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Measuring Insulin Sensitivity

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Last Updated: 02 July 2021

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General | Latest Info

Insulin resistance IS a condition in which cells in your body don't respond as well to hormone Insulin. Insulin IS produced by the pancreas and is important for transportation, use and storage of glucose, body's usual main source of energy. Insulin regulates transport of glucose into skeletal muscles, fat tissue and liver, where glucose IS needed for energy production. Normally, after a meal, carbohydrates that you eat are broken down into glucose and other simple sugars that are absorbed by the intestine. This causes blood glucose levels to rise and stimulates the pancreas to release Insulin into the bloodstream. The amount of Insulin released corresponds to the size and content of the meal. Insulin helps transport glucose into the body's cells, where it IS used for energy. As glucose moves into cells and IS breaks down, blood glucose level drops and the pancreas responds by decreasing release of Insulin. Insulin works together with glucagon, another pancreatic hormone, to maintain blood glucose levels within a narrow range. If your body's cells are less sensitive to Insulin, then less glucose IS transported from blood into cells. Blood glucose levels remain high but your cells starve. Your pancreas compensates by producing more Insulin to try to move more glucose into cells. In most cases, your pancreas IS able to keep pace with the need for extra Insulin for many years. Most people with Insulin resistance do not develop diabetes. In some cases, pancreas eventually can't keep up with demand and blood glucose continues to rise, causing Type 2 diabetes. The cause of Insulin resistance IS not fully understood. Experts think that major contributing factors are being overweight, especially having excess belly fat, and not getting enough exercise. Condition IS also thought to be due partly to genetic factors and ethnicity. Insulin resistance IS the main feature of Metabolic Syndrome. Metabolic Syndrome IS described as a set of features that link excess fat around the waist and Insulin resistance to increased risk of cardiovascular disease, as well as other problems, such as stroke. Obesity also increases the risk of various cancers. Elevate blood glucose elevates triglyceride level Low levels of high density lipoprotein cholesterol High blood pressure note that not everyone with Metabolic Syndrome will necessarily have all four of these features. Over time and left untreated, Insulin resistance can lead to other serious conditions. Harmful effects of Insulin resistance result from: consequences of Elevated blood Insulin itself inadequate effects of Insulin despite increase in blood Insulin levels elevate blood Insulin levels over time can have harmful effects, such as: hardening of arteries. Studies have shown a strong association between atherosclerosis and Elevated Insulin, but it IS unclear whether elevated Insulin itself causes atherosclerosis.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Overview

A total of 104 subjects were study: 15 lean nondiabetic, 38 obese nondiabetic, 38 subjects with type 2 Diabetes, and 13 subjects with IGT. Clinical and metabolic characteristics are summarized in Table 1. Subjects were classified according to World Health Organization criteria. Subjects with IGT were included only if they met criteria on at least two successive OGTTs. Data was compiled and aggregated from a larger database of CLAMP studies conducted during a 7 - year period, several of which have been published previously. Subjects randomly underwent OGTT and glucose CLAMP study within a 1 - month period, at stable weight and without other interventions. All subjects were in good general health, and none were taking medications known to affect glucose metabolism. Oral antidiabetic drugs were discontinued for 3 weeks before study. Purpose, nature, and potential risks of study were explained before obtaining writing consent from subjects. Study protocols were approved by the Human subject Committee of University of California, San Diego. All subjects were admitted 2 - 3 days before respective study to San Diego Veterans Administration Medical Centers Special Diagnostic and Treatment Unit, and consumed weight - maintenance diet containing 55% carbohydrate, 30% fat, and 15% protein. Studies were performed at 0800 after a 12 - h overnight fast. Standard 3 - h 75 - G OGTT was perform. Blood samples were collected at 0 30 60 90 120, and 180 min for measurement of plasma glucose and Insulin. Hyperinsulinemic - euglycemic glucose clamps were performed as described previously. Loading dose of Insulin was administered in a logarithmically decreasing manner over a 10 - min period, followed by a constant infusion rate of 120 mU min 1 M 2 for the next 240 min. In subjects with IGT, CLAMP studies were conducted at an Insulin infusion rate of 300 mU min 1 M 2. During CLAMP, serum glucose concentration was maintained at 90 5 mg / dL by monitoring glucose levels at 5 - min intervals and by adjusting the infusion rate of 20% glucose solution. The present OGTT method for assessing Insulin sensitivity is based on an equation that predicts glucose clearance during hyperinsulinemic - euglycemic CLAMP using values of glucose and Insulin concentration obtained from OGTT. The equation is derived from the model of glucose - Insulin relationship, which although simplify, is based on established principles of glucose kinetics and Insulin action. Model - derive Equation requires knowledge of parameters that cannot be directly calculated from OGTT. To circumvent the problem, we have introduced some assumptions and have determined unknown parameters by matching OGTT - predict glucose clearance with glucose clearance calculated from CLAMP. The outline of the modeling analysis is shown in Fig. 1. We assume that the relationship between glucose clearance and Insulin concentration is a linear relationship where Cl B is basal glucose clearance, I is increment over basal of Insulin concentration, and S is slope of line.


