THE METABOLIC SYNDROME, INSULIN RESISTANCE, THE POLYCYSTIC OVARY SYNDROME AND THE TYPE II DIABETES CONCERNING DIAGNOSIS AND TREATMENT

Dr.C B SRIDHAR

CONSULTANT ENDOCRINOLOGIST

Professor Odell: I have two patients for you to discuss:

            A 48 year old male, has had diabetes mellitus for 4 years and has been for by his family practitioner. he was initially treated with a sulfonylurea which did not adequately control his glucose, Metformin was added which also did not return glucose to normal. He was revealed the following : BMI was 24; BP=134/85; glycosylated hemoglobin=8.5, Urine microalbumin=35mg/day, fasting lipids: LDL=140mg/dl (normal 80-130). HDL=40mg/dl (30-70), total cholesterol=230mg/ml (130-200) triglycerides 220mg/ml (<160).

           

            A 23 year old female has been married 7 years and has never been pregnant Menses are irregular, occurring unpredictably each 2-4 months. On examination she has mild hirsutism with mild acne, mustache and cheek hair. Public hair dense but triangular in shape. Laboratory reveals: DHEAS=79.6ug/ml (45-430), total testosterone=not measured, androstenedione=2.37mg/ml (0.47-2.68), Androstanediol glucuronide=not measured. Glucose tolerance (2100mg glucose): Fasting glucose=68mg.dl, 1 hour=128mg/dl, 2 hours=98mg/dl; insulin: fasting=20uU/ml (2.1-30.8), 1 hour=68, 2 hours=128, 3 hours=75. After three treatment cycles she became pregnant.

Would you discuss the link between hyperinsulinism (insulin resistance) and infertility? Also please discuss whether to use 75 or 100 grams of glucose tolerance test.

            ODELL: The Metabolic Syndrome, the polycystic Ovary syndrome and Type II diabetes mellitus are all over lapping disorders caused in part by resistance to insulin action. The first , The Metabolic Syndrome, has been defined by two committees, the National Cholesterol Education Program Adult Treatment Panel III (NCEPATP - III) (I) and the World Health Organization (WHO) (2) The first defined this syndrome as having at least 3 of the following abnormalities:

1. Fasting plasma glucose>110mg/dl.

2. Abdominal obesity, circumference> 35 inches or women and, 40 in men.

3. Triglycerides>150/mg/dl; HDL<50mg/dl in women and 40 in men.

4. Blood pressure>130/80 mm Hg.

            The second committee (WHO) defined the syndrome has the presence of impaired glucose metabolism (# below) and at least two of the abnormalities #2-4 below.

1.Impaired glucose tolerance (IGT), impaired fasting glucose (IGT) and/or insulin resistance (fasting glucose X 22.5).

2. Abdominal obesity: Waist-to-hip ratio >0.85 in women and >0.9 in men or body mass index (BIM) >30 Kg.m2.

3.Triglycerides > 150 mg/dl and or HDL <40 mg/dl in women or 35< mg/dl in men.

4.Blood Pressure > 140/90 mm Hg.

5.Microalbuminuria> urinary ablbumin >20 ug/min or albumin - creatinie ratio>30mg/gm. 

             
 In answer to your first question-whether to use 100mgs or 75mgs oral glucose for a glucose tolerance test. Seventy five grams are usually used simply normal values are better defined after such a dose. If one defined normal insulin and glucose value after 100gms, use of the dose would be equally valid. As Dr. Sridhar has indicated normal insulin values after 100gms. Of glucose are not available to him.

            The interrelations of the metabolic syndrome and T2DM and Cardio vascular disease were highlighter by the NHANWES III study. In the United States the presence of the metabolic syndrome is 23% in men and women over 20 years of ages and 44% in those over 50 years of age. In men and women over 50, 87% of those with diabetes, 71% of those with impaired fasting glucose and 33% of those with impaired glucose tolerance had the metabolic syndrome. This very high incidence of the metabolic syndrome the USA is a result of the growing incidence of obesity. Coronary heart disease (CHD) was present in 8.7% of those over 50 with neither, diabetes ot the metabolic syndrome, 7.5% of those with only diabetes, 13.9% of those with the metabolic syndrome and 19.2% of those with both diabetes and the metabolic syndrome.

            The cause of T2DM are complex. Insulin resistance in present in a much as 92% of patients. Obesity is often the cause of insulin resistance, and some studies suggest insulin resistance in the primary cause of T2DM. However even if insulin resistance is the initial factor, impaired insulin secretion eventually is a key second factor, and the two, act synergistically in producing the disease. The decrease in insulin action in T2DM leads to increased hepatic glucose production and decreased peripheral tissue glucose utilization, both acting together to produce impaired glucose tolerance or hyperglycemia. The American Diabetes Association diagnostic criteria for diabetes mellitus are listed below.

