The pathogenesis of type ii diabetes mellitus. a polygenic disease,type 2 diabetes weight gain symptom,diabetes mellitus type 2 organs affected countries,freestyle diabetes companion youtube - Test Out


Type 2 diabetes mellitus has become an epidemic, and virtually no physician is without patients who have the disease. Diabetes mellitus has reached epidemic proportions and affects more than 170 million individuals worldwide. The medical and socioeconomic burden of the disease is caused by the associated complications,7-9 which impose enormous strains on health-care systems. Although lifestyle and overeating seem to be the triggering pathogenic factors, genetic elements are also involved in the pathogenesis of type 2 diabetes.
Since dizygotic twins share the environment (both intrauterine and extrauterine) but only 50% of their genes, concordance rates in monozygotic twins in excess of those in dizygotic twins have been used to distinguish genetic from non-genetic contributions.
Nevertheless, concordance rates in monozygotic twins might produce an underestimate of genetic effects, because the monochorionic intrauterine nutrition of monozygotic twins has been shown to result in growth retardation compared with dizygotic twins.32 And low birthweight itself is associated with increased risk of type 2 diabetes later in life.
To understand the cellular and molecular mechanisms responsible for type 2 diabetes it is necessary to conceptualise the framework within which glycaemia is controlled. In people with normal glucose tolerance (NGT) a quasi-hyperbolic relation exists between ß-cell function and insulin sensitivity.
However, not only deviation from but also progression along the hyperbola affects glycaemia. Insulin resistance is said to be present when the biological effects of insulin are less than expected for both glucose disposal in skeletal muscle and suppression of endogenous glucose production primarily in the liver.38 In the fasting state, however, muscle accounts for only a small proportion of glucose disposal (less than 20%) whereas endogenous glucose production is responsible for all the glucose entering the plasma.
Insulin secretion from the pancreas normally reduces glucose output by the liver, enhances glucose uptake by skeletal muscle, and suppresses fatty acid release from fat tissue. Insulin resistance is strongly associated with obesity and physical inactivity, and several mechanisms mediating this interaction have been identified. To understand the contribution of insulin resistance in a particular tissue to whole body glucose homoeostasis, conditional knockouts of the insulin receptor have been created using the Cre-lox system. In states of insulin resistance, one or more of the following molecular mechanisms to block insulin signalling are likely to be involved.
Insulin signalling involves binding of insulin to its receptor followed by a cascade of intracellular events, depicted as activation pathways. A close connection between insulin resistance and classic inflammatory signalling pathways has also recently been identified. In ß cells, oxidative glucose metabolism will always lead to production of reactive oxygen species, normally detoxified by catalase and superoxide dismutase. Islet amyloid consists of deposits of islet amyloid polypeptide, also known as amylin, which is co-secreted with insulin at a more than tenfold lower rate. It is possible that early in the disease, increased demands of insulin secretion lead to islet amyloid polypeptide aggregates, especially in the presence of raised concentrations of NEFA.
Although there is little doubt as to the importance of genetic factors in type 2 diabetes (table 2), it should be borne in mind that this disease is very heterogeneous.
The candidate gene approach examines specific genes with a plausible role in the disease process. The candidate gene approach in attempts to identify a causative factor among the obvious biological candidates for insulin resistance has been largely disappointing (table 4). Among the many candidate genes for insulin secretory dysfunction, those encoding SUR1 and KIR6·2 have been most extensively studied.
Genes involved in embryonic ß-cell development, such as components of the insulin-like growth factor pathways, have also been studied.
Several findings of positive associations of genomic regions with type 2 diabetes have been replicated in one or more studies (1q21-24, 1q31-q42, 9q21, 10q23, 11p15, 11q13-14, 12q12, 19q13, and 20q11-q13 ).114 Generally, such findings are followed by positional cloning of the causative gene, which to date has not been successful for most regions. A peculiar possibility is the relation of diabetes to imprinted genes--ie, genes for which expression varies depending on the sex of the transmitting parent. In making therapeutic choices (figure 7) in the management of type 2 diabetes, the major goal of protecting patients from the long-term complications of the disease must be considered. Drugs that enhance insulin sensitivity are primarily those of the thiazolidinedione class, which not only reduce glycaemia, but also enhance vascular function and ameliorate the dyslipidaemia and inflammatory milieu of type 2 diabetes.131 Thiazolidinediones primarily activate PPARgamma receptors in adipose tissue and alter adipose metabolism and distribution. Unlike metformin, the thiazolidinediones can be used in patients with reduced renal function, and they are better tolerated without significant gastrointestinal side-effects.
