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Rakel: Integrative Medicine, 2nd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier

Section 6–Metabolic/Endocrine Disorders
chapter 35–Insulin Resistance and the Metabolic Syndrome

Edward (Lev)Linkner,MD, ABHM[*]
*With assistance from Lauren Linkner Kaufman, ND.

Pathophysiology379
Insulin Sensitivity 380
Etiology382
Diagnosis383
Classic Clinical Case of Insulin Resistance 383
Integrative Therapy383
Lifestyle 383
Nutrition 384
Supplements 385
Antioxidants 386
Hormone Replacement 386
Botanicals 387
Pharmaceuticals 387
Therapies to Consider 388
Prevention Prescription388
Therapeutic Review389

This chapter discusses what metabolic syndrome is, how it affects physiologic function, and diagnostic tests that help identify patients with this disorder. A comprehensive list of therapeutic tools to treat metabolic syndrome and to prevent long-term complications of the disease is also offered.

Pathophysiology

Insulin resistance is essentially a new concept that has only recently been recognized by the medical community. Syndrome X, also called the metabolic syndrome and the syndrome of insulin resistance (IR), was coined in the 1980s by Gerald Reaven, MD, an endocrinologist at Stanford Medical School. Recently the American Diabetes Association has coined the term cardiometabolic risk, which I feel is more descriptive.

Metabolic syndrome has the following major characteristics: abdominal obesity (apple shape), hypertension, elevated serum lipid levels (usually elevated triglyceride levels, normal or elevated low-density lipoprotein [LDL] cholesterol, and decreased high-density lipoprotein [HDL] cholesterol), all caused by insulin resistance ( Table 35-1 ).

TABLE 35-1--ATP III[*] Criteria for Identification of the Metabolic Syndrome[†]

Abdominal obesity (waist circumference) / Men: >102 cm (40 inches) Women: >88 cm (38 inches)
Serum triglyceride level / >150 mg/dL
Serum high-density lipoprotein cholesterol level / Men: <40 mg/dL Women: <50 mg/dL
Blood pressure / >130/85 mm Hg
Fasting blood glucose value / >110 mg/dL

Adapted from Alexander CM, Landsman PB, Teutsch SM, Haffner SM: NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes 52:1210-1214, 2003.

* / Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.
† / Diagnosis of metabolic syndrome is made when 3 or more of these criteria are present.

Because we know that IR is a precursor to the metabolic syndrome, IR can be diagnosed before the full-blown condition is manifested. IR is a major cause of death and illness in the United States and is now becoming an epidemic, being associated with increased risks for type 2 diabetes mellitus (DM-2), coronary artery disease (CAD), hypertension, nonalcoholic fatty liver disease, sleep apnea, impotence, gout, female sexual dysfunction, hypercoagulability, gallstones, kidney stones, cerebrovascular accident, and some cancers. According to Ford and associates,[1] “The prevalence of metabolic syndrome is [about] 24% in the U.S. The 2000 census data shows: about 47 million [people] have the metabolic syndrome … [which] have important implications for the health care sector.”

Our country is essentially filled with a population at risk for chronic disease. Evaluation of the latest statistics reveals the dilemma that 55% of North Americans are overweight, 50 million have elevated serum cholesterol, 50 million have hypertension, and 16 million have diabetes. Without treatment, IR can lead to metabolic syndrome and DM-2. Statistics show that 6% of the U.S. population aged 45 to 64 years has DM-2, as well as 12% of the U.S. population older than 65 years, and 800,000 new cases of DM-2 are diagnosed yearly. Even though this chapter focuses on insulin resistance, there is an obvious overlap between it and DM-2.

Insulin Sensitivity

In a normal insulin-sensitive individual, insulin works effectively to manage glucose, so the pancreas secretes the proper amount of insulin to adequately clear glucose from the bloodstream. In a person with IR, however, insulin works ineffectively, and the pancreas must secrete large amounts of insulin to push glucose into the cells.

If we understand the pathophysiology of IR, then we know that glucose itself is not the culprit. The role of glucose is as a fuel for energy. Our body needs to get glucose into its cells to achieve this goal. This is where insulin comes into the picture. Insulin's major effect is to maintain glucose homeostasis (the brain needs 100 gm of glucose daily). Insulin stimulates the conversion of glucose to fat and modulates hepatic production of glucose ( Fig. 35-1 ).

