Insulin
Resistance — A Weighty Issue
Today’s Dietitian
By Alison J. Rigby, PhD, MPH, RD
Vol. 6, No. 9, p. 46
As a practicing dietitian, it is important to understand
the implications of insulin resistance (IR). Findings from the third
National Health and Nutrition Examination Survey (NHANES) indicate
that up to 20% of the U.S. population has 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).
The 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.
References for this article are available upon
request by e-mailing TDeditor@gvpub.com.
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