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Insulin Resistance: Associated Abnormalities and Clinical Syndromes

Page history last edited by Dhemy Padilla 11 years, 2 months ago

 

The Web diabetesmanager

 

 

Insulin Resistance: Associated Abnormalities and Clinical Syndromes  

 

Gerald M Reaven, MD 

 

 

Last Author Revision:  2009 

 


 

 

INTRODUCTION

Sensitivity to insulin-mediated glucose disposal varies more that six-fold in the population at large [1]. When insulin resistant individuals cannot maintain the degree of hyperinsulinemia needed to overcome the insulin resistance, type 2 diabetes develops [2][3]. However, the vast majority of these individuals continue to secrete the large amount of insulin needed to overcome this defect in insulin action, thereby maintaining normal or near-normal glucose tolerance. Unfortunately, this philanthropic effort on the part of the pancreatic beta cell is a mixed blessing. Although the compensatory hyperinsulinemia prevents the development of frank hyperglycemia, insulin resistant/hyperinsulinemic individuals are at greatly increased risk of having some degree of glucose intolerance, a high plasma triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentration, and essential hypertension [4]. In 1988 [5] it was proposed that individuals displaying this cluster of abnormalities associated with insulin resistance/compensatory hyperinsulinemia were at significantly increased risk of cardiovascular disease (CVD). Because it was felt that these relationships were not widely appreciated at the time, the concept that insulin resistance and its associated abnormalities should be thought of as CVD risk factors was subsumed under the rubric of Syndrome X.

 

 

Table 1. APT III Criteria for Diagnosing the Metabolic Syndrome
  • Abdominal obesity
    Men: Waist circumference >40 inches
    Women: Waist circumference >35 inches
  • Fasting glucose ≥ 110 < 126 mg/dL
  • Blood pressure ≥ 130/80 mm Hg
  • Triglycerides ≥ 150 mg/dL
  • HDL cholesterol
    Men <40 mg/dL
    Women <50 mg/dL
The metabolic syndrome is present when 3 or more of the 5 criteria are met

 

 

Since the introduction of the concept of syndrome X, considerable new information has evolved relevant to the role of insulin resistance in human disease. This has resulted in two somewhat disparate approaches to thinking about the clinical implications of insulin resistance and its consequences. One view represents an effort to acknowledge that the abnormalities related to insulin resistance have broadened considerably, and the adverse clinical outcomes extend beyond type 2 diabetes and CVD. Since CVD is recognized to be just one of the multiple clinical syndromes associated with insulin resistance, it seems appropriate to replace the term syndrome X with one that incorporates this new information. In this context, the Insulin Resistance Syndrome (IRS) seems to be a reasonable choice to provide a pathophysiological construct with which to view the different clinical syndromes that occur more commonly in insulin resistant individuals.

 

On a somewhat parallel tract, during this period when the list of abnormalities associated with insulin resistance was rapidly expanding, the cardiological community has formally acknowledged the importance of this defect in insulin action as increasing CVD risk with the report of the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program [6]. The ATP III recognized the importance as CVD risk factors of what they referred to as a “constellation of lipid and non-lipid risk factors of metabolic origin”, designated this cluster as the metabolic syndrome, and stated, “this syndrome is closely related to insulin resistance.” The 5 criteria selected by the ATP III to identify individuals with the metabolic syndrome (increased abdominal girth, elevated blood pressure, impaired fasting glucose, and a high TG and low HDL-C concentration) is a reflection of their view that insulin resistance is at the root of the problem. However, in contrast to the pathophysiological construct that underlies the concept of the IRS, the goal of the ATP III in establishing criteria for making the diagnosis of the metabolic syndrome is to identify individuals at increased CVD risk and initiate life-style changes in order to decrease this risk.

 

Based upon the above considerations, it is apparent that the concept of the IRS is much broader than that of the ATP III definition of the metabolic syndrome, and not limited to consideration of CVD. Consequently, the focus of this review will be on the abnormalities and clinical syndromes that can usefully be considered under the general heading of the IRS; an approach that will presumably be of greater relevance to the readers of ENDOTEXT.

