0021-972X/91/7304-0691/0 Journal of Clinical Endocrinology and Metabolism Copyright (p) 1991 by The Endocrine Society
Vol. 73, No. 4 Printed in U.S.A.
CLINICAL REVIEW 26 Insulin Resistance in Obese and Nonobese Man JOSfi F. CARO Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, School of Medicine, East Carolina University, Greenville, North Carolina 27858
O
BESITY is usually a descriptive term for excess body fat. Assessment of the presence and extent of obesity is often subjective and influenced by cosmetic and cultural considerations. However, recent interest has focused on the increased mortality and morbidity associated with both the extent and pattern of obesity (1, 2).1 Therefore, methods for accurate measurement of the amount and distribution of fat have become an important clinical consideration. The cause of the increased mortality and morbidity associated with obesity is not yet known. Obesity is associated with an increased incidence of diabetes, hypertension, increased levels of very low density lipoproteins (VLDL) triglycerides, low density lipoproteins (LDL) cholesterol, and decreased levels of high density lipoproteins (HDL) cholesterol, all of which are risk factors for the development of vascular disease. Whereas it has been known for many years that obesity is associated with insulin resistance, Reaven (3) has recently pointed out that approximately 20% of a nonobese population are equally as insulin resistant as obese subjects. Furthermore, since this group of relatively lean, insulinresistant subjects [referred to as "syndrome X" by Reaven (3) and as the "metabolically-obese, normalweight individual" by Ruderman (4)] have the same metabolic profile of increased risk factors present in obesity, it is tempting to speculate that insulin resistance is the common pathway leading to these metabolic derangements (Fig. 1). Since normal-weight, insulin-resistant, and obese subjects might develop metabolic consequences through this common pathway, it is also worth considering the possibility that the metabolically obese, normal-weight individual represents a genetically determined preobese state that together with environmental
factors (diet, exercise, etc.), results in obesity. From this discussion it is apparent that insulin resistance and obesity is not only one of the most common metabolic disorders, but also one of the most serious. It is therefore important from the clinical perspective to address the following questions: 1) What is obesity and how should it be measured?, 2) What is insulin resistance and how should it be measured?, and 3) What is the mechanism(s) of insulin resistance in obese and nonobese man? What is obesity and how should it be measured? The National Institutes of Health Consensus Development Panel (1) concluded in 1985 that "the evidence is now overwhelming that obesity, defined as excessive storage of energy in the form of fat, has adverse effects on health and longevity. Obesity is clearly associated with hypertension, hypercholesterolemia, noninsulin dependent diabetes mellitus, and excess of certain cancers and other medical problems. Thirty-four million adult Americans have a body mass index (BMI) greater than 27.8 (man) or 27.3 (woman); at this level of obesity, which is very close to a weight increase of 20 percent above desirable, treatment is strongly advised. When diabetes, hypertension, or a family history of these diseases is present, treatment will lead to benefits even when a lesser degree of obesity is present." Thus, obesity is the most common disorder of metabolism in man in the Western world and the associated morbidity and mortality are well established. The difficulty, however, is that body fat content is difficult to measure in a clinical setting and that by definition obesity exists when adipose tissue makes up a greater than "normal" fraction of total body weight. In male subjects, aged 18, approximately 15-18% of body weight is fat and in females, 20-25%. The percentage of body weight that is fat usually increases with age although this may not be necessary or desirable (2). Obesity has been defined as a body fat content greater than 25% of total body
Received September 18,1990. Address requests for reprints to: Dr. Jose Caro, Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, East Carolina University, Greenville, North Carolina 27858. This work was supported by NIH Grant DK-3629. 1 Space limitations have prevented citation of all of the available literature. A representative sample is included in this review.
691
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CARO
692
weight for men and greater than 30% for women. There are several laboratory methods that can determine the percent body fat with high accuracy, such as underwater weighing, 40K counting, total body water, and others (2). However, these methods are expensive and difficult to use and therefore impractical for day-to-day use. There is a portable device that measures body impedance by resistance to an electrical current applied through electrodes placed on the patient's hand and foot. The resistance is inversely proportional to total body water and it has been shown to correlate well with other laboratory methods (2). Thus, bioelectrical impedance appears to be the first portable, easy to use, and reproducible method for determining body composition outside the laboratory. Body fat content can also be estimated by measurement of skinfold thickness but this method is time consuming and often imprecise. The most simple and commonly used anthropometric measurements are weight and height. The weight of the person is compared with a table of standard weights published by the Metropolitan Life Insurance Company based on the weight associated with the lowest mortality at any given height. Also with the weight and height of the person, the BMI can be calculated as the weight in kilograms divided by the height in meters2. Several epidemiological studies have suggested that mortality begins to increase substantially at a weight of 20% greater than desirable which corresponds roughly to a BMI of 27 kg/m2. Accordingly, obesity may be defined as a weight greater than 20% of "desirable" or a BMI greater than 27 kg/m2 (1, 2). However, the Metropolitan Life Insurance table and the BMI provide a measure of obesity that may or may not correlate with body fat. For example, a heavily muscled athlete will have high values using either of these indices but a low fat content with none of the metabolic characteristics of obesity. Similarly, a sedentary individual may not be overweight but have decreased lean body mass and have the metabolic characteristics of an overweight, obese individual. It is in these special cases where the concomitant estimation of body composition by bioelectrical impedance will have the greatest use since it is clear that in some cases body weight cannot be equated Genetic Defect +/— Environmental Factors
Common Pathway
Insulin Resistance
Metabolic Consequences
LDL HDL VLDL BP
FIG. 1. Insulin resistance in obese and lean man.