FIGURE 35-1Sites of the three major pathogenic defects that lead to type 2 diabetes mellitus. Insulin resistance in muscle causes reduced glucose disposal from the bloodstream, and insulin resistance in liver causes greater glucose production. Impairment of insulin secretion by the pancreatic beta cells is a critical feature that leads to hyperglycemia when the amount of insulin secreted and the timing of the insulin response to glucose are defective. /

Inflammation and IR are closely related and can change with disease. “Under normal circumstances, insulin has anti-inflammatory and vasodilatory functions … [which] are lost or even reversed in the setting of insulin resistance. [The] regulation of nitric oxide synthase and its anti-inflammatory effects are disrupted.”[2] Nitric oxide synthase (NOS) is the enzyme that catalyzes the formation of nitric oxide (NO) from oxygen and arginine. NO has many diverse physiologic roles, including those of neurotransmitter, vasodilator, and cytotoxic agent.

Blood glucose metabolism is also multifaceted. The main mechanism by which glucose is transported into the cell is via the glucose transporter GLUT4, 90% of which is stored in the cell cytoplasm. Stimuli like insulin and exercise promote this pathway and become active by embedding in the cell membrane. Peroxisome proliferator-activator receptors (PPARs) are nuclear hormone receptor transcription factors that cause target genes to be expressed. They are important regulators of insulin action. Prescription medications such as thiazolidines bind to PPAR-gamma, reduce tumor necrosis factor-alpha (TNF-alpha) inhibition of GLUT4, and promote an increase in small adipocytes. Therefore PPAR agonists reduce sugar output by the liver, reduce serum triglyceride levels, increase HDL cholesterol levels, decrease LDL cholesterol levels, and decrease a variety of pro-inflammatory markers. As IR increases, it ultimately produces a cascade of oxidative responses, which raise the risk of vascular damage and ultimately can result in CAD and cerebrovascular accident ( Fig. 35-2 ).

FIGURE 35-2Insulin signaling pathways. AMP, adenosine monophosphate; ATP, adenosine triphosphate; CLA, conjugated linoleic acid; COX, cyclooxygenase; GLUT, glutamine transporter; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; NFkappaB, a B cell–specific transcription factor; PPAR, peroxisome proliferator-activator receptor; TNF, tumor necrosis factor. /

Insulin signaling involves a complex set of multiple pathways with nutrient connections depending on lifestyle and genetic predisposition. A person with defects in any one of these pathways has the propensity for development of IR. A variety of metabolic problems then ensue, including stimulation of 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase to raise cholesterol levels and decreased apolipoprotein (apo) A-I, which results in reduced HDL cholesterol levels, and inflammatory bowel disease. The following substances or conditions are also increased:

• / Triglycerides
• / Platelet adhesiveness
• / Plasminogen activator-inhibitor factor-1 (PAI-1) and, ultimately, markers of subacute inflammation (such as high-sensitivity C-reactive proteins [hsCRP], interleukin, and proinflammatory cytokines)
• / “Oxidized” LDLs
• / Free radicals, resulting in greater DNA damage and advanced glycation end products
• / Colorectal cancer (mitogen)
• / Estrogen and testosterone in women (polycystic ovary syndrome [PCOS])
• / Endothelial dysfunction
• / Uric acid (gout)
• / Calcium oxalate kidney stones
• / Sodium retention
• / Cortisol, accompanied by a decrease in dehydroepiandro-sterone (DHEA)

It is therefore apparent that there is a diabetes continuum. Glucose intolerance occurs first, followed by insulin resistance, syndrome X, and finally DM-2. Eventually, insulin-dependent type 2 diabetes, with all the medical consequences associated with aging throughout the body, is present. Understanding that the first defect in DM-2 is insulin resistance is of prime importance, enabling the implementation of treatment and preventive measures. It has been observed that defects in insulin receptor signaling capacity are the most likely cause of diminished insulin action. IR precedes and contributes to the development of the diabetic state ( Fig. 35-3 ).

FIGURE 35-3Natural history of diabetes, depicting the rising blood glucose level with progressive beta cell dysfunction. /

Insulin resistance is also closely related to CAD. According to cardiologist J. Meigs, MD,[3] “Insulin resistance appears to account in large part for the very high rates of cardiovascular disease risk factors.” In fact, 70% of diabetic patients die from cardiovascular disease (CVD). The European Association for the Study of Diabetes[4] concluded that “The risk for developing cardiovascular disease is 2-5-fold higher in patients with DM when compared with the general population. Cardiovascular events are the primary cause of the 5.4% annual rate of mortality among those with diabetes mellitus, a rate double their non-diabetic counterparts. As a result, diabetic patients can expect to have a 5 to 10 year reduction in their life expectancy.” Therefore, “diabetes is a coronary heart disease equivalent.… [It is a] similar risk to an individual with established CAD.”[5] IR is a progressive illness, as revealed in the Bogalusa Heart Study. This study showed that “Elevated insulin levels persist from childhood through young adulthood, resulting in a clinically relevant adverse cardiovascular risk profile in young adults … the first change for a cardiovascular risk in young people is a rising insulin level.”[6] Furthermore, this vascular risk is seen before the development of DM-2. Of their study on health risks, Janssen and colleagues[7] reported that their subjects without diabetes who had elevated fasting insulin values had a 31% higher risk of myocardial infarction or cerebrovascular accident.

