Mechanism of insulin resistance in type 2 diabetes pdf espa?ol,the cure to type 1 diabetes genetic,diabetes type 2 checking blood sugar - 2016 Feature

Science, Technology and Medicine open access publisher.Publish, read and share novel research. Oxidative stress and the use of antioxidants in diabetes: linking basic science to clinical practice. Determination of the production of superoxide radicals and hydrogen peroxide in mitochondria. High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria.
Many people like using lispro because it’s easier to coordinate eating with this type of insulin. Effect of intensive insulin therapy on ?-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial. But really stressing cognition is worthy a penny if bringing that kind of revolution was a 20 dollar bill.
Cardiovascular and Renal Complications in Obesity and Obesity-Related Medical Conditions: Role of Sympathetic Nervous Activity and Insulin ResistanceKazuko Masuo1, 2 and Gavin W. Alberi KG, Zimmet PZ,1998Definition, diagnosis and classification of diabetes mellitus and its complications. Anderson EA, Hoffman RP, Balon TW, Sinkey CA, Mark AL.1991Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. Join tens of thousands of doctors, health professionals and patients who receive our newsletters.
By blocking VEGF-B, a signaling protein, fat does not accumulate in muscles and the heart, and the cells within those tissues can respond properly to insulin again, researchers from the Karolinska Institute, Sweden, the Ludwig Institute for Cancer Research, based in New York, and the Australian biopharmaceutical company CSL Limited reported in the journal Nature. Professor Ulf Eriksson and team carried out experiments on rats and mice, and managed to prevent type II diabetes from developing in the first place, as well as reversing disease progression in animals with established diabetes type II. Typically, type II diabetes occurs after a person becomes obese, then insulin resistance occurs - the diabetes comes next.
We do know that a protein called VEGF-B impacts on the transport and storage of fat in body tissue.
In two different studies, they used rats and mice that had not been specifically bred to develop type II diabetes. The most common treatment for type II diabetes today involves initially placing the patient on a special diet; sometimes they may need to take pills which increase insulin secretion and also make the cells more sensitive to insulin. The most effective treatment today to prevent diabetes type II onset among very obese patients is bariatric surgery. Diabetes type II is seen today by many as a serious global health problem - some describe it as an epidemic. The experimental medicine, 2H10, is a monoclonal antibody (an antibody produced by a single clone of cells) which is being developed by CSL Limited, an Australian biopharmaceutical company.
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Please use one of the following formats to cite this article in your essay, paper or report:MLANordqvist, Christian. For any corrections of factual information, or to contact our editorial team, please see our contact page. Please note: Any medical information published on this website is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional. Learn all about diabetes, a lifelong metabolism disorder that causes high blood sugar levels. Learn all about type 1 and type 2 diabetes and the differences between the two conditions in our article about the diabetes mellitus metabolism disorder.
What is even more good news is that science has found there to be no difference in the amount of GLUT-4 transport proteins in skeletal muscle cells between healthy individuals and those who are either obese or have type II diabetes.
Western diets are characterized by both dietary omega-3 fatty acid deficiency and increased fructose intake. Network of interrelated functions, connected by physiological mechanisms, controlled by heredity and influenced by environmental factors [29].
A decrease in brain and retina DHA, resulting from nutritional deficiency or aging is associated with reduced cognitive ability, increased emotional behavior and decreased visual capacity [32]. In 2003 the WHO report on Diet and Chronic Diseases recommended that added sugar should not constitute more than 10% of energy intake [42].
The adipocyte-derived secretory factor adiponectin promotes insulin sensitivity, decreases inflammation and promotes cell survival. Adiponectin was originally described as an adipocyte-specific, secreted protein found in high abundance in serum1.
Previous studies have shown that ceramide accumulation is crucial in the etiology of obesity-induced insulin resistance10.
This causes closure of K+ATP channels, depolarization of the plasma membrane, increased cytoplasmic calcium concentrations through voltage-gated calcium channels, and exocytosis of insulin-containing secretory granules. IntroductionDiabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects of insulin action, insulin secretion or both [1]. The stress of obesity, combined with a genetically susceptible background, produces insulin resistance and impaired glucose tolerance. It’s that time of the year for the Juvenile Diabetes Research Foundation Walk For A Cure! Type 2 Diabetes Mellitus and Drugs View Drugs and Medication Side Effect Reports associated with Type 2 Diabetes Mellitus We introduced the potty sometime in the range of 18 months bu didn’t start actually training until about 28 months.
Almost 90 per cent of people with diabetes have Type 2 diabetes, and 80 per cent of those were overweight or obese at the time of diagnosis. Potential pathophysiological mechanisms in obesity, hypertension and type2diabetes (T2DM)4.
Subjects with deteriorations of renal function (creatinine clearance) carried higher frequency of the Gly16 allele of Arg16Gly, the ?2-adrenoceptor polymorphisms6. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation.
When this occurs, the cells do not respond properly to insulin, meaning that glucose does not enter the cells and blood glucose (sugar) levels rise. Prof Eriksson's research group found out about this in 2010 and published a report in the same journal. In one, diabetes-induced mice were given 2H10, a drug candidate which is an antibody that inhibits the actions of VEGF-B. By the end of 2030 over half-a-billion people are expected to be living with diabetes type II globally.
I know, many of you out there do not like exercising and see it as a chore or just another thing to cross off the old to do list. So there is no noticible deficit of this needed molecule even in individuals who are challenged with blood sugar control issues. The latter found in high amounts in added sugars such as sucrose and high fructose corn syrup (HFCS). IntroductionOver the past century, major changes have taken place in the food composition of Western diets, in terms of essential fatty acids and sugar intake, particularly fructose [1,2,3,4,5,6]. Epidemiological and clinical data link omega-3 fatty acid deficiency with mood disorders [33].The endocannabinoid system includes the two endogenous ligands 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anandamide or AEA) and two cannabinoid receptors (CB1 and CB2). A new study now shows that these beneficial effects of adiponectin are dependent on sphingolipid metabolism (pages 55–63).
These properties, together with the precedent set by the identification of leptin, the product of the ob (Lep) gene2, 3, led to the hypothesis that adiponectin, like leptin, may regulate energy homeostasis.
In conditions in which insulin demand is increased, -cell glucose metabolism can be enhanced by increased glucokinase enzyme activity (a) and by replenishment of tricarboxylic acid cycle intermediates by anaplerosis (b). Diabetes has taken place as one of the most important diseases worldwide, reaching epidemic proportions. Continued stress, from hyperinsulinaemia, gluco- and lipotoxicity, on the pancreatic-islet -cells results in failure to maintain sufficient insulin levels to compensate for the insulin resistance, leading to elevated glucose levels and the diagnosis of diabetes.
Diabetic neuropathy is an injury to the nervous system caused by underlying diabetes mellitus.
IntroductionElevated sympathetic activation, as assessed using a variety of indices, has been observed in lean hypertensive and diabetic patients, and obese individuals [Huggett et al.
When fat is stored in the "wrong" places in the body, insulin resistance is much more likely to occur. In the latest experiment, the scientists managed to block the VEGF-B signaling in laboratory rats and mice. The mice, which were specifically bred to spontaneously develop diabetes, neither developed insulin resistance nor diabetes. The animals' natural progression to diabetes was stopped, and also reversed to varying degrees after they were treated with 2H10. However, after a few years, for about one-third of all patients these treatments gradually lose their efficacy, and insulin injections are needed.