4 • • 4
Pathology
Vascular Disease
JCE & M • 1991 Vol73«No4
with fatness. These issues are further complicated by the recent recognition that the pattern of distribution of adipose tissue throughout the body affects metabolic consequences and may be a more important factor than total adipose tissue mass. As demonstrated by Kissebah et al. (2) a person with fat located predominantly in the abdominal region may be at greater risk of insulin resistance, hypertension, heart disease, and diabetes than another individual with a greater total amount of adipose tissue that is located predominantly in the gluteal area. Therefore, the simple measurement of body circumferences with a tape and calculation of the ratio of the measurement of the abdomen or waist at the smallest circumference below the rib cage and above the umbilicus to the gluteal region or hip at the largest circumference at the posterior extension of the buttocks [waist to hip ratio (WHR)] has important prognostic implications since a ratio greater than 0.9 in males and 0.8 in females is associated with increased risk of stroke and ischemic heart disease (2). In summary, obesity is a serious disease and useful information can be obtained with accurate measurement of weight, height, and body circumferences. The Metropolitan Life Insurance tables and the nomograms developed by Bray (2) for determination of BMI and WHR are useful materials for the assignment of these vital and inexpensive parameters. For more specialized clinical settings or in cases where the body weight does not correlate with the metabolic parameters, estimation of body composition by bioelectrical impedance will aid in the accurate diagnosis of obesity. What is insulin resistance and how should it be measured? Insulin resistance is a metabolic state in which physiological concentrations of insulin produce a less than normal biological response. Since the description by Himsworth in 1936 that human disease could be associated with insulin resistance, several methods have been developed to estimate in vivo insulin action and insulin resistance in man (3, 5). In the research setting the most widely used methods at present are the glucose clamp and the minimal model. The glucose clamp developed by DeFronzo, Tobin, and Andres involves a constant insulin infusion while maintaining euglycemia by infusing a variable amount of glucose. The glucose infusion rate provides a quantitative assessment of the biological effect of insulin. This method is purely investigative and not suitable for a clinical setting. The minimal model developed by Bergman (5) could be used in a highly specialized clinical setting. An iv glucose injection is followed by frequent determinations of plasma glucose and insulin. A computer program allows the calculation of the insulin
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CLINICAL REVIEW sensitivity index from the dynamic relationship between the plasma insulin and glucose concentration curves. A method available in most clinical settings is the oral glucose tolerance test. If plasma glucose and insulin concentrations are determined, the ratio of the area under the glucose curve over the area under the insulin curve provides an estimate of insulin sensitivity. Since the fasting plasma glucose concentration depends primarily on the rate of hepatic glucose release, which in turn is regulated by the insulin concentration, one might predict that the fasting plasma glucose/insulin concentration ratio may provide the simplest estimate of insulin resistance. Matthews et al. (6) proposed a computer model (homeostatic model assessment) to estimate insulin sensitivity from the fasting plasma glucose and insulin concentrations. The estimate of insulin sensitivity obtained by use of this model closely correlated with estimates obtained by use of the euglycemic clamp (P < 0.01, n = 12). We have recently observed that the glucose/insulin ratio calculated from single fasting plasma samples correlated with the measurement of insulin sensitivity determined by the euglycemic clamp (P < 0.001, n = 21), the minimal model technique (P < 0.01, n = 78), and the oral glucose tolerance test (P < 0.0001, n = 378). The higher the fasting plasma insulin concentration for a given fasting plasma glucose, the more insulin resistant an individual is. A glucose (mg/dL)/insulin (/iU/mL) ratio lower than 6 is characteristic of subjects with obesity, impaired glucose tolerance, and syndrome X. It should be recognized, however, that even though the glucose/insulin ratio is conceptually sound and technically simple and inexpensive, it also has pitfalls and limitations. First, it cannot be used in patients with defects in insulin secretion such as those with diabetes. Second, it provides indirect information on the feedback loop between the liver and /3-cells but not on the effect of insulin in peripheral tissues. Third, the range over which insulin is measured is small (fasting samples) and the results depend on the precision of the insulin RIA. Finally, the pulsatility of insulin secretion, uncertainty whether proinsulin is being measured as insulin, and the effects of stress could affect interpretation of assay results. Which patients might benefit from a clinical evaluation of insulin resistance? Clearly, the indication for this evaluation, if any, is not yet established since it is only recently that an explosion of publications have described the relationship between hyperinsulinemia, hypertension, and coronary artery disease. If the patient is obese, it can be assumed with a high degree of certainty that this patient is insulin resistant and, therefore, laboratory confirmation is not necessary and treatment of the obesity as recommended by the National Institute of Health
693
