemius muscle of young and elderly men and women.J. Our knowledge about the links between diet, exercise, and disease has vastly increased since Hippocrates time. Mitochondria wrench the electrons away from the protons, and then funnel the electrons through an “electron transport chain”, creating current.
Central obesity and insulin resistance as the initial preconditions and its consequences related to metabolic diseases and cardiovascular diseases are frequently found among the elderly.
Donath, Aging correlates with decreased ?-cell proliferative capacity and enhanced sensitivity to apoptosis.
A healthy lifestyle based on diet and physical activity is now considered the keystone of disease prevention and the basis for a healthy aging. This electrical energy is used to create ATP molecules, each of which includes a very high-energy phosphate bond. Decline in lean body mass and increase in body fat, particularly visceral adiposity that often accompanies aging, may contribute to the development of insulin resistance. Bolli, Demonstration of a critical role for free fatty acids in mediating counter regulatory stimulation of gluconeogenesis and suppression of glucoseutilization in humans. However, modern society has created conditions with virtually unrestricted access to food resources and reduced physical activity, resulting in a positive overall energy balance. ATP (adenosine triphosphate) is like a miniature chemical battery; our cells can break ATP phosphate bonds apart whenever they need energy to do anything. As for the mechanism of T2DM, it is known that aging induces a decrease of insulin sensitivity and alteration or insufficient compensation of beta cell functional mass in the face of increasing insulin resistance (Meneilly and Elliot, 1999). Ducimetiere, The metabolic syndrome and the carotid artery structure in non-institutionalized elderly subjects.
This is far from the environment of our ”hunter-gathered ancestros” whose genes were modulated over thousands of years adapting our metabolism to survive when food was scarce and maximizing energy storage when food became available.
Oxygen waits at the end of the ATP assembly line to catch the cascading electrons, and then binds to them, forming water as a harmless by-product. Related to beta cell functions, aging correlates with a decrease of beta cell proliferation capacity and enhances sensitivity to apoptosis (Maedler et al., 2006). Young, Effect of age on energy expenditure and substrate oxidation during experimental overfeeding in healthy men.
In terms of evolution, this radical and sudden lifestyle change in modern society has led to a dramatic increase in the incidence of metabolic diseases including obesity and type 2 diabetes mellitus (T2DM). It has recently been proposed that an age-associated decline in mitochondrial function contributes to insulin resistance in the elderly (Petersen et al., 2003). Lima, Age-related left ventricular remodeling and associated risk for cardiovascular outcomes. Gerich, Effect of aging on glucose homeostasis: Accelerated deterioration of ?-cell function in individuals with impaired glucose tolerance. It seems clear that the development of T2DM has a genetic component that becomes obvious when individuals are exposed to western lifestyle. However, environment plays a critical role in the incidence of the disease being obesity the main etiological cause of T2DM. Mitochondrial dysfunction as a potential mechanism underlying skeletal muscle insulin resistance6.1.
Thus, modest weight loss is enough for obese glucose intolerant subjects to prevent the development of T2DM (National Task Force on the Prevention and Treatment of Obesity, 2000).T2DM also known as “non-insulin-dependent diabetes mellitus” or “adult-onset diabetes”, is a metabolic disorder characterized by high blood glucose, insulin resistance, and relative insulin deficiency.


Lamb, The ageing male heart: myocardial triglyceride content as independent predictor of diastolic function. Age, mitochondrial dysfunction and inflammationMitochondria, a membrane-enclosed organelle found in most eukaryotic cells, generate most of the cell's supply of adenosine triphosphate (ATP), are used as a source of chemical energy, and are involved in a range of other processes such as signaling, cellular differentiation, cell death, as well as the control of the cell cycle and cell growth. T2DM is now considered to be a global epidemic with significant social and economic consequences both at the individual and population level.
Mitochondria have been implicated in several human diseases, including mitochondrial disorders, aging process and cardiac dysfunction.
The International Diabetes Federation estimates that 366 million people suffered from this disease in 2011 and predicts that these numbers will increase to 552 million people by 2030. Mitochondrial dysfunction is central to the theories of aging because age-related changes of mitochondria are likely to impair a host of cellular physiological functions in parallel and thus contribute to the development of all the common age-related diseases (Dai et al., 2012). Rising cellular oxidative stress due to any cause induces mtDNA and mitochondria damage and culminates in a mitochondria function crisis, cell death and aging.
The pathophysiology of prediabetes is characterized by alterations in insulin sensitivity and pancreatic beta-cell function, usually associated with increased adiposity (Dagogo-Jack et al., 2009). Otherwise, aging itself causes abnormal mitochondrial morphology and cell death or apoptosis (Seo et al., 2010). How old age can be a major risk factor for CVD via mitochondrial dysfunction has been completely reviewed by Dai et al.
While these data are encouraging, these interventions are costly, require a very high degree of commitment of the subjects, and are not always successful. Although the progress in understanding the metabolic derangements of T2DM has led to significant advances in the treatment of this disease, it remains unclear whether current therapeutic approaches can really improve the underlying metabolic defects. The role of NF-?B in bridging the explanation of how aging is associated with inflammation and endothelial dysfunction is reviewed well by Csiszar et al. Therefore, there is an urgent need to characterize the complex pathophysiology of the disease, to identify and target specific mechanisms in order to slow down the worldwide diabetes epidemic.2. Insulin action and insulin resistanceInsulin essentially provides an integrated set of signals that allow for the balancing of nutrient availability and caloric demands (Samuel et al., 2010).