I know you’ve read many headlines about why exercise is healthy for weight management, heart health, mental health, and detoxification. Both a low intake of omega-3 fatty acids or a high fructose intake contribute to metabolic syndrome, liver steatosis or non-alcoholic fatty liver disease (NAFLD), promote brain insulin resistance, and increase the vulnerability to cognitive dysfunction. Today’s Western diets are characterized by increases in total fat, especially in saturated fat and omega-6 fatty acids and decreases in omega-3 fatty acids in comparison to the fatty acid intake during evolution for which our genes were programmed to respond [1,3,6,7]. Central CB1 receptor activation by increased endocannabinoid levels or exogenous agonists induces hyperphagia along with increased lipogenesis and peripheral adiposity [34,35]. A large number of calories are obtained from beverages, processed food, and deserts made with sucrose or high fructose corn syrup, which are absorbed as a mixture of glucose and fructose. Higher intake of soft drinks was associated with greater energy intake, higher body weight, lower intake of other nutrients and worse health indices. Indeed, it is now well established that adiponectin has potent salutary actions on peripheral insulin sensitivity, and circulating adiponectin levels are reduced in obesity, insulin resistance and type 2 diabetes2, 3, 4. Using genetic approaches to manipulate circulating adiponectin concentrations, they found that increasing or decreasing adiponectin levels decreased or increased hepatic ceramide content, respectively8. Febbraio are in the Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Glucose-induced increases in citrate levels lead to increased amounts of malonyl CoA (c), which, through inhibition of carnitine palmitoyl transferase-1 (CPT1), leads to increased levels of long-chain acyl CoA, increased diacylglycerol (DAG) and signalling through protein kinase C (PKC). Global estimates predict that the proportion of adult population with diabetes will increase 69% for the year 2030 [2].Hyperglycemia in the course of diabetes usually leads to the development of microvascular complications, and diabetic patients are more prone to accelerated atherosclerotic macrovascular disease. Microvascular complications become apparent over time, depending on how well glucose levels can be controlled.
Test yourself on how to manage this clinical scenario including the use of high-dose insulin euglycemic therapy. Mediante la realizacin de test de findrisk se puede identificar individuos en riesgo de padecer diabetes tipo 2.
A bit of cution for first time users – If you do too much the first use it can irritate the skin. The scientists crossed the mice with diabetes with mice that could not produce VEGF-B - they found that their pups never developed diabetes.
But I’d like to give you JUST ONE MORE REASON to exercise today because this one you may not have heard yet. Omega-3 deficiency contributes to insulin resistance and the metabolic syndrome [1,8,9] brain metabolic abnormalities [10,11,12,13], liver steatosis or non-alcoholic fatty liver disease (NAFLD) [14].
CB1 receptors are predominantly expressed in the brain, but also in the peripheral tissues of the gastrointestinal tract, adrenal glands, liver, adipose tissue, and skeletal muscles [36]. Apart from weight gain from excess sweet calories there are a number of metabolic consequences harmful to health.
Further analyses from a larger trial confirmed these findings, specifically greater weight loss as sugar-sweetened beverage intake decreased [70]. Furthermore, liver-specific overexpression of the adiponectin receptors, AdipoR1 and AdipoR2, increased hepatic ceramidase activity and, concomitantly, reduced hepatic ceramide content.
Fatty acids influence insulin release by signalling through the G-protein-coupled receptor GPR40 (d) or through metabolism to fatty acyl CoA (e) and stimulation of insulin granule exocytosis, either directly or through PKC-dependent mechanisms. These complications account for premature mortality and most of the social and economical burden in the long term of diabetes [3].
Again diabetic weight los workout you have to track the price and make sure you’re getting a good deal.
Each recipe includes an estimate of time to table and, if anything, the estimates seem to run a little on the long side. Too much blood sugar and your vascular system can be become inflamed which can lead to vascular and organ damage. Multiple cognitive domains are affected by metabolic syndrome in adults and in obese adolescents, with volume losses in the hippocampus and frontal lobe, affecting executive function. In the liver, CB1 activation increases de novo lipogenesis through stimulation of cytosolic fatty acid synthase activity leading to fatty liver and obesity [35].
The best documented adverse effects known for decades is the dyslipidemia that develops with the ingestion of large amounts of sugar even when substituted calorie for calorie for fat [43]. The incretin GLP-1 potentiates glucose-stimulated insulin release through its G-protein-coupled receptor (f) by means of mechanisms that include stimulation of protein kinase A (PKA) and the guanine nucleotide exchange factor EPAC2. Increasing evidence suggests that oxidative stress plays a role in the pathogenesis of diabetes mellitus and its complications [4]. Diet Chart For Diabetic Patient With Kidney Problem we investigated the effect of low-dose insulin therapy in a group of obese and lean DKA patients. Understanding accents: Effective communication is Diet Chart For Diabetic Patient With Kidney Problem about more than simply pronunciation. Similarly, many epidemiological studies have shown that hypertensive patients, even those without increased adiposity, display a higher prevalence of insulin resistance, thereby indicating the possible association between sympathetic activation and insulin resistance in the pathogenesis of hypertension [Esler et al.
Studies have found that exercise is not only great for preventing the onset of type 2 diabetes, but that it also helps people who currently have the diagnosis.
Due to this interesting finding it is reasonable to consider a short walk if you have time after a meal. Fish oil supplementation maintains proper insulin signaling in the brain, ameliorates NAFLD and decreases the risk to metabolic syndrome suggesting that adequate levels of omega-3 fatty acids in the diet can cope with the metabolic challenges imposed by high fructose intake in Western diets which is of major public health importance. The largest increase in the intake of fructose occurred with the introduction of high fructose corn syrup (HFCS) in soft drinks and processed foods about 30 years ago [2,5,6].
Pharmacological blockade of the CB1 receptor is effective in treating obesity and related metabolic derangements. An important mechanism is the de-novo lipogenesis (DNL) synthesis of the saturated fat palmitate from glucose, fructose or both.
Adiponectin stimulates the cellular activity of ceramidase, which removes the fatty acyl chain from ceramides.
Whereas mice overexpressing adiponectin were protected from myocardial apoptosis and the ensuing mortality, adiponectin haploinsufficient and knockout mice were significantly more sensitive to apoptosis-induced mortality. Release of acetylcholine from parasympathetic nerve terminals activates the M2 muscarinic receptor (g), stimulating insulin release in a DAG- and PKC-dependent manner. Hyperglycemia increases oxidative stress, which contributes to the impairment of the main processes that fail during diabetes, insulin action and insulin secretion. On binding to its receptor, insulin induces activation of the insulin-receptor kinase (IRK) through autophosphorylation. Cardiovascular and renal complications in obesity, obesity-related hypertension and diabetes5.1. Since post meal time is when blood  sugars typically increase a good time to take advantage of your skeletal muscle GLUT-4 action is right then. This review presents the current status of the mechanisms involved in the development of the metabolic syndrome, brain insulin resistance, and NAFLD a most promising area of research in Nutrition for the prevention of these conditions, chronic diseases, and improvement of Public Health.
These dietary changes: the omega-3 fatty acid deficiency and the excessive fructose intake occurred as a result of agribusiness, modern agriculture and food processing, and not because there was any scientific evidence that required decreasing omega-3 fatty acid intake while increasing omega-6 fatty acids and fructose intake.
However serious psychiatric side effects, including depression and suicidal tendencies [37], caused marketplace withdrawal of Rimonabant, a selective CB1 antagonist [38]. There is a marked increase in DNL after excess carbohydrate calories [44] leading to high triglycerides, small dense LDL and low HDL that accelerate atherosclerosis.