Consensus Development Panel should be initiated (1). The group of individuals in whom determination of the fasting plasma glucose/insulin ratio might be of value are those normal weight individuals with hypertriglyceridemia, low HDL, high LDL, hypertension, or coronary artery disease. The hypothesis is that syndrome X and obesity, whether genetically determined or acquired, might act through insulin resistance to cause the metabolic abnormalities (Fig. 1). Insulin resistance will result in decreased insulin mediated glucose uptake into peripheral tissues and increased glucose release from the liver, defects that are partially compensated by increased insulin secretion. Insulin resistance will result in decreased catabolism of triglycerides, which by a mechanism not yet well defined, decreases HDL cholesterol concentrations, and increases LDL cholesterol concentrations. Since a partial compensatory response to insulin resistance is hyperinsulinemia and because insulin resistance may not be equally manifested in all insulin sensitive tissues, there may be a relative increase in insulin action in some tissues. For example, in the kidney, insulin is known to promote renal tubular sodium and water absorption and therefore may contribute to the development of hypertension. In the liver, hyperinsulinemia results in increased triglyceride synthesis contributing to hypertriglyceridemia. In vascular smooth muscle, insulin, by interacting with its receptor or the insulin-like growth factor I receptor, might increase endothelial proliferation and contribute to the development of atherosclerosis (7). The diagnosis of insulin resistance in these patient would fully justify the initiation of a diet and exercise program to improve insulin resistance and would also assess the effect of therapy. Since there is a wealth of clinical data demonstrating the benefit of weight loss in obese subjects and of training in middle age sedentary individuals it is not unreasonable to expect that in nonoverweight subjects improvement of insulin resistance will also result in improvement of carbohydrate and lipid metabolism, decreased blood pressure, and therefore lower risk of vascular disease. What is the mechanism of insulin resistance in obese and nonobese man? It is generally accepted that the increased insulin secretion in obesity serves as a mechanism to compensate for insulin resistance. However, the processes that trigger hyperinsulinemia in human obesity and the possible pathophysiological consequences of hyperinsulinemia are not fully identified nor do we know the cellular mechanism of insulin resistance. There are several reasons for these uncertainties. First, in vivo and in vitro studies in human obesity will continue to describe defects
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CARO
of insulin action and secretion but will not likely be able to provide insight into what is the primary defect, if any, responsible for insulin resistance or insulin hypersecretion since the preobese state in man has not yet been identified. For the present, information from the end stage of a syndrome that most likely represents the clinical expression of a collection of genetic diseases will continue to be useful but will not distinguish from primary and secondary defects. Second, we do not know yet what the normal mechanism of insulin action is. Therefore, it becomes particularly difficult to define the processes responsible for insulin resistance. Furthermore, in most tissues, insulin is involved in the metabolism of sugars, lipids, nucleotides, and amino acids with three major sites of metabolic regulation. At the plasma membrane, insulin increases the transport of glucose and other substrates. In the cytoplasm and its organelles, insulin activates a number of intracellular enzymes. In the nucleus, insulin regulates the synthesis of RNA and DNA. Because of this multiplicity of effects, it is unlikely that a single mechanism of action will be discovered for insulin. It is known, however, that the initial interaction of insulin with target cells is with a receptor protein located on the plasma membrane. The insulin receptor plays a critical role both in directing the hormone to a specific target tissue and programming the response of the tissue to the hormone. Accordingly, to investigate the transmembrane signaling mechanisms for insulin, a number of studies in human obesity have focused on this protein. The insulin receptor is a heterotetrameric glycoprotein consisting of two a-subunits and two /?-subunits linked by disulfide bonds to give a /3-«-«-/?-structure. The asubunit is extracellular and contains the insulin binding site. The /3-subunit is an insulin-sensitive protein kinase capable of phosphorylating itself and other substrates on tyrosine residues and its activation is a necessary step in the insulin signaling mechanism for most but not all biological actions of insulin (8). In vitro studies in human obesity have demonstrated tissue-specific impairment of both the a-subunit and /?subunit of the insulin receptor (9). In human liver, the number of insulin receptors is decreased but in each receptor the insulin sensitive tyrosine kinase is normal. In human adipose tissue, the number of insulin receptors is either decreased or normal but there is consensus that the insulin sensitive tyrosine kinase is normal. In human skeletal muscle, there is also general agreement that the number of insulin receptors is decreased but, furthermore, for each receptor the insulin sensitive tyrosine kinase is impaired. These in vitro data demonstrating decreased numbers of insulin receptors in human obesity at least partially explain the diminished insulin action at submaximal concentrations of insulin observed in vivo (3). Furthermore, the additional impairment in the p-
JCE & M • 1991 Vol73-No4
subunit of the insulin receptor in human skeletal muscle is consistent with in vitro data demonstrating that the skeletal muscle is more resistant to insulin than the adipose tissue with regard to glucose transport (9). Recent studies have indicated that a family of structurally related proteins with distinct but overlapping tissue distributions are responsible for facilitative glucose transport in mammalian tissues. Insulin primarily stimulates glucose transport by inducing the redistribution of a unique glucose transporter protein from an intracellular pool to the plasma membrane. This 509 amino acid integral membrane protein, termed GLUT-4, is the major insulin-responsive glucose transporter in adipose and muscle tissues and is therefore likely to play a key role in the mechanism of insulin resistance found in obesity. However, available studies in human obesity have demonstrated only a modest decrease in GLUT-4 in adipose tissue and skeletal muscle that by itself cannot