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One in three Americans, half of those aged 60 and older, have silent blood sugar problem known as insulin resistance. Insulin resistance increases the risk for prediabetes, Type 2 DIABETES and a host of other serious health problems, including heart attacks, strokes 2 and cancer. 3 insulin resistance is when cells in your muscles, body fat and liver start resisting or ignoring signal that hormone insulin is trying to send outwhich, is to grab glucose out of your bloodstream and put it into your cells. Glucose, also know as blood sugar, is the body's main source of fuel. We get glucose from grains, fruit, vegetables, dairy products, and drinks that bring break down into carbohydrates. While genetics, aging and ethnicity play roles in developing insulin sensitivity, driving forces behind insulin resistance include excess body weight, too much belly fat, lack of exercise, smoking, and even skimping on sleep. 4 as insulin resistance develop, your body fights back by producing more insulin. Over months and years, beta cells in your pancreas that are working so hard to make insulin wear out and can no longer keep pace with demand for more and more insulin. Then - years after insulin resistance silently begins - your blood sugar may begin to rise and you may develop prediabetes or Type 2 DIABETES. You may also develop non - alcoholic fatty liver Disease, growing problem associated with insulin resistance that boosts your risk for liver damage and heart disease. 5 insulin resistance is usually triggered by a combination of factors linked to weight, age, genetics, being sedentary and smoking. - Large waist. Experts say the best way to tell whether youre at risk for insulin resistance involves tape measure and a moment of truth in front of the bathroom mirror. Waist that measures 35 inches or more for women, 40 or more for men 6 increases the odds of insulin resistance and Metabolic Syndrome, which is also linked to insulin resistance. - You have additional signs of Metabolic Syndrome. According to the National Institutes of Health, 7 in addition to large waist, if you have three or more of following, you likely have Metabolic Syndrome, which creates insulin resistance. High triglycerides. Levels of 150 or higher, or taking medication to treat high levels of these blood fats. Low HDLs. Low - density lipoprotein levels below 50 for women and 40 for men - or taking medication to raise low high - density lipoprotein levels. High blood pressure. Readings of 130 / 85 mmHg or higher, or taking medication to control high blood pressure and high blood sugar. Levels of 100 - 125 mg / dl or over 125. High fasting blood sugar. Mildly high blood sugar may be an early sign of DIABETES. - You develop dark skin patches. If insulin resistance is severe, you may have visible skin changes. These include patches of darkened skin on the back of your neck or on your elbows, knees, knuckles or armpits. This discoloration is called acanthosis nigricans.
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With obesity and diabetes reaching epidemic proportions in the developed world, role of Insulin Resistance and its sequelae is gaining prominence. Understanding the role of Insulin across a wide range of physiological processes and influences on its synthesis and secretion, alongside its actions from molecular to whole body level, has significant implications for many chronic diseases seen in Westernised populations today. Consequently, more than a century after scientists began to elucidate the role of pancreas in diabetes, study of Insulin and Insulin Resistance remains at the forefront of medical research, relevant at all levels from bench to bedside and to public health policy.
Department of Pediatrics, University of Chieti, Chieti, Italy, insulin resistance is a pathological condition strongly associated with obesity. However, corticosteroids or growth hormone therapy and genetic diseases may affect insulin sensitivity lifelong. In obese children and adolescents of any age, there is an evident association between IR and increased prevalence of type 2 Diabetes and other elements contributing to metabolic syndrome, leading to higher cardiovascular risk. Therefore, early diagnosis and interventions in attempt to prevent T2D when glycemia values are still normal is fundamental. The Gold standard technique used to evaluate IR is hyperinsulinemic euglycemic clamp, however it is costly and difficult to perform in clinical and research sets. Therefore, several surrogate markers have been propose. Although treatment of insulin resistance in children is firstly targeted to lifestyle interventions, in select cases, integration of pharmacological intervention might be taken into consideration. The aim of this review is to present current knowledge on IR in children, starting with an outline of recent evidence about congenital forms of deficiency in insulin functioning and therefore focusing on physiopathology of IR, its appropriate measurement, consequences, treatment options and prevention strategies.
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Insulin is a hormone produced by beta cells of the pancreas. These cells are scattered throughout the pancreas in small clusters known as islets of Langerhans. Insulin produced is released into the blood stream and travels throughout the body. Insulin is an essential hormone that has many actions within the body. Most actions of insulin are direct to metabolism of carbohydrates, lipids, and proteins. Insulin also regulates the functions of the body's cells, including their growth. Insulin is critical for the body's use of glucose as energy. Insulin resistance is a condition in which the body's cells become resistant to the effects of insulin. That is, normal response to the amount of insulin is reduce. As a result, higher levels of insulin are needed in order for insulin to have its proper effects, and the pancreas compensates by trying to produce more insulin. This resistance occurs in response to the body's own insulin or when insulin is administered by injection. With insulin resistance, pancreas produces more and more insulin until the pancreas can no longer produce sufficient insulin for the body's demands, and then blood sugar rises. Insulin resistance is a risk factor for development of Diabetes and heart disease. Type 2 Diabetes mellitus is a type of Diabetes that occurs later in life or with obesity at any age. Insulin resistance precedes development of Type 2 Diabetes, sometimes by years. In individuals who will ultimately develop Type 2 Diabetes, research shows that blood glucose and insulin levels are normal for many years, until at some point in time, insulin resistance develop. High insulin levels are often associated with central obesity, cholesterol abnormalities, and / or high blood pressure. When these disease processes occur together, it is called metabolic syndrome. One action of insulin is to cause the body's cells to remove and use glucose from blood. This is one way by which insulin controls the level of glucose in the blood. Insulin has this effect on cells by binding to insulin receptors on the surface of cells. You can think of it as insulin knocking on doors of muscle and fat cells. Cells hear knock, open up, and let glucose in to be used. With insulin resistance, muscles don't hear knock. So the pancreas is notified it needs to make more insulin, which increases the level of insulin in the blood and causes louder knock. Resistance of cells continues to increase over time. As long as the pancreas is able to produce enough insulin to overcome this resistance, blood glucose levels remain normal. When the pancreas can no longer produce enough insulin, blood glucose levels begin to rise. Initially, this happens after meals - when glucose levels are at their highest and more insulin is needed eventually while fasting too. When blood sugar rises abnormally above certain levels, Type 2 Diabetes is present.
Insulin resistance is a metabolic disorder that does not happen in a vacuum. Instead, insulin resistance syndrome is one of several metabolic abnormalities that tend to occur together and sometimes, term, insulin resistance syndrome, is used in place of metabolic syndrome. These syndromes raise your risk of heart disease and, according to an article published in the journal, American Family Physician can include these symptoms. Insulin resistance Diabetes Hypertension, hyperlipidemia, obesity, Central adiposity, or too much fat around your waist International Code - 10 for metabolic syndrome is E88. 81. This Code is also used for similar conditions, such as insulin resistance, dysmetabolic syndrome X, and metabolic syndrome X.
Physical activity and weight loss help the body respond better to insulin. By losing weight and being more physically active, people with insulin resistance or pre - Diabetes may avoid developing type 2 Diabetes. The Diabetes Prevention Program and other large studies have shown that people with pre - Diabetes can often prevent or delay diabetes if they lose a modest amount of weight by cutting fat and calorie intake and increasing physical activity example, walking 30 minutes a day 5 days a week. Losing just 5 to 7 percent of body weight prevents or delays Diabetes by nearly 60 percent. In DPP, people aged 60 or older who make lifestyle changes lower their chances of developing Diabetes by 70 percent. Many participants in the lifestyle intervention group returned to normal blood glucose levels and lowed their risk of developing heart disease and other problems associated with diabetes. Dpp also shows that diabetes drug metformin reduces the risk of developing Diabetes by 31 percent. People with insulin resistance or pre - Diabetes can help their body use insulin normally by being physically active, making wise food choices, and reaching and maintaining a healthy weight. Physical activity helps muscle cells use blood glucose for energy by making cells more sensitive to insulin.