INSULIN SENSITIVITY AND RESISTANCE

Insulin resistance is defined as a clinical condition where cells fail to respond normally to exogenous or endogenous Insulin to increase glucose uptake and utilization as a consequence of impaired sensitivity to Insulin mediated by glucose disposal. In the majority of cases, this pathophysiological abnormality is related to several abnormalities and clinical syndromes. Nevertheless, it is important to distinguish between the role of Insulin resistance versus compensatory hyperinsulinemia, which is a mechanism to maintain normal blood glucose levels in response to peripheral Insulin resistance in muscle and adipose tissue. Hence, some subjects with Insulin resistance syndrome have more risk of developing diabetes because they lose capacity to secrete Insulin due to Insulin resistance, and if hyperinsulinemia continue, metabolic abnormalities increase the risk of onset of cardiovascular disease and NAFLD. Insulin resistance can be evaluated using several methods: euglycemic hyperinsulinemic clamp, which is the gold standard, and alternative methods such as mathematical models, including homeostasis model assessment of Insulin resistance and Quantitative Insulin Sensitivity Check Index. Scientific evidence points out that oxidative stress influences Insulin Sensitivity adversely by impairing glucose tolerance or increasing Insulin resistance. This state contributes to maintaining an oxidative environment that plays a critical role in the development of hepatic steatosis. Hence, low whole - body Insulin Sensitivity could be involved in progression from fatty liver to NASH. The prevalence of diabetes associated with NAFLD is 22. 5%, and it is 43. 6% in NASH. Generally, subjects with NAFLD are obese and present high abdominal fat, which is characterized by a decrease in Insulin Sensitivity and high levels of inflammatory and oxidative markers. Moreover, this state is more severe in subjects diagnosed with NASH than in individuals with FL. Supporting this last statement, study evaluated 32 subjects diagnosed with NAFLD by liver biopsy with Insulin resistance and without, and showed that subjects with Insulin resistance exhibit significantly higher levels of malondialdehyde in tissue and enhanced degree of steatosis and necroinflammatory grades compared to those without Insulin resistance. Furthermore, MDA levels increase the risk of developing NASH. In this context, Insulin resistance in NAFLD promotes hepatic necroinflammation and disease progression. In line with this, Gholam et al. Find that severely obese subjects with NASH present serious Insulin resistance in comparison to those only diagnosed with steatosis. Moreover, Videla et al. Indicate close association between oxidative stress and Insulin resistance in NAFLD, showing that dysregulation of ROS system and FFAs promotes impairment of tyrosine phosphorylation of Insulin receptor substrate proteins, leading to decrease of Insulin signaling pathway and inducing initial state of Insulin resistance in steatosis. Researchers suggest that Insulin resistance in NAFLD might be associated with overwhelmed intrahepatic and intramyocellular lipid content and / or depletion of liver n - 3 polyunsaturated fatty acids, which are involved as regulators in lipid metabolism.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Fasting blood glucose test

