Number 30, 2006
Metabolic syndrome and its management

What is insulin resistance?

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Gurushankar Govindarajan, Harvinder Gill, Michael Rovetto, James R. Sowers
University of Missouri School of Medicine, Departments of Internal Medicine and Medical Pharmocology and Physiology, and Harry S. Truman VA Medical Center, Columbia, MO, USA
Correspondence: James Sowers, Department of Internal Medicine, Division of Nephrology, MA410, DC043.00, One Hospital Dr., Columbia, MO 65212, USA.
E-mail: sowersj@health.missouri.edu

Definition of insulin resistance
Insulin resistance is a state in which there are impaired biological and physiological responses to insulin in tissue. In its early stages, there is a compensatory increase in insulin concentrations. Although hyperinsulinemia may compensate for resistance to some biological actions of insulin, it may result in overexpression of actions in tissues that retain normal or minimally impaired sensitivity to insulin. This metabolic dysfunction leads to a cluster of abnormalities with serious clinical consequences – most importantly, cardiovascular disease (CVD), chronic kidney disease and type 2 diabetes.

Mechanism of insulin resistance
Insulin resistance can be caused by prereceptor, receptor, or postreceptor abnormalities [1]. Prereceptor causes include the presence of anti-insulin antibody and abnormal insulin (mutation). The receptor causes for insulin resistance include decreased number of receptors, structural modification of the insulin receptor, and the presence of insulin receptor-blocking antibody. Both prereceptor and receptor causes of insulin resistance occur infrequently; the most usual cause is postreceptor in nature and involves the postreceptor signaling pathway.
Insulin has many physiological effects, which can be divided into acute and chronic: the acute effects include those that regulate intermediary metabolism, and chronic effects include the growth and proliferative effects of insulin. These two different actions are possible because of activation of two different cascades of actions by insulin. One pathway transmits the insulin signal through insulin receptor substrate (IRS) proteins and phosphatidyl inositol 3-kinases (PI3-K) to a series of intracellular proteins (Figure 1). Activation of this pathway is crucial for transducing the actions of insulin/insulin like growth factor-1 (IGF-1) in cardiovascular tissue, in addition to conventional insulin-sensitive tissues [1]. PI3-K mediates the increases in nitric oxide, Na⁺ pump, K⁺ channel, and calcium (Ca²⁺) myofilament sensitivity by increasing the trafficking and translocation of nitric oxide synthase and cation pump units, in addition to glucose transporters. The second pathway involves activation of the mitogen-activation protein kinase (MAPK) pathway^*, which increases growth and mitogenic processes [2,3]. In the vast majority of patients, the insulin resistance observed clinically is one that involves glucose metabolism through the PI3-K pathway (Figure 2). For this reason, the term ‘insulin resistance’, as used in clinical and experimental settings, is a state in which there is impaired glucose metabolism. Therefore, resistance to the actions of insulin and IGF-1 in these tissues occurs whenever there is reduced activation of PI3-K. In biological and physiological terms, however, it could apply to impaired response of the tissue to either of the two pathways.

Etiology of insulin resistance
Insulin resistance is postulated to have a genetic etiology, as it is observed to run in families. Other notable causes for insulin resistance include obesity and lack of exercise. Indeed, weight loss and exercise tend to reduce insulin resistance. Other causes of insulin resistance are listed in Table I.

Table I. Major causes of insulin resistance.

Prevalence of insulin resistance
The prevalence of insulin resistance in the general population varies with the criteria used for its definition. In certain studies it has been estimated that insulin resistance is prevalent in 30% of the adult population [4]. The prevalence of the condition is even greater in metabolic disease such as diabetes and the cardiometabolic syndrome [5]. Table II. lists the prevalence of insulin resistance in various disease entities. The increased prevalence of insulin resistance and the consequent cardiometabolic syndrome is being increasingly recognized in the USA, as obesity is becoming a major epidemic [6].

Table II. Prevalence of insulin resistance (IR) in certain clinical states. (From the Bruneck Study [5], with permission.)

Insulin resistance and type 2 diabetes mellitus
Insulin resistance predates the onset of clinical type 2 diabetes mellitus by years. Most people have β-cell function that is adequate to fulfill normal tissue insulin requirements; the majority of these people also have considerable reserve, and could increase their insulin secretion considerably if necessary. However, a significant segment of the population exists that has limited reserve function. In this population, insulin resistance increases the insulin requirement of the tissue beyond the secretory capacity of the β cells. The recent surge in the incidence of diabetes mellitus worldwide can be attributed to an increased prevalence of insulin resistance in the general population as a result of the epidemic of obesity.