Another study has shown that depletion of cellular (GSH) during aging plays an important role in regulating the hepatic response to IL-1? (Rutkute et al., 2007). In collaboration with the opposing hormone glucagon, it is responsible for maintaining glucose homeostasis, which is necessary to ensure proper function and survival of all organs. At rest, skeletal muscles of elderly people showed a lower number of macrophages, higher gene expression of several cytokines, and activation of stress signaling proteins, compared with skeletal muscles of young people (Peake et al., 2010).
The regulation of plasma glucose concentrations is vital for the entire body and both hypoglycemia and hyperglycemia can impair whole-body physiology, ultimately leading to cellular death. Human aging is associated with the development of insulin resistance, ?-cell dysfunction and glucose intolerance.
This is why it is critical to regulate and maintain plasma glucose levels around 5mM, the physiological set point in mammals (Saltiel, 2001).The primary targets of insulin action to maintain glucose homeostasis are skeletal muscle, liver, and adipose tissue. The level of suppression of the TNF-? production was observed and found to be significantly correlated with insulin action. Under physiological conditions, carbohydrates provided by the diet increase plasma glucose levels and promote insulin secretion from pancreatic ? cells of the islets of Langerhans.
Reduced suppression of TNF-? production in the elderly may in part contribute to the decline in insulin sensitivity (Kirwan et al., 2001). Once secreted, insulin binds to its receptor, triggering a cascade of downstream phosphorylation events that expand the initial signal (Figure 1).
Insulin binds to its receptor and activates its intrinsic protein tyrosine kinase activity, resulting in the phosphorylation of tyrosine residues located in the cytoplasmic face. Age and lipid metabolismAging and age are often associated with lipid metabolism disorders.
The activated receptor, in turn, recruits and phosphorylates a group of substrate molecules. They have the role of docking proteins and are known as “insulin receptor substrates” (IRS). After the age of 20 years, low-density lipoprotein cholesterol (LDL-C) increases significantly in both men and women. Among these, IRS1 and IRS2 appear to be the major adapter molecules that play a role in insulin cascade. LDL-C does not increase or is in a flat state between the age of 50-60 years (male) and 60-70 years (female) (Gobal and Mehta, 2010).
On the other hand, high–density lipoprotein cholesterol (HDL-C) levels decrease during puberty to young adulthood (in males). Throughout their lives women have lower total cholesterol compared to men, but the levels will rise sharply after menopause and will be higher in the age >60 years as compared to men.
Concentrations of triglyceride (TG) increase sharply in males, reaching a peak at the age 40-50 years and decline gradually thereafter. TG levels increase in women throughout their lives, especially in women taking estrogen replacement therapy (Gobal and Mehta, 2010). This event relieves the inhibitory phosphorylation of glycogen synthase (GS), which becomes activated and promotes glycogen synthesis;insulin-stimulated translocation of the glucose transporter GLUT4 at the plasma membrane, resulting in increased glucose uptake.
With the increase of age the composition of body fat also increases, which especially accumulates in the abdomen triggering the incidence of central obesity. TG composition in the muscle and liver are higher in older age compared with younger age groups (Cree et al., 2004).
AS160 normally inhibits translocation of GLUT4 through its interaction with RabGTPase protein.
Increased body fat composition is associated with reduced fat oxidation both at rest and in activity (Nagy et al., 1996). The inhibitory phosphorylation of AS160 favors the GTP-loaded state of Rab and relieves the inhibitory effect on GLUT4, stimulating its translocation to the plasma membrane.
Aging (age) affects the release of fatty acids (FFA),from fat tissue (adipose), and the capacity of peripheral tissues such as muscles, to oxidize fat.
These are some of the changes in lipid metabolism influenced by age and aging, which decreases lipolysis response and capacity of fat oxidation.Lipolysis is modulated by various hormones such as catecholamines, glucagon, adrenocorticotropic hormone, growth hormone, prostaglandin, and thyroid hormone (Toth and Tchernof, 2000). Decreased ability of catecholamines to stimulate lipolysis in the elderly is caused by decreased fat tissue response to adrenergic stimulation (Dillon et al., 1984). Pathogenesis of Type 2 Diabetes MellitusAn important early phenotype associated with increased T2DM risk is insulin resistance. This response involves reduced role of protein kinase A, G-protein complex adenylil cyclase, or the stages in the cyclic AMP signaling cascade (Toth and Tchernof, 2000). Effects of insulin on plasma FFA was different between in the elderly compared with in younger subjects. Given these data, it is alarming that the high prevalence of insulin resistance in the population predicts further dramatic increases in the worldwide epidemic of T2DM. Insulin infusions showed that plasma FFA, turnover and oxidation, and total lipid oxidation were higher significantly in the elderly than in the younger group (Bonadonna et al., 1994). Individuals with established T2DM show several physiological abnormalities, including elevation in fasting glucose levels, elevation in postprandial glucose levels, or both.
Aging is also associated with decreased sensitivity to antilipolysis effects of insulin (Toth and Tchernof, 2000). In adipose tissue, the major fat storage tissue in mammals, insulin resistance results in increased lipolysis and fatty acid release. In principle, the capacity of metabolically active tissues such as the muscles to oxidize fat represents a combination of the tissue mass and oxidative capacity of the tissue. Increased circulating fatty acids decrease the ability of insulin to suppress hepatic glucose production and allow a constant increase in fatty acid synthesis. Fat free mass decreases with age (Poehlman et al., 1992) and in resting condition fat oxidation tends to be influenced by the size of fat free mass itself. This dysregulation of carbohydrate and lipid metabolism accelerates the progression of insulin resistance.