This liberates sphingosine, which can subsequently be phosphorylated by sphingosine kinases to generate the antiapoptotic metabolite sphingosine-1-phosphate (S1P).Sphingolipids are a group of bioactive lipids with a panoply of cellular effects9. Notably, increased adiponectin concentrations were associated with reduced left ventricular ceramide content and higher S1P concentrations.
Dual actions on insulin secretion have been described for sympathetic nerves (h), with 2-adrenergic agonists inhibiting and -adrenergic agonists stimulating insulin secretion.
In addition, antioxidant mechanisms are diminished in diabetic patients, which may further augment oxidative stress [5, 6]. Recruitment of insulin-receptor substrate (IRS) proteins induces activation of phosphatidylinositol 3-kinase (PI3K) through binding the p85 subunit and activating the catalytic p110 subunit. Hyperglycemia and insulin resistance as risk factors of cardiovascular complications in type 2 diabetes5.2. Endocannabinoids are endogenous lipid mediators made from essential fatty acids available only from dietary sources.
Ceramide and S1P are sphingolipids of considerable interest—ceramide is linked to the induction of apoptosis, inflammation and insulin resistance, whereas S1P has potent cell-survival and anti-inflammatory actions9.
Both pathways act through adenylyl cyclase, resulting in a decrease or increase in cAMP levels, respectively. PI3K activation induces downstream effectors, such as phosphatidylinositol-dependent kinase 1 (PDK1) and protein kinase B (PKB; also known as AKT), leading to translocation of glucose transporter 4 (GLUT4) and glucose uptake in muscle, and inactivation of glycogen-synthase kinase 3 (GSK3). I think one of the most important things that someone can learn early is what type of Type 2 Diabetes: Type 2 diabetes is a disease characterized by high levels of blood uncontrolled diabetes and infertility glucose. Sympathetic nervous activity as a risk factor for cardiovascular complications and renal complications5.3.
Omega-3 fatty acids have been studied extensively since 1985 and have been shown to play an important role in growth and development and in health and disease [1,3].In epidemiological studies, animal experiments and clinical intervention studies the consumption of HFCS, or sugar sweetened beverages has been linked to the presence of unfavorable lipid levels, high triglycerides, high small dense LDL and low HDL [4], cardiovascular disease [5], type 2 diabetes [6,16,17], insulin resistance [18,19], the metabolic syndrome and liver steatosis [14]. The two best characterized endocannabinoids, 2-AG and AEA, are both metabolic derivatives of a single fatty acid precursor AA in phospholipids.

These opposing activities have led to the notion that the relative ratio of ceramide to S1P functions as a cellular rheostat (Fig.
Using mouse primary cardiomyocytes and a pancreatic beta cell line, Holland et al.8 showed that adiponectin prevents cell death induced by the saturated fatty acid palmitate and a short chain ceramide analog, C2-ceramide. Oxidative stress At the beginning of life, the organisms obtained their energy (ATP) by anoxygenic photosinthesis, for which oxygen was toxic. IR activation can also activate the c-Cbl-associated protein (CAP) and mitogen-activated protein kinase (MAPK) pathways (not shown). Easy and simpl Kerala Chicken Biriyani (Malabar juvenile diabetes reseach foundation careers Kozhi Biriyani) – iCookiPost.
Overweight and obesity is a growing problem across the globe and has reached “epidemic” proportions. Although some GLUT transporters (glucose transporter proteins) rely on insulin, the GLUT-4 transport protein responds to also EXERCISE! More recently it has been shown that moderate amounts of fructose and sucrose significantly alter hepatic insulin sensitivity and lipid metabolism compared with similar amounts of glucose [20,21,22,23]. Endocannabinoids are formed enzymatically on demand from the pool of AA plasma phospholipids formed from LA or ingested as AA. A 2% increase in body weight and similar increases in subcutaneous and visceral adipose tissue were measured by proton magnetic resonance spectroscopy. Most of the metabolic pathways were developed during this anaerobic stage of life, in which oxygen came later. The prevalence of diabetes, especially type 2 diabetes, and hypertension are significantly increased with the prevalence of obesity. Recent studies reveal the broad effects of the metabolic syndrome on mental health disorders, cognitive function, mood changes and depression [10,11,12]. The results showed for the first time a link between excess dietary sugar and the accumulation of liver fat by DNL a pathway uniquely stimulated by dietary sugar. Crucially, the inhibition of sphingosine kinase reversed the prosurvival effects of adiponectin. Cyanobacteria started producing oxygen from photosynthesis, which raised the atmospheric oxygen, and favored those organisms which have evolved into eukaryotic cells with mitochondria, able to use oxygen for a more efficient energy production [9].Whenever a cell’s internal environment is perturbed by infections, disease, toxins or nutritional imbalance, mitochondria diverts electron flow away from itself, forming reactive oxygen species (ROS) and reactive nitrogen species (RNS), thus lowering oxygen consumption. Activation of STAT3 through JAK2 phosphorylation induces translocation of STAT3 to the nucleus.
Obesity, itself, and type 2 diabetes and hypertension associated with obesity are known to be more closely linked with insulin resistance and elevated sympathetic nervous activity. This wild little transport protein answers to your body’s response to muscle contraction. Furthermore, diabetic and obese individuals have increased vulnerability to mental health [13].
This “oxidative shielding” acts as a defense mechanism for either decreasing cellular uptake of toxic pathogens or chemicals from the environment, or to kill the cell by apoptosis and thus avoid the spreading to neighboring cells [9]. STAT3 induces gene responses that reduce transcription of acetyl-coenzyme-A carboxylase (ACC), reducing malonyl CoA and fatty-acid synthesis, while increasing fatty-acid oxidation. It has been well documented that obesity, hypertension, and diabetes are risk factors for subsequent cardiovascular and renal complications. When you exercise your skeletal muscle cells release all sorts of chemicals in response to muscle contraction and these chemicals in skeletal muscles have been found to upregulate the GLUT-4 transport proteins. For these reasons the effects of metabolic syndrome on brain are being extensively investigated. Reducing LA in the diet and adding EPA + DHA reduced the AA phospholipid pool, normalized endocannabinoid tone and reversed the obesity.
The implication that a persistent excess of calories as dietary sugar can cause or exacerbate fatty liver by DNL lends additional support to public health recommendations to limit intake of sugars [2,42].
Endoplasmic-reticulum-bound or cytosolic PTP1B dephosphorylates membrane-bound or endocytosed insulin receptors and leptin receptors, causing their deactivation. Many patients are both diabetic and hypertensive while they are obese, but not all diabetic patients have hypertension, indicating that insulin resistance is not the only mechanism for blood pressure elevation in diabetic-hypertensive patients. The GLUT-4s when signaled by exercise then travel to the cell membrane surface where they can dock and accept a glucose molecule into the cell. In this paper I review the effects of the interaction of omega-3 fatty acid deficiency and high fructose intake in the development of metabolic syndrome, brain metabolic abnormalities, cognitive function, mental health, and liver steatosis or NAFLD.
Obesity is associated with neurological morbidity, including major depression [40], but the underlying pathophysiological mechanisms remain poorly understood. The increased liver fat resulting from increased DNL and the imbalance between triglyceride synthesis and secretion may increase oxidative stress, inflammation and insulin resistance (Figure 3) [4].
To investigate whether AdipoR1 and AdipoR2 possess intrinsic ceramidase activity, Holland et al.8 mutated residues that are conserved across ceramidases in these receptors. The term “oxidative stress” has been used to define a state in which ROS and RNS reach excessive levels, either by excess production or insufficient removal.