Table

ResultA1C
Normalless than 5.7%
Prediabetes5.7% to 6.4%
Diabetes6.5% or higher

The Oral glucose tolerance test is a simple test widely used in clinical practice to diagnose glucose intolerance and type 2 diabetes. After overnight fast, blood samples for determination of glucose and Insulin concentrations are taken at 0 30 60, and 120 min following standard oral glucose load. Oral glucose tolerance reflects the efficiency of the body at dispose of glucose after oral glucose load or meal. Ogtt mimics glucose and Insulin dynamics of physiological conditions more closely than conditions of glucose Clamp, IST, or FSIVGTT. However, it is important to recognize that glucose tolerance and Insulin sensitivity are not equivalent concepts. In addition to the metabolic actions of Insulin, Insulin secretion, incretin effects, and other factors contribute importantly to glucose tolerance. Thus, OGTT and meal tolerance tests provide useful information about glucose tolerance but not Insulin sensitivity / Resistance per se. The use of tracers for estimation of Insulin sensitivity was first introduced in 1986 to overcome shortcomings of FSIVGTT minimal model method does not allow segregation of glucose production from the liver from exogenously administered glucose during calculations of Insulin sensitivity and thus induces errors in Insulin sensitivity calculations. Label intravenous glucose can be differentiated from endogenously produced glucose and thus use of labeled glucose during IVGTT provides more precise and accurate measurements. Similarly, labelled glucose has been used in oral glucose tolerance tests and Insulin sensitivity has been calculated by minimal model technique similar to FSIVGTT. There is a strong correlation between Insulin sensitivity calculated from label oral minimal model with Insulin sensitivity calculated from gold standard euglycemic hyperinsulinemic Clamp, r = 0. 7, p < 0. 001. There are dual tracer and triple tracer methods as well to estimate hepatic / endogenous glucose production and discussion of these methods is beyond the scope of this review. The Basal hepatic Insulin Resistance index can then be estimated as a product of HGP rate and fasting plasma Insulin concentration. Use of tracer definitely allows for improvement over FSIVGTT. Use of labeled oral glucose allows for more precise measurements of Insulin sensitivity and glucose disposal from simple OGTT and this can be a useful tool in large studies. The triple tracer method is cumbersome and cannot be employed in large studies.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

Table2

ResultFasting Plasma Glucose (FPG)
Normalless than 100 mg/dl
Prediabetes100 mg/dl to 125 mg/dl
Diabetes126 mg/dl or higher

Table3

ResultOral Glucose Tolerance Test (OGTT)
Normalless than 140 mg/dl
Prediabetes140 mg/dl to 199 mg/dl
Diabetes200 mg/dl or higher
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When you should get tested

This test measures the amount of insulin in your blood. Insulin is a hormone that helps move blood sugar, know as Glucose, from your bloodstream into your cells. Glucose comes from foods you eat and drink. It is your body's main source of energy. Insulin plays a key role in keeping glucose at the right levels. If glucose levels are too high or too low, it can cause serious health problems. Glucose levels that are not normal are known as: hyperglycemia, blood glucose levels that are too high. It happens when your body doesn't make enough insulin. If there's not enough insulin, glucose can't get into your cells. It stays in the bloodstream instead. Hypoglycemia, blood glucose levels that are too low. If your body sends too much insulin into the blood, too much glucose will go into your cells. This leaves less in the bloodstream. Diabetes is the most common cause of abnormal glucose levels. There are two types of diabetes. Type 1 Diabetes. If you have Type 1 Diabetes, your body makes little or no insulin at all. This can cause hyperglycemia. Type 2 Diabetes. If you have Type 2 Diabetes, your body may still be able to make insulin, but cells in your body don't respond well to insulin and can't easily take up enough glucose from your blood. This is called insulin resistance. Insulin resistance often develops before Type 2 Diabetes. At first, insulin resistance causes the body to make extra insulin, to make up for ineffective insulin. Extra insulin in the bloodstream can cause hypoglycemia. But insulin resistance tends to get worse over time. Eventually, it decreases your body's ability to make insulin. As insulin levels drop, blood sugar levels rise. If levels don't return to normal, you may get Type 2 Diabetes. Other names: fasting insulin, insulin serum, total and free insulin

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

What Is Insulin Resistance?