Changes in lipid metabolism in the aging process are associated with dysfunction of endothelial cells pseudocapillarization of the liver sinusoid.
During the first stages of the development of the disease, pancreatic beta-cells have the ability to compensate for insulin resistance by increasing basal and postprandial insulin secretion to correct hyperglycemia. This change causes decreased endocytosis, increased leukocyte adhesion, decreased hepatic perfusion and will potentially reduce the passage of chylomicron remnants into hepatocytes (Denke and Grundy, 1990). When pancreatic beta-cells can no longer compensate they become unable to respond appropriately to glucose levels.
After activity or after meal, fat oxidation rate is more influenced by the oxidative capacity of muscle tissue. This pancreatic beta-cell failure leads to the deterioration of glucose homeostasis and the development of T2DM. This pattern of physiological abnormalities in skeletal muscle, adipose tissue, liver, and pancreas presents itself in the late stages of the disease (Saltiel, 2001).
Additionally, abnormal secretion and regulation of incretins in the gastrointestinal tract, hyperglucagonemia due to alterations in pancreatic alpha-cells, increased glucose reabsorption in kidney, and altered balance of central nervous system pathways involved in food intake and energy expenditure play an important role in the development of T2DM (Defronzo, 2009). This complex pathophysiology makes difficult to identify the primary events responsible for the development of T2DM.4. Skeletal muscle insulin resistance and T2DMAs mentioned above, insulin resistance is a key component for the development of T2DM. Disposal of non-oxidative free fatty acids into the liver will increase the formation of triglyceride-rich very low-density lipoprotein (VLDL) that plays a role in the formation of atherogenic dyslipidemia. Increased levels of TG and decrease HDL-C are features of atherogenic dyslipidemia in people with central obesity, hypertension and insulin resistance (Linblad et al, 2001). Himsworth and Kerr, using a combined oral glucose and intravenous tolerance test, were the first to demonstrate that tissue-specific insulin sensitivity was lower in T2DM individuals (Himsworth, 1940).
Ginsberg and colleagues provided another important evidence related to the decreased ability of insulin to promote glucose uptake in subjects with T2DM (Ginsberg et al., 1975). Later on, clear evidences about skeletal muscle insulin resistance in T2DM subjects were provided by DeFronzo and colleagues, who used the euglycemic-hyperinsulinemic clamp technique to quantify insulin-stimulated glucose uptake.
Skeletal muscle is the largest insulin-sensitive organ in humans accounting for more than 80% of insulin stimulated glucose disposal (DeFronzo et al., 1985). Moreover, several evidences linked mitochondrial defects to insulin resistance and T2DM (Lowell and Shulman, 2005), suggesting that these organelles are key players in maintaining energy homeostasis.In this chapter we will discuss the potential role that mitochondrial dysfunction plays in T2DM etiology.
Lower HDL cholesterol is an important risk factor for not only ischemic heart disease but also for cerebrovascular disease, especially in diabetic elderly individuals (Hayashi et al., 2009). Age, insulin resistance and metabolic syndrome Metabolic syndrome is a group of metabolic abnormalities of which central obesity and insulin resistance are believed to be the primary backgrounds.
Skeletal muscle fiber types and metabolismSkeletal muscle is a complex tissue composed of different fiber types, which have distinct mechanical and metabolic properties. The diagnostic criteria for metabolic syndrome have been proposed by several organizations and associations, all of which are based on five parameters i.e. Each of these functional systems is composed of a motor neuron and a group of muscle fibers. The pathogenesis of how central obesity causes insulin resistance and metabolic syndrome has been explained in many publications. Decreased insulin sensitivity, reduced muscle mass, and increased body fat mass, especially visceral fat that accompanies aging contribute to insulin resistance in the elderly. In adult human skeletal muscle type 2B fibers are not detectable and the oxidative capacity of type 2X fibers is lower than that observed in rats and mice (Schiaffino and Reggiani, 2011). Aging process is also associated with reduced compensatory beta cell mass function of the pancreas and to insulin resistance (Maneilly and Elliott, 1999) as well as with decreased mitochondrial function that contributes to insulin resistance (Petersen et al., 2003). For additional reading we recommend a review published in Physiological Reviews written by Stefano Schiaffino and Carlo Reggiani that provides an up to date and detailed understanding of this topic (Schiaffino and Reggiani, 2011). For the purposes of this discussion, it is important to keep in mind skeletal muscle diversity: distinct skeletal muscle fibers differ in their energy requirements for cellular function, including contractile activity. Energy is provided by adenosine triphosphate (ATP) hydrolysis to adenosine diphosphate (ADP) and inorganic phosphate (Pi). ATP can be generated by three main mechanisms that vary in their capacity and velocity to resynthesize ATP.
The Phosphocreatine (PCr)-creatine kinase (CK) system corresponds to a high-power and low-capacity ATP production reservoir.
Glycolysis is the metabolic process by which glycogen and glucose are metabolized to pyruvate and subsequently to lactate; this process has a lower power but a higher capacity for ATP generation than the PCr-CK system. The other energy production resource is the mitochondrial oxidative phosphorylation system, which can obtain ATP from different substrates: pyruvate, fatty acids, amino acids, and ketone bodies. Insulin resistance as risk factor for cardiovascular disease (CVD) is associated with increase of acute phase protein response and inflammatory markers. The oxidative phosphorylation system has a very high capacity for ATP generation but a lower power when compared to the other two ATP production systems.