Other PTP1B substrates, such as IRS1 and PTP1B, can downregulate IRK activity through a complex formed with growth-factor-receptor-bound protein 2 (GRB2). Several investigators have reported that sympathetic nervous activation plays an important role in cardiovascular complications in patients with hypertension, diabetes, and obesity.Sympathetic nervous activation accompanying insulin resistance is closely linked with left ventricular hypertrophy in otherwise healthy subjects [Masuo, et al. Fortunately, these adverse effects may be prevented or ameliorated with dietary repletion of omega-3 fatty acids. In 2009, the American Heart Association Nutrition Committee recommended that women and men consume no more than 100 and 150 kcal of added sugar per day, respectively [2]. Human 293-T cells transiently transfected with these mutant receptors were refractory to adiponectin-induced increases in ceramidase activity, suggesting that the adiponectin receptors do have intrinsic ceramidase activity.The beneficial effects of adiponectin have previously been suggested to be dependent on AMPK activation.
Being highly reactive molecules, the pathological consequence of ROS and RNS excess is damage to proteins, lipids and DNA [10]. By contrast, Holland et al.8 provided compelling evidence that the effects of adiponectin on sphingolipid metabolism, and its subsequent salutary health effects in reducing hepatic ceramide content and preventing apoptosis, are AMPK independent.
Consistent with the primary role of ROS and RNS formation, this oxidative stress damage may lead to physiological dysfunction, cell death, pathologies such as diabetes and cancer, and aging of the organism [11]. In addition, sympathetic activation may predict the development of renal injury in healthy normotensive subjects [Masuo, et al.
However, as an intriguing footnote to this study, the authors showed that adiponectin-induced AMPK activation is prevented by a broad-spectrum ceramidase inhibitor, implying that S1P generation is required for adiponectin to activate AMPK, as S1P activated AMPK to approximately equal levels in the presence and absence of ceramidase inhibition8.Despite the scope of this work, several questions remain unanswered.
The authors concluded “by linking diet to altered synaptic functions of the CB1R in relevant brain areas, our data provide the first synaptic substrate for the impairment of emotional behavior, including depression, associated with the low levels of n-3 PUFAs that are frequently observed in Western diets” [41].
Skeletal muscle is a key site of many of adiponectin's actions, and it will therefore be interesting to determine whether in this tissue adiponectin improves insulin sensitivity by increasing ceramidase activity and reducing the ceramide content.
Weight loss associated suppression of sympathetic nervous activity is associated with improvement of insulin sensitivity and resultant improvement in renal function in obese patients [Masuo, et al. Although Holland et al.8 argue that AdipoR1 and AdipoR2 possess intrinsic ceramidase activity, these receptors may also be required for the activation of previously characterized ceramidases. Adiponectin treatment of cells in which the expression of individual ceramidases is systematically reduced will help to address this question.
Furthermore, weight loss improved the prevalence of left ventricular hypertrophy [Masuo, et al. Fasting LDL and apoB concentrations were increased during consumption of fructose and HFCS but not with glucose indicating that the adverse effects associated with chronic consumption of sugar-sweetened beverages results from the specific effects of fructose [39] rather than from circulating glucose and insulin excursions [22,51,52,53,54].
2008], which is one of the predictors for future cardiac complications, renal complications (injury) [Masuo, et al. 2011].These findings suggest that elevated sympathetic nerve activity associated with insulin resistance may contribute to the onset and maintenance of cardiovascular and renal complications in diabetes, and hypertension in obesity. Furthermore, genetic polymorphisms of the ?2- and ?3-adrenoceptor gene have been associated with obesity [Masuo, et al. Thus, it is impossible for consumers to determine the amount of added sugars in foods or beverages or some drugs and cough syrups.
2005 & 2010} in epidemiological studies and may also be implicit in the close relationship between insulin resistance and sympathetic nerve activation. In addition, several voluntary food-labeling systems are in place or are being developed, some of which include criteria for limiting added sugars. These investigations suggest that ?2-adrenoceptor polymorphisms are related to sympathetic activation and insulin resistance and may contribute to cardiovascular- and renal complications in obesity and obesity-related hypertension or type 2 diabetes.This chapter will provide a synthesis of the current findings on the mechanisms of the onset and maintenance of cardiovascular and renal complications in obesity, hypertension and type 2 diabetes, with a particular focus on sympathetic nervous activity and insulin resistance. These include the Smart Choices Program [57], the Hannaford’s grocery chain Guiding Stars program [58], the Overall Nutrient Quality Index [59], and the Nutrient Rich Foods Coalition nutrient density score [60].It is ironic indeed, that originally fructose was proposed as the ideal sweetener for persons with Type 2 Diabetes because it does not raise blood sugar and is unable to stimulate insulin secretion. A better understanding of the relationships between sympathetic nervous activity and insulin resistance in these important clinical conditions might help with the clinical treatment of diabetes and hypertension in obesity and prevent further cardiovascular and renal complications in this at risk group. Fructose is now implicated in the epidemics of obesity and diabetes type 2, insulin resistance, hypertension, visceral adiposity, and the metabolic syndrome [2,4].
Prevalence of type 2 diabetes and hypertension in obesityThe clustering of cardiovascular risk factors associated with obesity, in particular abdominal obesity, is well established [Athyrus, et al.
A high consumption of sugar-sweetened beverages and foods is associated with evidence of increased inflammation and oxidative stress [65,66]. The prevalence of obesity and overweight increased in the United States between 1978 and 1991 [Mokdad, et al.
Fructose consumption induces insulin resistance, impaired glucose tolerance, hyperinsulinemia, hypertriglyceridemia, and hypertension in animal models [4] (Table 1). The National Health and Nutrition Examination Survey (NHANES) I (1971-1974), NHANES II (1976-1980), and NAHNES III (1988-1994) were conducted by the National Center for Health Statistics, Centers for Disease Control and Prevention (CDC). These data from the continuous NHANES studies have showed that the prevalence of obesity and overweight people increased significantly in the United States between 1960 and 2003 [Preis, et al. Evidence from several studies indicates that obesity and weight gain are associated with an increased risk of hypertension [Masuo, et al. They showed that impaired insulin action in skeletal muscle is related to triglyceride accumulation, suggesting intracellular glucose-fatty acid cycle involvement, and that long-chain omega-3 fatty acids in phospholipid of skeletal muscle may be important for efficient insulin action. In rats made insulin resistant with a high fat diet, the resistance could be prevented by the inclusion of omega-3 fatty acids in the diet, but only under circumstances in which the EPA and DHA became incorporated in the phospholipid component of the muscle cells. 1997], and that intentional weight loss reduces the risk that overweight individuals will develop hypertension [Masuo, et al. Skeletal muscle is the principle site of insulin mediated glucose disposal and the fatty acid composition of membranes influences the action of insulin within the skeletal muscle, whereas the fasting serum insulin concentration was positively correlated with the percentages of LA indicating that high or increased LA is associated with decreased insulin sensitivity [9].
The results of this study, in conjunction with the studies in cell systems and animals, suggest that variations in insulin sensitivity are related to differences in the membrane content of long-chain PUFA within skeletal muscle phospholipids.
Therefore, abnormalities in the fatty-acid composition of membranes may be involved in the pathogenesis of a cluster of disorders linked to insulin resistance and hyperinsulinemia, including obesity, hypertension, type 2 diabetes mellitus, and coronary artery disease, suggesting that diet may influence their development [1,3].