Insulin Resistance is a metabolic condition that causes body cells to require higher than normal amount of Insulin to convert glucose into energy. Besides having predisposition to Diabetes, Insulin - resistant people may have other health issues, too, including high blood pressure, high cholesterol, heart disease, and polycystic ovarian Syndrome, leading cause of infertility issues. When a person becomes resistant, they need much more Insulin to do the same work, explains Dr. Yehuda Handelsman, president of the American Association of Clinical Endocrinologists and Los Angeles - base endocrinologist. What happens is that when the body recognizes there is resistance, pancreas responds with higher Insulin levels. As long as the pancreas can respond with higher and higher insulin levels, person will not have Diabetes. Handelsman goes on to explain that up to 40 percent of people with Insulin Resistance also have defect in their Insulin - producing beta cells that prevent the pancreas from producing Insulin beyond certain level of demand. This Insulin max is different for every affected individual, but ultimately, the individual pancreas reaches its maximum Insulin output and then starts to burn out. Over time, those affected will need medications, including inject or infuse Insulin, to cope with the problem of excess glucose in the bloodstream. Insulin Resistance researchers have learnt that increased amount of fatty acids and inflammation from obesity causes cells to require more Insulin to do the same job. Losing weight and increasing activity can mitigate this, but genetic predisposition to Insulin Resistance is beyond a person's control. Before we begin to dwell on obesity as the principal cause of resistance, metabolism throw us a curve in that some Insulin - resistant people are thin. Doctors theorize that genetic beta cell defect predisposition is much higher in this group. In addition, some thin people are what is colloquially called skinny fat, meaning that although they may look thin on the outside, their body actually has a high percentage of body fat compared to muscle. Fat can be hidden in areas like muscle tissue and deep in the abdomen. This fat is called visceral fat, which is harder to see and more damaging than fat directly under the skin. High body fat ratio leads to Insulin Resistance, even if the BMI scale puts them below 30, number at which obesity begin.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Introduction

Measurement of Insulin sensitivity is often of interest in clinical investigation of diabetes and hypertension because of its key role in these diseases. Hyperinsulinemic - euglycemic Glucose CLAMP, which is reference method for Insulin sensitivity, has been used successfully in a large number of studies. The CLAMP technique is experimentally demanding and costly. As research on Insulin sensitivity has progressed from case - control studies to larger cross - sectional or longitudinal studies, CLAMP has proven to be an impractical tool and therefore rather limited in scope. Alternative methods applicable to large studies have been propose. Among these, intravenous Glucose Tolerance Test with minimal model analysis requires simpler experimental setup; however, its application to large number of subjects is problematic because of the necessity of frequent blood sampling and modeling analysis. Method easily applied is homeostasis model assessment, which requires only basal Glucose and Insulin samples, but its accuracy is not fully demonstrate. The test widely used for Glucose Tolerance classification is the Oral Glucose Tolerance Test. Ogtt, which for its simplicity would be a method suitable for large studies, provides information on Insulin secretion and action but does not directly yield measure of Insulin sensitivity. Indeed, various attempts have been made to obtain such measure, and recently, two methods have been proposed and successfully tested against CLAMP. In contrast to these approaches, which are based on empirical formulas, in this study we propose a method based on the physiological Glucose - Insulin model. Our method provides an index of Insulin sensitivity calculated using model - derive formula from OGTT Glucose and Insulin concentration. This index is comparable with Glucose clearance calculated during CLAMP and is validated against the CLAMP method in a population of lean and obese subjects, subjects with impaired Glucose Tolerance, and subjects with type 2 diabetes.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Research Design and Methods