 

 

 

THE INSULIN RESISTANCE SYNDROME - OVERVIEW

The IRS is a term used to describe a cluster of abnormalities and related clinical outcomes that occur more commonly in insulin resistant/hyperinsulinemic individuals. The IRS is not a specific clinical entity, nor does it refer to a specific clinical diagnosis. Insulin resistance is not a disease, but a physiological abnormality that increases the likelihood that one or more of the abnormalities listed in Table 2 will be present. Furthermore, because the abnormalities seen in Table 2 occur more commonly in insulin resistant individuals, they are at increased risk to develop the clinical syndromes listed in Table 3. However, the relationship between insulin resistance and the changes seen in Tables 2 and 3 is complicated; it is important to be aware that the abnormalities and clinical syndromes in these tables can occur in the absence of insulin resistance, and insulin resistant individuals do not necessarily develop any of the clinical syndromes listed in Table 3.

 

 

Table 2. Abnormalities Associated with Insulin Resistance and Compensatory/Hyperinsulinemia
  • Some degree of glucose intolerance
    • Impaired Fasting Glucose
    • Impaired Glucose Tolerance
  • Dyslipidemia
    • ↑ Triglycerides
    • ↓ HDL-C
    • ↓ LDL-particle diameter (small, dense LDL-particles)
    • ↑ Postprandial accumulation of TG-rich lipoproteins
  • Endothelial Dysfunction
    • ↑ Mononuclear Cell Adhesion
    • ↑ Plasma Concentration of Cellular Adhesion Molecules
    • ↑ Plasma Concentration of Asymmetric Dimethylarginine
    • ↓ Endothelial-dependent Vasodilatation
  • Procoagulant Factors
    • ↑ Plasminogen Activator Inhibitor-1
    • ↑ Fibrinogen
  • Hemodynamic Changes
    • ↑ Sympathetic Nervous System Activity
    • ↑ Renal Sodium Retention
  • Markers of Inflammation
    • ↑ C-reactive Protein, WBC, etc.
  • Abnormal Uric Acid Metabolism
    • ↑ Plasma Uric Acid Concentration
    • ↓ Renal Uric Acid Clearance
  • Increased Testosterone Secretion (ovary)
  • Sleep Disordered Breathing

 

 

 

Table 3. Clinical Syndromes Associated with insulin Resistance
  • Type 2 Diabetes
  • Cardiovascular Disease
  • Essential Hypertension
  • Polycystic Ovary Syndrome
  • Nonalcoholic Fatty Liver Disease
  • Certain Forms of Cancer
  • Sleep Apnea

 

 

In order to understand the relationship between insulin resistance and the abnormalities (Table 2) and clinical syndromes (Table 3) associated with the defect in insulin action, it is necessary to discuss the relative roles of insulin resistance versus compensatory hyperinsulinemia in bringing about these changes. As emphasized above, Insulin-mediated glucose disposal varies wdely in apparently healthy, nondiabetic individuals [7]. Despite this enormous variability from person to person, enough insulin is secreted in these individuals to prevent frank decompensation of glucose homeostasis [8][9]. However, not all tissues share the defect in insulin action [10][11][12][13], and the cost of secreting the amount of insulin needed to overcome insulin resistance located primarily in muscle and adipose tissue is the adverse impact of the compensatory hyperinsulinemia on tissues that remain normally insulin sensitive. However, even in this instance, muscle tissue and adipose tissue differ in the nature of their dose response to insulin. Adipose tissue is much more insulin sensitive, and plasma free fatty acid (FFA) concentrations are suppressed half-maximally at a plasma insulin concentration of ~20 mU/L [14]; a level of insulin that has little or no effect on muscle glucose uptake. Parenthetically, these differences in the insulin dose-response curve of the two tissues are essential for normal energy metabolism. When insulin levels are low after an overnight fast, the anti-lipolytic effect of insulin is minimal, FFA release from adipose tissue stores is accentuated, and relatively little glucose is taken up by muscle. Once food is consumed, plasma insulin concentrations increase, muscle glucose uptake is maximized, and the effect of insulin on adipose tissue is to enhance glucose disposal and inhibit further breakdown of stored TG to FFA.

