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The Diabetes Media Foundation is a 501(c)(3) tax-exempt nonprofit media organization devoted to informing, educating, and generating community around living a healthy life with diabetes. 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. Rituximab (a biologic antineoplastic agent) is a monoclonal antibody that directy targets the CD20 receptor of B-lymphocytes and is approved for the treatment of lymphoma and rheumatoid arthritis. Rituximab has shown to be effective in reducing the number of B-cells, without affecting other cells that play a key role in the immune system.
It is important to stress that rituximab should not be interpreted as a definitive curative treatment.
Actually researchers have recently demonstrated that rituximab effectively slow the destruction of pancreatic beta-cells in patients recently diagnosed with type-1 diabetes, thereby improving the management (by eliminating the need for daily insulin injections) and reducing long-term complications of the disease.
Scroll and find best options around your area for free diabetes testinginsight to diabetesEating right in diabetes! Science, Technology and Medicine open access publisher.Publish, read and share novel research. 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 Diabetes.org 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.
We examined the restoration of first-phase and total insulin response as well as hepatic and peripheral insulin sensitivity.
Recent studies have shown that rituximab may be helpful in preventing the progression of type-1 diabetes as well. Scientists have demonstrated that both T-lymphocytes and B-lymphocytes are involved in causing type-1 diabetes. It is through this mechanism that rituximab slows beta-cell destruction in the pancreas of patients affected by type-1 diabetes. It cannot be used to completely reverse type-1 diabetes, because the pancreas is usually too damaged by the time of diagnosis. 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. Lixisenatide is currently approved in more than 60 countries worldwide under the proprietary name Lyxumia®. 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). Additionally, to examine the mechanistic basis of observed outcomes, we quantified the change in fat content of the pancreas and liver The data are consistent with the hypothesis that the abnormalities of insulin secretion and insulin resistance that underlie type 2 diabetes have a single, common aetiology, i.e. While autoreactive T-cells directy attack and destroy pancreatic beta-cells, B-cells are believed to play a significative role in the pathogenesis and progression of the disease by triggering autorective T-cells to attack. Although by the time of diagnosis of type-1 diabetes, about 80% of beta-cells have already been destroyed, rituximab might help to slow the progression of the disease by preventing the destruction of the remaining 20 percent.
Introduction“Let food be your medicine and medicine be your food” stated Hippocrates, the father of Western medicine, in 400 B.C.
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. All the recorded marks and the names of the mentioned products belong to the respective owners.
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. 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.
This provides a unified hypothesis to explain a common disease that previously appeared to require separate disease processes affecting the pancreas and insulin-sensitive tissues. 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).
After the 8 weeks of "starvation", calorific intake can be increased but only to a maximum of two-thirds of the pre-diagnosis level. 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. Insulin resistance causes an over-release of fatty acids, a negative condition frequently seen in obesity-related diabetes. Prior to the onset of spontaneous diabetes in rodents, both total pancreatic fat and islet triacylglycerol content increase sharply.
Like diet, physical activity has been also considered an important starting point for people's health. In vitro, chronic saturated fatty acid exposure of beta cells inhibits the acute insulin response to glucose, and removal of fatty acids allows recovery of this response.
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).
The present data provide clear evidence that decreasing total pancreatic fat is associated with a return of beta cell function.
Our knowledge about the links between diet, exercise, and disease has vastly increased since Hippocrates time. However, it is probable that the negative effect on beta cell function is exerted by toxic intermediaries such as diacylglycerol and ceramides, which change rapidly in response to acute metabolic changes, rather than by stored triacylglycerol per se, which acts as an index of fatty acid intermediary concentration. A healthy lifestyle based on diet and physical activity is now considered the keystone of disease prevention and the basis for a healthy aging. However, modern society has created conditions with virtually unrestricted access to food resources and reduced physical activity, resulting in a positive overall energy balance.
Endless access to abundant calories from carbohydrate may be an evolutionarily novel, and thus pathology-inducing, situation. 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. 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 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. T2DM is now considered to be a global epidemic with significant social and economic consequences both at the individual and population level. 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. And yet everything happens only a certain number of times, and a very small number really Leave a Reply Cancel reply You must be logged in to post a comment. 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).
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.
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).
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. 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.