Minipigs are being used increasingly in Metabolic Research, underlining the necessity of valid methods to evaluate Insulin sensitivity in this species. Hyperinsulinemic, isoglycemic or euglycemic Clamp is considered the gold standard for evaluation of Insulin sensitivity in humans and presumably also in animal models. However, because of the laboriousness of this test, several attempts have been made to introduce and validate new and simpler methods to assess Insulin sensitivity in humans from both fasting measurements and dynamic tests. Some of the most extensively used alternative indexes are IVGTT - derive S I from minimal model and OGTT - derive ISI comp and OGIS, but indexes from ITT have also been exploit. All of these indexes have been shown to correlate significantly with Clamp measures in humans. In addition to evaluation of already existing methods, in this study new and simple IVGTT - derive Insulin sensitivity index, S2, was introduced and validated vs. Gold standard glucose Clamp and other previously described indexes from OGTT, IVGTT, and mITT in Gottingen minipigs. The Propose S2 index in minipigs is based on the same assumptions of the IVGTT - derive Insulin sensitivity index described in humans and in mice. Time period of 5 - 30 min used to calculate K G was chosen because this period avoids the initial mixing phase of glucose and corresponds to a period with Log - linear fall in plasma glucose in these pigs. To calculate S2, K G was divided by AUC Insulin in interval from 0 to 30 min to take into account possible delay in Insulin action. Distribution volume, Vd, was included to obtain measure totally comparable to Clamp - derive Insulin sensitivity in terms of measurement units. S2 significantly correlates with Clamp - derive M / GI, indicating its reliability for evaluation of Insulin sensitivity in pigs. Further support of validity of this index was obtained since, as expect, lower Insulin sensitivity was found in pigs on HED compared with pigs on lead, with both the S2 index and M / GI index. In addition, reproducibility of S2 was satisfactory, being in the same range as that of IVGTT - derive indexes of Insulin sensitivity in humans. When compared with other widely used indexes from OGTT, IVGTT, and mITT, S2 also correlates significantly with S I, ISI comp, OGIS, and ISI ITT, but not with QUICKI. Surprisingly, none of the other indexes correlate significantly with Clamp Insulin sensitivity. This may be due to inherent differences between various tests or to existing differences between tests in pigs and humans. Glucose Clamp quantifies Insulin effect under experimental steady - state conditions and thus does not take into account delay in Insulin action. Depending on Insulin concentration, hepatic glucose production is inhibited to varying degree;s when Insulin reaches high concentration levels, primarily peripheral Insulin sensitivity is estimate.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Discussion

Insulin Resistance is often present in multiple tissues long before onset of overt clinical disorders such as Type 2 Diabetes mellitus and cardio - vascular diseases. Abdul - Ghani et al. 19 propose score to quantify muscle - specific Insulin Sensitivity using five time point OGTT data which was validated against hyperinsulinemic - euglycaemic Clamp combined with Glucose tracer Infusion. Several studies have failed to reproduce correlation between MISI and Clamp report in original Study 20 21 22; these lower correlations are typically attributed to reduced heterogeneity in population composition. Analysis of correlations obtained for MISI computed on randomly selected sub - populations from the PRESERVE Study, relatively homogenous population with respect to BMI and Glucose Tolerance status when compared to original Study Population 19, with Clamp ssGIR highlighting the range of correlation coefficients which could be obtained through small variations in Population composition. The correlation for standard MISI computed on five time point OGTT data with Clamp ssGIR for whole data was 0. 513, which is considerably lower than 0. 79 reported in the original study, but is comparable with values achieved by other studies in 20 21 22. Our proposed modified MISI method yields improved correlation with Clamp of 0. 576. While the increase in correlation is non - significant, modified method is also numerically more robust than the original method. Application of the original Index to standard five time point OGTT would be expected to under - estimate glucose peak and nadir, As demonstrated in Fig. 1b. Use of cubic splining in our modified MISI method allows for inference of Glucose peak and nadir while also correcting for unequal sampling intervals when calculating mean Insulin concentration. Spearman rank base correlation was used as the relationship between Clamp ssGIR and MISI was observed to be Non - linear. While the hyperinsulinemic - euglycaemic Clamp performed during the PRESERVE Study was not combined with Glucose tracer Infusion, As Insulin Infusion rate was the same as in Abdul - Ghanis original paper 19, we assume this is sufficient to fully suppress endogenous Glucose production. We also acknowledge the need to further validate our modified MISI method, as well as the original Index, on a range of heterogeneous populations. The Composition of PRESERVE Study Population, consisting only of individuals with impaired fasting Glucose and / or impaired Glucose Tolerance, may limit the generalisability of our results. The Comparison of MISI computed on five versus seven time point OGTT data highlights several, previously unreported, situations in which numerical value obtained when automating calculation of MISI may not be biologically relevant. Abdul - Ghani addresses issues with glucose curves with a peak at 120, advising score not be apply to individuals with Type 2 Diabetes mellitus 19. Our analysis also reveals several additional, potentially problematic, curves requiring manual inspection; namely flat Glucose curves, which may arise from failure to capture rapid response to oral Glucose bolus due to infrequent sampling, and curves, where due to erroneous identification of nadir, Glucose rebound may not be negligible.