 

Although muscle and adipose tissue may differ in their relative degree of insulin sensitivity, they are quite similar in that when muscle is resistant to regulation by insulin, so is adipose tissue [15]. In contrast, most, if not all, of the other tissues in the body retain normal insulin sensitivity in the face of muscle and adipose tissue insulin resistance. Therefore, they can become innocent victims of the effort by pancreatic beta cells to maintain euglycemia by secreting the large amounts of insulin needed to compensate for the muscle and adipose tissue insulin resistance. For example, compensatory hyperinsulinemia aimed at maintaining normal glucose tolerance will act on a normally insulin-sensitive kidney to decrease uric acid clearance and increase sodium retention, resulting in the increase in uric acid concentration and salt sensitivity that occurs in insulin-resistant individuals [16][17]. Another obvious example of differential tissue insulin sensitivity is the increase in ovarian androgen secretion, secondary to compensatory hyperinsulinemia, resulting in polycystic ovary syndrome [18]. Perhaps the most relevant organ in this context is the liver; by remaining normally insulin sensitive, the liver is responsible for the development of nonalcoholic fatty liver disease [19], as well as the atherogenic lipoprotein profile that characterizes the IRS [20][21][22].

 

 

ABNORMALITIES ASSOCIATED WITH INSULIN RESISTANCE/HYPERINSULINEMIA

Insulin resistant/hyperinsulinemic individuals are at increased risk to develop the abnormalities listed in Table 2, and these manifestations of the IRS will be briefly reviewed in this section.

 

Glucose Intolerance

Although the majority of insulin resistant/hyperinsulinemic individuals will have a "normal" fasting plasma glucose (FPG) concentration, they will be more likely to have either impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) than are insulin sensitive individuals [23]. On the other hand, approximately 25% of an apparently healthy population that was sufficiently insulin resistant to be at increased risk to develop one of the adverse outcomes listed in Table 3 had absolutely normal oral glucose tolerance tests.

 

Dyslipidemia

Plasma TG concentrations are strongly correlated with insulin resistance/compensatory hyperinsulinemia [24][25], and once the plasma TG concentration increases, there will be a tendency for the HDL-C concentration to decline. Furthermore, insulin resistance/hyperinsulinemia are independently related to high TG and low HDL-C concentrations [26], as is the postprandial accumulation of TG-rich lipoproteins [27][28] and a shift in low-density (LDL) lipoprotein particles to a smaller and denser form [29].

 

Endothelial Dysfunction

The first step in the process of atherogenesis is the binding of monocytes to the endothelium [30], and mononuclear cells isolated from insulin resistant, hyperinsulinemic individuals have been shown to bind with greater avidity to cultured endothelium [31]. Other markers of endothelial dysfunction include increases in circulating levels of cellular adhesion molecules [32] and asymmetric dimethylarginine [33], and endothelium-dependent vasodilatation, an estimate of the functional capacity of the endothelium, has also been shown to be abnormal in insulin resistant/hyperinsulinemic individuals [34].

 

Procoagulant Factors

Population- based studies [35][36] have indicated that elevations of plasma insulin concentration, as a surrogate estimate of insulin resistance, are associated with increases in both plasminogen activator inhibitor-1 (PAI-1) and fibrinogen, although the relationship is stronger with PAI-1.  More recently, evidence has been published clearly documenting the fact that PAI-I levels are higher in insulin resistant individuals, associated with the compensatory hyperinsulinemia and dyslipidemia characteristic of the IRS [37].

 

Hemodynamic Changes

As discussed above, the kidney is not insulin resistant, and responds normally to physiological regulation by insulin [38][39]. As a consequence, the compensatory hyperinsulinemia that prevents the development of type 2 diabetes in insulin resistant individuals results in sodium and water retention [40]. The sympathetic nervous system (SNS) also retains normal insulin sensitivity in individual with muscle and adipose tissue insulin resistance [41], and enhanced SNS activity is another one of the consequences that results from compensatory hyperinsulinemia in insulin resistant individuals [42].

 

Markers of Inflammation

Given evidence that atherogenesis is an inflammatory process [43], and that insulin resistance and/or compensatory hyperinsulinemia increase the risk of CVD [44][45][46][47][48], it should not be surprising that plasma markers of inflammation are elevated in the IRS. This was first clearly indicated by the demonstration that the more insulin resistant an individual, the higher is the plasma white blood cell count [49]. More recently, it has also been shown that there is a significant relationship between plasma C-reactive protein concentration and insulin resistance/hyperinsulinemia [50].

