Does this sound like many of the patients we as nurses see today in any healthcare setting? You can probably answer “Yes,” but didn’t realize that this is a classic adult syndrome that can be detected and managed early before the cardiovascular problems develop.

In recent years, research and clinical practice have demonstrated that complex interrelationships exist between hyperglycemia, dyslipidemia, insulin resistance, obesity, and hypertension. These associated comorbidities are known by several names — syndrome X, insulin-resistance syndrome (IRS), metabolic syndrome, and cardiovascular-dysmetabolic syndrome. The latter term, coined by Prakash C. Deedwania, MD, professor of medicine at the University of California, San Francisco School of Medicine, reflects a strong connection between type 2 diabetes mellitus, insulin resistance, and cardiovascular disorders.

Although polycystic ovary syndrome has also been linked to insulin resistance, this module will only discuss type 2 diabetes mellitus and the cardiovascular problems associated with IRS.

A metabolic pathology

Insulin resistance is a metabolic state in which greater than normal amounts of insulin are required to produce a normal biological response. To understand how IRS develops, an understanding of the normal biological response caused by insulin’s actions is necessary. Insulin release occurs in two phases: an early phase within the first few minutes after the ingestion of carbohydrates triggers the release of insulin stored within the beta cells of the pancreas and a later phase includes insulin newly synthesized by the pancreas.

Likewise, the action of insulin involves two processes. First, insulin binds to a specific receptor on the cell surface (primarily of muscle and adipose). Second, the binding activates a series of intracellular events resulting in enhanced glucose transport. These intracellular events are known as “postbinding” events. Abnormalities in binding may reduce initial binding of insulin at specific cell surface receptors and lead to impaired insulin action. However, scientists believe a postbinding abnormality that occurs intracellularly is responsible for insulin resistance in persons with type 2 diabetes mellitus.¹

Insulin resistance is characterized by decreased uptake and metabolism of glucose in skeletal muscle and by hepatic overproduction of glucose. People with IRS have elevated insulin levels caused by the attempt to increase the uptake and metabolism of the glucose and prevent hyperglycemia (i.e., insulin resistance plus compensatory hyperinsulinemia). Eventually the pancreas is unable to secrete enough insulin to maintain euglycemia and the hyperglycemia of type 2 diabetes develops.

IRS and cardiovascular disease

Patients with IRS have a two- to three-fold increased risk of developing cardiovascular disease.² Several probable mechanisms underlie this relationship. IRS is characterized by dyslipidemias, including increased triglycerides, decreased HDL cholesterol levels, and compositional changes in low-density lipoprotein (LDL) cholesterol that makes it small and dense rather than fat and fluffy. Smaller, dense LDL particles are thought to be prone to oxidation, making them more likely to damage artery linings.³

Related to dyslipidemias, IRS may also increase CVD risk through its link to hypertension. Half of all people with hypertension are also insulin-resistant and have one or more of the clinical markers of IRS.⁴ Several studies have shown that the insulin resistance and compensatory hyperinsulinemia of IRS tend to raise BP. Changes in arterial walls in patients with hyperinsulinemia, and characteristic decreases in elasticity of the arterial wall have been noted in hypertensive persons with insulin resistance.⁵ An insulin-increased stimulation of the sympathetic nervous system is also believed to contribute to the hypertension. Hypertension is also associated with insulin-related salt and water retention.

IRS is also likely to be related to cardiovascular disease risk because of its role in promoting coagulation. An excess of both fibrinogen and PAI-1 (plasminogen activator inhibitor-1) have been found in people with IRS. Fibrinogen is a substance in the blood that causes the blood to clot to avoid excess bleeding. Once a clot has been formed and the body no longer needs it, fibrinolysis occurs. PAI-1 slows this fibrinolysis. This process takes place with both the “good” clots that are involved with normal wound healing and “bad” clots that form in blood vessel walls as part of the atherosclerotic process. People with IRS have higher levels of PAI-1, which then slows the breakdown of the clots that cause a myocardial infarction.