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It has been recognise for more than 80 years that resistance to Insulin - mediate Glucose uptake is key to the pathophysiology of type 2 diabetesand hypothesise for at least 25 years that impaired Insulin Action provides an important and early link between metabolic and cardiovascular disease. However, no consensus has emerged on the relative importance of Insulin Resistance over other pathways thought to be involved in accelerated CVD, or indeed on how these pathways interact. The Advent of thiazolidinedione Insulin sensitisers provided intense stimulus to research in the 1990s, but this was short - live owing to protracted period of uncertainty over safety. As interest in Insulin - sensitising therapeutic strategies reawakens, field remains hampered by a bewildering array of surrogate methods of measurement, each with its own formula and acronym. The Phrase Insulin Resistance does not have one simple meaning and covers a range of physiological processes. It is therefore not surprising that there is no widely accepted and user - friendly standardise method for measuring it, and different laboratories and investigators favour their own methods, rendering comparison of results across field problematic. The article by Otten et al in this issue of Diabetologia is therefore both timely and useful. In careful systematic review, authors have taken a reductionist approach and assessed performance of various surrogate measures of Insulin Resistance against hyperinsulinaemic - euglycaemic Clamp technique as reference method. Clamp is one of several direct methods for measurement of Insulin Resistance, requiring simultaneous intravenous infusion of Insulin and Glucose over several hours. At a steady state, endogenous Insulin production is suppressed by plateau of exogenous hyperinsulinaemia; under these conditions, whole body Insulin - mediate Glucose uptake approximates the rate of Glucose infusion required to maintain plasma Glucose at around 5. 0 mmol / L. Depending on the concentration of hyperinsulinaemia achieve, hepatic Glucose production can be almost completely suppress. Therefore, unless a lower dose of Insulin is used by design, Clamp - derived measurements of Insulin Sensitivity predominantly reflect peripheral Glucose uptake into muscle, with higher values indicating greater Insulin Sensitivity. There are only a handful of large cohort studies in which Insulin Resistance has been measured invasively using Clamp or another direct method, and these have provided some important insights into key scientific questions. However, in view of the time - consuming and labour - intensive nature of direct methods, surrogate methods are used much more often. All involve measuring Insulin and Glucose concentrations either in fasting blood sample or from a series of samples collected during OGTT. As detailed in paper by Otten et al, such methods have been derived either empirically or by mathematical modelling. Otten et al identify 120 published studies over the last 30 years in which surrogate measures of Insulin Resistance were reported in association with contemporaneous Clamp measurements. They extract data on eight fasting methods and ten OGTT - base methods. In pooling correlation coefficients, they find considerable heterogeneity between studies and evidence of publication bias for some methods.
A total of 286 subjects with a mean age of 41. 2 11. 0 years of study. Characteristics of study population stratified by gender are summarized in Table 1. The majority of participants were healthy, not suffering from medical morbidity, non - smokers, and did not drink alcohol. More than half of participants had a low level of PA. Subjects were primarily marry, holding university degree,s with income of less than 4000 per month. More than one third of participants were of normal weight, while the majority were overweight and obese. Mean glucose and insulin concentrations were 5. 0 0. 9 mmol / L and 12. 1 8. 0 uIU / mL, respectively. In the total sample, more than one third of participants were insulin resistant. Average dairy product intake in the total sample was 2. 2 1. 0 servings per day. More than 80% of participants were not meeting recommendation of 3 servings of diary / day with no statistically significant difference across genders. Across genders, men were significantly older than women. More men were smokers and alcohol drinkers compared to women. More than half of women were of healthy weight, whereas more than half of men were overweight and obese. Men had significantly lower PBF than women. Men had higher glucose levels than women 4. 8 0. 5 mmol / L, p < 0. 001 Table 1. Higher proportion of men 47. 0% were insulin resistant compared to women 31. 6%, p < 0. 01 fig. 1. Table 2 summarizes socio - demographic, dietary, lifestyle, anthropometric, and biochemical factors associated with dairy consumption. The higher proportion of married participants was 75. 3% were in quartile 3 of daily intake compared to quartile 4 50. 7%, p = 0. 024 while a higher proportion of single participants were in quartile 4 49. 3% of dairy intake. Individuals in quartile 3 of dairy product intake had lower BMI 25. 6 4. 3 kg / m 2, PBF 28. 4 7. 1% and waist circumference 92. 8 11. 6 cm than individuals in quartile 2 BMI: 28. 0 5. 2 kg / m 2, p = 0. 021; PBF: 31. 8 8. 1%, p = 0. 039; waist circumference: 98. 8 12. 0 cm, p = 0. 019. Subjects in lowest quartile of dairy intake had a lower intake of calcium 619. 5 435. 2 mg, magnesium 248. 5 142. 0 mg and potassium 2294. 5 1049. 1 mg compared to individuals with the highest intake of daily calcium: 887. 4 525. 3 mg, p = 0. 011; magnesium: 319. 7 154. 4 mg, p = 0. 025; potassium: 2890. 8 1288. 1 mg, p = 0. 026. Normal TG levels were more common among individuals in quartile 3 of dairy intake 78. 1% compared to individuals in quartile 2 57. 1% p = 0. 025 Table 2. Table 3 summarizes socio - demographic, dietary, lifestyle, anthropometric, and biochemical factors associated with HOMA - IR across genders. A higher proportion of obese males 42. 9% were insulin resistant compared to those who were 18. 3% p < 0. 001. In addition, males with HOMA - IR 2. 5 had significantly higher PBF 29. 4 6. 2% compared to those with HOMA - IR < 2. 5 25. 0 6. 5%, p < 0.
Treatments for Type 2 DIabetes include oral antihyperglycemic medications, non - Insulin injectables, and Insulin, in addition to lifestyle changes comprising healthy eating, exercise, and weight control. 1 2 Because T2D is a progressive disease, over time, effectiveness of oral medications and non - Insulin injectables is no longer sufficient to provide glycemic control and hence Insulin needs to be initiate. 3 Despite demonstrated efficacy of Insulin in achieving adequate glycemic control and lowering risks of long - term complications associated with T2D, 1 2 4 - 6 as many as 30% of people with T2D are reluctant to initiate Insulin for a significant period of time after initial recommendation to do so has been make by their healthcare provider. 7 Numerous studies have examined this phenomenon, term psychological Insulin resistance 8 - 15 and have documented that initiation of Insulin therapy is often delayed due to a variety of physician - related factors 11 - 13 as well as patient - related factors. 14 - 16 emerging research has suggested that HCP actionsparticularly, those suggesting collaborative approach tailored to individuals, meaningful impact on helping adults with T2D overcome PIR and initiate TreatMent. 17 - 19 For example, in multinational AccEpting Insulin TreatMent For Reluctant PeOple with Type 2 DIabetes MellitusA GlObal Study to IdeNtify Effective Strategies surveythe source of information. For the present studywe find that HCPs WHO are able to take time to address injection concerns by showing and / or demonstrating actual injection process, explaining benefits of Insulin, and adopting collaborative, communication style are most likely to help participants overcome PIR. 19 importance of HCP interventions in compliance with Insulin TreatMent has also been evaluated previously. For example, recent multinational study among people with T2D using Insulin found that people whose physicians take time to communicate TreatMent goals experience greater adherence to Insulin TreatMent. 20 Similarly, quantitative analysis from the EMOTION survey found that participants whose HCPs take time to explain the benefits of Insulin and dispel any myths around Insulin were less likely to discontinue Insulin for 7 + days after initiation. 19 present study builds on this previous quantitative research on how actions of HCPs can facilitate acceptance of Insulin among people with PIR, but more importantly, explores personal experiences of adults with T2D during the process of transitioning to Insulin TreatMent. Better understanding of people's perspective through key real - life examples may help HCPs to successfully facilitate the difficult process of Insulin initiation among adults with T2D. Specifically, this study provides deeper understanding about perceptions about Insulin before and after initiation as well as important patient - report behaviors of HCPs that help initially reluctant patients to start Insulin. Information was gathered from exploratory interviews conducted with a subset of participants from the aforementioned EMOTION Study. Base on study findings, actionable strategies suggest that HCPs can be used to help patients through the Insulin initiation process.