It is also important to highlight that mitochondrial mediated ATP resynthesis is highly dependent on oxygen and substrate availability.Due to its intrinsic characteristics, slow and fast muscle fibers differ in their relative contribution to energy production from PCr-CK, glycolysis, and oxidative phosphorylation processes.
The relative contribution of these metabolic pathways is mostly established during differentiation according to the specific function and energy demands of each fiber type. Thus, skeletal muscle is able to predominantly utilize both glucose and free fatty acids as fuel sources for energy production.
The association of metabolic syndrome and increased frequency of carotid plaque and thickening of the carotid artery intima media in elderly subjects (aged 65-85 years) was noted in a study by Empana et al.
This event, together with the activation of key enzymes in glucose metabolism, leads to a marked increase in muscle glucose oxidation.
Metabolic syndrome in the elderly was associated with two-times increase of CRP levels (3.1 vs. After glucose is transported into the myocytes trough the GLUT4 transporter, it is immediately phosphorylated by hexokinase II, and the phosphorylated glucose is stored as glycogen or enters the glycolytic pathway for energy production. Thus, during feeding conditions, the main source for energy production in skeletal muscle is glucose.Therefore, muscle energy metabolism has to be capable of switching from predominant oxidation of fatty acids during fasting state, to predominant oxidation of glucose during feeding state.
However, obese and type 2 diabetic subjects are unable to shift between substrates (fatty acids or glucose) demonstrating a high degree of metabolic inflexibility (Kelley et al., 1999). This inability to oxidize one substrate or another results in impaired glucose and fatty acid storage as glycogen and triglycerides, respectively. Sports activities >2 hours per week would be effective in lowering the risk of metabolic syndrome. Age and type 2 diabetes mellitus Similar to metabolic syndrome, the prevalence of impaired fasting glycemia (IFG) and T2DM increase with rising age. Pathogenesis of Insulin Resistance in Skeletal MuscleBoth obese subjects with or without T2DM have marked skeletal muscle insulin resistance compared to lean non-diabetic subjects.
In the United States, the estimated percentage of people aged 20 years or older having diagnosed or undiagnosed diabetes in 2005-2008 was increasing with age. The severity of the insulin resistance positively correlates with BMI (DeFronzo, 1982, Wedick et al., 2009).
The mechanism through which obesity causes insulin resistance in skeletal muscle seems to be associated with the accumulation of fatty acids in the myocytes. Similar feature was also observed n England, where the prevalence of diabetes was increasing with age. Among the various types of fatty acids, saturated long-chain ones, including palmitic and stearic acids, are strong inducers of insulin resistant state (Hirabara et al., 2009). Obese subjects with or without T2DM are characterized by an increase in plasma fatty acid concentration, which strongly correlates with reduced insulin-stimulated glucose disposal in skeletal muscle.In normal conditions, fatty acids are stored in the adipose tissue as triglycerides and released during fasting. During the postprandial state, blood glucose stimulates insulin secretion, which inhibits lipolysis in adipose tissue, therefore limiting the release of fatty acids. In insulin resistant individuals, the ability of insulin to inhibit lipolysis and reduce plasma fatty acid concentration is markedly impaired (Groop et al., 1991). There was a tendency of increasing frequency of IFG and T2DM with increasing age (Table 2).
They observed that incubation of rat heart with fatty acids was associated with an increase in intracellular concentrations of glucose-6-phosphate (G6P) and glucose. Moreover, incubation of diaphragm muscle with fatty acids led to an increase in glycogen accumulation. Hypertension, overt proteinuria, IFG and high total cholesterol were independent risk factors for new onset diabetes (Peng et al., 2006). Accumulation of citrate inhibits phosphofructokinase and increases intracellular concentrations of G6P, leading to activation of glycogen synthesis, inhibition of hexokinase II, increase in intracellular glucose content and, consequently, reduction in glucose uptake.
Thus, this model is based on the inverse relationship between fatty acid availability and glucose utilization. The main factors are that aging induces decrease insulin sensitivity and alteration or insufficient compensation of beta cell functional in the face of increasing insulin resistance (Chang and Halter, 2003). If there was a block at the hexokinase step, as proposed by Randle, intra-myocellular glucose concentrations would be expected to increase. Decrease in beta cell proliferation capacity and enhanced sensitivity to apoptosis are the states related with aging (Maedler et al., 2006). Instead, they noted that plasma fatty acid concentrations decreased the accumulation of intra-myocellular glucose, indicating that insulin-stimulated glucose transport activity was reduced. ER is an intracellular membranous network responsible for synthesis, folding, maturation, trafficking and targeting of secreted and transmembrane proteins. But aging per se has no effect on insulin sensitivity independent of change in body composition.
Decline in lean body mass and the increase in body fat particularly visceral adipocytes (“central obesity”) that accompanies aging may contribute to insulin resistance. In some diseases, protein synthesis increases in ER-lumen and proteins cannot fold correctly, affecting ER homeostasis. It has recently been proposed that an age-associated decline in mitochondrial function contributes to insulin resistance in elderly. Impairment of ER homeostasis activates an elaborate adaptive stress response, known as “unfolded protein response” (UPR), and results in the phosphorylation and activation of JNK. Mitochondrial oxidative and phosphorylation function was reduced about 40% in association with increased intramyocellular and intrahepatocellular lipid content and decreased insulin-stimulated glucose uptake (Petersen et al., 2003).
The link between T2DM, insulin resistance and ER stress in skeletal muscle is still unclear. The pathophysiological basis of sarcopenia (loss of muscle mass with age) has a relationship with oxidative stress, reduced neuronal stimulation, subclinical inflammatory and insulin resistant state.
