SYMPOSIUM ON INSULIN RESISTANCE

Understanding insulin resistance

What are the clinical implications?

William I. Sivitz, MD

VOL 116 / NO 1 / JULY 2004 / POSTGRADUATE MEDICINE

CME learning objectives

• To review the pathogenesis of insulin resistance
• To learn how insulin resistance is assessed in the research setting
• To understand the clinical implications of insulin resistance

The author discloses no financial interests in this article and no unlabeled uses of any product mentioned.

Preview: Insulin resistance is an important clinical issue in patients with other prominent components of metabolic syndrome, such as central adiposity and diabetes. However, its presence may be less evident in patients who are neither obese nor diabetic. Is measurement of insulin resistance important in clinical practice? How might its presence change management in individual patients? In this concise review, Dr Sivitz discusses the underlying mechanisms involved in insulin resistance, the issues surrounding assessment, and the implications for management in patients in whom insulin resistance is either detected or suspected.
Sivitz WI. Understanding insulin resistance: What are the clinical implications? Postgrad Med 2004;116(1):41-8

Insulin resistance is often considered a central component of metabolic syndrome, now a well-recognized clinical problem that significantly increases the risk of cardiovascular morbidity and mortality (1). In fact, among other names, metabolic syndrome has been referred to as insulin resistance syndrome. This article addresses the definition and identification of insulin resistance, the underlying pathophysiologic mechanisms involved, and the implications for clinical assessment and management.

Definition

Although insulin resistance is not difficult to appreciate when present in certain common clinical scenarios, the definition of this disorder is more conceptual than precise. As a medical student years ago, I recall being taught that insulin resistance was present when a patient required a dose of at least 100 U of insulin for blood glucose control. Today the definition is more commonly stated in conceptual terms, that is, that insulin resistance is present when an abnormally large amount of insulin (endogenous or exogenous) is required for a normal biologic response (2). Although this definition makes the clinical diagnosis somewhat subjective, it emphasizes the importance of the concept rather than strict definition.

Diagnostic considerations

In certain clinical situations, insulin resistance is very likely, and rigorous testing for its presence does not change management. For example, insulin resistance would be expected in obese persons with hypertriglyceridemia and low levels of high-density lipoprotein cholesterol (3). It is often, but not always, present in obese persons in spite of normoglycemia (3). In such persons, insulin secretion rates in the basal state and after meals are often more than twofold higher than those in their lean counterparts (4).

Insulin concentrations are usually high early in type 2 diabetes, but because there is a defect in pancreatic beta-cell function, the levels are not high enough to compensate for the insulin resistance (5,6). As diabetes worsens, circulating insulin concentrations begin to drop, resulting in progressively severe hyperglycemia. This concept is evident in figure 1, which illustrates recent data that my colleagues and I (7) collected mainly for characterization of a research population. The data were as expected and similar to that reported by many other investigators (8). Figure 1a shows that insulin resistance worsens with obesity and increasing glycemia and is marked even in relatively mild diabetes. Figure 1b typifies the inverted U-shaped curve noted when insulin concentrations are plotted against glycemia over a spectrum of persons with early to severe diabetes, a pattern that has been termed the Starling curve of the pancreas (6).

Insulin resistance is also present in many persons who are not obese or diabetic but who have other components of metabolic syndrome, such as hypertension, hyperlipidemia, or polycystic ovary syndrome (9,10). In these patients, insulin resistance may not be so evident. Nonetheless, it is not common clinical practice to test for the presence of insulin resistance because it is not simple to measure (see box "Techniques for assessing insulin sensitivity" at end of article) and because its documented presence or absence likely would not change management as long as attention is directed at the more clearly identifiable components of metabolic syndrome.