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. Under physiological conditions, carbohydrates provided by the diet increase plasma glucose levels and promote insulin secretion from pancreatic ? cells of the islets of Langerhans. 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. 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). Among these, IRS1 and IRS2 appear to be the major adapter molecules that play a role in insulin cascade. 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.
AS160 normally inhibits translocation of GLUT4 through its interaction with RabGTPase protein.
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. ATP - how does it works, how it was created  Gardening (4) How To Build Cabin Solar Powered for $2,000 7 Foods That Slow Down Ageing No Garden?
Here Are 66 Things You Can Can Grow In Pots 7 Natural Uses For Baking Soda In The Garden  Health (75) Natural Diabetes Cure type 2 Why You Can NEVER Lose Weight by Building Muscle Mass Form Vs. Pathogenesis of Type 2 Diabetes MellitusAn important early phenotype associated with increased T2DM risk is insulin resistance. 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. Individuals with established T2DM show several physiological abnormalities, including elevation in fasting glucose levels, elevation in postprandial glucose levels, or both.
In adipose tissue, the major fat storage tissue in mammals, insulin resistance results in increased lipolysis and fatty acid release. Increased circulating fatty acids decrease the ability of insulin to suppress hepatic glucose production and allow a constant increase in fatty acid synthesis. This dysregulation of carbohydrate and lipid metabolism accelerates the progression of insulin resistance. 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. When pancreatic beta-cells can no longer compensate they become unable to respond appropriately to glucose levels. Bill Gates Wants to be Immortal Cause of death in UK Health benefits of Cocoa and chocolate Leading Cause of Death Age 35 - 45 more from How To live to 100  Life Guide 101 (13) Because we don't know when we will die, we get to think of life as an inexhaustible well.
This pancreatic beta-cell failure leads to the deterioration of glucose homeostasis and the development of T2DM.
And yet everything happens only a certain number of times, and a very small number really Stress - Are we All Suffering from Anxiety ??? 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. Tips and Tricks - Happy Life Things we tell to our self which keep us from being Happy How to live a happier life - Rules, steps and tips for a happier life guide Why Are You Working So Hard?
Skeletal muscle insulin resistance and T2DMAs mentioned above, insulin resistance is a key component for the development of T2DM.
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).
Even small CR have huge efects on health and longevithy How To Build Cabin Solar Powered for $2,000 Ski is NOT a "dangerous" sport!!! 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. Skeletal muscle fiber types and metabolismSkeletal muscle is a complex tissue composed of different fiber types, which have distinct mechanical and metabolic properties. Not Bill Gates Wants to be Immortal more from Longevity  People of our days (13) excellent physicians are excellent not because of external incentives but because of their desire to be so, and they have a strong moral sense which drives them. A cup of Earl Grey 'as good as statins' at fighting heart disease, study finds - Since statins suck, this isn't a very high standard.
Each of these functional systems is composed of a motor neuron and a group of muscle fibers. Normal weight and occasionally fasting people probably won't increase their longevity further by severe caloric restriction. For those of you interested in activating telomerase, Geron has developed a telomerase inhibitor as a cancer therapeutic lack of adaptation to the agricultural diet can cause chronic disease Supplement website is full of distortions designed to sell products Robert Kiyosaki: Create your own reality. 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). 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). Evolution Improved Every Tiny Thing by 1 Percent and Here’s What Happened Cancer loves high carbohyrdrate diets. 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. 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.
Articles: Early Signs of Alzheimer’s Disease Coca cola bad for health, side effects Prolonged lack of sleep effects on brain and on the body function How Has Stephen Hawking Lived to 70 with ALS? Thus, skeletal muscle is able to predominantly utilize both glucose and free fatty acids as fuel sources for energy production.
This event, together with the activation of key enzymes in glucose metabolism, leads to a marked increase in muscle glucose oxidation. 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.
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. 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. 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). 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. 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.
If there was a block at the hexokinase step, as proposed by Randle, intra-myocellular glucose concentrations would be expected to increase. 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.
In some diseases, protein synthesis increases in ER-lumen and proteins cannot fold correctly, affecting ER homeostasis. 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.
The link between T2DM, insulin resistance and ER stress in skeletal muscle is still unclear.
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). 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.
This activation leads to degradation of the inhibitor of kappa beta (IKB) and Nuclear factor-kappa beta (NFKB) activation.
Biology of the mitochondriaMitochondria are doubled-membrane organelles that constitute the major site for oxidative energy production in the cell. 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). Besides generating the majority of cellular ATP via oxidative phosphorylation (OXPHOS), many other essential cellular functions take place in this organelle.
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. Oxidation of substrates generates reduced nicotinamide adenine dinucleotide (NADH) and reduced flavin adenine dinucleotide (FADH2) that will provide electrons to the ETS. 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. Mitochondrial biogenesis and dynamicsMitochondrial biogenesis is defined as the generation of more mitochondrial mass and takes place in response to increased energy demand.
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). 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).


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. 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. 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.
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. 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. It has also been shown to regulate multiple subunits of the respiratory chain as well as other proteins involved in other mitochondrial functions. 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).



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