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In the past, insulin levels were considered insignificant so long as blood sugar levels remained normal. This belief has been challenged. The following is excerpted from:
Allergy and Immunology, an Otolaryngic Approach.
Eds: Krouse JH, Chadwick SJ, Gordon BR and Dereberry MJ.
Lippincott Williams and Wilkins, Philadelphia, PA, USA 2002
Polycystic Ovary Syndrome
Polycystic Ovary Syndrome (PCOS) is increasingly of interest to clinicians (307). The syndrome is remarkably common, with an incidence of up to five to 10% of all women. It has been popularized by the press as "Syndrome X" (308). The most comprehensive review is by Dunaif (309). These patients are often chronically fatigued. Overlapping features in CFS and PCOS have been noted (299, 310). Characteristically, serum insulin levels are elevated (311). This is the principal underlying disorder causing the syndrome (307).
Consequences of hyperinsulinemia include excessive production of androgens (not always testosterone) from increased ovarian stromal hyperthecosis, causing acne and hirsutism. An abnormality of particular interest is reduced sex hormone binding globulin (307). This means that a test for "total testosterone" may fail to reveal the patient's elevated unbound testosterone, which is the biologically active form. The most accurate test is for "free testosterone". Standard laboratory tests for progesterone and estradiol are also tests of total hormone so their results may also be inaccurate in PCOS patients. Testing 24-hour urine samples or saliva samples may be valid alternatives to blood tests. Though these reflect levels of free hormone, one must recall that they are excretory tests effected by total production of hormone as well as blood levels.
While muscle and adipose cells are insulin resistant, the ovaries may have increased insulin sensitivity. Most patients have menstrual irregularities, usually starting with menarche. They have imbalanced LH and FSH (hyperprolactinemia) and are often infertile. Many patients are obese, at least partly due to the effects of insulin resistance. The frequent finding of elevated cholesterol is also related to high insulin (307). Insulin has an aldosterone-like effect on renal function and may contribute to hypertension (312). These effects act synergistically to create at least a seven-fold increased lifetime risk of myocardial infarction and equally increased risk for diabetes mellitus (307). As this syndrome responds well to treatment, it is obviously important to make an early diagnosis.
Dunaif astutely comments that the inherent bias in studies of PCOS is the use of polycystic ovaries as a diagnostic criterion (usually by ultrasound). Not all syndrome patients will express all features of the disorder, including polycystic ovaries. Family studies show that beyond an increased incidence of PCOS in female relatives of patients, some brothers also are insulin-resistant (308). The association of men and this disorder conceptually links PCOS and CFS with the syndrome of insulin resistance.
Ovarian hormone imbalances and their consequent symptoms are common in women with CFS. These may be secondary to the same stress which seems to precipitate CFS or simply to the stress of being sick with CFS. The interrelation between the ovarian and adrenal hormones is readily apparent. Insulin receptors in the ovaries may be overly activated to further complicate clinical symptoms. It is possible that ovarian pathology and the imbalance of the steroid sex hormones may be a primary contributor to the clinical picture of CFS.
Insulin resistance and hyperinsulinemia
Insulin resistance without diabetes mellitus may be of considerable importance in patients who are chronically fatigued and even with CFS. Does insulin resistance cause CFS? Academically the answer is "no", for then the patient would have insulin resistance, not CFS. Clinicians, though, may be well alerted to the possibility that insulin resistance and hyperinsulinemia are importantly associated with CFS. A number of investigators have studied parameters directly or obliquely associated with insulin resistance. These studies validate our attention to symptomatic insulin resistance in the context of CFS.
In controlled studies, Allain et al. found elevated insulin levels in CFS patients and Hotamisligil showed in mice that TNF-alpha (elevated in a large group of CFS patients cited above) induces insulin resistance (313, 314). Luo et al. report individual and interactive effects producing insulin resistance and hyperinsulinemia when the ventromedial hypothalamus of hamsters is infused with nor-epinephrine (NE) and serotonin (5-HT)(315). Both NE and 5-HT play roles in CFS. The importance of NE in stress, the HPA, neurally mediated hypotension and adrenal function is apparent as previously discussed. Serotonin is a potent stimulator of the CRH neurons in the lateral paraventricular nuclei (PVN) as well as the locus ceruleus-norepinephrine autonomic system (274). Demitrack stated that decreased serotonin activation of the HPA in CFS patients is an essential neuroendocrine feature of CFS and this observation is supported by others (316, 317). In work differentiating CFS from depressed patients, Cleare et al. suggest that CFS may be associated with increased 5-HT function and hypocortisolemia (318). These mediators which are important in CFS also contribute to insulin resistance.
A brief review of the physiologic roles of insulin is appropriate. Insulin causes glucose transport into cells. It activates anabolism by stimulating glucose utilization by both forming glycogen and breaking glucose down to precursors for fat and protein synthesis. It moves fats from circulation into storage, causing hydrolysis of circulating triglycerides to provide fatty acids for adipose uptake, then stimulates synthesis of triglycerides in adipose tissue and liver. It increases ribosomal protein synthesis. In addition, insulin inhibits catabolism. It blocks glycogenolysis and gluconeogenesis. It reduces lipolysis, the mobilization of free fatty acids and the oxidation of those fatty acids (319). It makes us "fat".
Other hormones contribute to the control of carbohydrate metabolism. In addition to insulin, the acute effect of growth hormone (GH) decreases blood glucose. This is opposed by the chronic effect of GH, ACTH and glucocorticoids, epinephrine (stress!) and glucagon and thyroxin. The net direction and activity of catabolism or anabolism is governed primarily by the relative concentrations of insulin and glucagon. Hypoglycemia is a brisk stimulus for production of glucocorticoids and growth hormone and this is useful for laboratory provocation testing (319).