Why not just measure insulin and glucose levels to determine insulin sensitivity? This is a reasonable approach for patients in the fasting state who are euglycemic. In this setting, high insulin levels would imply insensitivity. However, a major problem develops when insulin release is impaired, as in developing diabetes, because lower insulin levels lead to the false impression of greater sensitivity. Mathematical means have been proposed to get around this issue by considering the fasting glucose and insulin levels together (11). However, these methods suffer from variability and methodologic differences between laboratories and do not correlate rigorously with glucose clamp studies (12). Another problem is that normal plasma insulin concentrations are not standardized or typically reported relative to levels in healthy controls.

Pathogenic factors

The pathogenesis of insulin resistance can be understood on two levels: its effects on the metabolic processes involving the whole body and its effects at the cellular level.

Whole-body physiology
Figure 2 depicts the metabolic actions of insulin on energy utilization by major organs. The figure shows the positive and negative effects of insulin at specific peripheral sites and implies that blood glucose levels are regulated by the balance between glucose output and peripheral utilization. Muscle is the chief insulin-dependent site of glucose use; it accounts for about 95% of insulin-mediated glucose uptake (13). In the fasting state, whole-body glucose use is 2.0 to 2.5 mg/kg of body weight per minute, or about 10 g/hr in an adult weighing 70 kg (156 lb) (14). Because the liver is the primary site for storage and release of glucose, hepatic glucose output must keep pace.

Brain and blood cells have an obligate need for glucose independent of insulin, and they use the majority of the fasting hepatic output in the resting state. Nonetheless, the constant nature of this demand means that glucose use by brain and blood cells does not change the balance between overall glucose uptake and utilization and, therefore, does not have substantial effects on plasma glucose levels. In contrast, muscle needs glucose in variable amounts, depending on activity level and insulin concentration. Hence, the major determinant of circulating glucose levels is the balance between the insulin-dependent processes of hepatic glucose output and muscle glucose utilization.

Insulin also has significant effects on fat and protein metabolism, and the interplay between the fluxes of various nutrients is critical to understanding insulin resistance. With nutrient excess or obesity, wherein free fatty acids circulate in increased amounts, this interplay may be competitive, and overall substrate excess appears to lead to states termed lipotoxicity and glucotoxicity (14). These states have been implicated in the pathogenesis of insulin resistance. For example, infusion of glucose or lipid for a long enough period decreases insulin action on peripheral glucose uptake. Moreover, increased delivery of free fatty acids to the liver impairs the effect of insulin to reduce hepatic glucose output.

Fat distribution, as opposed to total body fat, may be a critical factor, because insulin resistance is now well known to be associated with intra-abdominal fat (15,16). This association may be due to increased delivery of fat directly to the liver through the portal circulation. Of interest, the enzyme 11-beta-hydroxysteroid dehydrogenase type 1 (11-beta-HSD1) may be up-regulated in obesity (17). The enzyme generates active cortisol from inactive cortisone and is expressed to a greater extent in omental fat than in subcutaneous fat. It has been hypothesized that this process results in a type of localized Cushing's syndrome, which potentially encourages central adiposity and insulin resistance. Thus, it is possible that inhibitors of 11-beta-HSD1 may be effective for treating insulin resistance.

Cellular mechanisms
Except in a few rare cases involving antibodies to the insulin receptor or mutations in the insulin receptor gene, the insulin resistance of diabetes results from impairments in cellular events distal to the interaction between insulin and its surface receptor (2). Significant progress has been made in recent years toward an understanding of the intracellular signaling events that mediate insulin action (18-22).

Figure 3 presents a highly simplified illustration of two major signaling pathways activated by insulin binding to its receptor. The pathways have been termed the phosphatidylinositol-3'-kinase (PI3K) pathway and the mitogenic, or mitogen-activated protein (MAP) kinase, pathway (19). As indicated in the figure, activation of these pathways has different consequences. Although the PI3K pathway is important in mediating the metabolic effects of insulin, activation of MAP kinase is associated with cell growth and proliferation and may also have procoagulant effects. As discussed later, the balance between the extent to which one or another pathway is impaired may be central to understanding how clinical complications of insulin resistance might arise.