Metformin is a highly effective antihyperglycaemic drug that works independently of the pancreas, sparing insulin. As inadequate ß-cell insulin secretion is fundamental to the development of hyperglycaemia in diabetes, insulin secretion enhancers also play an important role in control of blood glucose. The mode of action of sulfonylurea derivatives implies that they also act at low concentrations of plasma glucose, which explains the potential of (occasionally severe) hypoglycaemia. The recently introduced class of meglitinides consists of nateglinide, which binds to the same site of sulphonylurea receptor 1 as do the sulfonylurea derivatives, and repaglinide, which binds to a nearby site of the receptor, both leading to insulin release. Replacing circulating concentrations of insulin is essential to support the clinical effects of metformin and the thiazolidinediones, which are ineffective without adequate insulin availability, and may also have important beneficial effects in reducing inflammatory processes, especially in the vasculature.142 Thus, it is essential to initiate insulin injections when required to achieve glycaemic targets in type 2 diabetes, possibly in combination with oral insulin sensitisers. As specific drug targets are identified through improved understanding of the molecular pathogenesis of diabetes, novel therapeutics will become available in the future. The results of the HOPE study,147 in which use of ramipril was associated with a markedly lower risk of myocardial infarction, stroke, and death, favour use of the ACE inhibitor in diabetic patients with one additional risk factor, even if they do not have hypertension. The benefit of lipid-lowering drugs has now been firmly established, since the Scandinavian Simvastatin Survival Study showed a reduction in total mortality of 43%. Fibric acid derivatives might benefit diabetic patients because they raise concentrations of HDL cholesterol and reduce triglyceride levels. Whether therapy should be given for other risk factors such as hyperhomocysteinaemia (treated with folic acid), and whether antioxidants are of use, is still unclear because of the absence of studies with hard endpoints in patients with type 2 diabetes.
The goal of ultimately reducing the population burden of diabetes by early treatment and prevention is clearly of pivotal importance. A more complete understanding of the molecular mechanisms of diabetes will enable the identification of individuals at highest risk, which could lead to novel pharmacological concepts, risk stratification, and development of more targeted preventive measures. 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. A 34 year old Caucasian male with symptoms of polyuria, polydipsia, blurry vision and a 40 pound weight loss over a two month period presented to an outpatient specialty clinic.
Differentiation of type 1 diabetes mellitus (T1DM) from type 2 diabetes mellitus (T2DM) in adults may not always be straightforward. History of Present IllnessTwo weeks after being diagnosed by his Primary Care Provider (PCP) with T2DM, a 34 year-old white male was referred to the Diabetes Specialty Care Team for education and evaluation.
Physical exam revealed a 34-year-old slightly overweight Caucasian male in no acute distress.
Diabetes mellitus is a chronic disorder of the metabolism due either to a deficiency of insulin secretion, a decreased effectiveness of insulin, or both. For diabetic patients taking two-to-three insulin injections per day or more, the blood sugar should be monitored three to four times per day, usually before giving an injection and at bedtime. On his second appointment with the Diabetes Specialty Care Team (two days after his initial appointment), the patient stated that he was feeling a little better. Review of laboratory results ordered at the first appointment with the Diabetes Specialty Care Team that revealed that two of the three Islet Cell Autoantibodies (ICAs) tests were positive.
The patient was seen again 1 week and 2 weeks after the initial office appointment with the diabetes specialty care team and continued to do well.
This case represents the difficulty that clinicians may encounter in differentiating between T1DM, T2DM, and other less common types of diabetes mellitus. Continued support, education, and collaboration between the health care team, the patient and his family will offer the best alternatives for positive outcomes (see Table 7). 20.American Association of Clinical Endocrinologists Diabetes Mellitus Clinical Practice Guidelines Task Force. 34.National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).