Recent large cohort studies have showed an increasing prevalence of obesity in children and, importantly, obesity in children is strongly associated with several major health risk factors, including type 2 diabetes mellitus and hypertension [Hedley, et al.
Furthermore, these conditions are known to have genetic determinants for hypertension, type 2 diabetes, some forms of hyperlipidemia, obesity, and insulin resistance (Figure 1) [29] and have a common abnormality in smooth muscle response and insulin resistance [30,31].
2004].Focusing on the close associations between obesity, hypertension and diabetes, the NHANES and the Behavioural Risk Factor Surveillance System (BRFSS) investigations [Mokdad, et al. Figure 2 is a hypothetical scheme of how a decrease in EPA and DHA in muscle cell membrane phospholipids from (1) a decrease in dietary intake per se, (2) increased dietary intake of trans fatty acids, (3) increased intake of LA, or (4) genetic variants in delta-6 and delta-5 desaturases may lead to a decrease in EPA and DHA muscle cell membrane phospholipids [31]. 2003] showed very close relationships between the prevalence of obesity, hypertension, and diabetes.
Such a decrease contributes to insulin resistance and hyperinsulinemia, with the subsequent development of obesity, hypertension, type 2 diabetes, and coronary artery disease (including asymptomatic atherosclerosis and microvascular angina) [31].
2009] showed that diabetic subjects had a 2-fold higher mortality risk consisting of cardiovascular and non-cardiovascular mortality.
Sympathetic nervous activity in obesity, hypertension and diabetesThe sympathetic nervous system represents a major pathophysiological hallmark of both hypertension and renal failure, and is an important target of the therapeutic intervention [Grassi, et al.
The sympathetic nervous system participates in regulating the energy balance through thermogenesis. Reduced energy expenditure and resting metabolic rate are predictive of weight gain (obesity).
It is also widely recognized that insulin resistance or hyperinsulinemia relates to obesity [Minicardi, et al. Many epidemiological and clinical studies have shown a close relationship between sympathetic nervous system activity and insulin levels in obesity [Masuo. Several studies of longitudinal design have examined the effect of body weight changes (weight loss or weight gain) on sympathetic nervous system activity and insulin sensitivity (fasting plasma insulin levels and the (homeostasis model assessment of insulin resistance, HOMA-IR). Elevations of sympathetic nervous system activity and insulin levels during weight gain [Masuo, et al. 2003], and reductions of sympathetic activity and insulin levels during weight loss [Anderson, et al.
While these longitudinal studies have clearly shown that heightened sympathetic nerve activity and insulin resistance are closely linked to obesity (weight gain), the onset of obesity and the maintenance of obesity, it remains to be elucidated, whether sympathetic hyperactivity or insulin resistance is the prime mover. The response of the sympathetic nervous system to change in plasma insulin levels after oral glucose loading (oral glucose tolerance test) are different between subjects with and without insulin resistance [Masuo, et al.
Recently, changes in the sympathetic nerve firing pattern were observed with sympatho-inhibition during weight loss [Lambert, et al. These observations provide the evidence of a strong linkage between the activity of the sympathetic nervous system and insulin levels.
2003] examined muscle sympathetic nerve activity (MSNA) in four groups of subjects, patients with essential hypertension and type 2 diabetes, patients with type 2 diabetes alone, patients with essential hypertension alone, and healthy normotensive controls.
They found higher MSNA in the hypertensive-type 2 diabetic patients as compared with hypertensive alone patients or type 2 diabetic alone patients, and higher MSNA in hypertensive alone patients or type 2 diabetic alone patients as compared with healthy normotensive controls. Fasting insulin levels were greater in hypertensive-type 2 diabetic patients and type 2 diabetic patients compared to hypertensive patients or healthy normotensive subjects. These findings, although obtained in patients still under medication, provided evidence that type 2 diabetic patients had elevated sympathetic nerve activity regardless of the prevailing blood pressure levels, and that the combination of hypertension and type 2 diabetes resulted in an augmentation in sympathetic nerve activity and levels of plasma insulin. Several investigations on the contributions of ?2- and ?3-adrenoceptor polymorphisms to type 2 diabetes also support a strong relationship between sympathetic nerve hyperactivity and insulin resistance in type 2 diabetes [Masuo, et al. Many investigations have shown that insulin resistance, sympathetic nervous activation, and adrenoceptor polymorphisms play important roles in the onset and maintenance of obesity, type 2 diabetes and hypertension. Insulin resistance in obesity, hypertension and type 2 diabetesInsulin resistance [Ferrannini, et al. The clinical evaluation of insulin resistance is growing interest because it is a strong predictor and plays an important role in the development of the metabolic syndrome, type 2 diabetes mellitus and hypertension. Table 1 shows the criteria for metabolic syndrome characterisation, as can be seen insulin resistance is prominent [Alberti, et al. Table 2 summarizes the methods usually used in clinical and epidemiological studies (Table 2). The hyperinsulinemic-euglycemic glucose clamp method is the gold standard and may be suitable for research investigations in specialized laboratories, but the homeostasis model assessment of insulin resistance (HOMA-IR) or fasting plasma insulin concentrations is more practical for epidemiological studies comprising a large number of subjects. Hyperinsulinemia as a marker of insulin resistanceInsulin is an exceptional hormone in that its action is regulated not only by changes in concentration but also by changes in the sensitivity of target tissues. Inadequate insulin action can be the consequence of: (i) insufficient insulin concentration at the site of action, (ii) decreased tissue (effectors) responses to insulin, or (iii) a combination of low concentration and a decreased response.
Regulation of circulating insulin levels is mainly (but not exclusively) achieved by changes in secretory rates. Nevertheless, the major determinant of insulin secretion, and therefore of plasma insulin concentration, is glucose. Any change in glucose concentration from the narrow normal range results in an insulin response appropriate to restore homeostasis. Thus, changes in insulin sensitivity occur in various physiological states and pathological conditions.For any amount of insulin secreted by the pancreas, the biological response of a given effector is dependent on its insulin sensitivity. Any decrease in insulin sensitivity (insulin resistance) is immediately translated into minute increases in blood glucose concentrations that will in turn act on the ?-cell to produce a compensatory stimulus of insulin secretion, leading to a degree of hyperinsulinemia that is approximately proportional to the degree of effector resistance.
In steady-state conditions, this compensatory hyperinsulinemia prevents a more exaggerated hyperglycaemia. The inability of ?-cells to enhance insulin secretion means that blood glucose will keep increasing until the level of hyperglycaemia produces an adequate ?-cell stimulus to attain the required insulin response.
When the ?-cell is unable to compensate for the prevalent insulin resistant state by further augmenting insulin secretion, hyperglycaemia continues to increase, producing impaired fasting glucose, impaired glucose tolerance and diabetes mellitus development. Relationships between sympathetic nervous activity and insulin resistance in obesity, hypertension, and type 2 diabetesIt is widely recognized that insulin resistance or hyperinsulinemia relates to obesity [Ferrannini, et al. Many epidemiological and clinical studies have shown a close relationship between sympathetic nervous system activity and insulin levels in obesity [Anderson, et al. Several studies of longitudinal design have examined the effect of body weight changes (weight loss or weight gain) on sympathetic nervous system activity and insulin sensitivity (fasting plasma insulin levels and HOMA-IR). 2007} and reductions of sympathetic nerve activity and insulin levels during weight loss [Masuo, et al. These longitudinal studies have shown that heightened sympathetic nerve activity and insulin resistance are closely linked to obesity (weight gain), the onset of obesity and the maintenance of obesity.