Although much has been accomplished, the signaling pathways are still a work in progress. More information is needed about not only the PI3K and MAP kinase pathways but also other potential signaling mechanisms. For example, there is now ongoing effort to determine the role of a putative separate pathway triggered by insulin action on surface receptors within cell invaginations known as caveolae (18). This pathway may be important in mediating the effects of actin on the movement of glucose transporters.

Any molecular genetic defect in the insulin-signaling cascade could potentially cause the insulin resistance seen in metabolic syndrome and type 2 diabetes. Although isolated cases may be explained by specific defects, no particular abnormality is currently identified that can explain insulin resistance in its commonly appreciated clinical form.

Ultimately, insulin-mediated peripheral glucose uptake is mediated through glucose transporters. Glucose transporter subtype 4 (GLUT4) is the insulin-responsive transporter in muscle, the major site of insulin-mediated glucose disposal. Because no defect in the expression of GLUT4 has been identified in persons with type 2 diabetes or obesity, the likely explanation for resistance to the glucose-lowering effect of insulin is a defect in the signaling pathways that regulate the cycling or translocation of GLUT4 (20).

Glucotoxicity or lipotoxicity may impair insulin-mediated pathways. For example, it has been proposed that glucose may activate the glucosamine 6-phosphate pathway, which inhibits the signal cascade from the insulin receptor to glucose transport (14). Lipotoxicity may be explained by the Randle (glucose-fatty acid) cycle. The underlying concept is that fatty acid oxidation and glucose oxidation are competitive, so excessive fat metabolism impairs the oxidation of glucose, perhaps as a means of protecting the cell against excessive fuel utilization. However, other, more recent explanations for lipotoxicity involve fatty acid inhibition of cellular glucose entry through inhibition of one or more steps in the insulin-signaling cascade (23). Fatty acids also decrease glucose incorporation into glycogen for storage and stimulate hepatic glucose output (22).

Clinical implications

The main implications of insulin resistance for clinical care are listed in the box "Main clinical implications of insulin resistance" at the end of this article. As detailed in the article by Dr. Doelle in this symposium, insulin resistance keeps bad company with diabetes, obesity, hypertension, hyperlipidemia, and atherosclerotic events. Nonetheless, it is reasonable to question whether insulin resistance, in itself, is actually a negative process. In most cases, no exact metabolic step can be assigned as the causative mechanism. In fact, a glance at figure 3 indicates that any of a multitude of genetic defects in known or unknown pathways might be involved in a given person. Would all of these defects be harmful? Or could insulin resistance even have benefits? For example, resistance to insulin at the adipose cell may protect against further nutrient accumulation within fat cells, thereby acting in a compensatory fashion.

There is good reason for concern about detrimental effects. If insulin resistance involved only a receptor defect, it might be overcome by simply treating with enough insulin. However, as mentioned, receptor defects are responsible for insulin resistance only in rare cases. So, it seems that the location of the defect in insulin action should have a major impact on the consequences of insulin therapy.

For example, consider that insulin resistance, as generally seen in metabolic syndrome, appears to involve the PI3K pathway. In order to control blood glucose levels, the pancreas must secrete enough insulin (or enough exogenous insulin needs to be administered) to overcome resistance in this pathway. However, the resulting hyperinsulinemia would increase the activity of other pathways, particularly the MAP kinase pathway. The consequences of this activity may be proatherogenic and include, for example, smooth-muscle proliferation, increased expression of cell adhesion molecules, and elevated levels of plasminogen activator inhibitor.