It has been demonstrated that ER stress occurs in vivo in skeletal muscle when mice are fed a high fat diet (Deldicque et al., 2010a). Those conditions contribute to the development of glucose intolerance and type 2 diabetes (Khamseh et al., 2011). Fatty acids activate inflammatory signals by promoting secretion of pro-inflammatory cytokines including TNFalpha, IL-1beta, and IL-6.


Furthermore, fatty acids can directly interact with members of the Toll-like receptor (TLR) family, promoting activation of JNK and IKKbeta. They also proposed that adipose tissue p53 tumor suppressor mediated the lipid abnormalities and cardiovascular morbidity associated with obesity. This activation leads to degradation of the inhibitor of kappa beta (IKB) and Nuclear factor-kappa beta (NFKB) activation. The study found that excessive calorie intake caused accumulation of oxidative stress in the adipose tissue of mice with type 2 diabetes–like disease and promoted senescence-like changes, such as increased activity of senescence-associated ?-galactosidase, increased expression of p53 and increased production of proinflammatory cytokines. Inhibition of p53 activity in adipose tissue decreased the expression of proinflammatory cytokines and improved insulin resistance. Biology of the mitochondriaMitochondria are doubled-membrane organelles that constitute the major site for oxidative energy production in the cell.
Age and cardiovascular diseases Cardiovascular disease remains to be the most important cause of death in all countries over the world. Mitochondria are the only mammalian organelles that contain extra-nuclear DNA (mtDNA), which encodes for 37 genes including 13 subunits of the electron transport chain (Kelly and Scarpulla, 2004). Although certain reports from some developed countries indicate the incidence tends to decrease, from many countries there are reports mentioning that its incidence tends to increase.
Besides generating the majority of cellular ATP via oxidative phosphorylation (OXPHOS), many other essential cellular functions take place in this organelle. Cardiovascular disease is a complex disease; too many risk factors are involved in its pathogenesis. In general, risk factors for CVD can be divided into two main groups, namely traditional and non-traditional risk factors. Oxidative phosphorylation (OXPHOS)Mitochondria are able to generate energy by oxido-reduction reactions and proton translocation derived from carbohydrates (TCA cycle), amino acids and fatty acids (?-oxidation). For this purpose, oxygen is consumed to generate water, heat and adenosine triphosphate (ATP). The inner membrane invaginations of the mitochondria, called cristae, contain all transmembrane proteins of the electron transfer system (ETS) and the ATP synthase (Benard and Rossignol, 2008, Vonck and Schafer, 2009). All components of the TCA cycle and ?-oxidation pathway are located inside the mitochondrial matrix.
Age itself may be an independent risk factor or may have other risk factors related to aging or exposure to risk factors during their lifetime.
Oxidation of substrates generates reduced nicotinamide adenine dinucleotide (NADH) and reduced flavin adenine dinucleotide (FADH2) that will provide electrons to the ETS. In the United States, CVD was the leading cause of death for persons 65 years of age and over in 2007, which accounted for 28% of deaths in this age group (National Center for Health Statistics, 2011).
Electrons flow from donors (NADH at complex I and FADH2 at complex II) to an oxygen molecule forming H2O at complex IV. There is a parallel translocation of protons to the intermembrane space from the matrix that creates an electrochemical gradient used by ATP synthase in a coupled manner to generate ATP.
This electrochemical gradient can also dissipate through uncoupling proteins (UCPs) using a non-ATPase-coupled proton leak and generating heat in a process called thermogenesis. The high electronegative potential generated can also drive the entry of calcium into the matrix.
Age in the group with CHD (old myocardial infarction and myocardial ischemia) was significantly higher than those without CHD (65.0 vs. Mitochondrial biogenesis and dynamicsMitochondrial biogenesis is defined as the generation of more mitochondrial mass and takes place in response to increased energy demand.
This increase includes luminal enlargement with wall thickening and a reduction of elastic properties at the level of large elastic arteries. Long standing arterial pulsation in the central artery has a direct effect on the structural matrix proteins, collagen and elastin in the arterial wall, disrupting muscular attachments and causing elastin fibers to fatigue and fracture.
It has been recently established that mitochondrial fission and fusion contribute to multiple essential functions including calcium handling, ROS production and energy output (Chen and Chan, 2005, Parone et al., 2008, Soubannier and McBride, 2009). Increased vascular calcification and endothelial dysfunction is also characteristic of arterial aging. The relevance of these events in mitochondrial and cell physiology has been partially unraveled and observed that the disruption of such processes results in mitochondrial heterogeneity and dysfunction (Zorzano et al., 2009, Chan, 2006). These changes lead to increased pulse wave velocity, especially along central elastic arteries, and increase in systolic blood pressure and pulse pressure (Lee and Oh, 2010). Therefore, a fine-tune regulation of mitochondrial biogenesis and dynamics is necessary to obtain and maintain functional mitochondria.Mitochondrial biogenesis is a complex process that requires the expression of a large number of proteins encoded by both nuclear and mitochondrial genomes. Aging cardiovascular tissues are exemplified by pathological alterations including hypertrophy, altered left ventricular (LV) diastolic function, and diminished LV systolic reverse capacity, increased arterial stiffness, and impaired endothelial function.
The mitochondrial genome encodes only 13 proteins, which are essential subunits of the respiratory complexes. This genome also provides the 22 tRNAs and 2 rRNAs necessary for the translation of these mitochondrial-encoded proteins. In contrast, transcription of the mitochondrial genome is encoded by the nuclear genome, which is under the control of a single transcription factor named TFAM.