Subjects and Methods

The Glucose Clamp procedure was performed as earlier described and validated in detail. 7 14 To arterialize venous blood, right forearm was placed in heating sleeve with temperature set at 52C. Subjects rested supine for 20 minutes in the presence of an examining physician before baseline Blood Pressure and heart rate recordings and baseline blood sampling were undertake. Insulin was infused at a fixed rate of 1 mU / kg body wt per minute. Patients ' fasting glucose level was determined 20 minutes after the heating sleeve was adapted as average of 3 bedside measurements. Clamp procedure was performed for 2 hours, with Glucose infusion during the last 60 minutes used as basis for calculations of insulin sensitivity. Glucose disposal rate expresses milligrams of Glucose disposed per kilogram of body weight per minute in response to standardized hyperinsulinemic stimuli; thus, insulin - sensitive subjects have higher GDR than insulin - resistant subjects. This technique for measuring insulin sensitivity has a coefficient of variation of 5% in our laboratory. 7 14 we perform hyperinsulinemic, isoglycemic Glucose Clamp procedure. 14 This involves clamping Glucose at fasting level and not at a predetermined level. By using euglycemic Clamp, one would tend to underestimate insulin sensitivity in patients with elevated fasting Glucose. Second, in patients with elevated fasting Glucose, one would have to lower Glucose levels with subsequent risk of hypoglycemic counterregulation, including hepatic Glucose production and activation of the sympathetic nervous system. Insulin levels during our Clamp procedure 7 13 are found to be sufficient to suppress hepatic Glucose production in subjects with normal body weight and normal fasting Glucose.


INTRODUCTION

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.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Background

During the past few years, it has been established that pre - diabetic conditions of isolated impaired fasting glycemia, isolated impaired glucose tolerance, and combined fasting and postchallenge hyperglycemia represent distinct pathways to Diabetes. These pre - diabetic states are characterized by different degrees of insulin sensitivity, insulin secretion, and hepatic glucose output as well as secretion of glucagon and incretin hormones. Nevertheless, primary abnormalities inherent in different pre - diabetic conditions are still unknown. Randomize trials have shown beneficial effects of lifestyle intervention on Diabetes risk in individuals with I - IGT and IFG / IGT, but whether lifestyle interventions have the same preventive effects in individuals with I - IFG is not know. Indeed, more profound insight into pathogenesis of disease is needed to optimize prevention and treatment of Type 2 Diabetes. In particular, focus on initial defects responsible for hyperglycemia in fasting and postprandial states is essential for interrupting progression from normal to abnormal glucose metabolism. Most previous studies have examined pathophysiology of pre - Diabetes in cross - sectional settings without knowing time of onset of glycemic abnormalities. However, observed abnormalities in pre - Diabetes may be related to traits already apparent in normoglycemic state. Prospective studies are therefore needed to clarify whether this is the case or whether metabolic abnormalities associated with I - IFG, I - IGT, and IFG / IGT develop simultaneously with increases in fasting and / or postchallenge plasma glucose levels. The aim of this study was to describe the natural history of insulin sensitivity and insulin secretion during progression from normal glucose tolerance to pre - diabetic states of I - IFG, I - IGT, and combined IFG / IGT.


RESEARCH DESIGN AND METHODS

Recruitment advertisements were placed at local institutions and on the Sport Science Institute of South Africa website. Subjects were screened and subsequently placed into four groups. Successful weight reduction has been defined as weight loss of 10%, maintained for over 12 months with weight fluctuations of 3% considered acceptable. 30 31 During recruitment, it was stipulated that previous weight loss had to be intentional / deliberate, without use of unregulated products, lifestyle - related approach, unrelated to stress and / or anxiety and free of eating pathology. Base on these criteria, successfully reduce individuals were recruit, having previously lost 15% of their body weight from BMI 27 kg M 2 and maintained this for over 12 months with a 5% fluctuation from goal BW over the previous 12 months. Age - match, stable low - weight controls were recruited with a BMI of 27 kg M 2, but with no prior weight loss history. Weight - relapse individuals were recruited with a BMI of 27 kg M 2, having previously lost 15% of their BW, but subsequently regained all of this weight. Age - match, overweight and obese stable weight controls were then recruited with BMI of 27 kg M 2 but no weight - loss history. Sample size was determined from a study that compared lean participants with weight - reduce and obese individuals, indicating sample size of nine participants per group would be required to detect significant differences in fasting Insulin at significance of 0. 05 and power of 0. 80. 32 participants were female, aged between 20 and 45 years. Old Exclusion criteria cover being pregnant or lactating, irregular menstrual cycles, diagnosis of chronic medical condition and / or condition requiring chronic medication known to affect metabolic rate, finger - prick fasting blood glucose exceeding 7. 0 mmol l 1 for screening, medication or Supplementary Appendix for weight loss, diagnosis of thyroid dysfunction or diagnosis of eating condition. Study protocol was approved by the University of Cape Town Faculty of Health Science and Human Research Ethics Committee. Before testing, all participants were given full information of test procedures, signed informed consent forms and were at liberty to withdraw at any time.