In addition, a calorie restricted diet and exercise may have different mechanism on weight loss-induced blood pressure reduction.
Figure 2 shows changes in neurohormonal parameters over a 24-week period weight loss regimens with a mild calorie restricted diet alone, mild exercise alone, or a combination with a mild calorie restricted diet and mild exercise. In addition, calorie restricted diet and exercise may have different mechanisms on weight loss-induced blood pressure reduction [Masuo, et al. Reduced energy expenditure and resting metabolic rate are predictive of weight gain and obesity development. The sympathetic nervous system participates in regulating energy balance through thermogenesis (Figure 1).
Landsberg and other investigators hypothesized that energy intake stimulates hyperinsulinemia and sympathetic nerve activity resulting in blood pressure elevations in a cycle in order to inhibit thermogenesis.
Insulin-mediated sympathetic nerve stimulation in obese subjects is therefore considered part of a compensatory mechanism aimed at restoring the energy balance by increasing the metabolic rate [Landsberg.
Hyperinsulinemia and insulin resistance in obese subjects are all part of a response to limit further weight gain via stimulating sympathetic nerve activity and thermogenesis [Landsberg, 2001]. On the other hand, Julius and Masuo generated a hypothesis based on data from their longitudinal studies that increased sympathetic nerve activity in skeletal muscle causes neurogenic vasoconstriction, thereby reducing blood flow to muscle and consequently inducing a state of insulin resistance by lowering glucose delivery and uptake in hypertension and obesity.
Both blood pressure elevations and weight gain may reflect a primary increase in sympathetic nervous tone.

1997, 2000, and 2003] demonstrated that high plasma norepinephrine could predict future blood pressure elevations accompanying deterioration in insulin resistance. This was observed in HOMA-IR (homeostasis model assessments of insulin resistance) in nonobese, normotensive subjects using longitudinal studies. 1990] reported that clonidine prevented insulin resistance development in obese dogs over a 6-week period, suggesting that sympathetic nervous activity might play a major role in the development of insulin resistance accompanying blood pressure elevation. 2000, 2001b, 2003, 2005a, 2012] might provide strong evidence for a close linkage of high sympathetic nervous activity accompanying insulin resistance with the onset of hypertension. Heightened sympathetic nerve activity might play a major role in blood pressure elevations, and insulin resistance might play an ancillary mechanism for blood pressure elevation and genesis of hypertension.
In hypertensive patients who already have heightened sympathetic nerve activity and insulin resistance, both heightened sympathetic nerve activity and insulin resistance are related to further blood pressure elevations. During weight loss with a mild calorie restricted diet, normalization of sympathetic activation measured by plasma norepinephrine was observed following significant weight loss and normalization of insulin resistance (HOMA-IR).
On the other hand, in exercise alone group, normalization of insulin resistance was observed, and then weight loss and suppression of sympathetic activation. 2012]Figure 2.When significant changes were observed comparisons between a calorie restricted diet vs. 2012} showed the differences in mechanisms of weight loss-induced blood pressure reductions with neurohormonal parameters changes over 24 weeks with loss regimens (Figure 2). BMI and blood pressure decreased after significant reductions in both plasma norepinephrine and HOMA-IR (Figure 2). However, at least their hypotheses showed a strong linkage between sympathetic activation, insulin resistance, obesity and hypertension. 2004] reported attenuation of hemodynamic and energy expenditure responses to isoproterenol infusion in hypertensive patients. Their findings that a generalized decrease of ?-adrenergic responsiveness in hypertension supports the hypothesis that heightened sympathetic nerve activity through down-regulation of ?-adrenoceptor-mediated thermogenesis, may facilitate the development of obesity in hypertension.
Their results suggested that sympathetic nerve activity-induced hypertension may subsequently lead to the development of obesity. 1999] investigated the effects of the acute induction of hyperglycemia on sympathetic nervous activity and vascular function in eight young normal control subjects. Muscle sympathetic nerve activity (MSNA) and forearm vascular resistance were measured before and during systemic infusion of 20% dextrose with low dose insulin with 60 min of hyperglycemia.
Moreover, both acute and chronic hyperglycemia and hyperinsulinemia may enhance adrenergic vasoconstriction and decrease vasodilation in animal models (pithed rats) [Takatori, et al.
Insulin causes forearm vasoconstriction in obese, insulin resistant hypertensive humans [Gudbjornsdotti, et al.
1999] found that hyperglycemia induced vasodilation in the forearm, but this vasodilation was not modified by hyperinsulinemia. Sympathetic nervous activity and leptin in obesity and the metabolic syndromeInteractions between the sympathetic nervous system and leptin are widely acknowledged with each being able to influence the other. Indeed, the leptin system mediates some of its action through the sympathetic nervous system [Haynes, et al.
1996] investigated the effect of acute sympathetic nerve activation caused by exposure to cold on the expression of the leptin gene in white adipose tissue of lean mice, but not in obese mice.
These studies, together with others, indicate that both insulin resistance and leptin may be regulated by the sympathetic nervous system.Masuo et al.
2008] showed during oral glucose loading that plasma insulin and plasma norepinephrine increased in both insulin-sensitive and insulin-resistant subjects, but plasma leptin levels decreased in insulin-sensitive nonobese subjects and increased in insulin- resistant nonobese subjects. 2005] also reported the blunted responses of whole-body norepinephrine spillover, insulin, and plasma leptin during oral glucose loading in obese subjects with insulin resistance as compared to insulin sensitive subjects. In subjects with the metabolic syndrome, weight loss with a low caloric diet diminished the whole-body and regional sympathetic nerve activity, as indicated by determinants of the whole-body norepinephrine spillover to plasma and muscle sympathetic nerve activity. Sympathetic nervous activity and insulin resistance in the metabolic syndromeThe metabolic syndrome is a cluster of abnormalities with basic characteristics being insulin resistance and visceral obesity. Importantly, obesity and the metabolic syndrome are associated with significant co-morbidities, such as type 2 diabetes, cardiovascular disease, stroke, and certain types of cancers. 2003 % 2004] demonstrated in a series of studies using microneurography (muscle sympathetic nerve activity, MSNA) that type 2 diabetic patients had elevated sympathetic nerve activity regardless of the prevailing level of blood pressure, and that the combination of hypertension and type 2 diabetes resulted in an augmentation in sympathetic nerve activity and levels of plasma insulin.
They also compared MSNA and insulin levels in 23 non-diabetic offspring of type 2 diabetic patients and 23 normal control individuals [Huggett, et al.
Sympathetic activation occurred in not only subjects with the metabolic syndrome, diabetic patients, but also in normotensive non-diabetic offspring of patients with type 2 diabetes with the degree of activation being in proportion to their plasma insulin levels. This series of studies indicates the presence of a mechanistic link between hyperinsulinemia and sympathetic activation, both of which could play a role in the subsequent development of cardiovascular risk factors.5. Cardiovascular and renal complications in obesity, obesity-related hypertension and diabetesIt has been documented that patients with obesity, hypertension and type 2 diabetes frequently have cardiovascular and renal complications.