This pattern of ventricular remodeling confers significant cardiovascular risk, particularly when present earlier in life. Peripheral artery disease (PAD), a marker of systemic atherosclerosis, is frequently related with age. Therefore, fine-tuned coordination is required between the mitochondrial and the nuclear genomes to orchestrate the expression of proteins necessary for a successful mitochondrial biogenesis. This coordination is achieved by complex regulatory mechanisms that involve the action of a relatively small number of nuclear transcription factors, which are discussed in detail below. These transcription factors are in turn regulated by cofactors that integrate physiological signals with the activity of the transcription factors to regulate mitochondrial biogenesis in response to environmental stimuli. A study by Kuswardhani and Suastika (2010) on elderly patients who visited the Geriatric Outpatient Clinic, Sanglah Hospital showed that diabetic patients with PAD had higher age (70.7 vs.
Nuclear transcription factors involved in mitochondrial biogenesisThrough their DNA-binding domain, transcription factors bind to specific sequences in the gene promoter region to regulate transcription of a subset of genes. Several transcription factors have been shown to regulate expression of genes involved in the respiratory chain and mitochondrial metabolism, however only a few are considered the major transcription factors crucial for mitochondrial biogenesis. By multivariate analysis (logistic regression), it was found that only age played a role in PAD event. Nuclear Respiratory Factor 1 (NRF-1)NRF-1 has a fundamental role in coordinating nuclear and mitochondrial transcription. It induces expression of TFAM, TFB1M and TFB2M (Virbasius and Scarpulla, 1994, Gleyzer et al., 2005), which are essential proteins for the transcription of the mitochondrial genome, and also TOMM20, a key protein required for the transport of nuclear-encoded proteins into the mitochondria. ConclusionThe number of elderly population has increased worldwide, and recently it has been increasing sharply in the developing countries. It has also been shown to regulate multiple subunits of the respiratory chain as well as other proteins involved in other mitochondrial functions. Prolong survival in the elderly creates an impact on the appearance of metabolic diseases and CVD. This respiratory factor was named NRF-2 and was subsequently identified as the human homolog of the mouse GABP (Virbasius et al., 1993). Similarly to NRF-1, disruption of the NRF-2 gene also produces a lethal phenotype (Ristevski et al., 2004).
Instead, it is a member of a family of orphan nuclear receptors that also include ERRbeta and ERRgamma. Unlike NRF-1 and NRF-2 where gene knockout proves lethal, disruption of ERRalpha results in a viable phenotype showing decreased body weight and adipose depot size (Luo et al., 2003). This mouse shows normal energy expenditure with no major decrease in mitochondrial proteins. Other transcription factorsWhile not directly involved in transcription of mitochondrial biogenesis or respiratory chain genes, other transcription factors including PPARalpha, PPARdelta, and YY1 are also important for providing other mitochondrial proteins. PGC-1 coactivator familyWhile the transcription factors discussed above are part of the transcriptional machinery necessary for mitochondrial biogenesis, the members of the PGC-1 coactivator family provide the integration of physiological stimuli with the transcription factors to adapt mitochondrial biogenesis to changes in the environment. PGC-1 coactivators lack a DNA-binding domain, but they are able to interact with and activate several transcription factors by recruiting other cofactors with chromatin-remodeling activities (Monsalve et al., 2000). PPARgamma coactivator 1alpha (PGC-1alpha), the founding member of the PGC-1 family, was first identified by its ability to activate PPARgamma in brown adipocytes (Puigserver et al., 1998). PGC-1beta and PRC where subsequently identified based on their structural similarity with PGC-1alpha (Lin et al., 2002a, Andersson and Scarpulla, 2001).
It is this regulatory capacity that allows PGC-1alpha to respond to physiological stimuli and activate the mechanisms leading to increased mitochondrial biogenesis. Physical exercise has also been recognized as a main activator of mitochondrial biogenesis. In the muscle cell, the AMP-dependent protein kinase (AMPK) responds to low energy levels (increase in AMP content) by inducing a signaling cascade that results in the activation of catabolic pathways and inhibition of anabolic pathways in an attempt to restore energy levels. Therefore, AMPK has been recognized as a key mediator in the physiological and metabolic adaptation to physical exercise. Interestingly, AMPK can directly phosphorylate PGC-1alpha and activate its transcriptional activity regulating expression of mitochondrial genes (Jager et al., 2007). Mitochondrial dysfunction as a potential mechanism underlying skeletal muscle insulin resistanceMitochondrial adaptations (biogenesis and dynamics) and function largely affect muscle metabolism and have a significant impact on whole-body metabolism (Patti et al., 2010). As mentioned before, metabolic flexibility is defined as the ability to rapidly modulate substrate oxidation as a function of environmental, hormonal and different energy conditions (Storlien et al., 2004). Defects in pathways controlling glucose and energy homeostasis in skeletal muscle have been shown to impair these adaptations, leading to metabolic inflexibility. For the purposes of this chapter, we will define mitochondrial dysfunction as both the reduction in mitochondrial oxidative activity and in mitochondrial adenosine triphosphate (ATP) synthesis. Early evidences relating insulin resistance and skeletal muscle mitochondrial dysfunctionSeveral key studies published between 1999 and 2005 laid the foundation for understanding the underlying mechanisms between mitochondrial dysfunction and subsequent insulin resistance in skeletal muscle and development of T2DM. Dysregulation of skeletal muscle fat oxidation in obesityThe first studies that identified a relationship between alterations in muscle metabolism and insulin resistance did not mention any link with mitochondrial dysfunction (Kelley et al., 1999).
