Insulin Resistance - A Weighty Issue

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October 18, 2004

Insulin Resistance — A Weighty Issue
By Alison J. Rigby, PhD, MPH, RD
For The Record
Vol. 16 No. 21 Page 28

Findings from the third National Health and Nutrition Examination Survey (NHANES) indicate that up to 20% of the U.S. population has insulin resistance (IR), of which approximately one in four will ultimately develop type 2 diabetes mellitus1 when the beta cells of the pancreas can no longer secrete sufficient insulin to maintain euglycemia.

Diabetes mellitus and obesity are reaching epidemic proportions, and cardiovascular disease (CVD) continues to be the leading cause of death in the United States. The core metabolic defects associated with diabetes mellitus include impaired glucose tolerance, IR, and proinflammatory and prothrombotic states, which lead to endothelial dysfunction and accelerated atherogenesis.2

As a result of the Adult Treatment Panel (ATP) III report, “The 2001 National Cholesterol Education Program guidelines on the detection, evaluation and the treatment of elevated cholesterol in adults,” this has substantially increased the number of persons considered at risk for coronary heart disease (CHD).3 Patients can be assessed for absolute CHD risk based on the Framingham Point Scale. Therefore, this has also expanded the number of persons eligible for drug and lifestyle interventions, including exercise and diet.

ATP III Criteria
ATP III guidelines recommend that the clinical diagnosis of metabolic syndrome (MS) require the presence of three or more of the following components:

• abdominal obesity (waist circumference >102 centimeters in men and >88 centimeters in women);

• elevated blood pressure level (systolic blood pressure =130 millimeters of mercury or diastolic =85 millimeters of mercury);

• elevated triglycerides (=150 milligrams per deciliter);

• decreased high-density lipoprotein (HDL) cholesterol (<40 milligrams per deciliter in men and <50 milligrams per deciliter in women); and

• elevated fasting glucose (>110 milligrams per deciliter).

MS is a constellation of lipid and nonlipid risk factors for cardiovascular disease, including fasting hyperglycemia, abdominal obesity, dyslipidemia, and hypertension. The syndrome is closely linked to the generic metabolic condition called IR and behavioral risk factors such as smoking, physical inactivity, and excess body fat.

The World Health Organization has also outlined specific criteria for the diagnosis of MS. These criteria include a body mass index (BMI) of >30 kilograms per square meter, waist/hip ratio >0.9 in men and >0.85 in women, and microalbuminuria (with specifics for urinary albumin excretion rate). There are slight differences in hypertension and dyslipidemia cut-off points and with the glucose parameter requiring diabetes mellitus-type 2 or impaired glucose tolerance (IGT).4 MS is confirmed with two criteria with type 2 diabetes mellitus or IGT and three criteria with normal glucose tolerance. Drug therapy may also be used to treat individual components of the syndrome, such as elevated blood pressure, dyslipidemia, and elevated glucose levels.5

MS was proposed as being diagnostic. However, it is clearly recognizable that there are potential problems associated with this—for example, measuring waist circumference and the reliability of this being done if at all and also accurately in a standardized format in a physician’s office. A recent study that critically evaluated the ATP III criteria in identifying IR with dyslipidemia found IR was associated with increased waist circumference, fasting glucose, triglycerides, and decreased levels of HDL cholesterol.6 Only 12.2% of study subjects met ATP III criteria for MS, and ATP III criteria exhibited low sensitivity for detecting IR. Although high in specificities (>90%), the sensitivity of ATP III criteria ranged only between 20% and 50%.

Syndrome X
The definition of syndrome X is a cluster of abnormalities associated with resistance to mediated glucose uptake that increase risk of CHD. This concept was pioneered in 1988 by Gerald Reaven, MD, at Stanford University, an international authority on IR and carbohydrate metabolism.7

Characteristics of syndrome X include the following:

• IR;

• hyperinsulinemia;

• varying degree of glucose intolerance;

• hypertension;

• elevated plasma triglyceride concentration; and

• decreased plasma HDL cholesterol concentration.

Effects of IR
IR is a cause of human disease. It occurs when target tissues in the body cannot respond properly to normal concentrations of insulin. The cells of the body are resistant to the action of insulin, such that glucose, fatty acids, and amino acids are not being metabolized properly. The abnormality of macronutrient metabolism, or the accumulation of fatty acids and fat deposits, leads to the buildup of arterial plaque and development of atherosclerosis, increasing the risk for myocardial infarction, peripheral artery disease, and stroke.