Five years ago, a new system of classification of the various types of diabetes was proposed. Schreiben Sie eine Kundenbewertung zu diesem Produkt und gewinnen Sie mit etwas Gluck einen 15,- EUR buecher.de-Gutschein! Whereas insulin insensitivity is an early phenomenon partly related to obesity, pancreas ß-cell function declines gradually over time already before the onset of clinical hyperglycaemia. The incremental costs of patients with type 2 diabetes arise not only when the diagnosis is established but at least 8 years earlier.10 The devastating complications of diabetes mellitus are mostly macrovascular and microvascular diseases as a consequence of accelerated atherogenesis. Insulin is the key hormone for regulation of blood glucose and, generally, normoglycaemia is maintained by the balanced interplay between insulin action and insulin secretion. When insulin action decreases (as with increasing obesity) the system usually compensates by increasing ß-cell function.
Endogenous glucose production is accelerated in patients with type 2 diabetes or impaired fasting glucose.39,40 Because this increase occurs in the presence of hyperinsulinaemia, at least in the early and intermediate disease stages, hepatic insulin resistance is the driving force of hyperglycaemia of type 2 diabetes (figure 3). The various factors shown that contribute to the pathogenesis of type 2 diabetes affect both insulin secretion and insulin action.
A number of circulating hormones, cytokines, and metabolic fuels, such as non-esterified (free) fatty acids (NEFA) originate in the adipocyte and modulate insulin action. Among the five conditional insulin receptor knockouts shown in table 3, only liver47 and ß-cell specific knockouts50 became glucose intolerant whereas, unexpectedly, knockout models specific for muscle46 and fat cells48 did not. Negative modulation of insulin action can be mediated via various pathways leading to insulin resistance: various inhibitory triggers affect their respective signal modulators (partly via transcription factors), which lead through deactivating pathways (tyrosine phosphatases, serine kinases, lipid phosphatases and degradation pathways) to inhibitory actions on insulin signalling (activation pathways). Basal insulin concentrations may be raised to roughly double the usual value, especially in obese hyperglycaemic patients, but this finding is presumably due to increased plasma glucose.
Further degradation leads to formation of pyruvate, which is then taken up in the mitochondria in which further metabolism leads to ATP formation. Generally, in both non-diabetic and diabetic obese patients, NEFA concentrations are raised as a result of enhanced adipocyte lipolysis.
The physiological role of islet amyloid polypeptide is unclear, and diverse roles such as inhibition of insulin action, inhibition of insulin secretion, and inhibition of glucagon secretion have been proposed.
The finding that first-degree relatives of patients with type 2 diabetes have decreased islet amyloid polypeptide (and insulin) responses to intravenous glucose, however, challenges this speculation.96 Also, amyloid is not observed in middle-aged insulin-resistant individuals. For this purpose the statistical association of a given allele and a phenotype (eg, type 2 diabetes, or insulin resistance) is tested in unrelated individuals.
The two genes--ABCC8 and KCNJ11, respectively--are adjacent to one another on chromosome 11. Genetic variation near or in the P2-promoter of the MODY-1 gene HNF4A gene (chromosome 20q) has been proposed to relate to common type 2 diabetes,128 but this finding requires independent confirmation.
The class III allele of the variable number tandem repeat near the insulin gene (chromosome 11p15) might relate to type 2 diabetes.129 The class III allele is associated with decreased amounts of insulin mRNA. Because insulin resistance plays a fundamental role in the pathogenesis of type 2 diabetes and especially its adverse cardiovascular outcomes, interventions should initially be aimed towards improvement in tissue insulin sensitivity. The redistribution of tissue triglyceride from visceral stores reduces levels of circulating NEFA apparently by sequestration in a less lipolytic subcutaneous compartment.132 Thiazolidinediones also reduce circulating concentrations of pro-inflammatory cytokines that promote insulin resistance (eg, TNFalpha and interleukin 6) and at the same time increase concentrations of adiponectin, which has insulin-sensitising and anti-inflammatory properties. A major adverse effect associated with clinical use of the thiazolidinediones is weight gain, which seems to be coupled to the effects of the drugs on adipose cell differentiation and triglyceride storage.