explain the alterations in insulin-stimulated glucose transport, suggesting additional defects in glucose transporter translocation and/or activation possibly related to abnormalities in insulin signaling (9). The contribution that skeletal muscle and adipose tissue make to the peripheral insulin stimulated glucose uptake is currently under debate. It was suggested several years ago that only a small fraction of an iv glucose load could be recovered in the adipose tissue generating the idea that insulin stimulated peripheral glucose use could be equated to skeletal muscle glucose use. However, recent studies (10) have suggested that glucose uptake in human adipose tissue, the majority of which is released as lactate, might well be of significance for total body glucose homeostasis, being about 11% in lean subjects and in obese subjects perhaps amounting for up to onethird to one-half of an oral glucose load. The greater insulin stimulated use of glucose by the adipose tissue in obesity could be due to the expanded adipose tissue mass and perhaps also because the adipose tissue is less resistant to insulin than the skeletal muscle (9). From the preceding discussion it should be apparent that our current understanding of insulin resistance present in obesity is fragmented and inconclusive. Furthermore, much less is known about the insulin resistance in nonobese subjects since no in vitro studies from this population have been reported yet. Ruderman et al. (4) predicted that those individuals with insulin resistance and normal BMI will have increased body fat mass in comparison to individuals matched for age and BMI or in comparison to the patient himself at an earlier time in life. We believe his predictions are correct. Figure 2 shows data from sedentary males 41 ± 4 years of age with BMI between 22 and 26. The lower panel of Fig. 2 demonstrates that within this narrow range of BMI there is no correlation between insulin sensitivity and BMI. However, the upper panel of the same figure demon-
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CLINICAL REVIEW
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Health Consensus Development Panel (1) have been reviewed. Insulin resistance, one of the characteristic metabolic features of obesity, has recently been identified in a subset of normal weight individuals (3, 4). Furthermore, these individuals with insulin resistance also have elevated triglycerides, low HDL cholesterol, high LDL cholesterol, and hypertension and, therefore, metabolically resemble overweight individuals. In fact, the normal-weight, insulin-resistant subjects have increased body fat when compared with insulin sensitive subjects with comparable BMI. If "insulin resistance" turns out to be a "secret killer" as suggested by Foster in a recent editorial (7), practical ways to uncover it in a clinical setting need to be established and alternative methodologies were reviewed. Once insulin resistance is identified, a healthy diet and a well structured exercise program needs to be initiated. Fitness and weight loss improve insulin action and decrease coronary artery disease risk factors in obese man and, therefore, it is reasonable to believe that they would have a similar effect in the insulin-resistant, normal-weight individual. For the individual refractory to these prudent prescriptions a drug is not yet available that improves insulin resistance without the potential of hypoglycemia. A better understanding of the pathogenesis of insulin resistance in these subjects will be required before an effective pharmacological approach can be designed.
o —1
25
B MI FIG. 2. Relationship between the insulin sensitivity index (X1O~4 min"1 n\J ml"1) and BMI (kg/m2) (upper panel) and percent body fat (lower panel).
strates a negative correlation between percent body fat calculated by underwater weighing and insulin sensitivity (Caro, J. F., and G. Israel, unpublished observation). Thus, individuals with an identical BMI may have differing amounts of fat that correlate with the degree of insulin resistance. The implication is that normalweight, insulin-resistant subjects must have a reciprocal decrease in lean body mass; and, since it is known that basal metabolic rate correlates with lean body mass, it is likely that nonobese insulin-resistant subjects will have decreased basal metabolic rate. Also nonobese insulin resistant subjects have an increased pool of energy stored as fat resulting from a positive energy balance at some time in their life. Therefore, it is possible that the nonobese insulin resistant subject might represent the earliest stages of obesity or the elusive preobese state itself.
Conclusions The health implications of obesity, diagnosis, and treatment recommendations by the National Institute of
Acknowledgments Thanks are given to Dr. Peter Butler, Dr. Eugene Furth, and Dr. David Snyder for reviewing and editing the manuscript and Joyce Compton for the typing and preparation of the manuscript.
References 1. National Institute of Health Consensus Development Panel on the health implications of obesity. Consensus Conference Statement. Ann Int Med. 1985;103:1073-1077. 2. Bray GA. Obesity: basic aspects and clinical implications. Med Clin North Am. 1989;73:l-264. 3. Reaven GM. Role of insulin resistance in human disease. Diabetes. 1988;37:1595-1507. 4. Ruderman NB. The "metabolically-obese" normal-weight individual. Am J Clin Nutr. 1981;34:1617-1621. 5. Bergman RN. Toward physiological understanding of glucose intolerance. Minimal model approach. Diabetes. 1989;38:1512-1527. 6. Matthews DR, Hosker JP, Rodenski AS, Naylor BA, Treacher DF, Turner RC. Homeostatic model assessment: insulin resistance and /3-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412-419. 7. Foster DW. Insulin resistance—a secret killer? N Engl J Med. 1989;320:733-734. 8. Kahn CR, White MF. The insulin receptor and the molecular mechanism of insulin action. J Clin Invest. 1988;82:1151-1156. 9. Caro JF, Dohm GL, Pories WJ, Sinha MK. Cellular alteration in liver, skeletal muscle and adipose tissue responsible for insulin resistance in obesity and type II diabetes. Diab/Metab Rev. 1989;5:665-689. 10. Marin P, Ruseffe-Scrive, Smith J, Bjorntorp P. Glucose uptake in human adipose tissue. Metabolism. 1988;36:1154-1164.