Obesity was closely associated with an increase in blood pressure, left ventricular mass, and with early signs of disturbed left ventricular diastolic function [Wikstrand, et al. It is well known that sudden cardiac death is the most common cause of death in dialysis patients and is usually preceded by sudden cardiac arrest due to ventricular tachycardia or ventricular fibrillation [Alpert, et al. Left ventricular (LV) mass and loading conditions that may affect LV mass are important determinants of corrected QT intervals (QTc) in normotensive severely obese subjects [Mukergi, et al. The RICARHD study (Cardiovascular risk in patients with arterial hypertension and type 2 diabetes study), was a multicenter and cross-sectional study, conducted in Spain and included 2,339 patients who were 55 years or more with hypertension and type 2 diabetes of greater than 6 months duration. The combined presence of both hypertension and type 2 diabetes were associated with an increased prevalence of established cardiovascular diseases. Similarly, the presence of both cardiac and renal damage was associated to the higher prevalence of cardiovascular diseases [Cea-Calvo, et al. The Lifestyle Interventions and Independence for Elders (LIFE) study in 8,029 patients with stage II-III hypertension with LVH on ECG showed high prevalence of co-existence of LVH and albuminuria [Wachtell, et al.
In patients with moderately severe hypertension, LVH on two consecutive ECGs is associated with increased prevalence of micro- and macro-albuminuria compared to patients without persistent LVH on ECG. Hyperglycemia and insulin resistance as risk factors of cardiovascular complications in type 2 diabetesHyperglycemia and hyperinsulinemia or insulin resistance that is a characteristic of type 2 diabetes and obesity play major roles in the cardiovascular complications of type 2 diabetes mellitus and obesity.
Hyperglycemia is the major risk factor for microvascular complications (retinopathy, neuropathy, and nephropathy) in type 2 diabetes, however 70% or 80% of patients with type 2 diabetes die of macrovascular disease.
Atherogenic dyslipidemia (elevated triglyceride levels, low HDL-cholesterol levels, high LDL-cholesterol levels) is the major cause of atherosclerosis in patients with type 2 diabetes [Reasner, et al. 2008].Several investigators have demonstrated that insulin resistance could predict future type 2 diabetes even in nonobese individuals [Morrison, et al. 2008] Insulin resistance accompanying sympathetic nerve activation may also predict future hypertension development [Masuo, et al.
Insulin resistance coexisting with inflammation may predict cardiac disease but, interestingly, not stroke in the Japanese diabetic population [Matsumoto, et al.
Sympathetic nervous activity as a risk factor for cardiovascular complications and renal complicationsHeightened sympathetic nerve activity plays an important role in cardiovascular complications and cardiac risk in humans [Esler, et al. There is consistent evidence that high plasma norepinephrine level, as an index of heightened sympathetic nerve activity, predicts mortality in cardiovascular diseases such as chronic congestive heart failure [Cohn et al. 2010], structural changes in obesity {Benedict, 1996}, and end-stage renal disease (ESRD) [Masuo, et al. 2001] reported that acute myocardial infarction (AMI) in hypertensive patients resulted in greater sympathetic nervous activity, persisting for at least 6 months longer than in normotensive subjects, indicating that AMI further augmented the sympathetic nerve hyperactivity of hypertension. Sympathetic nerve hyperactivity could be one mechanism involved in the reported worse prognosis in AMI in hypertensive patients [Hogarth, et al. The sympathetic activation that follows AMI has been associated with increased morbidity and mortality in both anterior-AMI and inferior-AMI, with a similar magnitude of sympathetic nerve hyperactivity [Graham, et al.
Patients with congenital long-QT syndrome are susceptible to life-threatening arrhythmias, and the sympathetic nervous system may have an important triggering role for cardiovascular events this condition [Shamsuzzaman, et al. 2001].Changes in heart rates during exercise and recovery from exercise are mediated by the balance between sympathetic and vagal activity, and changes in heart rates were evaluated in a total of 5,713 asymptomatic working men cohort (between the ages of 42 and 53 years) in whom there was no evidence of the presence or history of cardiac disease over the preceding 23 years. Baseline heart rates, changes in heart rates during exercise and recovery were strongly related to an increased risk of sudden death from myocardial infarction [Jeuven, et al.
2002 & 2004] examined the relationships between sympathetic nerve activity (plasma norepinephrine levels) and mortality and cardiovascular events in 228 patients undergoing chronic hemodialysis originally without heart failure. They found 45% of dialysis subjects had significantly high plasma norepinephrine levels located in the upper limit of the normal range. One-hundred and twenty four (124) fatal and nonfatal cardiovascular events occurred in 85 patients during the follow-up period (34±15 months). Plasma norepinephrine levels proved to be an independent predictor of fatal and nonfatal cardiovascular events in a multivariate Cox regression model.
They also found that plasma norepinephrine levels were associated with concentric left ventricular hypertrophy in these patients [Zoccali, et al. 2002] showed that increased cardiac sympathetic nervous activity in renovascular hypertension might lead to high cardiovascular mortality and morbidity. Prolonged sympathetic nerve stimulation and elevated circulating norepinephrine levels can induce changes in intra-renal blood vessels. Catecholamines can induce proliferation of smooth muscle cells and adventitial fibroblasts in vascular wall.The association between hypertension, obesity and chronic kidney disease (CKD) is well recognized [White, et al. In the majority of cases, ESRD occurs as a result of complication of diabetes or hypertension [WHO.
Obesity, hypertension and type 2 diabetes are characterized as stimulated sympathetic nervous activity and insulin resistance states, indicating renal injury and ESRD are strongly related to sympathetic nervous activity and insulin resistance. The findings suggest that strong linkage between sympathetic nervous activity, insulin resistance and renal function.
The 40-minute infusion of NE into the renal artery of dogs produced a reversible ischemic model of acute renal failure [Bulger, et al. Another study demonstrated renal protection by ?-adrenergic receptor blockade in a nephrectomized rat experiment without any BP changes [Amam, et al. There is consistent evidence that high plasma norepinephrine levels, as an index of heightened sympathetic nervous activity, predicts mortality in cardiovascular disease, such as chronic congestive heart failure [Cohn, et al. These investigations have shown strong associations between sympathetic nervous activation, cardiovascular complications and renal complications. Sympathetic nerve hyperactivity in patients with ESRDEvidence now strongly indicates a role for the sympathetic nervous system in the pathogenesis of hypertension in renal failure (ESRD) [Hausberg, et al. Hypertension occurs commonly and early in renal disease and is paralleled by increases in sympathetic nerve activity, as indicated by increased muscle sympathetic nerve activity and circulating norepinephrine.
This appears to be driven by the diseased kidneys, because nephrectomy or denervation has been shown to correct blood pressure and sympathetic nerve activity both in human and animal studies [Jacob, et al. 1995 & 2010] showed that plasma norepinephrine levels were significantly higher in patients with ESRD regardless of hemodialysis compared with those in blood pressure- and body mass index-matched hypertensive patients or healthy normotensive subjects (Figure 3). Further, this was recognized significantly in subjects with a shorter duration of ESRD with hemodialysis compared with those with longer duration, suggesting that sympathetic nerve hyperactivity may be of particular importance in the onset or the early development of ESRD or, alternatively, be influenced by long-term renal replacement therapy (hemodialysis). In the normal state, interactions between the kidney and sympathetic nervous system serve to maintain blood pressure and glomerular filtration rate within tightly controlled levels, but in renal failure, a defect in renal sodium excretory function leads to an abnormal pressure natriuresis relationship and activation of the renin-angiotensin system (RAS), contributing to the development of hypertension and progression of kidney disease [Hall, et al.
Another mechanism could involve the sympathetic nervous modulation of baroreflex regulation and vasculature tone through the central nervous system and angiotensin II [Burke, et al. Afferent signals from the kidney, detected by chemoreceptors and mechanoreceptors, feed directly into central nuclei regulating sympathetic nerve activity by circulating and brain-derived angiotensin II [Philips, et al.