It decreases hepatic glucose output and has been shown to have a beneficial effect on cardiovascular outcomes.136-138 Metformin has less robust effects on insulin resistance, inflammatory markers, and vascular function compared with the thiazolidinediones, but its benefit in abrogating some of the weight gain commonly observed with insulin-sensitisers and insulin secretion enhancers adds important value to this drug. Sulfonylurea derivatives act by closing pancreatic cell potassium channels, which leads to enhanced insulin secretion. These agents cannot further stimulate insulin release in patients on maximal doses of sulfonylurea derivatives. However, combined use of insulin and thiazolidinediones seems to infer an increased risk of oedema and cardiac failure.
This incretin hormone has potent glucose-dependent insulinotropic properties, trophic effects on ß cells, and inhibitory effects on intestinal motility, all of which reduce plasma glucose.
Conversely, increasing adiponectin secretion or administration of an adiponectin receptor agonist would probably enhance glucose metabolism in skeletal muscle and liver and also confer beneficial effects in the endothelium. The benefit of antihypertensive therapy is larger in diabetic than in non-diabetic hypertensive patients. They can decrease endothelial cell activation possibly because of their capacity for binding PPARalpha. A number of studies have shown that diabetes can be delayed or prevented in individuals at high risk undergoing an intensive diet and exercise programme, and intervention with medications including metformin, acarbose or thiazolidinediones has also shown to be effective (table 5). A long-term goal is to develop drugs that restore normoglycaemia by targeting specific pathogenic defects. 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.
This article describes the evidence-based evaluation and management by the advanced practice nurse (APN) of a patient with newly diagnosed diabetes mellitus.
Despite a 40-pound weight loss over the past two months, the PCP diagnosed the patient with T2DM. Despite these lab results indicating early metabolic acidosis, the patient denied having any symptoms of diabetic ketoacidosis (DKA); a potential risk. The patient presented with the typical symptoms of hyperglycemia, including polyuria, polydipsia, blurry vision, and fatigue. This patient was suspicious for T1DM due to his weight loss, metabolic acidosis, and the ketones present in the urine.
Initiate InsulinInsulin glargine (Lantus ® ) was prescribed and the patient was instructed to take 15 units subcutaneously at bedtime. Glutamic acid decarboxylase – 65 (GAD-65) and protein tyrosine phosphatase IA-2 (IA-2) were both positive. The glargine insulin was titrated up over the following 3 weeks to 25 units each night at bedtime. This patient was initially diagnosed with T2DM based largely on age and phenotype, despite a 40-pound weight loss. In addition, this author would like to extend many heartfelt thanks to Joanne Hickey, PhD, RN, ACNP-BC, FCCM, FAAN for her continuous support and motivation, and to Susan Ruppert, PhD, RN, ANP-BC, NP-C, FCCM, FAANP for her continued encouragement during the writing of this manuscript. Evaluation of the new ADA and WHO criteria for classification of diabetes mellitus in young adult people (15-34 yrs) in the diabetes incidence study in Sweden (DISS).
Ketone bodies: A review of physiology, pathophysiology and application of monitoring to diabetes. Autoimmune diabetes not requiring insulin at diagnosis (latent autoimmune diabetes of the adult): Definition, characterization, and potential prevention. A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies.
Latent autoimmune diabetes in adults: Definition, prevalence, ?-cell function and treatment. American association of clinical endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. This publication provides an inte grated picture of the latest information on the similarities and dissimilarites of two types of diabetes. Several mechanisms have been proposed, including increased non-esterified fatty acids, inflammatory cytokines, adipokines, and mitochondrial dysfunction for insulin resistance, and glucotoxicity, lipotoxicity, and amyloid formation for ß-cell dysfunction.
Importantly, the normal pancreatic ßcell can adapt to changes in insulin action--ie, a decrease in insulin action is accompanied by upregulation of insulin secretion (and vice versa).
An increased mass of stored triglyceride, especially in visceral or deep subcutaneous adipose depots, leads to large adipocytes that are themselves resistant to the ability of insulin to suppress lipolysis. These findings clearly support a central role of hepatic insulin resistance in the pathogenesis of type 2 diabetes, and suggest that an adequate insulin signal in the pancreatic ß cell is needed to maintain its function. Adiponectin has an ameliorating function on glucose metabolism apart from insulin signalling.