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Vol. 73, No. 4 Printed in U.S.A.
CLINICAL REVIEW 26 Insulin Resistance in Obese and Nonobese Man JOSfi F. CARO Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, School of Medicine, East Carolina University, Greenville, North Carolina 27858
O
BESITY is usually a descriptive term for excess body fat. Assessment of the presence and extent of obesity is often subjective and influenced by cosmetic and cultural considerations. However, recent interest has focused on the increased mortality and morbidity associated with both the extent and pattern of obesity (1, 2).1 Therefore, methods for accurate measurement of the amount and distribution of fat have become an important clinical consideration. The cause of the increased mortality and morbidity associated with obesity is not yet known. Obesity is associated with an increased incidence of diabetes, hypertension, increased levels of very low density lipoproteins (VLDL) triglycerides, low density lipoproteins (LDL) cholesterol, and decreased levels of high density lipoproteins (HDL) cholesterol, all of which are risk factors for the development of vascular disease. Whereas it has been known for many years that obesity is associated with insulin resistance, Reaven (3) has recently pointed out that approximately 20% of a nonobese population are equally as insulin resistant as obese subjects. Furthermore, since this group of relatively lean, insulinresistant subjects [referred to as "syndrome X" by Reaven (3) and as the "metabolically-obese, normalweight individual" by Ruderman (4)] have the same metabolic profile of increased risk factors present in obesity, it is tempting to speculate that insulin resistance is the common pathway leading to these metabolic derangements (Fig. 1). Since normal-weight, insulin-resistant, and obese subjects might develop metabolic consequences through this common pathway, it is also worth considering the possibility that the metabolically obese, normal-weight individual represents a genetically determined preobese state that together with environmental
factors (diet, exercise, etc.), results in obesity. From this discussion it is apparent that insulin resistance and obesity is not only one of the most common metabolic disorders, but also one of the most serious. It is therefore important from the clinical perspective to address the following questions: 1) What is obesity and how should it be measured?, 2) What is insulin resistance and how should it be measured?, and 3) What is the mechanism(s) of insulin resistance in obese and nonobese man? What is obesity and how should it be measured? The National Institutes of Health Consensus Development Panel (1) concluded in 1985 that "the evidence is now overwhelming that obesity, defined as excessive storage of energy in the form of fat, has adverse effects on health and longevity. Obesity is clearly associated with hypertension, hypercholesterolemia, noninsulin dependent diabetes mellitus, and excess of certain cancers and other medical problems. Thirty-four million adult Americans have a body mass index (BMI) greater than 27.8 (man) or 27.3 (woman); at this level of obesity, which is very close to a weight increase of 20 percent above desirable, treatment is strongly advised. When diabetes, hypertension, or a family history of these diseases is present, treatment will lead to benefits even when a lesser degree of obesity is present." Thus, obesity is the most common disorder of metabolism in man in the Western world and the associated morbidity and mortality are well established. The difficulty, however, is that body fat content is difficult to measure in a clinical setting and that by definition obesity exists when adipose tissue makes up a greater than "normal" fraction of total body weight. In male subjects, aged 18, approximately 15-18% of body weight is fat and in females, 20-25%. The percentage of body weight that is fat usually increases with age although this may not be necessary or desirable (2). Obesity has been defined as a body fat content greater than 25% of total body
Received September 18,1990. Address requests for reprints to: Dr. Jose Caro, Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, East Carolina University, Greenville, North Carolina 27858. This work was supported by NIH Grant DK-3629. 1 Space limitations have prevented citation of all of the available literature. A representative sample is included in this review.
691
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CARO
692
weight for men and greater than 30% for women. There are several laboratory methods that can determine the percent body fat with high accuracy, such as underwater weighing, 40K counting, total body water, and others (2). However, these methods are expensive and difficult to use and therefore impractical for day-to-day use. There is a portable device that measures body impedance by resistance to an electrical current applied through electrodes placed on the patient's hand and foot. The resistance is inversely proportional to total body water and it has been shown to correlate well with other laboratory methods (2). Thus, bioelectrical impedance appears to be the first portable, easy to use, and reproducible method for determining body composition outside the laboratory. Body fat content can also be estimated by measurement of skinfold thickness but this method is time consuming and often imprecise. The most simple and commonly used anthropometric measurements are weight and height. The weight of the person is compared with a table of standard weights published by the Metropolitan Life Insurance Company based on the weight associated with the lowest mortality at any given height. Also with the weight and height of the person, the BMI can be calculated as the weight in kilograms divided by the height in meters2. Several epidemiological studies have suggested that mortality begins to increase substantially at a weight of 20% greater than desirable which corresponds roughly to a BMI of 27 kg/m2. Accordingly, obesity may be defined as a weight greater than 20% of "desirable" or a BMI greater than 27 kg/m2 (1, 2). However, the Metropolitan Life Insurance table and the BMI provide a measure of obesity that may or may not correlate with body fat. For example, a heavily muscled athlete will have high values using either of these indices but a low fat content with none of the metabolic characteristics of obesity. Similarly, a sedentary individual may not be overweight but have decreased lean body mass and have the metabolic characteristics of an overweight, obese individual. It is in these special cases where the concomitant estimation of body composition by bioelectrical impedance will have the greatest use since it is clear that in some cases body weight cannot be equated Genetic Defect +/— Environmental Factors
Common Pathway
Insulin Resistance
Metabolic Consequences
LDL HDL VLDL BP
FIG. 1. Insulin resistance in obese and lean man.