Therefore, the pathogenesis of hypertension in renal failure (ESRD) is complex and arises most likely from the interaction of hemodynamic and neuroendocrine factors. Sympathetic nerve activity has strong relationships with regards to increased risk of cardiovascular disease including hypertension [Zoccali, et al.
The sympathetic nerve hyperactivity is at least in part independent of increased blood pressure levels or obesity. Further, patients with early-ESRD without hemodialysis had already significantly higher plasma norepinephrine levels compared with hypertensive subjects as well as normotensive subjects.
Therefore, sympathetic nervous activation in ESRD patients may be independent from obesity or hypertension. In addition, plasma norepinephrine levels did not change between before- and after-hemodialysis therapy (data was not shown), and between after-hemodialysis therapy and before-next hemodialysis therapy. Thus, one could speculate that plasma norepinephrine levels in ESRD patients are reflective of the degree of sympathetic nerve activity. ?2-adrenoceptor polymorphisms accompanying sympathetic nervous activation may relate to renal injury Rao et al. 2007] have shown strong associations between ?2-adrenoceptor polymorphisms, elevated plasma norepinephrine levels and elevated HOMA-IR (insulin resistance) or future renal injury, suggesting that stimulated sympathetic nerve activity associated with insulin resistance, may independently play a major role in the onset and development of ESRD without obesity or hypertension. However, the precise mechanisms underlying sympathetic activation in CKD and ESRD have not been clarified.Furthermore, Masuo et al.
2011b] measured renal function (creatinine, BUN and creatinine clearance), plasma norepinephrine levels and HOMA-IR (insulin sensitivity) annually over a 5-year period in nonobese, normotensive men with normal renal function. Subjects who had a significant deterioration of renal function (more than 10% increases from baseline of creatinine and BUN or decrease in creatinine clearance) over a 5-year period had higher plasma norepinephrine at the entry period, and greater increases in plasma norepinephrine over 5 years [Masuo, et al.
In this study, subjects who had significant changes in body weight or blood pressure were excluded, indicating the contributions of obesity or hypertension might be excluded.
Further, subjects who had significantly higher levels of plasma norepinephrine had a higher frequency of the Gly16 allele of the ?2-adrenoceptor polymorphism [Masuo, et al. The Gly16 allele of the ?2-adrenoceptor polymorphism has been shown to be related to obesity [, Masuo, et al. Thus, high plasma norepinephrine levels appear to be a predictor that is determined genetically by the ?2-adrenoceptor polymorphism (Arg16Gly) for renal injury, obesity, hypertension and metabolic syndrome.In 154 nonobese, normotensive subjects, renal function (creatinine clearance) was measured over a 5-year period.
The deterioration of renal function was defined as >10% decreases in creatinine clearance over a 5-year period. Subjects with deterioration of renal function had higher frequency of Gly allele or Gly homozygous compared to those without changes in renal function.
Obstructive sleep apnea in obesity is a risk factor for cardiovascular diseasesVozoris [Vozoris.
2012] investigated the relationships between prevalence of obstructive sleep apnea (OSA), obesity, and hypertension, diabetes, congestive heart failure, myocardial infarction, and stroke using a population-based multi-year cross-sectional study design including 12,593 individuals with data from the 2005-2008 United States National Health and Nutrition Examination Surveys (NHANES).
They found individuals with OSA had elevated rates of cardiovascular diseases compared to the general population [Vozoris. OSA is a common disorder that has been associated with many cardiovascular disease processes, including hypertension and arrhythmias. OSA has also been identified as an independent risk factor for stroke and all-cause mortality.
OSA is highly prevalent in patients with transient ischemic attacks and stroke [Das, et al.
The mechanisms underlying the link between OSA and cardiovascular disease are not completely established. A number of studies have consistently shown that patients with OSA have high levels of sympathetic nerve traffic [Narkiewicz, et al.
In animal studies, intermittent hypoxia that simulates changes seen in OSA leads to chemoreceptor and chromaffin cell stimulation of sympathetic nerve activity, endothelial damage and impaired blood pressure modulation. Human studies reveal activation of sympathetic nerves, endothelial damage and exaggerated pressor responses to sympathetic neurotransmitters and endothelin [Ziegler, et al.
Gout and hyperuricacidemia in obesityGout is a growing worldwide health problem, and is associated with increased prevalence of obesity. Gout and hyperuricacidemia are associated with the metabolic syndrome, diabetes mellitus, obesity and hypertension.
Several epidemiological studies have shown the close linkage between hyperuricemia, obesity and hypertension [Robinson, et al.
2012] reviewed prevalence of hyperuricemia in Australia in 25 articles and 5 reports using a systematic journal search method. Similar result has been reported in Taiwanese populations that, using a multivariate analysis, showed that BMI (obesity) was an important factor associated with hyperuricemia in both males and females, whereas age was associated with hyperuricemia only in males. In addition, the associations of basic and repeated measures of uric acid level with treatments for uric acid over a 11-year period, and risk of coronary heart disease (CHD) and stroke events were assessed in Taiwanese populations [Chien, et al. The study showed that uric acid had significant risk only in hypertension and metabolic syndrome subgroups, but not in their counterparts. They also observed that uric acid, in the baseline and time-dependent variables, could predict cardiovascular events in the community of relatively low CHD but high stroke risk.
Furthermore, they compared these effects between a mild calorie restricted diet alone, combination with a low calorie diet and exercise and control groups.
Interestingly, moderate weight loss in obese patients with metabolic syndrome is associated with a reduction in serum uric acid levels, albuminuria and an improvement in eGFR which is augmented by exercise co-intervention [Straznicky, et al. Improvement of insulin resistance and sympathetic activation were synchronized with a reduction in serum uric acid levels.
ConclusionThe role of the sympathetic nervous activity and insulin resistance plays important roles in the etiology of obesity, hypertension, and type 2 diabetes.
Several investigations have demonstrated that the sympathetic nervous activation and insulin resistance are strongly related to cardiovascular complication (i.e. Interestingly, relevant investigations of sympathetic nervous activity and ?2-adrenoceptor polymorphisms indicate their contribution to the onset and maintenance of renal injury and LVH in healthy subjects and in patients with chronic renal failure and cardiovascular events in ESRD patients. Interestingly, the prevalence of OSA and hyperuricemia (gout) are significantly linked with increases in obesity, and both states are connected with the cardiovascular risks associated with sympathetic nervous activation.
Serum uric acid, which may be affected strongly by sympathetic nervous activity, may be a predictor for future hypertension and renal injury (ESRD) development. Recently, it has been demonstrated that renal sympathetic nerve denervation provides promising results in patients with refractory hypertension [Krum, et al. Besides the demonstrable effect on reducing blood pressure, renal denervation significantly and favourably influences LV mass and improves diastolic function, which might have important prognostic implications in patients with resistant hypertension at high cardiovascular risk [Brandt, et al. Further, renal denervations showed an accompanying improvements in insulin resistance [Mahfoud, et al.
Renal sympathetic denervation may conceivably be a potentially useful option for patients with co-morbid refractory hypertension, glucose intolerance, and obstructive sleep apnea.A better understanding of the relationships between sympathetic nervous activity, insulin resistance, cardiovascular complications, and renal complications, will help to develop appropriate treatment strategies targeting renal injury or cardiac risk in hypertensive and diabetes patients with and without ESRD or LVH.

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