Similarly, after a meal, concentrations of insulin in plasma can appear higher than normal, because of substantially raised plasma glucose.
ATP is necessary for the delivery of energy needed for the release of insulin, but it is also involved in the cell membrane depolarisation. Fatty acids lead to enhanced insulin secretion in acute studies, but after 24 h they actually inhibit insulin secretion. It has been suggested that small aggregates are cytotoxic,94 possibly related to radical production. Thus, the role of amyloid deposits (a post-mortem finding) in pancreatic islets in the pathophysiology of type 2 diabetes remains unclear.
In general, two methods are used for studying genetic factors involved in a specific disease: the so-called candidate gene approach and the genome-wide scan approach.
The genome-wide scan or linkage approach is not based on assumptions but locates genes through their genomic position and is based on the rationale that family members sharing a specific phenotype will also share chromosomal regions surrounding the gene involved.
This often involves lifestyle intervention, with modest exercise and weight loss, which clearly reduces the risk of progression of impaired glucose tolerance to overt diabetes12,13 and can improve many of the cardiovascular risk parameters of the metabolic syndrome. Fluid retention is also linked to the PPARgamma-agonist activity of the thiazolidinediones, leading to peripheral oedema and a mild haemodilution in some patients. The results of the UK Prospective Diabetes Study8 showed a clear risk reduction for the occurrence of microvascular complications by the use of sulfonylurea derivatives, while the risk reduction of macrovascular disease was around 16%. However, because circulating glucagon-like peptide 1 is immediately inactivated by dipeptidyl peptidase IV, it is therapeutically impractical.
Recent evidence for amelioration of insulin resistance by salicylates by favourable interference with the inflammatory kinase cascade in insulin signalling might lead to entirely novel therapeutic approaches.
The interesting observation that improvement in one or more major pathogenic factors offsets the progression of impaired glucose tolerance to diabetes underscores the contribution of each of these factors to the development of the disease, including insulin sensitivity, ß-cell function, and actual glucose excursions. One example would be to advance the thiazolidinedione concept to design compounds that could restore defects in individuals with a defective PPARgamma regulatory system. Introduction“Let food be your medicine and medicine be your food” stated Hippocrates, the father of Western medicine, in 400 B.C.
Special emphasis is given to the criteria necessary for differentiation between type1 diabetes mellitus (T1DM) and other types of diabetes, particularly type 2 diabetes mellitus (T2DM) and latent autoimmune diabetes in adults (LADA).
Correct differentiation between T1DM and these other types of diabetes is important in developing a treatment plan, in particular, whether or not to initiate insulin.
The patient also reported having vision problems for two months prior to diagnosis of T2DM. The symptoms of DKA include lethargy, confusion, extreme fatigue, abdominal pain, vomiting, extreme thirst, or dry mucous membranes. The patient was well developed, well nourished and his appearance was consistent with his stated age. The fasting plasma glucose is the preferred test for diagnosing diabetes in children and non-pregnant adults. Although most patients with T1DM are either children or adolescents, the ADA [8] states that age should not be a determining factor in T1DM.
Additionally, the random urine microalbumin was negative, the urinalysis was now negative for ketones and urine glucose had decreased from 4+ to 2+. A simple dipstick urinalysis revealed large amounts of ketones, which indicated insulin deficiency.
Patterns of metabolic progression to type 1 diabetes in the diabetes prevention trial –type 1. The PROCAM experience and pathophysiological implications for reverse cholesterol transport. It contains contributions from morphologists, physiologists, biochemists, immunologists, pathologists, geneticists, clinicians and epidemiologists. It contains contributions from morphologists, physiologists, biochemists, immunologists, pathologists, geneticists, clinicians and epidemiologists.
Thus, even with (theoretically) unlimited ß-cell reserve, insulin resistance paves the way for hyperglycaemia and type 2 diabetes. Insulin resistance pathways affect the action of insulin in each of the major target tissues, leading to increased circulating fatty acids and the hyperglycaemia of diabetes. Additionally, reactive oxygen species are known to enhance NFkappaB activity, which potentially induces ß-cell apoptosis.