4 • • 4
Pathology
Vascular Disease
JCE & M • 1991 Vol73«No4
with fatness. These issues are further complicated by the recent recognition that the pattern of distribution of adipose tissue throughout the body affects metabolic consequences and may be a more important factor than total adipose tissue mass. As demonstrated by Kissebah et al. (2) a person with fat located predominantly in the abdominal region may be at greater risk of insulin resistance, hypertension, heart disease, and diabetes than another individual with a greater total amount of adipose tissue that is located predominantly in the gluteal area. Therefore, the simple measurement of body circumferences with a tape and calculation of the ratio of the measurement of the abdomen or waist at the smallest circumference below the rib cage and above the umbilicus to the gluteal region or hip at the largest circumference at the posterior extension of the buttocks [waist to hip ratio (WHR)] has important prognostic implications since a ratio greater than 0.9 in males and 0.8 in females is associated with increased risk of stroke and ischemic heart disease (2). In summary, obesity is a serious disease and useful information can be obtained with accurate measurement of weight, height, and body circumferences. The Metropolitan Life Insurance tables and the nomograms developed by Bray (2) for determination of BMI and WHR are useful materials for the assignment of these vital and inexpensive parameters. For more specialized clinical settings or in cases where the body weight does not correlate with the metabolic parameters, estimation of body composition by bioelectrical impedance will aid in the accurate diagnosis of obesity. What is insulin resistance and how should it be measured? Insulin resistance is a metabolic state in which physiological concentrations of insulin produce a less than normal biological response. Since the description by Himsworth in 1936 that human disease could be associated with insulin resistance, several methods have been developed to estimate in vivo insulin action and insulin resistance in man (3, 5). In the research setting the most widely used methods at present are the glucose clamp and the minimal model. The glucose clamp developed by DeFronzo, Tobin, and Andres involves a constant insulin infusion while maintaining euglycemia by infusing a variable amount of glucose. The glucose infusion rate provides a quantitative assessment of the biological effect of insulin. This method is purely investigative and not suitable for a clinical setting. The minimal model developed by Bergman (5) could be used in a highly specialized clinical setting. An iv glucose injection is followed by frequent determinations of plasma glucose and insulin. A computer program allows the calculation of the insulin
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CLINICAL REVIEW sensitivity index from the dynamic relationship between the plasma insulin and glucose concentration curves. A method available in most clinical settings is the oral glucose tolerance test. If plasma glucose and insulin concentrations are determined, the ratio of the area under the glucose curve over the area under the insulin curve provides an estimate of insulin sensitivity. Since the fasting plasma glucose concentration depends primarily on the rate of hepatic glucose release, which in turn is regulated by the insulin concentration, one might predict that the fasting plasma glucose/insulin concentration ratio may provide the simplest estimate of insulin resistance. Matthews et al. (6) proposed a computer model (homeostatic model assessment) to estimate insulin sensitivity from the fasting plasma glucose and insulin concentrations. The estimate of insulin sensitivity obtained by use of this model closely correlated with estimates obtained by use of the euglycemic clamp (P < 0.01, n = 12). We have recently observed that the glucose/insulin ratio calculated from single fasting plasma samples correlated with the measurement of insulin sensitivity determined by the euglycemic clamp (P < 0.001, n = 21), the minimal model technique (P < 0.01, n = 78), and the oral glucose tolerance test (P < 0.0001, n = 378). The higher the fasting plasma insulin concentration for a given fasting plasma glucose, the more insulin resistant an individual is. A glucose (mg/dL)/insulin (/iU/mL) ratio lower than 6 is characteristic of subjects with obesity, impaired glucose tolerance, and syndrome X. It should be recognized, however, that even though the glucose/insulin ratio is conceptually sound and technically simple and inexpensive, it also has pitfalls and limitations. First, it cannot be used in patients with defects in insulin secretion such as those with diabetes. Second, it provides indirect information on the feedback loop between the liver and /3-cells but not on the effect of insulin in peripheral tissues. Third, the range over which insulin is measured is small (fasting samples) and the results depend on the precision of the insulin RIA. Finally, the pulsatility of insulin secretion, uncertainty whether proinsulin is being measured as insulin, and the effects of stress could affect interpretation of assay results. Which patients might benefit from a clinical evaluation of insulin resistance? Clearly, the indication for this evaluation, if any, is not yet established since it is only recently that an explosion of publications have described the relationship between hyperinsulinemia, hypertension, and coronary artery disease. If the patient is obese, it can be assumed with a high degree of certainty that this patient is insulin resistant and, therefore, laboratory confirmation is not necessary and treatment of the obesity as recommended by the National Institute of Health
693