RESULTS

Table 2 shows that OSW consumes significantly more energy than LSW and RED, but when adjusted for BW, this was not significantly different. Lsw consumes more carbohydrates and less fat than the other three groups, although only significant between LSW and OSW. There were no significant differences in sedentary, light and moderate activity. Red engaged in more vigorous activity compared with the other three groups, but this was only significant between RED and OSW. In terms of overall fitness, LSW had higher maximal oxygen consumption compared with OSW and RED was higher than both OSW and REL, whereas two lean groups were not different. There were no differences in RMR or substrate utilization between groups. Results of the 75 g oral glucose tolerance test show that although blood glucose levels are largely comparable across all groups, RED has significantly lower fasting and 2 h insulin levels compared with all other groups. Eight individuals recorded fasting PG 7. 0 mmol l 1, diagnostic criteria for T2DM, despite having previously had fasting blood glucose levels < 7. 0 mmol l 1 at screening. Of these, two subsequently recorded 2hr PG levels 11. 1 mmol l 1, which is diagnostic criterion for T2DM. Removing these individuals from analysis does not alter results significantly. Red were significantly more insulin sensitive than all other groups. This was shown using fasting values and determining insulin sensitivity as measured by HOMA - IR. Rel was not different to either LSW or OSW. Lsw - CTL had lower HOMA - IR values compared with OSW, whereas both OSW and REL were not different. The same result was shown in Figure 1b using both fasting and two hour values as determined by ISI. Lsw was more insulin sensitive compared with both overweight groups, whereas REL and OSW were not different on either measure. The total sample was analyse to identify significant associations of variables against both log HOMA and ISI. Regression models were able to predict 61. 4% and 59. 7% of variability in log HOMA - IR and log ISI, respectively, in this sample. Using - coefficients, strongest predictors in Model 1 were% BW lose followed by% BW regain and RQ ratio, whereas for Model 2,% BW lose,% BW regain and RQ ratio, respectively. Light activity contributed to Model 1 but was not a strong predictor in Model 2 and for Model 2, waist - to - hip ratio was a stronger predictor than% body fat. Removing two individuals who exceed diagnostic criteria for T2DM from analysis does not significantly alter these results. Applying report mean or median values for these predictors into fitted Model equation, reduction in predicted HOMA - IR of 15% could be achieved for this sample through 4. 5% reduction in BW, 55 min per day increase in light activity or 5 min per day increase in vigorous activity, holding all other variables constant.


Insulin Sensitivity

Insulin levels can also be used to assess Insulin resistance versus sensitivity. In Insulin resistance, ability of cells to respond to action of Insulin in transporting glucose into tissues is diminish; consequently, resistant individual begins secreting above - normal amounts of Insulin to obtain a quantitatively normal response. Insulin resistance develops long before the appearance of disease signs. A study by Kraft found borderline diabetes in 14% of subjects with normal oral glucose tolerance tests who had been randomly referred for such evaluation. There are multiple methods available to assess Insulin resistance, including the following: each of these methods has its own limitations. Lack of standardization of Insulin assay procedures prevents comparison of results between studies; as result, studies can be compared only qualitatively. The American Diabetes Association organized a task force to standardize Insulin assays. Homa equations have been one of the tools widely used in research to estimate Insulin resistance. Two equations are as follow, with HOMA - IR used to assess Insulin resistance and HOMA - B used to assess pancreatic beta - cell function: fasting Insulin levels can serve as a tool to help guide choice of therapy in patients newly diagnosed with type 2 Diabetes. A study by Saxena et al found that such patients with normal to low initial fasting serum Insulin levels respond better to glipizide than to metformin. On the other hand, those with high fasting serum Insulin levels respond significantly better to metformin than to glipizide.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Lab Studies