 

Uric Acid Metabolism

Plasma uric acid concentrations are higher in insulin resistant individuals [51]. As mentioned previously, this is an excellent example of an abnormality that is the inevitable consequence of compensatory hyperinsulinemia, attempting to maintain normal glucose tolerance, acting on a normally insulin sensitive organ (the kidney) to decrease uric acid clearance. The consequence is that insulin resistant/hyperinsulinemic individuals will tend to have higher plasma uric acid concentrations than insulin sensitive persons.

 

Increases in Testosterone Secretion

The ovary is another example of an organ that continues to respond to the stimulatory effects of insulin in the face of muscle and adipose tissue insulin resistance, and elevated plasma testosterone concentrations are seen in insulin resistant/hyperinsulinemic women with PCOS [52]. However, not all insulin resistant/hyperinsulinemic individuals develop PCOS, and the effect of elevated circulating insulin levels on testosterone secretion in normally ovulating women has not been thoroughly evaluated. Indeed, it is possible that the ovary in women with PCOS is actually hypersensitive to the stimulatory effects on testosterone secretion of elevated plasma levels of insulin.

 

Sleep Disordered Breathing

The fact that manifestations of sleep-disordered breathing are commonly seen in obese individuals has led to the notion that the primarily disturbance is mechanical in origin, secondary to the obesity. However, insulin resistance and compensatory hyperinsulinemia are also more likely to occur in overweight/obese individuals [53][54]. Thus, it is possible that the relationship between obesity and sleep-disordered breathing may not be entirely mechanical, but at least partly related to the effects of insulin resistance and/or compensatory hyperinsulinemia, and evidence has recently been published in support of this notion [55].

 

 

CLINICAL SYNDROMES ASSOCIATED WITH INSULIN RESISTANCE

 

Type 2 Diabetes

Although the majority of insulin resistant/hyperinsulinemic individuals do not develop type 2 diabetes (2 DM), they are at increased risk to become frankly hyperglycemic. Indeed, the notion that insulin resistance could lead to human disease began with a series of papers published in the fourth decade of the 20th century demonstrating that the most common form of diabetes resulted from “insulin insensitivity [56]”. Although many years passed before these earlier studies were repeated [57][58], it is now quite clear that insulin resistance (or hyperinsulinemia as a surrogate measure of insulin resistance) is a powerful and independent predictor of the development of 2 DM [59][60][61].

 

Most insulin-resistant individuals can maintain normal or near-normal glucose tolerance as long as they are able to secrete the large amounts of insulin needed to prevent the increases in plasma glucose and free fatty acid (FFA) concentrations seen in patients with type 2 DM [62]. Once frank hyperglycemia ensues, insulin resistant individuals are at increased risk to develop the specific microangiopathic changes seen in patients with type 2 DM. Thus, it should be emphasized that insulin resistance only increases the likelihood that an individual will develop 2 DM, whereas the specific organ manifestations associated with the diabetic syndrome, retinopathy, nephropathy, and neuropathy represent the consequences of hyperglycemia, per se, not insulin resistance.

 

Cardiovascular Disease

Several population-based studies have demonstrated that hyperinsulinemia, both fasting and post-glucose challenge, predicts the development of CVD in nondiabetic individuals [63][64][65]. More recently, it has been shown that insulin resistance, as quantified by a specific measure of insulin-mediated glucose disposal, is also predictive of increased CVD risk, and that this risk is present in the approximately one-third of an apparently healthy population that has the greatest defect in insulin-mediated glucose disposal [66][67].

 

Nondiabetic individuals that are insulin resistant and hyperinsulinemic are more likely to develop the abnormalities shown in Table 2, and it is not clear which of these changes plays the major role in the process of accelerated atherogenesis. Hypertriglyceridemia was the initial abnormality in lipid metabolism shown to be associated with insulin resistance and compensatory hyperinsulinemia [68][69], and the increase in plasma TG concentration in insulin resistant individuals is a good example of the complex relationship between insulin resistance, hyperinsulinemia, and differential tissue insulin sensitivity in the development of the abnormalities of the IRS. Individuals with the IRS have comparable defects in the ability of insulin to mediate muscle glucose disposal and inhibit adipose tissue lipolysis [70]. The muscle and adipose tissue insulin resistance lead to higher daylong ambient levels of both insulin and free fatty acids (FFA), and these two changes stimulate hepatic TG secretion, leading to the increase in plasma TG concentration in insulin-resistant individuals [71][72]. The higher circulating insulin concentrations present in insulin-resistant individuals act on the normally insulin sensitive liver to increase the rate at which the incoming FFA are converted to TG; the higher the plasma FFA concentration at any given portal vein insulin concentration, the greater the increase in hepatic TG secretion and plasma TG concentration.