Consensus Development Panel should be initiated (1). The group of individuals in whom determination of the fasting plasma glucose/insulin ratio might be of value are those normal weight individuals with hypertriglyceridemia, low HDL, high LDL, hypertension, or coronary artery disease. The hypothesis is that syndrome X and obesity, whether genetically determined or acquired, might act through insulin resistance to cause the metabolic abnormalities (Fig. 1). Insulin resistance will result in decreased insulin mediated glucose uptake into peripheral tissues and increased glucose release from the liver, defects that are partially compensated by increased insulin secretion. Insulin resistance will result in decreased catabolism of triglycerides, which by a mechanism not yet well defined, decreases HDL cholesterol concentrations, and increases LDL cholesterol concentrations. Since a partial compensatory response to insulin resistance is hyperinsulinemia and because insulin resistance may not be equally manifested in all insulin sensitive tissues, there may be a relative increase in insulin action in some tissues. For example, in the kidney, insulin is known to promote renal tubular sodium and water absorption and therefore may contribute to the development of hypertension. In the liver, hyperinsulinemia results in increased triglyceride synthesis contributing to hypertriglyceridemia. In vascular smooth muscle, insulin, by interacting with its receptor or the insulin-like growth factor I receptor, might increase endothelial proliferation and contribute to the development of atherosclerosis (7). The diagnosis of insulin resistance in these patient would fully justify the initiation of a diet and exercise program to improve insulin resistance and would also assess the effect of therapy. Since there is a wealth of clinical data demonstrating the benefit of weight loss in obese subjects and of training in middle age sedentary individuals it is not unreasonable to expect that in nonoverweight subjects improvement of insulin resistance will also result in improvement of carbohydrate and lipid metabolism, decreased blood pressure, and therefore lower risk of vascular disease. What is the mechanism of insulin resistance in obese and nonobese man? It is generally accepted that the increased insulin secretion in obesity serves as a mechanism to compensate for insulin resistance. However, the processes that trigger hyperinsulinemia in human obesity and the possible pathophysiological consequences of hyperinsulinemia are not fully identified nor do we know the cellular mechanism of insulin resistance. There are several reasons for these uncertainties. First, in vivo and in vitro studies in human obesity will continue to describe defects
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of insulin action and secretion but will not likely be able to provide insight into what is the primary defect, if any, responsible for insulin resistance or insulin hypersecretion since the preobese state in man has not yet been identified. For the present, information from the end stage of a syndrome that most likely represents the clinical expression of a collection of genetic diseases will continue to be useful but will not distinguish from primary and secondary defects. Second, we do not know yet what the normal mechanism of insulin action is. Therefore, it becomes particularly difficult to define the processes responsible for insulin resistance. Furthermore, in most tissues, insulin is involved in the metabolism of sugars, lipids, nucleotides, and amino acids with three major sites of metabolic regulation. At the plasma membrane, insulin increases the transport of glucose and other substrates. In the cytoplasm and its organelles, insulin activates a number of intracellular enzymes. In the nucleus, insulin regulates the synthesis of RNA and DNA. Because of this multiplicity of effects, it is unlikely that a single mechanism of action will be discovered for insulin. It is known, however, that the initial interaction of insulin with target cells is with a receptor protein located on the plasma membrane. The insulin receptor plays a critical role both in directing the hormone to a specific target tissue and programming the response of the tissue to the hormone. Accordingly, to investigate the transmembrane signaling mechanisms for insulin, a number of studies in human obesity have focused on this protein. The insulin receptor is a heterotetrameric glycoprotein consisting of two a-subunits and two /?-subunits linked by disulfide bonds to give a /3-«-«-/?-structure. The asubunit is extracellular and contains the insulin binding site. The /3-subunit is an insulin-sensitive protein kinase capable of phosphorylating itself and other substrates on tyrosine residues and its activation is a necessary step in the insulin signaling mechanism for most but not all biological actions of insulin (8). In vitro studies in human obesity have demonstrated tissue-specific impairment of both the a-subunit and /?subunit of the insulin receptor (9). In human liver, the number of insulin receptors is decreased but in each receptor the insulin sensitive tyrosine kinase is normal. In human adipose tissue, the number of insulin receptors is either decreased or normal but there is consensus that the insulin sensitive tyrosine kinase is normal. In human skeletal muscle, there is also general agreement that the number of insulin receptors is decreased but, furthermore, for each receptor the insulin sensitive tyrosine kinase is impaired. These in vitro data demonstrating decreased numbers of insulin receptors in human obesity at least partially explain the diminished insulin action at submaximal concentrations of insulin observed in vivo (3). Furthermore, the additional impairment in the p-
JCE & M • 1991 Vol73-No4
subunit of the insulin receptor in human skeletal muscle is consistent with in vitro data demonstrating that the skeletal muscle is more resistant to insulin than the adipose tissue with regard to glucose transport (9). Recent studies have indicated that a family of structurally related proteins with distinct but overlapping tissue distributions are responsible for facilitative glucose transport in mammalian tissues. Insulin primarily stimulates glucose transport by inducing the redistribution of a unique glucose transporter protein from an intracellular pool to the plasma membrane. This 509 amino acid integral membrane protein, termed GLUT-4, is the major insulin-responsive glucose transporter in adipose and muscle tissues and is therefore likely to play a key role in the mechanism of insulin resistance found in obesity. However, available studies in human obesity have demonstrated only a modest decrease in GLUT-4 in adipose tissue and skeletal muscle that by itself cannot explain the alterations in insulin-stimulated