Three primary sites of Insulin Resistance are muscle, liver, and adipose tissue. Insulin Resistance is supposed to begin in muscle tissue with immune - mediated inflammatory change and excess free fatty acids, causing ectopic lipid deposition. Muscle accounts for up to 70% of glucose disposal. With impaired muscle uptake, excess Glucose returns to the liver, increasing de novo lipogenesis and circulating free fatty acids, further contributing to ectopic fat deposition and Insulin Resistance by use of hyperinsulinemic - euglycemic clamp technique, researchers determined that lipolysis is most sensitive to Insulin. Failure of Insulin to suppress lipolysis in Insulin - resistant adipose tissue, especially visceral adipose tissue, increases circulating free fatty acids. Higher levels of circulating FFAs directly affect both liver and muscle metabolism, further exacerbating Insulin Resistance. After intake of caloric load and conversion to Glucose, muscle is the primary site for glucose disposal, accounting for up to 70% of tissue glucose uptake. With excess calorie loads, glucose uptake by muscle exceeds capacity, and excess glucose returns to the liver where it triggers DNL. An increase in DNL increases triglyceride and FFA production, causing ectopic fat deposition into liver, muscle, and adipose tissue. As a result, Insulin Resistance increases as well as the production of inflammatory markers. Additional factors influencing Insulin Resistance in muscle tissue include physical inactivity and genetic risk. Insulin Resistance in muscle results in increased delivery of Glucose substrate to liver, which triggers DNL, with associated inflammation, and ectopic lipid deposition. Insulin Resistance in adipose tissue results in increased lipolysis in adipocytes, resulting in increased circulating FFA and further exacerbating steatosis and Insulin Resistance in muscle tissue. In presence of caloric intake, Insulin reduces hepatic Glucose production via inhibition of glycogenolysis, limiting postprandial rise in Glucose. With Insulin Resistance, this feedback mechanism is impair, and hepatic Glucose production continues to rise, even as postprandial Glucose rises. Glucotoxicity, associated with elevated Glucose levels, further contributes to Insulin Resistance.
Predicting Insulin Sensitivity in normoglycemic individuals is important, as diabetes intervention programs are more likely to be successful at this stage rather than after development of impaired glucose tolerance. Most studies have investigated predictors of Insulin resistance; However, almost all studies have included people with IGT and Diabetes, rather than normoglycemic individuals in the general population. In our study, fasting Insulin alone was as accurate at predicting Insulin resistance in normoglycemic population as HOMA, Insulin - to - glucose ratio, and Bennett index. Our finding is comparable with that of Laakso, who demonstrated that fasting Insulin alone was less variable and had higher correlation with ISI in individuals with normoglycemia than in individuals with IGT and Diabetes. Thus, any method to predict Insulin Sensitivity in normoglycemic individuals should be compared with fasting Insulin. Cross - reactivity with proinsulin is unlikely to alter these findings, because proinsulin levels are low in Insulin - resistant normoglycemic individuals, and the pattern of response is similar to that of specific Insulin. A number of clinical and metabolic abnormalities have been associated with Insulin resistance. Mykkanen et al. It has been confirmed that low Insulin Sensitivity is associated with clusters of metabolic disorders and that ISI decreases with increased number of disorders. Metabolic disorders were classified as dyslipidemia, hypertension, and IGT. Howard et al. Compare several alternative methods for measuring Insulin Sensitivity to predict cardiovascular risk. Many methods, including the modified Galvin method and other methods based on frequently sampled IVGTT, are invasive and time - consuming, and they are not appropriate for general population screening. However, they do confirm that the best method was dependent on glucose status. Galvin and HOMA methods were most useful across all glucose levels. In addition, data for individuals with normal glucose tolerance from these two methods were consistent with our own method, showing that fasting Insulin was as good, if not better, than HOMA, Insulin - to - glucose ratio, or Bennett index. Berglund and Lithell have used BMI and either triglycerides or serum alanine - amino transferase to predict Insulin resistance in hypertensive patients. They find either combination to be as useful as fasting Insulin, but they do not add fasting Insulin to either combination. However, glucose status was not reported in all of the groups they evaluate. More recently, Strumvoll et al. Assess 104 nondiabetic individuals to determine whether age, BMI, WHR, and glucose and Insulin Levels during oral glucose tolerance test could predict Insulin Sensitivity. They find that BMI, Insulin at 120 min, and glucose at 90 min best predict Insulin Sensitivity. These parameters appear robust in individuals with normal glucose tolerance, as well as in individuals with IGT. Other studies have not found 120 - min Insulin measurement as useful as fasting Insulin measurement. It is worth noting that in Strumvoll et al. Study, correlation coefficient between fasting Insulin and ISI was remarkably similar to that between ISI and 120 - min Insulin, suggesting little difference between fasting Insulin and 120 - min Insulin as predictors.
Shutting off gene implicated in Insulin Resistance leads to damaged mitochondria and decreased exercise capacity in mice. Stanford Medicine integrates research, medical education and health care at its three institutions - Stanford University School of Medicine, Stanford Health Care, and Lucile Packard Children's Hospital Stanford. For more information, please visit the Office of Communication & Public Affairs site at http: / mednews. Stanford. Edu. Health researchers have known for decades that Type 2 Diabetes results from a phenomenon called Insulin Resistance, but what causes Insulin Resistance is a mystery. Now, researchers at Stanford University School of Medicine and University of Wisconsin - Madison have begun to untangle a web of connections that include gene;s mitochondria, which produce energy for cells; Insulin Resistance; and how well the body's metabolism functions. Weve identified a mechanism for Insulin Resistance that involves a gene that ties Insulin resistance to mitochondrial function, said Joshua Knowles, MD, PhD, assistant professor of cardiovascular Medicine at Stanford. A paper describing the work was published in the Oct. 4 issue of Cell Reports. Knowles is senior author, and Indumathi Chennamsetty, PhD, postdoctoral scholar at Stanford, is lead author. Insulin is a hormone secreted by the pancreas that helps fat and muscle cells take Glucose from the blood. When people's cells stop responding to Insulin, person has Insulin Resistance and Glucose builds up in the blood, signaling pancreas to produce ever more Insulin. Insulin resistance severe enough to damage body tissues is common. One 2015 study estimated that nearly 35 percent of all US adults are sufficiently Insulin - Resistant to be at greater risk of diabetes and cardiovascular disease. Environmental causes of the skyrocketing rate of Insulin Resistance in the United States include poor diet and sedentary habits, but molecular mechanisms have been unknown, say Knowles. Previous work by Knowles and his team linked a variant of human gene called NAT2 with Insulin Resistance in humans. In mice, suppressing a similar gene, called Nat1, causes metabolic dysfunction, including decreased Insulin sensitivity and higher levels of blood sugar, Insulin and triglycerides. A new study shows that suppressing expression of Nat1 gene in mice interferes with the function of mitochondria cell structure that makes ATP, energy currency of cells. Without ATP, cells cannot live and function. In addition, mice whose Nat1 gene had been eliminated gained more weight and had larger fat cells and higher levels of biomarkers indicating inflammation than do regular mice, even though all mice got the same amount of food and water. Mice without Nat1 also had decreased ability to use fat for energy, said Knowles, and they were also pretty slow on exercise wheel. When we put mice on a treadmill and make them exercise really, really hard, mice that lack this Nat1 gene do have the ability to keep up with normal mice, Knowles say. And that supports the hypothesis that poorly functioning mitochondria are part of the problem. Insulin Resistance is a known forerunner to Type 2 Diabetes.