Lipids are also involved in this scenario. IR sets up an inflammatory process that results in enhanced lipid deposition in the arterial wall. In addition, oxidized LDL cholesterol is toxic to endothelial cells, leading to decreased nitric oxide release and an enhanced expression of cytokines and adhesion molecules. These effects in turn lead to vascular inflammation.[8] Inflammation may determine plaque stability, because unstable plaques have exacerbated leukocytic infiltrates. The T lymphocytes and macrophages predominate at these rupture sites. Inflammatory cytokines and metalloproteinases (which are responsible for the degradation of extracellular matrix and have an important role in tumor metastases) influence the stability and degradation of the fibrous cap. This chapter focuses on the glucose regulation difficulties in IR ( Fig. 35-4 ).

FIGURE 35-4Summary of insulin resistance and its effects. DM, diabetes mellitus. /

Etiology

The etiology of IR is multifactorial, having both genetic and lifestyle components. Genetics show that there are single nucleotide polymorphisms (SNPs), with variable expression depending on the host and environmental factors. These individual expressions are seen with the β3-adrenergic receptors, metabolism in the adipocytes, and secretion of adrenomedullin as well as other hormones. The β3-adrenergic receptors are expressed predominantly on adipocytes. It is proposed that dysfunction of these receptors results in obesity and IR. Research has taught us that diabetes is a polygenic disorder with a variable phenotype and an uneven expression of the genome, depending on environmental issues. It is more prevalent in African Americans, Native Americans, and Hispanics.

Lifestyle appears to be the major determinant, however, largely because of our “standard American diet” (SAD), which results in deficiencies in both macronutrients and micronutrients. Stress and lack of exercise are also compounding factors. Because IR is the first metabolic defect, it should be regarded as “pre-diabetes.” Its detection would be the perfect time for intervention to prevent the usual transition to DM-2. Of course, an emotional component is often present as well. The metaphysical cause of diabetes, according to Louise Hay, a metaphysical lecturer and teacher, is “Longing for what might have been. A great need for control. Deep sorrow. No sweetness left.”[9] Lastly, sugar cravings and overeating can be either emotionally related or secondary to issues in the patient's family of origin.

In addition, many antipsychotic medications have now been shown to raise the incidence of IR. Other prescription medications, such as diuretics and beta blockers, are also risk factors.

Diagnosis

IR is actually quite simple to diagnose. Outside a research laboratory, the standard of practice is to conduct a 2-hour glucose and insulin tolerance test (GITT), which can easily be ordered through any outpatient laboratory. The protocol is (1) 2 days of carbohydrate (CHO) loading, (2) obtaining blood specimens for fasting glucose and insulin measurements, and (3) a 75-gm glucose drink. Thereafter, blood specimens for glucose and insulin measurements are obtained (but not always necessarily) at half-hour intervals for the first hour, followed by a final specimen 2 hours later. For most patients, just the fasting and 2-hour measurements are sufficient. Essentially, this is just the usual glucose tolerance test (GTT) with concomitant insulin testing. One caveat is that the clinician should make sure that the laboratory used is familiar with diagnostic procedures involving insulin, which is a very unstable hormone in vitro. If only a fasting insulin specimen is obtained, a false-negative diagnosis may be made. Without regular drawing of blood specimens for measurement of insulin, the test is no longer functional. The clinician must learn how the body's insulin serves to manage glucose once it has been ingested.

Classic Clinical Case of Insulin Resistance

A 52-year-old man presents with chief complaints of fatigue and an inability to lose weight. He craves sugar and has a family history of DM-2 and depression. He rarely exercises and is under stress. Physical examination shows skin tags, and he is 25% overweight (apple-shaped), with a body mass index (BMI) of 29, and blood pressure (BP) of 165 mm Hg systolic, 95 mm Hg diastolic. Laboratory testing showed elevations of triglycerides, uric acid, and ferritin, and low levels of HDL cholesterol, red blood cell magnesium, and DHEA sulfate. Glucose and insulin tolerance test results are shown in Table 35-2 .