Fortunately, congestive heart failure is quite rare with use of thiazolidinediones, but remains a serious concern that requires caution in selection of patients to receive these agents.135 The ability of thiazolidinediones to ameliorate risk of atherosclerotic events is being assessed in several large outcomes studies. Thus, careful attention needs to be applied to determine appropriate public interventions for the varied populations of the world. 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.
As a result of his history of Pigmentation Disbursement Syndrome, the patient initially made an appointment with an ophthalmologist. Pre-breakfast hyperglycemia is sometimes due to the Somogyi effect in which nocturnal hypoglycemia causes release of counter-regulatory hormones that produce hyperglycemia by 7:00 AM. Is latent autoimmune diabetes in adults distinct from type 1 diabetes or just type 1 diabetes at an older age? Implications of recent clinical trials for the national cholesterol education program adult treatment panel III guidelines. Evaluation of the safety and tolerability of prolonged-release nicotinic acid in a usual care setting: the NAUTILUS study.
In the first section, the basis for the present classification and its limitations are discussed. Management includes not only diet and exercise, but also combinations of anti-hyperglycaemic drug treatment with lipid-lowering, antihypertensive, and anti platelet therapy. Thus, ß-cell dysfunction is a critical component in the pathogenesis of type 2 diabetes. In turn, the raised concentrations of glucose and fatty acids in the bloodstream will feed back to worsen both insulin secretion and insulin resistance.
The closure of the potassium channels will alter the membrane potential and open calcium channels, which triggers the release of preformed insulin-containing granules (figure 5). However, long-chain acyl coenzyme A itself can also diminish the insulin secretory process by opening ß-cell potassium channels (figure 6).
Combined management with both sulfonylurea derivatives and antihypertensives improves the risk reduction even more. Lifestyle modification has been difficult to maintain over a long term, and has costs associated with regular visits to various health-care professionals and lifestyle coaches. Antisense inhibition of PTP1B, a tyrosine phosphatase, currently undergoing phase II trials, could become the treatment of choice for patients with a genetic variant in PTP1B.156 Generally, with an optimised risk-benefit ratio, patients who respond to treatment may also benefit from specific drugs in a preventive approach. 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). Pupils were equal, round and reactive to light and accommodation, with a faint circular line of darker pigment around the outer edges of both irises.
When instituting a basal-prandial regimen, patients should decrease the calculated 50 percent basal regimen by 20 percent to avoid hypoglycemia.
The patient did not fit the phenotypic characteristics or the diagnostic criteria for LADA, since he required insulin at the time of his diagnosis to correct his ketosis. Since this patient presented with ketosis requiring insulin within 6 months of diagnosis, he did not fit the criteria for LADA. Prevalence and phenotypic distribution of dyslipidemia in type 1 diabetes mellitus: effect of glycemic control. In addition, there is a discussion of gestational diabetes and heterogeneity of some sub-classes of diabetes. A second mechanism might be increased expression of uncoupling protein-2, which would lead to reduced ATP formation and, hence, decreased insulin secretion. Until that day, diet and exercise remain the pillars of prevention and treatment of type 2 diabetes. 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. However, after several appointments the ophthalmologist determined that the symptoms were unrelated to his eye condition and suggested he see his PCP for further evaluation. At the initial appointment with the PCP, the patient had been placed on metformin (Glucophage ® ) 500 mg twice daily and pioglitazone (Actos ® ) 15 mg once daily. The reported C02 in the serum refers to the total C02 in the blood, including that contained in bicarbonate.
The diagnosis must be confirmed on a subsequent day in the absence of unequivocal hyperglycemia. Diagnostic testing for islet cell antibodies is a definitive way to determine if a patient has autoimmune T1DM versus KP-T2DM. The “dawn phenomenon” is due to the normal physiologic reduction in insulin sensitivity to insulin between 5 AM and 8 AM as a result of spikes of growth hormone that were released at the onset of sleep. Intermediate insulin has an onset of action of between two to four hours, achieves a peak in approximately six to seven hours, and can last up to 20 hours.