Editorial, see p 347 | Meet First Author, see p 296 insulin resistance plays a key role in the pathophysiology of both type 2 diabetes mellitus and cardiovascular disease. Clinical risk factors for IR include obesity, dyslipidemia, inflammation, hyperinsulinemia, and dysglycemia. 1 in addition to these classical clinical risk factors of IR, genetic variation modulates risk of IR, either directly or indirectly by modulating aforementioned risk factors. Annotation of genetic risk loci of IR has yielded insights into the causes of T2D and CVD. 2 3 Complete annotation of genetic risk loci and their effector genes will facilitate prediction, prevention, and personalized treatment of cardiometabolic diseases. Genome - wide association studies have identified 60 gene loci associated with risk of IR. The top 10 IR - associate loci were replicated in 2 GWAS studies 2 4 and were also associated with T2D. They are located in noncoding regions of PPARG, IRS1, GRB14, PEPD, PDGFC, MAP3K1, ARL15, FAM13A, RSPO3, and LYPLAL1. The Polygenic risk score, comprising risk alleles of 10 loci, was not only associated with risk phenotypes of higher fasting insulin and triglyceride levels, but also with classical cardiometabolic phenotypes of lower BMI, lower body fat percentage, smaller hip circumference, and decreased leg fat mass. These findings suggest that limited storage capacity of subcutaneous adipose tissue and consequent increase in ectopic fat deposition are likely responsible for genetic associations with IR. 2 3 SAT serves as a buffering system for lipid energy balance, particularly fatty acids, and plays a protective role in metabolic and cardiovascular disease risk. 5, despite the success of GWAS in identifying genetic loci associated with IR, it remains challenging to pinpoint causal genes in each of these loci. 6 Recently, chromosome conformation capture technology and expression quantitative trait loci studies have identified structural and functional links between GWAS loci and regional or distal genes. 7 8 However, chromosome conformation capture experiments are costly, eQTL studies do not identify all effector genes for locus and neither is capable of pinpointing causal genes and mechanisms of disease risk loci. The alternative strategy employed in this study prioritize candidate causal genes in disease - associate loci by investigating disease - relevant functions of candidate genes in risk - relevant cell types. To this end, we developed an in vitro knockout - screening platform and functionally assessed 16 IR candidate genes in human preadipocytes and adipocytes to both validate candidates and discover underlying molecular mechanisms. Among 16 candidates, except PPARG and IRS1, functions of the remaining 14 candidate genes have not been characterized in human preadipcytes and adipocytes. We targeted candidate genes individually in human Simpson - Golabi - Behmel syndrome preadipocyte. 9 SGBS preadipocyte cell strain originates from adipose tissue specimen of patient with SGBS. They provide an unlimited source of adipogenic cells as well as opportunity for gene editing because of their ability to proliferate for up to 50 generations while retaining capacity for adipogenic differentiation.
Testing was done after 12 - h fasting. Pst involves continuous infusion of glucose, crystalline insulin and octreotides for 3 h. Under such conditions, endogenous insulin production is suppressed by octreotides and steady - state serum insulin is raised in subjects to stimulate muscle uptake of glucose. During PST, serum insulin levels are kept stable, while allowing serum glucose to change, as function of muscle insulin sensitivity. Steady - state - plasma glucose becomes an inverse function of insulin sensitivity. Plasma glucose measurements were obtained at 0 - 30 - 60 - 90 - 120 - 150 - 160 - 170 and 180 min. Sspg values < 150 mg / dL indicate non - insulin - resistant status whereas values of 150 mg / dL indicate IR status. Additionally, each patient was categorized as eugonadal or hypogonadal. A sample to measure serum testosterone was taken at the start of PST. Plasma glucose was measured with the glucose - oxidase method. Results are expressed as mean standard error of mean.
Insulin Resistance is defined as an experimental or clinical condition in which Insulin exerts biological effect lower than expect. This phenomenon is due to marked defects in Insulin - stimulate glucose uptake, particularly, in glycogen synthesis and, to a lesser extent, glucose oxidation. The Effects of Insulin Resistance in different tissues depend on the physiological as well as metabolic function of tissues. Due to their high metabolic demand, Insulin Resistance has significant effects on skeletal muscle, adipocytes and liver tissue, which are main targets of intracellular glucose transport as well as glucose and lipid metabolism. Skeletal muscle and adipocytes account for about 60 - 70% and 10% of Insulin - stimulate glucose uptake respectively via GLUT 4 receptors. Insulin Resistance causes impaired glycogen synthesis and protein catabolism in skeletal muscles and inhibits lipoprotein lipase activity in adipocytes, leading to increased release of free fatty acids and inflammatory cytokines such as IL - 6, TNF, and leptin. Additionally, liver accounts for 30% of Insulin - stimulate glucose disposal and Insulin Resistance leads to impaired glucose output and fatty acid metabolism leading to increased triglyceride content and VLDL secretion from liver. Insulin Resistance causes endothelial cell dysfunction by decreasing production of Nitric Oxide from endothelial cells and increasing release of pro - coagulant factors leading to platelet aggregation. In Insulin resistant state, PI3K pathway is affected whereas MAP kinase pathway is intact, which causes mitogenic effect of Insulin on endothelial cells leading to Atherosclerosis. Interestingly, low levels of circulating Insulin and Insulin Resistance have significant physiological roles in regulating metabolic adaptation during starvation and pregnancy. During starvation, low glucose levels lead to decreased secretion of Insulin, which facilitates mobilization of glucose from the liver, fatty acids and glycerol from adipocytes and amino acids from muscle tissue. These compensatory mechanisms help maintain blood glucose levels and utilization by vital systems like brain and red blood cells. Insulin Resistance increases in pregnancy, particularly in the second to third trimester. This ensure adequate supply of metabolic substrates and nutrients to the fetus for its proper growth and development. In contrast, Insulin Resistance is a key player in the pathogenesis of metabolic diseases like type 2 diabetes and can be observed in several clinical conditions such as breast cancer, rheumatoid arthritis, polycystic ovary Syndrome, non - alcoholic fatty liver disease, and CVD. Excess of lipids in cardiomyocyte shunt into non - oxidative pathways results in accumulation of toxic lipid species, which alter cellular signaling and cardiac structure. Disruptions in several cellular signaling pathways such as in mitochondrial dysfunction and endoplasmic reticulum stress have been associated with lipotoxicity. Mediators such as reactive oxygen species, Nitric Oxide, ceramide, phosphatidylinositol - 3kinase, diacylglycerol, ligands of PPAR nuclear receptors, leptin have been proposed to promote these lipotoxic effects and enhance rates of apoptosis.