 

However, it is apparent from inspection of Table 2 that hypertriglyceridemia is only one of the changes in lipoprotein metabolism present in insulin resistant/hyperinsulinemic individuals that increases CVD risk. Furthermore, the dyslipidemic CVD risk factors present in insulin resistant/hyperinsulinemic individuals is not limited to the associated atherogenic lipoprotein profile of a low HDL-C concentration, smaller and denser low-density lipoprotein particles, and greater accumulation of postprandial remnant lipoprotein particles [73][74][75][76], but also includes multiple manifestations of endothelial dysfunction, a procoagulant state, and evidence of inflammatory changes in the vessel wall [77][78][79][80][81][82][83]. It is beyond the purpose of this presentation to explore the relative importance of insulin resistance vs. compensatory hyperinsulinemia in the development of all of these changes, but it is quite likely that many of them, if not all, are secondary to the hyperinsulinemia that while preventing the development of 2 DM is responsible for the increased CVD risk. 

 

Essential Hypertension

The relationship between insulin resistance and essential hypertension is a complex one, and cannot discussed in detail in the context of this presentation. However, the following considerations provide ample evidence that such a relationship exists: 1) patients with essential hypertension, as a group, are insulin resistant and hyperinsulinemic [84][85][86]; 2) normotensive first degree relatives of patients with essential hypertension are relatively insulin resistant and hyperinsulinemic as compared to a matched control group without a family history of hypertension [87][88][89]; and 3) hyperinsulinemia, as a surrogate estimate of insulin resistance, has been shown in population-based studies to predict the eventual development of essential hypertension in children, adolescents, and adults [90][91][92][93]. These findings provide substantial support for the view that insulin resistance/hyperinsulinemia plays a role in the pathogenesis of essential hypertension, but it must be emphasized that no more than 50% of patients with essential hypertension are likely to be insulin resistant [94]. Thus, just as there are insulin resistant individuals that do not develop essential hypertension, not all patients with essential hypertension are insulin resistant. On the other hand, there is substantial evidence that it is the subset of patients with essential hypertension that are also insulin resistant, and likely to have the other abnormalities of the IRS, that are at greatest CVD risk [95][96].

 

Finally, although the mechanistic links between insulin resistance/compensatory hyperinsulinemia are not totally clear, what is understood provides another example of the adverse effects of compensatory hyperinsulinemia in persons whose muscle and adipose tissue are resistant to insulin. For example, insulin infusions will increase renal sodium retention in individuals with insulin resistant muscle and adipose tissue [97]. Furthermore, the ability of increased sodium intake to increase salt and water retention occurs primarily in insulin resistant individuals [98], and salt sensitivity is characteristic of normotensive and hypertensive insulin resistant individuals [99][100]; changes that are dependent upon the ability of the kidney to respond normally to the sodium-retaining properties of insulin. In a similar manner, insulin can activate the sympathetic nervous system in insulin resistant individuals, leading to a variety of changes that increase the likelihood of essential hypertension developing [101][102][103]. The ability of insulin to normally enhance renal sodium retention and stimulate sympathetic nervous system activity may not be the only explanations for an increased prevalence of essential hypertension in insulin resistant/hyperinsulinemic individuals, but they contribute to this phenomenon, and are another example of the important of differential tissue insulin sensitivity in the etiology of the clinical syndromes that make up the IRS.