An important corollary of the aforementioned process is that treatment of insulin resistance distal to the insulin receptor in a way that would selectively enhance the PI3K pathway would decrease levels of glucose and circulating insulin and diminish the activity of the MAP kinase pathway, thereby reducing factors that favor atherogenesis. In fact, this corollary provides important rationale for the use of thiazolidinediones to activate peroxisome proliferator activator receptor gamma in the hope that these agents will reduce vascular risk in diabetic patients (21). Nevertheless, caution is warranted because outcome data for thiazolidinediones in terms of actual vascular events is still lacking, and there are potential adverse effects. Metformin hydrochloride (Glucophage) also enhances insulin action and lowers plasma insulin levels. However, the site of action of this drug is not clear, so little can be surmised about its effects on particular metabolic pathways.

Quantifying insulin resistance
Is it important to quantify insulin resistance in the clinical setting? Unfortunately, the best methods to measure insulin sensitivity are either too expensive, too labor-intensive, or too involved and uncomfortable for practical use in clinical medicine. Probably the easiest way to measure insulin sensitivity is to obtain the fasting insulin level at euglycemia. However, this measurement is not very useful once the blood glucose level begins to increase, it lacks accuracy, and it is difficult to standardize because of variation between assays (24). In contrast, a means of identifying insulin resistance has recently been proposed that is based on cut points in values not only for insulin, but for triglycerides or the ratio of triglycerides to high-density lipoprotein cholesterol (3). Although such measures might impact therapy in some patients, it could be argued that in patients with features of metabolic syndrome, management would always include nutritional counseling and exercise with additional focus, as needed, on specific, more easily quantified components of the syndrome.

Treating insulin resistance
Is there value in treating insulin resistance per se in the absence of hyperglycemia or in patients with impaired fasting glucose? There appear to be situations in which treatment directed at insulin resistance in euglycemic or mildly hyperglycemic patients may be of value. Certainly, treatment with proper nutrition and exercise is advisable. In patients who have impaired fasting glucose or impaired glucose tolerance, treatment with diet and exercise or metformin reduces the risk of diabetes (25). Perhaps this approach can be extended to euglycemic persons at high risk for diabetes. Another potential scenario for treating insulin resistance is polycystic ovary syndrome, in which use of metformin in insulin-insensitive normoglycemic patients may improve menstrual dysfunction (26).

Conclusion

The pathogenesis of insulin resistance as commonly seen in diabetes, obesity, and metabolic syndrome remains unresolved and may be diverse. Many potential molecular defects may lead to insulin resistance, and the disorder may manifest in diverse cells and tissues. Insulin resistance and reduced beta-cell function are the major factors leading to type 2 diabetes. Insulin resistance is also strongly associated with other components of metabolic syndrome. Although it remains unclear whether insulin resistance per se is a primary cause of some or all of these components, common treatment strategies that improve insulin resistance also improve other components of metabolic syndrome and should reduce the risk of vascular disease.