For the first time, researchers led by Prof. Paul Spagnuolo have shown how compounds found only in avocados can inhibit cellular processes that normally lead to diabetes. In safety testing in humans, team also found that the substance was absorbed into blood with no adverse effects on the kidney, liver or muscle. The study was recently published in the Journal Molecular Nutrition and Food Research. About one in four Canadians is obese, chronic condition that is the leading cause of Type 2 Diabetes. Insulin resistance in diabetic patients means their bodies are unable to properly remove glucose from the blood. Those complications can arise when mitochondria, or energy powerhouses in the body's cells, are unable to burn fatty acids completely. Normally, fatty acid oxidation allows the body to burn fats. Obesity or Diabetes hinders that process, leading to incomplete oxidation. U of G researchers discovered that avocatin B, fat molecule found only in avocados, counters incomplete oxidation in skeletal muscle and pancreas to reduce insulin resistance. In their study, team fed mice high - fat diets for eight weeks to induce obesity and insulin resistance. For the next five weeks, they added AvoB to the high - fat diets of half of the mice. Treat mice weigh significantly less than those in the control group, showing slower weight gain. More important, says Spagnuolo, treating mice show greater insulin sensitivity, meaning that their bodies are able to absorb and burn blood glucose and improve their response to insulin. In a human clinical study, AvoB given as a dietary supplement to participants eating a typical western diet was absorbed safely into their blood without affecting kidney, liver or skeletal muscle. Team also saw reductions in weight in human subjects, although Spagnuolo said the result was not statistically significant. Having demonstrated its safety in humans, they plan to conduct clinical trials to test AvoB's efficacy in treating metabolic ailments in people. Spagnuolo said safety trial helped the team to determine just how much AvoB to include in supplement formulation. Having received Health Canada approval for compound as human supplement, he will begin selling it in powder and pill forms as soon as 2020 through SP Nutraceuticals Inc., Burlington, Ont. - Base natural health products company. He says eating avocados alone would likely be ineffective, as the amount of natural avocatin B varies widely in fruit and we still do not fully understand exactly how it is digested and absorbed when we consume whole avocado. Although avocados have been touted as weight - loss food, Spagnuolo says more study is needed. He says healthy diet and exercise are recommended to prevent metabolic disorders leading to obesity or diabetes. Phd student Nawaz Ahmed, lead author of the paper, say, we advocate healthy eating and exercise as solutions to problem, but that's difficult for some people. We 've known this for decades, and obesity and diabetes are still significant health problem.Ssssss
Despite being one of the pressing healthcare challenges of our time, the of type 2 Diabetes is still incompletely understood. Although the proximate cause of T2D is failure of pancreatic islet to increase or maintain Insulin production, ultimate cause has not yet been conclusively identify. Overall, there is a link between an unhealthy Western diet and lack of physical activity, and the development of T2D. In terms of progression of disease, T2D manifests as slow and worsening decrease of Insulin sensitivity affecting multiple organs, during which time blood glucose levels are maintained within normal levels, whereas Insulin levels rise to compensate, followed by eventual failure of pancreatic islet. Several groups report impairment of systemic glucose tolerance, as well as Insulin signalling, in the brain or liver after only very few days of feeding obesogenic highfat diet to rodents, with diet typically consisting of 60% of calories from fat and 20% each from protein and carbohydrates. These early impairments of glucose homeostasis typically present as failure of elevated glucose or Insulin levels to supress hepatic glucose output, leading to decreased glucose tolerance. Development of profound Insulin Resistance in major metabolic organs muscle and adipose tissue takes longer and has been linked to inflammation. By contrast, manifestation of systemic glucose intolerance, as a consequence of starvation or ingestion of very low carbohydrate, ketogenic diets for several days, has been recognized for at least a century in animals and humans and is termed starvation Diabetes. Starvation Diabetes has been shown to be linked to increase in hepatic gluconeogenesis by tracer studies in humans, yet any mention of term starvation Diabetes or citation of related studies is absent from recent literature concerning effects of longerterm KD feeding on glucose tolerance and Insulin sensitivity. Even though the efficacy of chronic KD feeding with respect to causing weight loss is accept, there is significant controversy about its effect on glucose tolerance and Insulin sensitivity. Kennedy et al. Show that KD improves glucose tolerance and Insulin signalling in mice compared to mice maintained on HFD for 12 weeks. Badman et al. Show that KD increases glucose sensitivity in ob / ob mice independently of weight loss. On other hand, Jornayvaz et al. Show that, in C57BL / 6 mice, 5 weeks on KD induce hepatic Insulin Resistance, decrease glucose tolerance, and increase gluconeogenesis, despite preventing weight gain and increasing energy expenditure. Furthermore, Garbow et al. Find increased hepatic steatosis and inflammation, as well as decreased glucose tolerance, despite high muscle and adipose tissue Insulin sensitivity, in mice on KD for 12 weeks.
Since Reaven introduced the concept in 1988, thousands of papers relating to MS have been publish. A search of PubMed in August 2010 resulted in over 31 000 responses demonstrating a high level of interest in the concept and in 2006 Journal of CardioMetabolic Syndrome appear. The reason for such interest is not surprising as Ford et al. Have estimate that using revised National Cholesterol Education Program / adult Treatment Panel III criteria show that between 32% and 34% of all US adults have MS. Base on International Diabetes Federation criteria, estimates were 39%, with 40% of men and 38% of women; similar classification occur 93% of time for two definitions. This equates to greater than 100 million in the US based on population estimate of 310 million. A Multiethnic representative US sample of 12 363 men and women 20 years and older from the Third National Health and Nutrition Examination Survey were evaluated for MS as defined by ATP III diagnostic criteria and disorder was found to be present in 22. 8% and 22. 6% of men and women, respectively. Ms was present at 4. 6%, 22. 4%, and 59. 6% of normal - weight, overweight, and obese men, respectively, and physical inactivity was associated with increased risk of developing syndrome. When Reaven published his paper in 1988, he state, many studies have investigated syndrome as a possible independent Risk Factor for CHD. In 2007, meta - analysis of Longitudinal Studies involving 172 573 individuals, Gami et al. The Report that relative risk for individuals with MS compared to those without MS was 1. 78 for cardiovascular events and death; for women, RR was 2. 63. After adjusting for traditional cardiovascular risk factors, those with MS still had an RR of 1. 54 for cardiovascular events and death. In 2006, results from another meta - analysis conducted by Galassi et al. Show that MS is associated with increased incidence of cardiovascular disease, CHD, and stroke. Individuals with MS had increased all - cause mortality and cardiovascular mortality. Again, risks were higher in women compared to men. In his 1988 paper, Reaven pointed out that resistance to Insulin - stimulate glucose uptake was present not only in patients with T2D but also in the majority of individuals with impaired glucose tolerance as well as those with MS. Thus, it was speculated that individuals with MS and Insulin Resistance might be AT high Risk for Development of T2D; this turned out to be the case. In meta - analysis of 16 cohort studies, Ford et al. Report that RR for T2D in individuals with MS ranges from 4. 42 to 5. 17 depending on criteria used to define MS. Authors conclude that MS, however define, has stronger association with T2D than previously demonstrated for CHD. Although MS appears to be a well - accepted syndrome associated with increased risk for both CHD and T2D, use of the term MS has been questioned for a variety of reasons.