Chronic fatigue syndrome patients have been observed to have abnormalities in these relationships. Decreased GH release in response to insulin-induced hypoglycemia has been reported in controlled studies of CFS patients by Allain et al. and Moorkins et al., though not observed in a smaller study by Cleare et al. (313, 320, 321). Conflicting data exist regarding the GH metabolite IGF-1, also called somatomedin C (52, 322). The larger series showed that somatomedin C in CFS patients was lower than in healthy controls (52).
Causes of insulin resistance are heterogeneous. Autoimmunity can play a role, directed against circulating insulin (common but usually insignificant) and receptors (rare). Cross-reactivity of insulin and IGF-1 exists with low affinity binding of little consequence (323). Decreased numbers of insulin receptors (down-regulation) are seen in obesity, following glucocorticoid therapy, oral contraceptive therapy, and in acromegaly (324). Hypercortisolism from chronic or maladaptive stress predictably might also decrease numbers of insulin receptors. Hypothyroidism causes reduced binding of insulin to rat liver membranes (325). Receptor down-regulation is caused by insulin secreting tumors and is a feature of both a severe form of ovarian dysfunction with virilization and acanthosis nigricans in young women and PCOS (318).
The insulin receptor in the cell membrane surface seems of less consequence than the glucose transporters which it stimulates like a garage door opener on the ceiling opens the door. There are five species or isoforms of these glucose transporters located in different tissues and having different properties. The most important of these is Glut-4, highly expressed only in skeletal muscle, adipose tissue and heart muscle. The isoforms Glut-1 (erythrocytes and other tissues) and Glut-3 (brain) have a high affinity for insulin and are thought less likely effected by insulin resistance. Glut-4, which accounts for most post-prandial glucose uptake (skeletal muscle absorbs 80 to 90% of all insulin-stimulated glucose uptake) has a much lower affinity for insulin and Glut-2 (liver and pancreatic B-cells) has the lowest affinity for insulin (324, 318). The skeletal muscle, liver and B-cells then may be most effected by insulin resistance. This may explain some of the clinical features of insulin-resistant non-diabetic patients. In summary, the exact mechanisms of insulin resistance are complex, multiple and remain incompletely defined.
Unfortunately, there is no real discussion of clinical symptoms in hyperinsulinemic insulin-resistant patients. The texts of endocrinology seem to discuss the phenomenon solely as a pre-diabetic condition (324). From the foregoing discussion of PCOS in which insulin resistance is the underlying cause of the disorder and through the preceding paragraphs it is evident that insulin resistance and hyperinsulinemia can cause symptoms.
My first contact with this was Pullen's paper describing hyperinsulinemia mimicking Meniere's disease and causing migraine headache, given at the 1985 World Congress of ORL (326). Clinical experience with our series of patients confirms that symptoms include and far exceed vertigo and headache. Prominent are CFS symptoms and hypoglycemic symptoms in which patients feel anxious, irritable and lightheaded (brain = Glut-3) while peripheral blood is hyperinsulinemic but euglycemic (muscle, liver and B-cells = Glut-4 and 2). Patients are usually physically obese but they may be very slender indeed and as has often been observed about CFS patients, these are the sickest ones.
Pullen advocated the four-hour oral glucose tolerance test (oGTT) with paired glucose and insulin assays to diagnose hyperinsulinemia and this is an excellent test (326). Once prohibitively expensive, it now costs only $200 at our county hospital laboratory. Normal data is provided by a 1987 study of 100 healthy volunteers who were "pedigreed" normal with both a euglycemic insulin clamp test and standard oGTT, then given a 75 gm oGTT with blood aliquots divided for both glucose and insulin assay (327). These data are consistent with work cited by Olefsky (324). As a rule of thumb, serum insulin normally should not exceed 100mcU/mL after the 75gm oral challenge. Many patients demonstrate significant hypoglycemia when the high levels of insulin suddenly seem to break through the resistance: what I call the "ketchup bottle effect". A large series of patients will show a spectrum of responses grading to type II diabetes mellitus.
Treatment of symptomatic insulin resistance is simple: Nutritional supplementation, reduction of dietary carbohydrates (since they stimulate further hyperinsulinemia) and as needed, prescription drugs designed to increase insulin receptor sensitivity (metformin and rosiglitazone) (328). These steps are basically the same as the treatment for PCOS, which shares the same underlying pathology (307, 309). Patients' results are dramatic and improvement is sustainable.
Insulin resistance and hyperinsulinemia are importantly associated with CFS. Studies have shown elevated insulin levels in CFS patients. Insulin resistance may be induced by TNF-alpha, NE and 5-HT, all abnormal in CFS patients. Insulin is opposed by both glucocorticoids and epinephrine, both elevated by the chronic stress important in the histories of many CFS patients. Causes of insulin resistance are complex and multiple, with insulin receptor sites reduced in number after therapeutic doses of glucocorticoids and steroid sex hormones. The most vulnerable parts of the receptor apparatus are the glucose transporters with insulin affinity which varies by tissue-specific isoform. I suspect that the high insulin-affinity of brain receptors compared to the low affinity of pancreas and liver receptors explains hypoglycemic symptoms in insulin resistant patients with normal values of blood glucose. At the brain, insulin function is excessive relative to glucose levels. This creates symptoms.
A conceptually simple and relatively inexpensive test seems to be diagnostic for the little-recognized condition of symptomatic insulin resistance and hyperinsulinemia. Recently nearly replaced by the use of fasting glucose levels and hemoglobin A1c assays, the oGTT has found new utility in comparing glucose and insulin response. Treatment is also conceptually simple and gives results which are most gratifying both to patient and physician.
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