Recently, the immune system has emerged as a player in the relationship between IRS and CVD. Macrophages contain most of the insulin-signaling molecules, although the biological function of this pathway in these cells is largely unknown.⁶ When macrophages in the arterial wall become insulin-resistant, it can lead to a number of abnormalities which in turn lead to larger lipid-rich cores, increased inflammation, and therefore more vulnerable plaques.⁶

Inflammatory factors may also link IRS with CVD. C-reactive protein (CRP) and other markers of inflammation are associated with both an increased risk of CVD and with insulin resistance.^7,8 Further research is necessary to better understand this potential link.

Making the diagnosis

Unfortunately, accurate and cost-effective tests for detecting insulin resistance and hyperinsulinemia are not currently available. Instead, patients are screened for insulin resistance and possible cardiac risks using a variety of tools, including physical findings and laboratory data. The National Cholesterol Education Program - Third Adult Treatment Panel (NCEP ATP III) has established a set of clinical criteria for the identification of IRS.⁹ According to this definition, three or more of the following five risk factors are required for diagnosis:

1. Central obesity: waist circumference of >40 inches for men or >35 inches for women
2. Triglyceride levels of >150 mg/dL; or specific treatment for this lipid abnormality
3. HDL cholesterol levels of <40 mg/dL for men or <50 mg/dL for women; or specific treatment for this lipid abnormality
4. Blood pressure: systolic BP Ž130 mmHg or diastolic BP Ž 85 mmHg or treatment of previously diagnosed hypertension
5. Fasting glucose >110 mg/dL or previously diagnosed type 2 diabetes

Excessive upper body or abdominal fat is often cited as a major risk factor for insulin resistance and CVD. These people tend to have bodies that are apple- as opposed to pear-shaped. One of the easiest (and cheapest) tests to perform is the waist-to-hip girth ratio (WHR) for evaluating fat distribution. For these reasons waist-to-hip ratio is also sometimes used as a diagnostic marker of IRS.¹⁰ The ratio is derived from measuring the waist at the umbilicus and then measuring the hips at the widest point of the buttocks. Men with WHR values above 0.9 and women with WHR values above 0.85 are assumed to have dangerous percentages of abdominal body fat.¹⁰

It should be noted that several different guidelines have been put forth for the diagnosis of metabolic syndrome. There is also some uncertainty regarding its pathogenesis and even its value as a risk factor for CVD; as a result, some have seriously questioned its designation as a “syndrome.”¹¹ However, most major health organizations accept it as a legitimate condition, and further research should help answer many of the remaining questions.

Nonpharmacological interventions

Lifestyle modifications to achieve weight loss  are the cornerstone of managing insulin resistance syndrome. Nurses are in a key position to evaluate lifestyle behaviors and to promote regular physical activity  and dietary changes.

Weight loss will occur with proper diet and exercise. Even modest weight loss of 5% to 10% of body weight has been shown to improve lipids, glucose levels, and blood pressure.¹² It is important to emphasize this to patients who are disappointed with the results of their attempts to lose weight. Insulin sensitivity may improve regardless of weight loss if exercise and diet plans are implemented.¹²

Aerobic exercise has been shown to reduce insulin resistance by improving blood supply to the muscles, which allows for more glucose uptake into muscle tissue. Exercise should be frequent and regular to be effective. The 2005 Dietary Guidelines for Americans recommend that adults engage in at least 30 minutes of moderate-intensity physical activity, above usual activity, at work or home on most days of the week. It should be stressed to patients that even small increases at a gradual pace are beneficial. An “easy” exercise program might include a brisk walk around the neighborhood in the late afternoon. Remind patients that they should be able to talk normally during the exercise. If they are gasping for breath, they are probably exercising too hard.

Based on a review of the current evidence, a set of dietary recommendations for the treatment and prevention of IRS has been proposed:¹³

• Protein should contribute 10% to 20% of total daily energy intake
• Saturated and trans fats (combined) should contribute no more than 10% of total daily energy intake and should be less than 8% if blood LDL levels are high
• Cholesterol intake should be limited to 300 mg or less per day
• Carbohydrate intake should contribute 45% to 60% of total daily energy intake

A diet that is high in fiber is also thought to be beneficial. High dietary fiber intake has been shown to improve glucose tolerance, lower triglyceride and cholesterol levels, and reduce BP. Unfortunately, Americans typically consume only small amounts of whole grains and rely far more on refined carbohydrates, including white bread and pasta. Excessive refined carbohydrates may have a negative impact by raising blood glucose, insulin, triglycerides, and very low-density lipoprotein levels. Confusion over “good” carbohydrates (whole grains) versus “bad” (refined) ones may have contributed to the recent popularity of low-carbohydrate, “fad” diets that recommend limiting or eliminating carbohydrate intake.