However, research performed by Kelley and co-workers addressed why the pattern of fatty acid utilization in skeletal muscle during fasting conditions might be associated with obesity-related insulin resistance, which is relevant for the scope of this chapter. The study included 16 lean and 40 obese volunteers with leg balance measurements of glucose and free fatty acid uptake. Indirect calorimetry across the leg was also measured in order to determine substrate oxidation during fasting and insulin-stimulated conditions. This study demonstrated that fatty acids were the predominant substrate oxidized by skeletal muscle during fasting conditions in lean subjects. However, rates of fatty acid oxidation during fasting were significantly lower in obese subjects, even though rates of fatty acid uptake were similar to those of lean subjects.
Furthermore, the respiratory quotient values across the leg showed a reduced reliance on lipid oxidation in obese subjects. What it is also important is that weight loss only partially improved these patterns; the leg respiratory quotient in obese subjects was unchanged between pre- and post-weight loss, so the reliance of skeletal muscle in fat oxidation during fasting conditions was not improved. The authors suggested that their data pointed to these defects as primary impairments leading to obesity, rather than resulting from obesity. Muscle mitochondria in obesity and type 2 diabetesIn this study, Kelley and co-workers provided early evidence that mitochondrial dysfunction in human skeletal muscle contributes to the development of insulin resistance and progression to T2DM (Kelley et al., 2002b). Previous work by the same group demonstrated that the severity of skeletal muscle insulin resistance in T2DM and obesity is related to diminished activity of oxidative enzymes (Simoneau and Kelley, 1997). Furthermore, triglyceride accumulation in skeletal muscle is also correlated with the severity of insulin resistance and with diminished oxidative enzyme activity.
Because it was known that skeletal muscle depends on oxidative phosphorylation to produce energy and that insulin resistance in T2DM and obesity involves altered oxidation of carbohydrates and lipids, the authors attempted to elucidate the potential contribution of mitochondrial dysfunction to skeletal muscle insulin resistance in humans.
For this purpose vastus lateralis muscle samples from lean controls without T2DM, obese subjects with or without T2DM were obtained. An assessment of the activity of the mitochondrial OXPHOS system and a quantitative study of the mitochondria morphology by transmission electron microscopy was performed in the different muscle biopsies.
Creatine kinase and citrate synthase activities were measured as markers of muscle fiber content and mitochondrial content, respectively. Results showed that skeletal muscle mitochondria structure and functional capacity were impaired in T2DM subjects and, to a lesser degree, in obese subjects. Mitochondrial respiratory complex I activity was reduced by 40% in skeletal muscle from subjects with T2DM when compared to lean controls without diabetes. Moreover, skeletal muscle mitochondrial area and size were smaller in obesity and T2DM and, in some instances, particularly in T2DM, severely damaged.
Although age can affect the size of mitochondria, in this case aging did not account for the ~30% reduction in size in obesity and T2DM.Based on their results, authors proposed a potential mechanism that could explain how impaired mitochondrial function leads to insulin resistance in skeletal muscle, which would be lipid accumulation within myocytes. This was not a new finding, as previous studies (Kelley et al., 2002a) from the same group had shown that increased lipid accumulation in skeletal muscle is associated with insulin resistance and, in turn, lipid accumulation in skeletal muscle in obesity and T2DM is related to a reduced oxidative enzyme activity. Downregulation of oxidative metabolism genes in humans with insulin resistance and diabetesPatti and colleagues addressed how gene regulation was modulated by T2DM (Patti et al., 2003).
The results showed that skeletal muscle from subjects with prediabetes and T2DM had decreased expression of oxidative phosphorylation genes, many of which are regulated by nuclear respiratory factor (NRF)-dependent transcription.
A decreased expression of the co-activators PGC-1alpha and PGC-1beta, both of which induce NRF-dependent transcription, was also found. Therefore, subjects with insulin resistance and T2DM have a reduced expression of multiple (NRF-1)-dependent genes encoding key enzymes in oxidative metabolism and mitochondrial function.
PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetesThis study extended the results obtained by Patti and colleagues (Patti et al., 2003). Mootha and co-workers used Gene Set Enrichment Analysis, designed to detect modest but coordinated changes in the expression of groups of functionally related genes to study differential expression among healthy individuals, impaired glucose tolerance subjects, and subjects with T2DM (Mootha et al., 2003). They named OXPHOS-CR to a subset of genes, which include about two-thirds of the OXPHOS genes, strongly expressed in skeletal muscle, heart and brown adipose tissue.
No relationship was found between body mass index (BMI) or waist-to-hip ratio and OXPHOS-CR expression, and neither between quantitative measures of fiber types and OXPHOS-CR. However, expression of OXPHOS-CR correlated positively with the aerobic capacity of the individuals under study and negatively to diabetes. In summary, a set of genes involved in oxidative phosphorylation, whose expression was coordinately decreased in skeletal muscle of T2DM subjects, were identified. Thus, authors hypothesized that the decreased expression of OXPHOS-CR genes might contribute to T2DM. Impaired mitochondrial activity in insulin-resistant offspring of subjects with T2DMIn this study Petersen and co-workers aimed to determine the potential mechanism for the intra-myocellular accumulation of lipids leading to insulin resistance (Petersen et al., 2004). Young and lean insulin-resistant offspring of subjects with T2DM and insulin-sensitive subjects were studied. To test their hypotheses, authors utilized hyperinsulinemic-euglycemic clamps in these subjects to measured intra-myocellular lipid and intrahepatic triglyceride content, assessed whole-body and subcutaneous fat lipolysis rates and determined mitochondrial oxidative-phosphorylation activity in muscle by magnetic resonance spectroscopy. The insulin-stimulated rate of glucose uptake was 60% lower in the insulin-resistant subjects, which could be explained by a 70% reduction in insulin-stimulated non-oxidative muscle glucose metabolism. They also observed an 80% increase in intra-myocellular lipid content and a 30% reduction in mitochondrial oxidative phosphorylation, suggesting that subjects with T2DM have an inherited reduction in mitochondrial content in muscle, which in turn may be responsible for the reduced rates of mitochondrial oxidative phosphorylation.