Insulin resistance and hypertension
It is estimated that about 25–47% of individuals with hypertension have insulin resistance [7]. Similarly, there is considerable evidence for an increased prevalence of hypertension in disease processes associated with insulin resistance, such as type 2 diabetes mellitus [8]. Several mechanisms have been postulated for the high prevalence of insulin resistance in patients with essential hypertension (Table III) [9,10]. Some of the mechanisms suggested to underlie the coexistence of insulin resistance and hypertension include [11–17]:

• upregulation of the renin–angiotensin–aldosterone system;
• activation of the sympathetic nervous system;
• increased renal tubular sodium retention;
• increased intracellular calcium concentration;
• vascular smooth muscle cell proliferation and atherosclerosis;
• impaired nitric oxide metabolism in skeletal muscle.

Table III. Mechanisms of insulin resistance in hypertension.

Insulin resistance and the cardiometabolic syndrome
Metabolic dysfunction associated with insulin resistance leads to a cluster of abnormalities with serious clinical consequences – most importantly, CVD, type 2 diabetes mellitus, or both. This cluster of CVD and diabetic risk factors (which include central obesity, hypertension, dyslipidemia, microalbuminuria, and hypercoagulability) is known as the cardiometabolic syndrome. It was identified in 1988 by Reaven, who named the cluster ‘syndrome X’ [20]. Since Reaven, it has been given many other names; the more popular ones that are still applied to it include: the insulin resistance syndrome, the deadly quartet, obesity dyslipidemic syndrome, and the metabolic syndrome. This collection of risk factors increases the risk of CVD endpoints, such as stroke, congestive heart failure, chronic kidney disease, and overall mortality [6,10,21–23] (Table IV). The presence of even one or two of the risk factors multiplies the risk for both CHD and CVD [24]. The World Health Organization (Table V) [25] and the National Cholesterol Education Program (Table VI) [26] have produced diagnostic criteria for the identification of this syndrome among the general population (Figure 2).

Table IV. The manifestations of metabolic syndrome that are associated with increased risk of cardiovascular disease.

Table V. World Health Organization (WHO) clinical criteria for metabolic syndrome. (Data from Alberti et al. [26].)

Table VI. National Cholesterol Education Program–Adult Treatment Panel III clinical identification of the metabolic syndrome. (Adapted from McFarlane et al. [6], with permission.)

Polycystic ovarian disease
Polycystic ovary syndrome (PCOS) is an exceptionally common disorder of premenopausal women, characterized by hyperandrogenism and chronic anovulation. The condition affects about 5–10% of women in the reproductive age group. Insulin resistance has proved to be a key factor in the pathogenesis of PCOS. The treatment of PCOS has, so far, been focused on treatment of the clinical signs and symptoms. Oral contraceptives have been the standard treatment. There is now a greater focus on the management of the metabolic consequences of PCOS, primarily through lifestyle intervention to achieve weight loss and increase physical activity. Insulin-sensitizing drugs such as metformin and thiazolidinediones have proved to be effective in the management of the metabolic disturbances, anovulation, and hirsutism, and are now widely accepted therapies.

Laboratory studies to identify insulin resistance
The gold standard for the assessment of insulin resistance is the euglycemic hyperinsulinemic clamp test [27]. This technique involves the continuous intravenous administration of insulin and glucose over 3 hours, and the calculation of insulin sensitivity (the inverse of insulin resistance) by measuring the amount of glucose required to maintain normal glucose concentrations (euglycemia). However, the technique is impractical for routine clinical use, and therefore a number of surrogate indexes for insulin sensitivity or insulin resistance have been developed. The simplest and most commonly used marker in clinical practice is the homeostasis assessment (HOMA) model, which requires measurement only of the fasting plasma insulin and plasma glucose [28]. Using a patient's fasting blood values, the HOMA index for insulin resistance (HOMA-IR) can be calculated (Table VII):

Table VII. HOMA index for insulin resistance (HOMA-IR).

Treatment of insulin resistance
Therapeutic lifestyle changes and drug treatment for individual components of insulin resistance are the current norm of clinical practice. Lifestyle changes – including a healthy diet and regular exercise – contribute to weight loss, improved blood glucose control, and reduced hypertension and other cardiovascular risk factors, and can even prevent the development of type 2 diabetes mellitus in persons with insulin resistance. When the therapeutic lifestyle changes are not sufficient, pharmacotherapy with an insulin sensitizer should be added. The thiazolidinediones are the only drugs approved specifically for the treatment of insulin resistance. Thiazolidinediones are novel drugs that specifically target insulin resistance. They are agonists for the nuclear transcription factor, peroxisome proliferator-activated receptor-γ, and reduce insulin resistance and increase the uptake of glucose into peripheral tissues, which results in decreased insulin concentrations; they are also involved in lipid metabolism.

Conclusion
In summary, the development of insulin resistance can have a profound impact upon a number of disease states and has led to the widespread prevalence of the cardiometabolic syndrome. As researchers are becoming able to identify the mechanism of insulin resistance, health care professionals will be able to counsel and treat their patients in a more effective manner. This will be of the utmost importance in the years to come, as the epidemic of diabetes continues to grow and afflict people all around the world.
^* See glossary for definition of these terms.

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