TABLE 35-2--Glucose and Insulin Tolerance Test Results for Classic Case of Insulin Resistance

FASTING / AT 2 HOURS[*]
MEASURED VALUE / NORMAL / MEASURED VALUE / NORMAL
Serum glucose (mg/dL) / 100 / <115 / 160 / <200
Plasma insulin (μU/mL) / 28 / <15 / 136 / <30
* / 2 hours after 75-gm glucose load.

This patient meets the criteria for metabolic syndrome, which has an ICD-9-CM (International Classification of Diseases–Ninth Revision, Clinical Modification) code of 277.7. This can be considered “pre-diabetes.” The standard for the diagnosis of type 2 diabetes is a fasting blood glucose value higher than 115 mg/dL, a 2-hour glucose tolerance test glucose value higher than 200 mg/dL, or a glycohemoglobin value greater than 7%. A free measurement is the waist-to-hip ratio, which is abnormal if the ratio is greater than 1.0 in men or 0.8 in women; patients with higher ratios are considered obese and apple-shaped. According to the American College of Endocrimology, “The emergence of the insulin resistance syndrome is among the most pressing problems of public health in the developed world. We are supportive of current concepts in medically supervised therapeutic lifestyle change.”[10]

Integrative Therapy

Lifestyle

Lifestyle modification is the foundation of treatment of IR. Lifestyle as prevention for IR and diabetes has been extensively described. For example, Knowler and colleagues,[11] researchers in the Diabetes Prevention Program, compared lifestyle modification with diet and medication in more than 3000 patients with “pre-diabetes.” They assigned patients to three groups, which received (1) metformin 850 mg twice daily, (2) a lifestyle modification program with goals of at least 7% weight loss and at least 150 minutes of physical activity per week, or (3) placebo. After 3 years of follow-up, the metformin group contained 31% fewer subjects with diabetes, and the lifestyle modification group 58% fewer subjects with diabetes than the placebo group.

Education

It is important to increase patient awareness and accountability. The patient should understand the wide ramifications of IR itself and the potential disease processes that are related to it. Providing reading material, classes, and support groups, as well as nutritional and healthy lifestyle choices, allows patients to become responsible and competent. Referrals to nutritionists and personal trainers will assist in this education.

Exercise

The next important component of an integrative holistic medical treatment program for IR is exercise. Exercise helps facilitate glucose entry into cells without the need for insulin. Schneider[12] said that “Exercise enhances insulin sensitivity and promotes the non-insulin mediated uptake of glucose into muscle tissue.” Exercise is a perfect therapy, because it burns calories and increases weight loss. Regular workouts also build muscle, decrease body fat, and promote a greater sense of well-being. Exercise also decreases IR by increasing GLUT4 transporters, enhancing immunity, and lowering blood pressure. Muscles conditioned from exercise are more insulin sensitive. Also, this form of therapy is inexpensive and (with time) becomes an endorphin-inducing pastime. Proper fitness is paramount for patients with diabetes. In a study conducted by Erkelens,[2] “low cardiovascular fitness in patients with DM-2 was associated with a 2.1-fold increased risk of death compared with fit men with DM-2.”

Weight Management

Obesity greatly contributes to IR, so the patient with IR should employ measures to lose weight.

At the beginning of treatment, one must deal with weight loss. Henry[13] reported that a loss of 7% to 10% of body weight significantly improves IR. Although most patients with IR are overweight, a minority of patients do have a normal BMI. Obesity is the direct cause of more than 300,000 deaths per year in the United States and its rate has risen by more than 75% in the last 20 years. “In 2001, the prevalence of obesity (which is defined as a BMI >30) was 20.9% vs. 19.8% in 2000. The prevalence of diabetes increased 8.2% in the same time period.”[14] As we know, however, obesity is a preventable disease.

Visceral fat is a key factor in IR. Increased visceral fat releases an abundance of free fatty acids and increases IR. Affected patients are literally “bathed in cortisol,” and can actually look like they have Cushing's syndrome. This fat goes to all the organs, causing dysfunction and increasing the markers of inflammation. Adipose cells are not, as previously believed, just passive depots for energy. They secrete multiple hormones called “adipokines.” Adipose cells also secrete TNF-alpha, adiponectin, resistin, leptin, and other markers of inflammation. These secretions all end up promoting IR. Hu and coworkers[14] found that, irrespective of exercise levels, sedentary behaviors (especially watching television) were associated with significantly elevated risks of visceral adiposity.[15] Of interest, the Diabetes Prevention Program showed that just “a 6% weight loss from baseline reduced the risk of developing type 2 diabetes in patients with impaired glucose tolerance by 58%.”[16] Clinicians must treat patients with IR with education, compassion, and hope. Such patients must be taught that obesity is a chronic, serious disease requiring diligent monitoring for their entire lifetimes.