The American Diabetes Association’s guidelines about carbohydrate intake include —

1. Monitoring total grams of carbohydrate using either exchanges or carbohydrate counting. Carbohydrate-rich foods should be spaced out so the body can pace carbohydrate absorption. Both sugar and starch need to be considered, as both digest into sugar.
2. The type of carbohydrate should also be considered by using the glycemic index/glycemic load to determine the glycemic effect of a food. Glycemic effect is the speed and degree to which a particular food raises blood glucose levels. In general, whole foods usually have a lower glycemic effect than refined, processed foods and juices. Good choices include fruits, vegetables, and whole grains, as well as legumes. When eaten alone, legumes have a very low glycemic effect. When eaten with other carbohydrates, they can actually lower the glycemic effect of the other foods. Legumes are also high in fiber.

There is some evidence that replacing trans and saturated fats with monounsaturated fats can enhance insulin sensitivity.¹⁴ This could be achieved by the substitution of animal fats with olive and canola oils and by substitution of red meat with fish and plant protein sources, such as beans, nuts, and soy.

Finally, sodium restriction is often recommended, especially for patients who have high BP. The DASH diet for blood pressure reduction provides a plan that lowers sodium consumption to around 1,500 mg per day. (See “Your Guide to Lowering Your Blood Pressure with DASH”, www.nhlbi.nih.gov/health/public/heart/hbp/dash/new_dash.pdf).

To be most successful, diet and physical activity plans must be highly individualized and involve a collaborative effort among the patient, the nurse, and other healthcare professionals. Also, it is usually better for a patient to make one or two small changes at a time, and allowing them to become normal habit before making more small changes. A major lifestyle overhaul that is done all at once is much less likely to be sustained over the long term.

Pharmacological interventions

Pharmacological treatment of IRS involves treating the medical conditions associated with the syndrome.

Hypertension: Management of hypertension in a person with insulin resistance is no different than managing hypertension in general. The first goal is to reduce the BP to <140/90 mmHg in people without type 2 diabetes, and 130/80 mmHg in those with diabetes.¹⁵

Six classes of drugs are used in the treatment of hypertension: diuretics, beta blockers, alpha blockers, calcium-channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs). There are special considerations when using these agents in patients who have both hypertension and the hyperglycemia of type 2 diabetes mellitus.

Diuretics, predominantly the thiazide diuretics, work by helping to reduce the amount of salt and water in the body. This, in turn, reduces blood volume and lowers BP. However, these agents have been known to increase triglyceride levels and lower HDL levels, which is just the opposite effect that is desired. Clinicians have also found over the years that there is a wide window between the antihypertensive effect of thiazide diuretics and their negative effect on glucose, lipid, and electrolyte metabolism. A very low dose of 12.5 mg of a thiazide diuretic can effectively lower BP without having a negative impact on the other clinical manifestations of IRS. If a patient who is taking a diuretic regularly monitors blood sugar, lipid, and potassium levels, adverse effects can be avoided with optimum BP control.

Beta blockers cause vasodilatation and a slowing of the heart rate. Beta blockers also reduce the level of catecholamines in the body. It is this effect that makes them effective in prolonging life after a heart attack. As with diuretics, there is also some risk that they may have negative metabolic effects, such as increasing blood LDL and triglyceride levels, or worsening insulin resistance.¹⁴ One study suggests that the beta blocker carvedilol may not exhibit these adverse effects.¹⁶

Alpha blockers, on the other hand, act by blocking the action of the alpha receptors, thus causing vasodilatation of the blood vessels as well. They do not cause any adverse effects on glucose or lipids.

Calcium-channel blockers were originally used and approved for treatment of angina. They have since been used widely for treatment of hypertension as well. None of the currently available agents have adverse effects on the clinical conditions associated with IRS.