 

Polycystic Ovary Syndrome (PCOS)

PCOS is the most common endocrine abnormality in premenopausal women, and there is compelling evidence that the prevalence of insulin resistance/hyperinsulinemia is significantly increased in patients with this syndrome [104]. PCOS is another example in which adverse consequences of muscle and adipose tissue insulin resistance are due to the associated hyperinsulinemia acting on normally insulin sensitive tissues. In this instance, it appears that the clinical features of PCOS result from an increase in testosterone secretion by ovaries which are at least normally insulin sensitive, secondary to the higher circulating insulin concentrations seen in these patients. On the other hand, PCOS cannot be a simple function of insulin resistance. At the simplest level, not all insulin resistant/hyperinsulinemic women develop PCOS, nor are all women with PCOS insulin resistant and hyperinsulinemic. Indeed, there is significant interaction between insulin resistance/hyperinsulinemia and the diagnosis of PCOS [105]. Specifically, it has been shown in a study of equally overweight women, with a history of PCOS or normal ovulation, that the highest plasma testosterone concentrations are seen in women with PCOS, who are also insulin resistant. However, although plasma testosterone concentrations are lower in women with PCOS, who are insulin sensitive, their values are still higher as compared to insulin resistant women, with a history of normal ovulation. This demonstration of significant interaction between the presence of PCOS and insulin resistance is consistent with the notion of ovarian hypersensitivity to insulin stimulation of testosterone production in women with PCOS as  proposed by Baillargeon and Nestler [106]. The importance of hyperinsulinemia, per se, in the pathogenesis of PCOS, is supported by the results of pharmacological intervention studies.  Thus, both rosiglitazone [107] and metformin [108] have been shown to be clinically effective in the treatment of PCOS. Rosiglitazone both improves insulin sensitivity and lowers daylong circulating insulin concentrations [109]. However, although ambient insulin levels are lower in metformin-treated subjects, there is no improvement in insulin-mediated glucose disposal by muscle [110]. Finally, it is worth emphasizing as concluded by Dunaif and colleagues that “PCOS women have significant insulin resistance that is independent of obesity, changes in body composition, and impairment of glucose tolerance [111].”

 

Nonalcoholic Fatty Liver Disease

As discussed above, resistance to insulin action at the level of the muscle and adipose tissue results in daylong increases in circulating plasma insulin and FFA concentrations, leading to increased hepatic TG synthesis. If the rate at which the liver is able to incorporate the newly synthesized TG into very-low density lipoprotein (VLDL) and secrete it as VLDL-TG lags behind the liver’s synthesis of TG, the result will be an increase in hepatic fat content. There is now ample evidence that patients with nonalcoholic fatty liver disease (NAFLD) are insulin resistant and hyperinsulinemic, and the presence of increased hepatic fat content in patients who are neither alcoholic nor have any viral infection is being recognized and commented upon with ever-increasing frequency [112][113]. As is often the case, the association between obesity and insulin resistance has resulted in an emphasis on a central role of excess adiposity in the causality of NAFLD. However, the results of the study by Seppala-Lindros and associates [114] in normal weight and moderately overweight subjects demonstrated that hepatic fat content (proton spectroscopy) was independent of BMI and either visceral or subcutaneous fat (magnetic resonance imaging). In contrast, liver fat content was significantly correlated (p>0.001) with both fasting insulin (r=0.64) and TG concentrations (r=0.60). Thus, although obesity makes it more likely that an individual will be insulin resistant, it is the insulin resistance/hyperinsulinemia that is responsible for the increase in hepatic fat content.

 

Cancer

A growing body of evidence has accumulated in the past few years suggesting that the prevalence and clinical course of several forms of cancer may be related to insulin resistance/hyperinsulinemia [115]. Perhaps studies of breast cancer provide the most compelling evidence of a link between insulin resistance and neoplastic disease. Reports have been published of higher plasma C-peptide and/or insulin concentrations in both pre- and postmenopausal women with breast cancer, as well as evidence that fasting insulin concentration predicts outcome in women with early breast cancer [116][117][118]. Indirect support for a relationship between insulin resistance/hyperinsulinemia and breast cancer can be found in reports of increased prevalence of breast cancer in association with hypertriglyceridemia, obesity and type 2 DM [119][120][121].

 

Although the evidence does not seem quite as persuasive, reports have been published suggesting a relationship between insulin resistance/hyperinsulinemia and both colorectal and prostate cancer. As with breast cancer, the evidence consists of reports that both cancers are more likely to occur in individuals who are overweight and/or have type 2 DM [122][123][124][125][126], as well as the presence of higher plasma insulin concentrations in patients with colorectal or prostate cancer [127][128][129][130]. Finally, epidemiological evidence has also been published that liver cancer is more likely to develop in hyperinsulinemic subjects [131], possibly related to the increase in NAFLD and subsequent cirrhosis in these individuals.