Fifty percent of this TDI dose is given as the long acting basal insulin (glargine) and the remaining fifty percent given as rapid-acting (RAI) insulin (aspart).
A third mechanism might involve apoptosis of ß cells, possibly via fatty acid or triglyceride-induced ceramide synthesis or generation of nitric oxide. Further clinical trials comparing these and newer medications that may affect diabetes pathogenesis (such as glucagon-like peptide 1 analogues) are needed to balance safety and efficacy with the costs of these different agents in various regions. The implementation and sensible use of the available pharmacological agents, including insulin, and the management of other cardiovascular risk factors, remain the practical challenge to the clinician. Like diet, physical activity has been also considered an important starting point for people's health.
The patient also reported symptoms of polyuria, polydipsia, fatigue and frequent headaches for several weeks in addition to blurry vision and the 40-pound weight loss. Pre-diabetes is the term now used for patients with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). The third section discusses abnormalities of insulin secretion and act ion on both the receptor and post .
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).
Results of laboratory tests ordered by the PCP at the initial appointment are listed in Table 1. Past Medical HistoryThe patient’s past medical history was significant for mild-intermittent asthma since childhood, seasonal allergic rhinitis, diverticulosis, and pigment dispersion syndrome of the eye. The patient quickly mastered carbohydrate counting, and was started on a 1:15 insulin to carbohydrate ratio for his bolus insulin. Of notable significance was the fact that a thorough history revealing the patient’s recent weight loss was the single-most important factor that triggered the APN to proceed with further work-up.
Our knowledge about the links between diet, exercise, and disease has vastly increased since Hippocrates time.
This chronic problem is the result of a loss of pigment from the neuroepithelial posterior surface of the iris, which is spread throughout various structures of both anterior and posterior chambers. A lipid profile was ordered since diabetic patients are at higher risk for lipid abnormalities and should be screened.
C-peptide levels are considered a reliable marker of residual beta-cell function, however, according to the findings in the Diabetes Prevention Trial – Type 1 (DPT-1), a normal C-peptide is not unexpected at the onset of T1DM clinical disease.
The insulin: carbohydrate ratio is used to calculate the number of grams of carbohydrates that will be covered by 1 unit of rapid acting insulin (RAI).
Results of the Diabetes Control and Complications Trial (DCCT) clearly show that achieving near-normal glycemia in patients with diabetes reduces the risk for long-term microvascular and neurological complications such as retinopathy, nephropathy and neuropathy. A healthy lifestyle based on diet and physical activity is now considered the keystone of disease prevention and the basis for a healthy aging. The pigment is carried forward and deposited along the routes of aqueous flow, creating decreased outflow of the trabecular meshwork.
Metabolic acidosis may be caused by an overproduction of keto-acids with a respiratory alkalosis due to the compensatory increase in ventilation, in an effort to decrease C02 and bicarbonate (H2C03) levels. Discontinue Metformin and Pioglitazone: The patient was instructed to discontinue metformin and pioglitazone. However, modern society has created conditions with virtually unrestricted access to food resources and reduced physical activity, resulting in a positive overall energy balance. Metformin may increase the risk of lactic acidosis, especially in patients with metabolic acidosis or impaired renal function. 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 the last section, both types of diabetes are compared with respect to diabetic complications.
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). T1DM is further divided into two categories: Type 1-A (Immune-mediated), and Type 1-B (Idiopathic, non-autoimmune). The pioglitazone package insert recommends not using this medication in patients with ketoacidosis, or who are insulin deficient, since the mechanism of action is dependent on the presence of insulin. The closing sec tion summarizes the present status and offers a stimulating view of future development.
It seems clear that the development of T2DM has a genetic component that becomes obvious when individuals are exposed to western lifestyle. His surgical history was significant for an appendectomy and bilateral inguinal hernia repairs as a child. The package insert also recommended that pioglitazone be taken at least three months before maximum results are seen, therefore this medication would not be able to rapidly bring this patient’s hyperglycemia under control. Based on lipid results, this patient also had primary mixed hyperlipidemia (type 5) which is characterized by the pathologic presence of chylomicrons after a 12-14 hour period of fasting.