Insulin resistance is an important risk factor for Type 2 Diabetes and cardiovascular disease. There is increasing evidence supporting the fact that by time glucose tolerance or fasting glucose levels become impaired, appreciable - cell destruction may have already occur. Thus, it seems likely that attempts to prevent Type 2 Diabetes will be more successful if intervention is commenced when blood glucose levels are still in normal range. Therefore, simple test for identifying insulin - resistant individuals is important both for population - base research and clinical practice. Euglycemic insulin clamp and intravenous glucose tolerance test are standard methods for measurement of insulin resistance in research, but they are impractical in clinical practice and are difficult to perform in population - base research studies. Fasting insulin, homeostasis model assessment, insulin - to - glucose ratio, and Bennett index are all used to predict insulin sensitivity; and several other individual variables, such as family history of Diabetes, BMI, blood pressure, waist and hip circumference, fasting triglycerides, HDL, glucose, insulin, and hepatic enzymes, are known to correlate with insulin resistance. Combinations of variables used to predict insulin resistance have been assessed in a small number of studies, and most studies have assessed prediction in individuals with impaired glucose tolerance and Diabetes. Few studies have specifically evaluated prediction of insulin resistance in significant number of individuals with normal glucose tolerance. We have compared standard techniques, several individual variables, and scores based on weighted combination of select variables with euglycemic insulin clamp to evaluate the best method of predicting insulin resistance in normoglycemic individuals.


RESEARCH DESIGN AND METHODS

Participants were recruited by voluntary participation through advertising among hospital staff and personnel. Sample selection was performed using a random sampling method. After clinical screening, only healthy subjects with inclusion criteria were randomized into study. A total of 65 subjects, 44 men and 21 women aged 30 - 60 years, were study. Following inclusion criteria were used in this study: normal Glucose metabolism, fasting plasma triglyceride level < 2. 25 mmol / l, and general analytical evaluation within normal limits. All subjects were nonsmokers and were not taking any medications. Alcohol consumption was < 35 g per day. Body weight and physical activity habits had been stable for 3 months preceding study. Following exclusion criteria were used in this study: age outside the range of 30 - 60 years, consumption of hypocaloric diet, or weight gain or loss > 10% in 3 months preceding study. Other exclusion criteria include hypothyroidism; liver, kidney, or heart failure; and neoplasia. Clinical history was obtained from all subjects, including age, sex, personal medical history, intake of drugs, smoking and alcohol consumption, levels of physical exercise, previous history of high blood pressure or diabetes, and symptoms of coronary heart disease, ischemic stroke, or peripheral vascular disease. Family history of high blood pressure, diabetes, coronary heart disease, or dyslipidemia was also ascertain. In all participants, blood pressure was measured after a 10 - min rest period, and readings were recorded at 5 - min intervals. Body weight and height, BMI, and waist circumference were measured using standard methods. Blood samples were collected after 12 - h overnight fast and deposited in dry tubes with EDTA. The plasma was separated immediately using refrigerated centrifugation at 2 500 - 3 000 rpm for a period of 10 min. Samples were processed either immediately or during the first week after conservation at 20C. As previously describe, plasma total cholesterol, triglyceride, free fatty acid, and glucose levels were determined using enzymatic methods; HDL cholesterol was measured after precipitation with polyanions. Apolipoprotein B was determined by immunoturbidimetry and insulin by radioimmunoassay.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Hyperinsulinemic Euglycemic Glucose Clamp

During Clamp, insulin is administered as constant infusion and, therefore, does not reflect variations inherent in endogenous secretion. Moreover, also unlike physiological case, insulin is given peripherally, which reverses the normal gradient between portal and peripheral insulin. Finally, peripheral and hepatic responses to insulin are assumed to occur in parallel, which, based on known dose responses, is not likely to occur. Nevertheless, because glycemia is kept constant, Ginf and, therefore, k depend only on I, and ratio is considered as the most reliable measure of S I. It has been widely applied and provides good discrimination between normal subjects and those with insulin resistance.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Sources

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

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