 

Obstructive Sleep Apnea

There is abundant evidence that the prevalence of obstructive sleep apnea (OSA) is increased in obese individuals, just as the more overweight an individual, the more likely they are to be insulin resistant. However, not all obese individuals are insulin resistant, nor are all patients with OSA obese. Although OSA is conventionally viewed as a local abnormality of the respiratory tract, there is a substantial amount of evidence suggesting that it may be systemic disease related to insulin resistance. Vgontaz and associates have recently reviewed this issue [132], and among the observations supporting the association between insulin resistance/compensatory hyperinsulinemia are the following. There is evidence that obese patients with OSA are more insulin resistant and/or hyperinsulinemic than equally obese individuals without any abnormality of breathing, and insulin resistance has been demonstrated in nonobese persons with OSA. Furthermore, patients with diseases known to be related to insulin resistance appear to be more at risk to develop manifestations of sleep-disordered breathing, and this has been demonstrated both in patients with type 2 diabetes, and even more clearly in patients with PCOS. Obviously, this area of clinical investigation is just beginning, and it is premature to decide if OSA is simply more likely to occur for mechanical reasons in obese individuals, and insulin resistance represents an epiphenomenon, or if insulin hyperinsulinemia/hyperinsulinemia may play a casual role in the genesis of sleep-disordered breathing.

 

 

SUMMARY

The goal ofthis review has been to summarize the clinical consequences that can arise from resistance to insulin-mediated glucose disposal and the homeostatic efforts to compensate for this fundamental defect. Perhaps the single point that deserves the most emphasis is that insulin resistance is not a disease, but the description of a physiological state, that greatly increases the chances of an individual developing a number of closely related abnormalities and associated clinical syndromes. Insulin resistance does not necessarily result in the abnormalities and clinical syndromes listed in Tables 2 and 3, and, to varying degrees, they can all occur in the absence of insulin resistance. The primary value of the concept of an IRS is pedagogic; it provides the conceptual framework with which to place a substantial number of apparently unrelated biological events into a pathophysiological construct. Its primary goal is not to make a diagnosis, but to increase understanding of why, for example, a woman with PCOS is more likely to develop type 2 diabetes than a woman with a normal menstrual history. This does not imply that the notion of an IRS is without clinical utility, and the apparent link between insulin resistance/compensatory hyperinsulinemia and the clinical course of breast cancer provides an obvious mechanistic target with which to evaluate try new treatment options.

 

Finally, it should be emphasized that although the terms metabolic syndrome and IRS are often used interchangeably, the names are reflective of very different concepts. The metabolic syndrome, as defined by the ATP III [133], is a diagnostic entity, not a physiological construct, is focused on only one of the clinical syndromes associated with insulin resistance listed in Table 3, and its goal is explicitly to make a clinical diagnosis in order to implement therapeutic efforts with the goal of decreasing CVD risk. The reason to address the metabolic syndrome in the context of this review is to differentiate it from the IRS. A discussion of the clinical utility of making, or not making, a diagnosis of the metabolic syndrome is beyond the purview of this presentation, but it should be noted that questions have been raised as to the value of the concept of the metabolic syndrome as defined by the ATP III, as well as its ability to provide an effective means of identifying individuals that are likely to be insulin resistant and/or at increased CVD risk [134][135][136][137][138].

 

In conclusion, approximately one-third on an apparently healthy adult population in the United States is sufficiently insulin resistant to be at sufficiently increased risk to develop the abnormalities and clinical syndromes listed in Tables 2 and 3 [139][140]. Based upon evidence gathered in nondiabetic Pima Indiana and Caucasians [141], it appears that the more obese an individual, and the less fit, the more likely they are to be insulin resistant, and each of these variables accounts for approximately 25% of the six-fold variability in insulin action that exists in the population at large [142]. Given the fact that the world is getting both heavier and more sedentary, it is obvious that insulin resistance, and its consequences, the IRS, is the plague of the 21st century.