glucose transport, suggesting additional defects in glucose transporter translocation and/or activation possibly related to abnormalities in insulin signaling (9). The contribution that skeletal muscle and adipose tissue make to the peripheral insulin stimulated glucose uptake is currently under debate. It was suggested several years ago that only a small fraction of an iv glucose load could be recovered in the adipose tissue generating the idea that insulin stimulated peripheral glucose use could be equated to skeletal muscle glucose use. However, recent studies (10) have suggested that glucose uptake in human adipose tissue, the majority of which is released as lactate, might well be of significance for total body glucose homeostasis, being about 11% in lean subjects and in obese subjects perhaps amounting for up to onethird to one-half of an oral glucose load. The greater insulin stimulated use of glucose by the adipose tissue in obesity could be due to the expanded adipose tissue mass and perhaps also because the adipose tissue is less resistant to insulin than the skeletal muscle (9). From the preceding discussion it should be apparent that our current understanding of insulin resistance present in obesity is fragmented and inconclusive. Furthermore, much less is known about the insulin resistance in nonobese subjects since no in vitro studies from this population have been reported yet. Ruderman et al. (4) predicted that those individuals with insulin resistance and normal BMI will have increased body fat mass in comparison to individuals matched for age and BMI or in comparison to the patient himself at an earlier time in life. We believe his predictions are correct. Figure 2 shows data from sedentary males 41 ± 4 years of age with BMI between 22 and 26. The lower panel of Fig. 2 demonstrates that within this narrow range of BMI there is no correlation between insulin sensitivity and BMI. However, the upper panel of the same figure demon-
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CLINICAL REVIEW
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Health Consensus Development Panel (1) have been reviewed. Insulin resistance, one of the characteristic metabolic features of obesity, has recently been identified in a subset of normal weight individuals (3, 4). Furthermore, these individuals with insulin resistance also have elevated triglycerides, low HDL cholesterol, high LDL cholesterol, and hypertension and, therefore, metabolically resemble overweight individuals. In fact, the normal-weight, insulin-resistant subjects have increased body fat when compared with insulin sensitive subjects with comparable BMI. If "insulin resistance" turns out to be a "secret killer" as suggested by Foster in a recent editorial (7), practical ways to uncover it in a clinical setting need to be established and alternative methodologies were reviewed. Once insulin resistance is identified, a healthy diet and a well structured exercise program needs to be initiated. Fitness and weight loss improve insulin action and decrease coronary artery disease risk factors in obese man and, therefore, it is reasonable to believe that they would have a similar effect in the insulin-resistant, normal-weight individual. For the individual refractory to these prudent prescriptions a drug is not yet available that improves insulin resistance without the potential of hypoglycemia. A better understanding of the pathogenesis of insulin resistance in these subjects will be required before an effective pharmacological approach can be designed.
o —1
25
B MI FIG. 2. Relationship between the insulin sensitivity index (X1O~4 min"1 n\J ml"1) and BMI (kg/m2) (upper panel) and percent body fat (lower panel).
strates a negative correlation between percent body fat calculated by underwater weighing and insulin sensitivity (Caro, J. F., and G. Israel, unpublished observation). Thus, individuals with an identical BMI may have differing amounts of fat that correlate with the degree of insulin resistance. The implication is that normalweight, insulin-resistant subjects must have a reciprocal decrease in lean body mass; and, since it is known that basal metabolic rate correlates with lean body mass, it is likely that nonobese insulin-resistant subjects will have decreased basal metabolic rate. Also nonobese insulin resistant subjects have an increased pool of energy stored as fat resulting from a positive energy balance at some time in their life. Therefore, it is possible that the nonobese insulin resistant subject might represent the earliest stages of obesity or the elusive preobese state itself.
Conclusions The health implications of obesity, diagnosis, and treatment recommendations by the National Institute of
Acknowledgments Thanks are given to Dr. Peter Butler, Dr. Eugene Furth, and Dr. David Snyder for reviewing and editing the manuscript and Joyce Compton for the typing and preparation of the manuscript.
References 1. National Institute of Health Consensus Development Panel on the health implications of obesity. Consensus Conference Statement. Ann Int Med. 1985;103:1073-1077. 2. Bray GA. Obesity: basic aspects and clinical implications. Med Clin North Am. 1989;73:l-264. 3. Reaven GM. Role of insulin resistance in human disease. Diabetes. 1988;37:1595-1507. 4. Ruderman NB. The "metabolically-obese" normal-weight individual. Am J Clin Nutr. 1981;34:1617-1621. 5. Bergman RN. Toward physiological understanding of glucose intolerance. Minimal model approach. Diabetes. 1989;38:1512-1527. 6. Matthews DR, Hosker JP, Rodenski AS, Naylor BA, Treacher DF, Turner RC. Homeostatic model assessment: insulin resistance and /3-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412-419. 7. Foster DW. Insulin resistance—a secret killer? N Engl J Med. 1989;320:733-734. 8. Kahn CR, White MF. The insulin receptor and the molecular mechanism of insulin action. J Clin Invest. 1988;82:1151-1156. 9. Caro JF, Dohm GL, Pories WJ, Sinha MK. Cellular alteration in liver, skeletal muscle and adipose tissue responsible for insulin resistance in obesity and type II diabetes. Diab/Metab Rev. 1989;5:665-689. 10. Marin P, Ruseffe-Scrive, Smith J, Bjorntorp P. Glucose uptake in human adipose tissue. Metabolism. 1988;36:1154-1164.
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