ACE inhibitors are first-line agents for people with diabetes. ACE inhibitors lower blood pressure by blocking the angiotensin-converting enzyme and preventing the conversion of angiotensin I into angiotensin II, a powerful vasoconstrictor. In addition to their antihypertensive effect, they are also considered useful in reducing the progression of renal disease in people with diabetes. Cough is the major adverse effect noted with this class of drug, and they should be used cautiously in those with deceased renal function. Examples include ramipril (Altace), lisinopril (Zestril), and enalapril (Vasotec).

ARBs act by blocking the effect of angiotensin II on specific tissue receptors. They also should be used cautiously in persons with decreased renal function. Examples include valsartan (Diovan) and losartan (Cozaar).

Hypertriglyceridemia: Triglyceride levels rarely rise unless a person is experiencing insulin resistance and the compensatory hyperinsulinemia. Drugs used to treat this include the fibric acid derivatives, gemfibrozil (Lopid) and fenofibrate (Tricor). Niacin (nicotinic acid) is also used, but glycemic control needs to be monitored closely with this agent.

Elevations of LDL, more specifically the small, dense LDL, can be managed with a class of lipid-lowering agents known as HMG CoA reductase inhibitors or “statins.” Examples include pravastatin (Pravachol) and atorvastatin (Lipitor). Second-line agents for this form of dyslipidemia are the bile acid-binding resins, such as cholestyramine (Questran).

Hyperglycemia: Insulin resistance and the subsequent hyperinsulinemia, of course, progress to the hyperglycemia of type 2 diabetes. When the pancreas can’t continue to keep up with the demand for more insulin, hyperglycemia results. Until the last few years, clinicians treated this hyperglycemia with drugs that stimulated the pancreas to produce more insulin to the point of beta-cell exhaustion. A relatively new class of drugs, known as the thiazolidinediones (TZDs) or insulin sensitizers, may be able to prevent some of the hyperglycemia and beta cell exhaustion that occurs. Informally known as “glitazones,” TZDs make available insulin more effective by making muscle cells more sensitive to insulin and decreasing insulin resistance. They don’t stimulate the production of insulin that would only further contribute to hyperinsulinemia. These drugs make the cells more sensitive to their own insulin via stimulation of peroxisome-proliferator-activated receptor-gamma (PPAR-y) in the nucleus of the individual cells. This action enhances insulin action at the receptor and postreceptor level in hepatic and peripheral tissues. Adverse effects associated with this class include elevated liver enzymes. Rare cases of severe idiosyncratic hepatocellular injury occurred with troglitazone (Rezulin), the first drug in this class. Troglitazone was subsequently withdrawn from the market. Weight gain is a most-noted effect seen with the TZDs. The two TZDs currently on the market are pioglitazone (Actos) and rosiglitazone (Avandia).

Finally, insulin resistance can result in hepatic overproduction of glucose, which is regulated by insulin. A class of medications — biguanide agents such as metformin (Glucophage) — can reduce the hepatic overproduction of glucose caused by insulin resistance. This reduction in hepatic glucose production is achieved primarily by a reduction of glycogenolysis — the breakdown of glycogen, a storage form of glucose in muscle and the liver. There are some reported reductions in triglyceride concentrations with the use of metformin. It should not be used in people with renal or hepatic dysfunction. The typical candidate for metformin therapy is the patient with type-2 diabetes, hyperlipidemia, and obesity.

Inflammation: While no specific drug is available to reduce the inflammation that accompanies IRS, drugs that are commonly used (statins, fibrates, ACE inhibitors, and thiazolidinediones) may have some antiinflammatory action.¹⁴ So when these drugs are otherwise indicated, a reduction in CRP and other inflammatory proteins may also result.

So let’s take a closer look at Jim. Do you think he has IRS? The only objective data we know so far is that he is obese, has a history of hypertension, and has developed cardiovascular disease. We don’t know if he has hyperglycemia or hyperlipidemia. What if he does have elevated triglycerides and hyperglycemia, too? Could we have intervened earlier? If you had been able to intervene earlier, what type of things would you have done before he reached this stage in the health-illness continuum?