 

 

 

 

Footnotes

  1. Yeni-Komshian H, Carantoni M, Abbasi F, Reaven GM. Relationship between several surrogate estimates of insulin resistance and quantification of insulin-mediated glucose disposal in 490 healthy, nondiabetic volunteers. Diabetes Care 23:171-175, 2000.
  2. Lillioja S, Mott DM, Spraul M, et al. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin dependent diabetes mellitus N Engl J Med 329:1988-1992, 1993.
  3. Warram JH, Martin BC, Krowlewski As, et al. Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the off-spring of the diabetic parents. Ann Intern Med 113:909,1990.
  4. Reaven GM. Role of insulin resistance in human disease. Diabetes 37:1595-1607, 1988
  5. Reaven GM. Role of insulin resistance in human disease. Diabetes 37:1595-1607, 1988
  6. Executive summary of the third report of he national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA 285:2846-2497,2002
  7. Yeni-Komshian H, Carantoni M, Abbasi F, Reaven GM. Relationship between several surrogate estimates of insulin resistance and quantification of insulin-mediated glucose disposal in 490 healthy, nondiabetic volunteers. Diabetes Care 23:171-175, 2000.
  8. Reaven GM. Role of insulin resistance in human disease. Diabetes 37:1595-1607, 1988
  9. Reaven GM.The insulin resistance syndrome. Curr Atheroscler Rep 2003; 5; 364-371.
  10. Bernstein RJ, Davis BM, Olefsky JM, Reaven GM. Hepatic insulin responsiveness in patients with endogenous hypertriglyceridemia. Diabetologia 1978; 14:249-253.
  11. Skott P, Vaag A, Bruum NE, Hother-Nielsen O, Gall M-A, Beck-Nielsen H,Parving H-H. Effect of insulin on renal sodium handling in hyperinsulinemic type 2 (non-insulin-dependent) diabetic patients with peripheral insulin resistance. Diabetologia 1991; 34:275-281.
  12. Facchini FS, Riccardo A, Stoohs A, Reaven GM. Enhanced sympathetic nervous system activity- the linchpin between insulin resistance, hyperinsulinemia, and heart rate. Am J Hypertens 1996; 9:1013-1017.
  13. Reaven GM. The kidney: An unwilling accomplice in Syndrome X. Am Journal of Kidney Diseases 1997; 30: 928-931.
  14. Swislocki ALM, Chen Y-DI, Golay A, Chang MO, Reaven GM. Insulin suppression of plasma-free fatty acid concentration in normal individuals and patients with type 2 (non-insulin-dependent) diabetes. Diabetologia 1987; 30:622-626.
  15. Abbasi F, McLaughlin T, Lamendola C, Reaven GM. The relationship between glucose disposal in response to physiological hyperinsulinemia and basal glucose and free fatty acid concentrations in healthy volunteers. J Clin Endocrinol Metab 2000; 85:1251-1254.
  16. Facchini F, Chen YD-I, Hollenbeck C, Reaven GM. Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. JAMA 1991; 266:3008-3011.
  17. Facchini FS, DoNascimento C, Reaven GM, Yip JW, Ni PX, Humphreys MH. Blood pressure, sodium intake, insulin resistance, and urinary nitrate excretion. Hypertension 1999; 33:1008-1012.
  18. Dunaiff A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 1997; 18:774-800.
  19. Sanyal AJ, Campbell-Sargent C, Mirashi F, Rizzo WB, Contos MJ, Sterling RK, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 2001; 120:1183-1192.
  20. Reaven GM. Role of insulin resistance in human disease. Diabetes 37:1595-1607, 1988.
  21. Reaven GM.The insulin resistance syndrome. Curr Atheroscler Rep 2003; 5; 364-371.
  22. Bernstein RJ, Davis BM, Olefsky JM, Reaven GM. Hepatic insulin responsiveness in patients with endogenous hypertriglyceridemia. Diabetologia 1978; 14:249-253.
  23. Tuan C-Y, Abbasi F, Lamendola C, McLaughlin T, Reaven G. Usefulness of plasma glucose and insulin concentrations in identifying patients with insulin resistance. Am J Cardiol 2003; 92: 606-610.
  24. Reaven GM, Lerner R., Stern M, Farquhar JW. Role of insulin in endogenous hypertriglyceridemia. J. Clin. Invest. 46:1756-1767, 1967.
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