Section Overview will focus on an overview of molecular aspects of insulin resistance. Insulin resistance has been suggested as major underpinning link between physical inactivity and MS. Many tissues, including skeletal muscle, liver, and adipose tissue may exhibit insulin resistance. Give clinical benefit of treating those with insulin resistance, techniques have been developed to assess insulin sensitivity in vivo. Euglycemic - hyperinsulinemic glucose clamp involves injecting a fixed dose of insulin to increase insulin to postprandial or to supraphysiological levels with normal glucose concentrations being maintained by infusing glucose. Glucose infusion rate reflects insulin sensitivity and is generally considered an inverse measure of insulin resistance; glucose disposal is often also determine. Fsigt can estimate insulin sensitivity and acute insulin response using Bergman's minimal model, yielding a hyperbolic relationship between insulin secretion and insulin sensitivity. Product of these two indices is referred to as disposition index, marker of - cell function. As depicted in Figure 1, exercise training / physically activity status modifies insulin sensitivity and insulin secretion in accordance with this relationship, and failure of insulin secretion to compensate for fall in insulin sensitivity leads to elevated fasting glucose and prediabetes, and depending on genetic predisposition, continue progressive decline in both insulin secretion and insulin sensitivity to T2D. Generally, use of EHC and FSIGT are gold standard methods for estimation of insulin sensitivity and / or - cell function. However, these methods are expensive, not simple to perform and generally not applicable in standard clinical practice. The Oral glucose tolerance test is less expensive and its simplicity allows for more widespread use. Other techniques used include insulin suppression testing, insulin tolerance testing and continuous glucose monitoring systems.
As previously discuss, many studies have documented that AT improved whole body insulin sensitivity. Skeletal muscle, most important target tissue for insulin action, has received most attention for mechanistic studies with emphasis on insulin signaling pathway study from biopsy samples. While effects of AT - induced increases in glucose disposal have been attributed primarily to increases in insulin signaling protein and / or activities, data are not consistent. Studies comparing endurance - trained subjects versus untrained subjects have indicated differences in glycogen storage in response to insulin, insulin signaling proteins, such as increased GS, GLUT4, GLUT4 vesicle - associate protein, and PI3 - K activation, but decreased IRS - 1, IRS - 2, insulin receptor, and no difference in AKT. Using 31P NMR spectroscopy, Perseghin et al. Note that despite lower glucose transport phosphorylation in offspring of T2D patients compared with normal subjects, both exhibited increases in whole body insulin sensitivity after AT by 40% or more and whole body nonoxidative glucose metabolism by 60% to 70%, mediated by increase in glucose transport - phosphorylation. Training - induced improvement in glucose disposal has been attribute, AT least in part, to increased insulin - stimulate glucose storage and GS fractional velocity, which correlate with insulin - stimulate glucose storage. Dela et al. Also note increases in nonoxidative glucose disposal associated with increased GS mRNA and Frosig et al. Note increased GS activity with short - term training. Ferrara et al. Note similar effects on GS fractional activity in response to insulin, with no change in total activity. Dela et al. Note maximum insulin binding and that basal - and insulin - stimulate receptor kinase activity do not change; however, GLUT4 protein concentration increase and training - induced increase in GLUT4 matched increase in maximum insulin - stimulate leg glucose uptake in the same subjects, and individual values of two variables were correlate. In subjects with IGT, independent of changes in body composition, glucose disposal AT high insulin concentration during EHC increased approximately 60% and GLUT4 and glycogen increased after training. Several additional studies have noted increases in GLUT4 content. For example, 60% in middle - age subjects, approximately 80% in nondiabetic men, 38% and 22% in overweight nondiabetic and diabetic men, 40% in healthy men and 23% in men with T2D. Short et al. Noted increases in GLUT4 mRNA and protein content, independent of age, in subjects ranging from age 21 to 87. Furthermore, short - term training increases GLUT4 protein similarly in both younger and older subjects. Frosig et al. Note AT - induced increases in insulin - stimulate glucose uptake of 60% and increase in muscle Akt1 / 2, AS160, GLUT4, HK2 and insulin - responsive aminopeptidase protein content and activities Akt1, GS and AS160 phosphorylation. However, IRS - 1associated PI3K activity was reduce. Short - term training studies report no change in mRNA expression of IR, IRS - 1, IRS - 2 and p85 - subunit of PI3K, but there were noted increases after short - term training in insulin receptor autophosphorylation and PI3K activity in concert with increased insulin sensitivity, and PI3K activity in chronic - trained young men. On other hand, Christ - Roberts et al.
According to the International Diabetes Federation, number of people with Diabetes in the world is expected to increase from 463 million in 2019 to 700 million in 2045, with 83. 9% of cases occur in low and middle income countries. In Lebanon, World Health Organization statistics show that diabetes is standing as the fourth leading cause of death with a prevalence rate of 12. 6%, higher than that reported by the United States. Type 2 Diabetes, most common form of Diabetes, is mainly caused by insulin resistance. Insulin resistance can be defined as a condition in which the pancreas is required to secrete more insulin than normal in order to achieve normal blood glucose levels due to reduced sensitivity or responsiveness of tissues to insulin biologic activity. The prevalence of insulin resistance varies across countries. Studies show that it is estimated to be lowest among European adults with a prevalence of 15. 5%, while higher prevalence rates were reported in other countries, reaching 23. 3 39. 1 and 46. 5% in Thailand, Texas, US and Venezuela, respectively. Lebanon reports one of highest prevalence rates compared to other countries, reaching 44. 6% among a national sample of 308 adults with an average age of 41. 0 15. 5 years. Several factors could increase the likelihood of developing insulin resistance. For instance, age increases the risk of having insulin resistance due to high proportion of visceral fat, oxidative stress and mitochondrial dysfunction. Abdominal adiposity and increased body fat are other risk factors for insulin resistance and this is due to high amount of free fatty acids and Pro - inflammatory cytokines released from visceral fat tissue into portal vein of obese subjects, causing development of hepatic insulin resistance and Type 2 Diabetes. Other risk factors include gender, physical inactivity. Further, dieting has been shown to be effective in improving insulin resistance and reducing the incidence of Type 2 Diabetes. A Study conducted among subjects with impaired Glucose tolerance showed that diet was able to reduce the incidence of Type 2 Diabetes by 33%, after a follow up period of 6 years. In a study conducted among overweight and obese middle age women, diet alone was able to reduce insulin resistance by 24%. Accordingly, more research is focusing on the role of specific food groups in improving insulin resistance. Consumption of dairy products makes an important contribution to the human diet. They were found to provide more calcium, protein, magnesium, potassium, zinc, and phosphorus per calorie than any other type of food. In Lebanon, as well as in other countries in the Levant Region such as Jordan and Syria, dairy products constitute an important part of the traditional food heritage, typically in fermented form like yogurt, labneh and white cheese. However, not only in Lebanon, but among all Middle Eastern countries, globalization has led to a decrease in consumption of dairy products over time and a shift to a Western diet, including high consumption of fast foods as result of rapid economic and social changes.
Fasting Adipo - IR increased twofold in obese NGT and IGT versus lean NGT and threefold in T2DM. Fasting Adipo - IR was significantly greater in obese T2DM versus lean T2DM and inversely correlated with - cell function, indicating that high fasting plasma FFA concentrations and impaired FFA suppression were mainly the result of insulin secretion deficiency. This finding was confirmed by analysis of euglycemic - hyperinsulinemic clamp data showing that plasma FFA concentrations at end of hyperinsulinemic clamp were similar in all study groups. Although fasting Adipo - IR rises continuously in transition from NGT to IGT to T2DM, OGTT Adipo - IR increases from lean NGT to obese NGT to IGT and then decreases progressively in T2DM groups I - III, following U - shaped insulin response curve during OGTT. Thus, markedly deficient insulin secretion during OGTT results in paradoxical decline in OGTT Adipo - IR in T2DM, making OGTT Adipo - IR unreliable in subjects with diabetes. In multivariable regression analysis, ln was found to be independently correlated with BMI, insulin sensitivity, and male sex. By performing the same analysis separately in males and females, we found that in both females and males, association held with BMI and insulin sensitivity. In subgroup of 54 subjects for whom plasma was available, adiponectin correlated negatively with ln independently of age, sex, and BMI.