References

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6. DeFronzo RA. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 1988;37(6):667-87
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12. Pacini G, Mari A. Methods for clinical assessment of insulin sensitivity and beta-cell function. Best Pract Res Clin Endocrinol Metab 2003;17(3):305-22
13. Flakoll P, Carlson MG, Cherrington A. Physiologic action of insulin. In: LeRoith D, Taylor SI, Olefsky JM, eds. Diabetes mellitus: a fundamental and clinical text. Philadelphia: Lippincott-Raven, 1996:121-31
14. Sivitz WI. Lipotoxicity and glucotoxicity in type 2 diabetes: effects on development and progression. Postgrad Med 2001;109(4):55-64
15. Bonora E. Relationship between regional fat distribution and insulin resistance. Int J Obes Relat Metab Disord 2000;24(Suppl 2):S32-5
16. Kelley DE, Goodpaster BH. Skeletal muscle triglyceride: an aspect of regional adiposity and insulin resistance. Diabetes Care 2001;24(5):933-41
17. Stewart PM, Tomlinson JW. Cortisol, 11 beta-hydroxysteroid dehydrogenase type 1 and central obesity. Trends Endocrinol Metab 2002;13(3):94-6
18. Khan AH, Pessin JE. Insulin regulation of glucose uptake: a complex interplay of intracellular signalling pathways. Diabetologia 2002;45(11):1475-83
19. Reusch JE. Current concepts in insulin resistance, type 2 diabetes mellitus, and the metabolic syndrome. Am J Cardiol 2002;90(5A):19-26G
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Techniques for assessing insulin sensitivity Elaborate methods have been developed to quantify insulin sensitivity in the research setting (1,2). Many investigators consider the euglycemic clamp technique to be a "gold standard." In this method, a high but steady circulating insulin level is maintained by constant insulin infusion while the blood glucose level is frequently monitored. Glucose concentrations are maintained at euglycemia (for the fasted state) by an adjustable-rate glucose drip. The amount of glucose needed to maintain normoglycemia per unit of time is an index of sensitivity to the administered insulin. Isotopic techniques can be used during euglycemic clamp experiments to determine the amount of endogenous glucose released by the liver (an index of hepatic insulin sensitivity), whereas the difference between the administered glucose and endogenous glucose represents peripheral (mainly muscle) insulin sensitivity. Another common research technique to assess insulin sensitivity is known as the minimal model, or frequently sampled intravenous glucose tolerance test. This technique requires intravenous infusion of glucose followed by frequent blood sampling to measure insulin and glucose concentrations. The data are then fitted to a mathematical, computerized model of insulin-dependent glucose utilization. The computer fits the data, calculates model parameters from the data fit, and uses these parameters to calculate the insulin sensitivity index. This method is easier to perform than the euglycemic clamp technique and does not require constant insulin administration. However, the minimal model is not precise in the very subjects in whom it might be most useful, that is, patients with diabetes or more marked insulin resistance. This approach may be best suited for studies of large numbers of subjects, wherein variability tends to average out. Several other methods for determining insulin sensitivity have been described, including variations of the clamp technique, insulin action after oral intake, and glucose clearance (1). Some of these methods (as well as the minimal model) enable assessment of insulin secretory capacity in addition to sensitivity. References Pacini G, Mari A. Methods for clinical assessment of insulin sensitivity and beta-cell function. Best Pract Res Clin Endocrinol Metab 2003;17(3):305-22 Bergman RN, Finegood DT, Ader M. Assessment of insulin sensitivity in vivo. Endocr Rev 1985;6(1):45-86

Main clinical implications of insulin resistance Insulin resistance is strongly associated with the other features of metabolic syndrome. It remains unclear whether insulin resistance is a primary cause of vascular disease or other aspects of metabolic syndrome. The potential causes of insulin resistance are diverse. Different causes may eventually prove to have different clinical implications. Insulin resistance can be quantified in research studies, but the methods are complex and not suited to individual patients in the clinical setting. Improving insulin resistance with diet, exercise, or pharmacologic insulin sensitizers generally improves other aspects of metabolic syndrome. The indications for treating insulin resistance with pharmacologic insulin sensitizers in the absence of hyperglycemia are still evolving.

Dr Sivitz is professor of medicine, department of internal medicine, division of endocrinology and metabolism, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, and staff physician, Iowa City Veterans Affairs Medical Center. Correspondence: William I. Sivitz, MD, Department of Internal Medicine, The University of Iowa Hospitals and Clinics, 3E-17 VA, Iowa City, IA 52246. E-mail: william-sivitz@uiowa.edu.

Symposium Index

• THE CLINICAL PICTURE OF METABOLIC SYNDROME: An update on this complex of conditions and risk factors. By Gregory C. Doelle, MD
• UNDERSTANDING INSULIN RESISTANCE: What are the clinical implications? By William I. Sivitz, MD
• Clinical Commentary. NEW CHALLENGES IN CARING FOR DIABETIC PATIENTS: Primary care physicians can get caught in the middle. By Robert Spanheimer, MD

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