Reaven’s research group at Stanford was the first to quantify insulin-mediated glucose disposal. IR is precisely measured in the lab by quantifying steady-state plasma glucose (SSPG) and steady-state plasma insulin concentrations. From infusion of somatostatin, which limits endocrine insulin release, followed by insulin and glucose infusion, venous samples are collected and analyzed. The higher SSPG, the more insulin resistant an individual is. There is a huge variation in IR in the general population.

There is a relationship between BMI and SSPG (ie, how heavy people are), which is an important variable affecting IR. Being overweight is likely to make an individual more insulin-resistant; however, overweight people can also be insulin-sensitive (the opposite of insulin-resistant). One-half of the variability is most likely due to genetics and the other half lifestyle, according to Reaven. There is also a relationship between being more physically fit and being more insulin-sensitive. The most insulin-resistant group of people are those from South Asian and East Indian ancestry, who are essentially twice as insulin-resistant compared with those from European ancestry. Ethnicity is therefore a powerful regulator of IR.

The abnormalities associated with IR include compensatory hyperinsulinemia, glucose intolerance, dyslipidemia, increased triglycerides, decreased HDL cholesterol, accumulation of smaller and denser low-density lipoprotein (LDL) cholesterol, and postprandial accumulation of triglyceride-rich lipoproteins. There are also potential vascular abnormalities and changes in markers of inflammation, such as an increase in plasma C-reactive protein and white blood cell count (evidence of vascular inflammation). Interestingly, IR is also associated with abnormalities of uric acid metabolism. There is often an elevation of plasma uric acid and problems with renal clearance of uric acid, potentially reflecting problems with the kidneys as a result of IR.

Alterations in glucose metabolism, including hyperglycemia associated with IR, can also occur in critical illness. This is a result of an adaptive endocrine response including the release of catecholamines, cortisol, and glucagons and a reduced capacity for glucose uptake. Neuroendocrine changes lead to more extensive metabolic effects with chronic critical illness, leading to the development of potential septic complications and poor prognosis.

Insulin Resistance Syndrome
Insulin resistance syndrome (IRS), according to Reaven, is a description of a physical state vs. a disease. The increased chance of an individual developing IRS is closely related to the abnormalities. Not all the manifestations of IRS are related to the physical effects of compensatory hyperinsulinemia associated with IR, acting on normally insulin-sensitive cells. Factors that increase the likelihood of one being insulin-resistant include a diagnosis of CVD or hypertension; a family history of type 2 diabetes mellitus, hypertension, and/or CVD; and an increase in age (an older person is more likely to have IR than a younger person).

Epidemiological studies have concurred with the increasing prevalence of IR in older populations. Patients with IRS are at an increased risk for the development of cardiovascular disease and type 2 diabetes mellitus, two of the most significant health problems for people >65 years of age.8 There are 2 million more women than men in the United States categorized as being obese, with the trend of obesity and diabetes mellitus increasing.9 This is another potential problem for the increased mortality from cardiovascular disease in women.

Testing IR by measuring SSPG is mainly limited to research circumstances as a result of the high cost of time and physician care in administering the test. Surrogate markers for insulin sensitivity should be identified and include plasma triglycerides and HDL cholesterol (ie, low plasma triglycerides and high HDL cholesterol). Therefore, priority lipid goals should be to decrease triglycerides and increase HDL cholesterol in our population of hyperlipidemic patients and clients. An LDL cholesterol level below 100 milligrams per deciliter for most individuals is now considered optimum.

A nice analogy of how to explain the number of disorders that comprise IRS to a patient is that of a flower. In a recent paper on IRS,10 it is compared with a daisy where “each petal represents one of the risk factors manifested in IRS, all united by a stem, which represents CVD. Insulin resistance is the root.”

Application to Diet
Medical nutrition therapy plays a critical role in the successful management of blood lipids and prevention of CVD. The ATP III recommends a program of therapeutic lifestyle change vs. the old Step I and Step II diets. It is important to emphasize the benefits of keeping trans fatty acid intake low and to add plant stanol/sterol esters to the diet to reduce LDL cholesterol. We should also be deemphasizing total fat and focus on the kinds of fat ingested, such as promoting the omega-3 fatty acids and fish oil in our diets and unsaturated fatty acids with olive oil and canola oil. Although low-fat/high-carbohydrate diets have traditionally been recommended to reduce the risk for diabetes mellitus and CVD, recent understanding has suggested that such diets may actually increase risk among individuals who are already insulin-resistant. We must endorse regular physical activity and weight loss, if appropriate, as first steps in reversing the unwanted metabolic effects of these classic syndromes.

— Alison J. Rigby, PhD, MPH, RD, is a researcher at Stanford University School of Medicine. She also teaches nutrition/dietetics classes at San Francisco State University.

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