Glucose is one of the body's most important sources of energy. Glucose is absorbed from blood into cells where it provides energy for a range of cellular functions. This cellular uptake of glucose is facilitated by the hormone Insulin, which is secreted by beta cells of the pancreas. Insulin also helps convert excess glucose into glycogen for storage in the liver. In people with Insulin resistance, muscles, fat and liver cells fail to respond to Insulin in this way and glucose remains in the blood rather than being taken up, even when Insulin levels are raise. Instead, triglycerides in fat or adipose cells are broken down to provide free fatty acids as an energy source. Failure of liver cells to respond to Insulin by converting glucose to glycogen, means glycogen stores are also decrease. As glucose remains in the blood rather than being taken up and used, hyperglycemia or raised blood glucose level results. This hyperglycemia triggers beta cells to produce even more Insulin, raising the level of Insulin further still. This Insulin resistance and hyperglycemia can lead to Type 2 Diabetes and metabolic syndrome. Metabolic syndrome is characterized by excess distribution of abdominal fat, high blood pressure, raised levels of blood cholesterol and triglycerides and decreased levels of good cholesterol or high density lipoprotein cholesterol. Together, these symptoms increase the risk of cardiovascular disease and stroke. A variety of genetic and environmental factors are thought to raise the risk of Insulin resistance but being overweight and physically inactive are major causative contributors.
Ir, defined as reduced sensitivity of liver, skeletal muscles, and adipose tissue to insulin action, is a frequent finding in CKD from the earliest stages of disease. 183 184 in ESRD, IR is believed to be present in virtually all patients, 185 although direct correlation between insulin sensitivity and degree of decline of eGFR is weak or absent. 184 Inflammation, especially potentiate by oxidative stress, is one of the established causative factors predisposing CKD patients to IR. Proinflammatory cytokines may promote IR by inhibiting insulin - signaling pathways on post receptor level in skeletal muscles and liver, whereas adiponectin mediates insulin - sensitizing effects. 186 187 Interestingly, immune cells do not develop IR. This protective mechanism, ensuring sustained energy flow in acute inflammation, becomes debilitating in chronic and persistent conditions of immune stimulation. In cross - sectional studies, homeostatic model assessment of insulin resistance was positively associated with CRP, IL - 6, fibrinogen, and TNF - in in different cohorts of dialysis patients. 188 - 190 Many factors typically coexisting with Inflammation and CKD, such as physical inactivity, anemia, vitamin D deficiency, leaky gut, acidosis, and others, also contribute to IR and constitute a vicious circle of mutual interplay. Ir profoundly influences outcomes because it is associated with cardiovascular events, mortality, and CKD progression. On the other hand, IR is a modifiable risk factor, and administration of angiotensin receptor blockade has shown promising results ameliorating IR and decreasing inflammatory markers in patients with CKD stages 2 to 4. 191 IR develops simultaneously with deterioration of kidney function in the early stages of chronic Kidney disease. 133 After PD initiation, partial correction of uremia and metabolic acidosis improve IR, which is once again deranged by glucose - containing PD fluids. 134 As acknowledge cardiovascular risk factor in PD patients, even in the absence of Diabetes, strategies are being investigated to reverse this process. 135 Replacement of dextrose solutions by icodextrin in CAPD and APD, in diabetic and nondiabetic patients, seems to reduce hyperinsulinemia and improve IR according to homeostatic model assessment. 128 insulin, acting through insulin receptor, activates intracellular messenger cascade, resulting in redistribution of intracellular glucose transport molecule to cell surface to facilitate glucose uptake by cell. Glut4 is the principal molecule involved in glucose uptake from plasma by adipose and muscle cells in response to insulin. Abnormalities in GLUT4 expression affect insulin resistance. These effects may not be tissue specific. Experimental models have shown that a decrease in GLUT4 expression in specific organs results in insulin resistance in other organs with normal GLUT4 expression. Abnormalities in function of GLUT - 4 and decreased expression of IR as result of PI exposure have both been proposed as possible additional mechanisms for insulin resistance seen in HIVLD, although the exact nature of abnormalities remains unclear. The etiology of insulin resistance in HIVLD is obviously complex, involving interactions with insulin action and fat metabolism, and probable role for molecules synthesise in one tissue having an effect on insulin sensitivity of other tissues.
Obesity in childhood and adolescence has been shown to increase the risk of Insulin resistance syndrome 1 and cardiovascular mortality in adult life. 2 clustering of major IRS components, including obesity, hypertension, dyslipidaemia, and atherosclerosis, has been shown in children and adolescents 3 4 and tracks strongly into adult life. 5 this tracking has been shown to increase with increasing age and obesity. 5 Many studies have shown that individual IRS components such as Insulin resistance, dyslipidaemia, and hypertension are highly inter - correlate and significantly more common in obese children than in those of normal weight. 6 - 9 However, prevalence of IRS in obese children and adolescents has been poorly document. Epidemiological data from the USA suggest that clustering of obesity with two or more of hyperinsulinaemia, dyslipidaemia, and hypertension is seen in 20% of obese children and adolescents. 8 However, this data is drawn from historical cohort of US white and black children, who do not use modern more restrictive definitions of obesity, 10 and do not use the standardised definition of IRS. 11 prevalence of syndrome in contemporary obese UK children of different ethnicities is not document. Identification of obese children with additional IRS components may define a high risk group within the obese child population. There is little consensus on which obese children require treatment, as available guidelines focus on assessment in primary care 12 and there are no accepted definitions of extreme or morbid obesity in childhood. Give scale of problem, paucity of effective interventions, 13 and lack of available clinical resources, there is urgent need to identify high risk groups WHO require treatment within the obese child population. Additionally, little guidance is available for clinicians on appropriate investigations required for children and adolescents with obesity. Guidance has been published on screening for lipids and Blood Pressure, 14 but with little information available on screening for glucose and Insulin abnormalities, particularly as to whether fasting samples alone or oral glucose tolerance test are required to identify abnormal glucose homoeostasis. In adults, there is increasing evidence that measurements of fasting glucose do not pick up many subjects with impaired glucose tolerance, particularly in certain ethnicities. 16 we assessed the prevalence of major components of IRS in a clinical sample of obese UK children and adolescents of different ethnicities using two definitions of obesity. We then examined whether demographic, clinical, and laboratory factors were associated with increased risk of IRS. Finally, we explore whether fasting Insulin and glucose are sufficient to screen for abnormalities in glucose homoeostasis in childhood obesity.
Nowadays, body mass index is increasing in many populations and childhood obesity is an emerging problem. In the United States, prevalence rates of obesity between 1971 and 1974 in 6 - 11 - year - old white / black children were 4%. Between 1999 and 2002, these prevalence rates increased to 13% and 20% in white and black children, respectively. In 2012, overall prevalence rate of obesity in 2 - 19 - year - old American children was 17. 3%. In developing countries, prevalence rate of overweight and obesity in preschool children in 2010 was estimated to be 6. 1% and 11. 7%, respectively. Moreover, prevalence of overweight in children under 5 years of age raised in African continent between 2000 and 2013 5. 1 to 6. 2%, while on American continents, prevalence increased with 0. 5%. The rising prevalence of obesity will cause an increase in obesity related complications such as insulin resistance, hypertension, dyslipidemia, and type 2 diabetes mellitus. Energy excess in obesity may result in hyperplasia and hypertrophy of adipocytes, leading to oxidative stress. This oxidative stress of adipocytes induces chronic low - level inflammation in adipose tissue and production of adipokines, free fatty acids, and inflammatory mediators. This inflammation is related to peripheral IR, IR of hepatocytes, and impaired insulin secretion by pancreatic beta cells. Finally, this process causes dysregulation of glucose homeostasis and development of T2DM. Although obesity plays a key role in the pathophysiology of IR, IR is an independent risk factor for cardiovascular and metabolic diseases. Therefore, it is important to know the extent of IR in pediatric populations. Knowledge of prevalence rates of IR and its clinical consequences during childhood will increase awareness of physicians and other health care professionals. Despite the report's association between IR and increased cardiovascular risk in pediatric populations, there is no overview of data on the epidemiology of IR in this population. Many studies focus on the extent of IR in overweight and obese populations, but limited studies have population - base study design. The aim of this study is to systematically review all available population - base studies on epidemiology of IR in pediatric populations. We will describe weight and sex specific prevalence and incidence rates of IR in included studies, together with the study - specific definition used to define IR.