Putting the pieces together, the link between mitochondrial dysfunction and T2DMIn the year 2005 Drs. Lowell and Shulman wrote a viewpoint where they hypothesized that insulin resistance and hyperglycemia could be caused by a primary mitochondrial dysfunction (Lowell and Shulman, 2005). Insulin resistance occurs due to the accumulation of intracellular fatty acyl CoA and diacylglycerol, which in turn activate critical signal transduction pathways, leading to suppression of the insulin signaling pathway. DAG would then activate the phosphorylation of serines and threonines of the insulin receptor susbtrate 1 (IRS-1) through enzymes such as protein kinases C (PKC). PKCs activate the serine kinase cascade and increase the IRS-1 serine (Ser, S) phosphorylation of the the insulin receptor susbtrate 1 (IRS-1).
The phosphorylation of serines located in critical sites leads to a blockage of the IRS-1 tyrosines (Tyr, Y) phosphorylation by the insulin receptor, inhibiting insulin-induced phosphatidyl inositol 3-kinase activity (PI3-kinase) resulting in a decreased insulin-stimulated Akt activity.
Akt reduced activity fails to activate the translocation of GLUT4 to the membrane, diminishing the insulin-induced glucose uptake and impairing the removing of glucose from blood.It is still uncertain whether skeletal muscle mitochondrial dysfunction is a cause or rather a consequence of the metabolic derangements that contribute to insulin resistance in T2DM, including lipid accummulation, pro-inflammatory signals or endoplasmic reticulum stress.
However, given its complex pathophysiology, establishing causality has proved difficult and the mechanisms leading to insulin resistance remain elusive.7. These features, together with impaired energy substrate utilization and the observation that these deleterious effects are not restricted to skeletal muscle, led to the hypothesis that mitochondrial dysfunction plays a major role in T2DM etiology (Lowell and Shulman, 2005).
Since the publication of this hypothesis, there has been a growing interest in further assessing the potential implication of mitochondrial function in the etiology of this metabolic disease. One of the first attempts to clearly prove this hypothesis used transgenic mice with defective mitochondria in order to observe whether they would develop T2DM (Pospisilik et al., 2007). Earlier reports from this same group have shown that conditional deletion of apoptosis inducing factor (AIF) provokes OXPHOS dysfunction (Vahsen et al., 2004). Initially, AIF was considered as a mitochondrial protein involved in signaling events leading to cell death. Subsequent studies have demonstrated that the primary physiological role of AIF is the maintenance of an efficient mitochondrial respiratory system. Studies assessing whole body glucose homeostasis and diet-induced obesity and diabetes either in tissue specific (liver and skeletal muscle) AIF knockout mice or in mice with ubiquitous OXPHOS defects showed that these mice were more insulin sensitive and were protected against diet-induced obesity and diabetes, in contrast with previous hypotheses (Pospisilik et al., 2007). Recently, this observation has been confirmed in another study using rats fed with an iron-deficient diet, which provokes a reduction in the iron containing proteins of OXPHOS (Han et al., 2011). Controversy about the effects of high fat diet feeding in skeletal muscle oxidative capacityIn 2007, two different studies were published addressing whether a high fat diet (HFD) decreases or improves skeletal muscle mitochondrial oxidative capacity. In one (Garcia-Roves et al., 2007), rats were fed with a HFD during 4 weeks in order to raise circulating fatty acids and therefore to study the mechanisms that regulate the already reported improved fatty acid oxidation capacity of glycolytic skeletal muscle.
Rats fed with the HFD regime showed higher fatty acids content, increased skeletal muscle fatty acid oxidative capacity in the epitrochlearis (glycolytic muscle), increased expression of enzymes of the fatty acid oxidation pathway and increased protein content of carboxylic acid cycle and OXPHOS system markers. Furthermore, this study showed that this metabolic adaptation occurs through activation of the peroxisome proliferated activated receptor delta (PPARdelta), a nuclear receptor responsible for regulating transcription of enzymes that belong to the fatty acid oxidation pathway and mitochondrial biogenesis process. Fatty acids, mostly unsaturated, are ligands and activators of PPARs, which explain the metabolic regulations observed in this study (Garcia-Roves et al., 2007).
Similar results were published, almost simultaneously, by Cooney and colleagues in mice (Turner et al., 2007). In both periods of time HFD mice showed an increased capacity to oxidize fatty acid in skeletal muscle, concomitantly with an increased enzymatic activity of key proteins in the fatty acid oxidation pathway and higher protein content of different mitochondrial markers.
Most importantly, these improvements in fatty acid handling and mitochondrial respiration in fat-fed mice occurred at the time these animals showed skeletal muscle insulin resistance and impaired whole body glucose handling (Turner et al., 2007). Name Email WebsiteSubmit Comment Recent Posts One Size May Not Fit All on GI Foods Low GI Foods May Help You Sleep What Exactly Is the Glycemic Index Diet?



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