Continued education and encouragement of patient involvement in the control of their diabetes is essential for a positive prognosis. We hope that this book will be a useful source of information for both researchers and practicing clinicians.
However, environment plays a critical role in the incidence of the disease being obesity the main etiological cause of T2DM. Diabetes is a chronic, lifelong illness that requires management of the disease by the patient. 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.
Begin Aspirin (ASA) 81 mg once daily Aspirin should be used as a primary or secondary prevention strategy in patients with known cardiovascular disease (CVD), or with T1DM or T2DM at increased risk including those over 40, or with a family history of CVD, who smoke, have HTN or dyslipidemia. Numerous sources of excellent patient information and education as well as clinician support exist (see Table 6). Antibodies to several of the autoantigens, such as glutamic acid decarboxylase-65 (GAD65), protein tyrosine phosphatase IA-2 (IA-2), and insulin autoantibody (IAA), are highly predictive of T1DM. T2DM is now considered to be a global epidemic with significant social and economic consequences both at the individual and population level.
Acute life-threatening complications of uncontrolled diabetes are hyperglycemia with ketoacidosis or nonketotic hyperosmolar syndrome. 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.
A prescription for glucagon 1mg kit was given, and his wife was instructed to give him 0.5 to 1mg subcutaneously or intramuscularly if he should become unconscious. Hollenberg v ACKNOWLEDGEMENTS The symposium from which this volume arose (June 28-29, 1984) was organized by the Banting and Best Diabetes Centre, University of Toronto.
In DKA, the lack of insulin stimulates lipolysis in the adipose tissue, and ketogenesis in the liver, resulting in increased free fatty acids and a rise in hydrogen ions leading to metabolic acidosis.
Patients with LADA also have a phenotypic presentation more closely resembling T2DM, including obesity and central adiposity. Individuals with poorly controlled T1DM frequently have high levels of triglycerides and LDL-cholesterol, but levels usually improve with improved glycemic control. We would like to express our appreciation to the following sponsors: Ames Educational Institute, Ayerst Laboratories, Becton Dickinson Canada Inc. 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). Gaining an understanding of the earliest symptoms of not only the general symptoms of hypoglycemia such as hunger, perspiration, nervousness, and confusion, but also their individual initial symptoms may help prevent more severe hypoglycemia episodes from occurring, and allows these events to be easily managed with a snack or another glucose source.
A partial or relative insulin deficiency leads to decreased glucose utilization by the muscles, and increased hepatic glucose output. The term LADA was created to describe a subset of adult patients that are initially non-insulin requiring, but have the autoimmune markers of T1DM and go on to require insulin within a few years. Educating patients on the differences between major and minor hypoglycemia and how to manage each one is an important part of diabetes education. The presence of even a small amount of circulating insulin can prevent ketosis by inhibiting lipolysis. The inhibition of lipolysis and subsequent lack of available free fatty acids restricts the rate at which ketones are formed, thereby preventing severe ketosis. In addition, these patients do not require long-term insulin administration to maintain glycemic control. If a patient is unable to maintain adequate fluid intake, severe dehydration can occur, leading to renal insufficiency, decreased glucose excretion, and a marked rise in serum glucose and osmolality. Once euglycemia is achieved with insulin at the initial event, patients can be switched to oral hypoglycemics. Intense education and frequent follow-up would be needed to ensure that he had an adequate understanding of proper insulin administration, carbohydrate counting, dietary changes, his medication regimen, and to ensure that his ketosis and metabolic acidosis were resolving.
While these data are encouraging, these interventions are costly, require a very high degree of commitment of the subjects, and are not always successful.
Adjustments in his medication would continue until his blood glucose levels were controlled and his symptoms alleviated.
Starting therapy at low doses, and gradually titrating the dose, can minimize the side effects of flushing, dizziness, or itching.
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.
Giving the dose with aspirin, or the use of longer-acting preparations, such as Niaspan ® , also reduces side effects. 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. 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. 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. 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. Skeletal muscle fiber types and metabolismSkeletal muscle is a complex tissue composed of different fiber types, which have distinct mechanical and metabolic properties. Each of these functional systems is composed of a motor neuron and a group of muscle fibers.
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). 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.
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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