The subjects were children and adolescents 2 - 18 years of age. Who underwent Assessment of obesity in our joint paediatric and adolescent endocrine service between 1999 and 2002. Subjects were referred by their GP or local paediatrician for medical assessment of obesity. Subjects assessed prior to June 2002 were identified through retrospective examination of hospital records. Subjects from July 2002 onwards had data collected prospectively. Only those WHO had had secondary or known genetic causes of obesity excluded were included in this analysis. Obesity is defined in two ways: firstly, as body mass Index 95 centile for age and sex according to UK 1990 growth reference; 17 secondly, we define extreme obesity as BMI z score 3. 0 as there are no standard definitions of extreme obesity in childhood. Subjects were assessed after 12 hours overnight fast. Subjects underwent OGTT with plasma Insulin and blood glucose concentrations measured at 0 30 60, and 120 minutes. Plasma Insulin was estimated by Abbott AxSYM Method. Fasting serum lipid concentrations were measure. Clinical policy means that HDL cholesterol was measured in all adolescents but only in those children with abnormal total cholesterol or triglycerides. Blood pressure was measured in recumbent position using an oscillometric method with appropriate size cuff for arm diameter. Data is reported as an average of two consecutive readings. Birth weight, ethnicity, pubertal status, presence of acanthosis nigricans, and family history of components of IRS were recorded or obtained from hospital records. Abnormal glucose homoeostasis and IRS were defined following modified WHO criteria 11 adapted for children. Hyperinsulinism was defined by norms for pubertal stage: 18 prepubertal 15 mU / l, mid - puberty 30 mU / l. Post - pubertal hyperinsulinism was defined as per adult WHO criteria. 11 Hypertension was defined as systolic blood pressure of 95 centile for age and sex. 19 Abnormal fasting lipids were defined from normative data. 20 IRS was defined as having three or more IRS components. 11 Insulin sensitivity from fasting samples was estimated using Homeostasis Model Assessment, 21 Quantitative Insulin Check Index, 22 and fasting Insulin: glucose ratio. 23 HOMA - IR was calculated as fasting Insulin fasting glucose / 22. 5. Quicki was calculated as 1 / log fasting Insulin + log fasting glucose. Figr was calculated as fasting Insulin / fasting glucose. Homoeostasis Model Assessment was used to estimate pancreatic cell function and was calculated as 20 fasting Insulin /.
All insulin resistance indices were closely correlate, and the frequency of insulin resistance in the general population was similar. The risk of insulin resistance, adjusted for age, gender and BMI, increased with category of glucose tolerance, and in patients with newly diagnosed diabetes mellitus it was almost twice as high for HOMA and QUICKI indices, and four times higher for Matsuda index than for fasting insulinemia. Ms, defined according to EGIR criteria, was diagnosed in 33 - 39% of the study population. The rate of MS was similar in the general population when defined according to NCEP, but 10% higher when defined according to WHO. The Predictive value of insulin resistance indices was similar when using WHO criteria, whereas with EGIR criteria, insulin resistance indices were differentiated in population with impaired glucose metabolism regulation, confirming the observation that the Matsuda index identifies the widest segment of the population with potential insulin abnormalities. The Matsuda index also had the highest sensitivity to diagnosing MS according to NCEP as compared with remaining insulin resistance indices.
Clinical concerns over obesity in childhood and adolescence should focus on the presence of additional IRS components, including abnormalities of glucose homoeostasis, hypertension, and dyslipidaemia. We suggest that clinicians should consider screening all significantly obese children and adolescents regardless of age, ethnicity, or pubertal status for IRS. Fasting measures have acceptable sensitivity and specificity if fasting insulin is measured as well as glucose. Those with three or more IRS components may form the appropriate group for intervention, which may include medical therapy for hyperinsulinaemia, 36 dyslipidaemia, or hypertension as well as multidisciplinary weight control program. The value of such interventions needs to be assessed by formal clinical trials with long term follow up of outcome.
More research focusing on the relationship between dairy intake and insulin resistance is needed, especially in the Arab and Middle - Eastern region.S Further, Middle Eastern dairy products are unique, have different nutrient content and thus might have different effects on insulin resistance. Moreover, several nutrients found in dairy products may have an effect on insulin resistance, whether beneficial or harmful. More studies are needed to elucidate which nutrient has the strongest effect. Finally, future studies should also examine the association between dairy products with different fat content and insulin resistance, as this association might be confound with the fat content of dairy products.
Insulin resistance was initially recognized in insulin - treated patients who required larger than usual doses of insulin. Infections, endocrinopathies, allergy to insulin, and antibodies to insulin were recognized as early causes. Recognition of insulin resistance in patients who were not receiving insulin await introduction of 1 insulin tolerance test, 2 measurement of effects of insulin infused into arterial blood of forearm 52 53 3 immunoassay of insulin first reliable quantitative measure of endogenous circulating insulin 54, and 4 clamp techniques. Our discussion here is devoted to moderate insulin resistance, ie, few - fold diminution in sensitivity to insulin extreme insulin resistance, eg, 5 - to 10 - fold or more reduction in sensitivity to insulin was first described in patients with lipoatrophic diabetes and later in patients with high concentrations of anti - insulin antibodies after treatment with insulin. Later, patients with autoantibodies against insulin receptor and patients with inborn defects of insulin receptor were added to the list. In period just before widespread acceptance of immunoassay, bioassays were in ascendancy, which detected plasma components that diminish insulin action in these assays; These substances were collectively labelled circulating insulin antagonists 55 - 57. The Immunoassay swept away all but circulating anti - insulin antibodies and well - defined hormones such as catecholamines, glucocorticoids, growth hormone, and glucagon. Immunoassay also leaves behind negative attitude toward other circulating antagonists or inhibitors of insulin action. In our opinion, PC - 1 and other well - defined circulating molecules deserve greater attention than they have been receiving. In retrospect, it is highly likely that the circulating antagonist of insulin action that everyone was searching for may be insulin itself. The introduction of direct studies of insulin receptors and later of postreceptor pathways make those insights possible. Whereas insulin resistance in general was linked to metabolism of glucose and later to other substrates in patients with obesity and type 2 diabetes, link between hyperinsulinemia and other conditions arrive later. In 1981, hyperinsulinemia had been ascribed to a pathogenetic role in obese hypertension via increased renal sodium retention 58. In 1985, Modan et al. 59 propose that hyperinsulinemia, reflecting peripheral insulin resistance, is linked to hypertension, obesity, and glucose intolerance in humans, and in 1988, Modan et al. 60 further report that hyperinsulinemia is characterized by jointly disturbed plasma lipids. The same year, Reaven 1 proposed the term Syndrome X for cluster of insulin resistance and hyperinsulinemia, impaired glucose tolerance, abnormalities of plasma lipids, and hypertension, now commonly called metabolic Syndrome.
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