PLASMA GLUCOSE FASTING>8hrs                  2 Hrs POST 75gms oral glucose

Normal Values               <110mg/dl         <140mg/dl

Impaired glucose tolerance <126 >140 - 200

Diabetes mellitus                        126 -------------------------

Diabetes mellitus                        <126                 >200

            The Polycystic Ovary Syndrome (POS) is the third syndrome in this triad of insulin resistance metabolic disorder. In 1935, Stein and Leventhal described their findings in seven women with hirsutism, obesity, amenorrhea and polycystic ovaries. This disorder was called the Stein - Leventhal Syndrome, and later termed the Polycystic Ovary Syndrome. In 2004, an international consesus group defined diagnostic criteria for this syndrome. A diagnosis must first exclude other disorders that lead to androgen excess and oligomenorrhea (e.g. Virilizing adrenal or ovarian tumor, congential adrenal hyperplasia, Cushing’s Syndrome). The diagnosis must include at least two of the following criteria oligonovulation or anovulation (usually manifested as oligo or amenorrhea), hyperandrogenemia mainfestedd by elevated levels of circulating androgens or by clinical manifestation of androgen excess, and polycystic ovaries as defined by ultrasound. Polycystic ovaries do not have to be present to make a daignosis, and alternatively the presence of polycystic ovaries alone does not make a diagnosis. The pathophysiology of POS is also complex and no single cause produces the disorder. The ovarian thecal cells synthesize and secrete androgens and this process is stimulated the secretion of estrogen by granulosal cells by regulating

Aromatase activity. Thse estrogens are formed from the androgen precursos secreted by the thecal cells. In the PCO syndrome the concentrations of LH are increased relative to FSH, thereby favoring androgen production. As in the previously discussed syndrome, insulin resistance is also a factor in pathogenesis of PCO. Insulin amplifies LH stimulation of androgen’s by thecal cells. Insulin also inhibits the hepatic synthesis of sex hormone - binding globulin (SHBG) the circulating globulin that binds testosterone,, an effect that increases the unbound or “free” circulating testosterone. These effects explain why total testosterone concentration may be upper “normal” in patients with PCO. Free testosterone concentrations are expected to be elevated. As stated earlier obesity, which is common in patients with PCO is another factor leading to insulin resistance. Thus, as in the metabolic syndrome, this insulin resistance is associated with an increased incidence of cardiovascular disease, impaired glucose tolerance and over type II diabetes. PCOS has been termed a sex specific form of the metabolic syndrome (II). Impaired glucose tolerance is found in 30-40% of patients with PCO, and up to 10% developed type II diabetes by the fourth decade. Coronary artery disease (CAD) is also increased in patients with PCO. Recently, Orio et al, reported  a study of 150 women with PCOS and 150 age and BMI matched control women. Both blood white cell count and C reactive protein (makers of atherogenesis risk) were significantly increased in women with PCOS. Strikingly median fasting insulin concentrations were 75.3 pmo/lite in the PCO patients and 54.2 in the matched controls. In fact, as Dr. Sridhar has pointed out to me, the glucose/insulin ration is an excellent measure of insulin sensitivity in women with PCOS, Christian et al. reported that premenopausal women with PCOS and a higher prevalence of coronary artery calcification as detected by electron-beam computed tomography. PCO patients also have increased levels of very-low-density lipoprotein cholesterol (VLDL) and of low density lipoprotein cholesterol (LDL), and low levels of high - density lipoprotein cholesterol (HDL); all risk factors for coronary heart disease.

The mechanisms by which obesity insulin resistance are many and are not completely known. However, a brief discussion would include the following factors. Obesity is associated with an increased number of adipocytes, Hirsch and Knittle estimated that a lean adult has about 35 billion adipocytes, while an extremely obese individual has about 125 billion adipocytes. Fat cells synthesize and secrete a signal peptide termed resistin which cause insulin resistance. Another signal peptide produce by adipocytes is lepting. Leptin has many effect regulating hypothalamic neuroendocrin function modifying food intake and energy expenditure and modifying reproductive function. In addition adipocytes synthesize and export triglycerides. The ectopic distribution of these triglycerides may be involved in complications of obesity. In cross-sectional studies, Insulin resistance was highly correlated with intramyocellular concentrations of triglycerides (21). It is not known whether triglycerides directly interfere with insulin action, or are a maker for some other fatty acid derived entity that cause insulin resistance. Treatment of these three syndrome follows from the discussion of pathophysiology. In initial diagnosis    and for all three syndromes, evaluation for the possible presence of associated risk factors is necessary. This includes the following: 1. Assessment of mean blood pressure. This is done by repeated measurement of BP after at least 5 minutes rest on several days. Normal is <130/80. 2. Assessment of fasting lipid concentrations, by measurement after a 10 hour fast: total cholesterol, HDL cholesterol and triglycerides. 3. Measurement of fasting blood glucose (normal<110mg/dl.) and hemoglobin A_1c  (normal=3.8-6.4%). 4. Calculated body mass index (BMI). BMI=body weight in Kg/height in meter squared. Normal <25. If obesity is present introduction of a weight reduction and daily exercise program is the first line treatment. This step is the most difficult to achieve, particularly in sedentary individuals. Exercise increases insulin sensitivity. Loss of even small amounts of body weight has important effects on blood pressure and insulin sensitivity. I usually recommend starting with daily walks of at least a mile, with gradual increase to several miles daily at increased pace over 4-12 weeks as tolerated. Exercise, coupled to modified diet with decreased fat and carbohydrates intake, resulting in moderate reduction is totally daily calories, consist of major modifications of behavior. As indicated, these are usually the most difficult to achieve. Consideration of behavior. As indicated, these are usually the most difficult to achieve. Consideration of further treatment of each of the three syndromes is specific for the syndrome and is discussed below.

           

            Polycystic ovary syndrome (PCOS): Additional test to be done in women suspected of having PCOS include measurement of serum androgens and (optionally) ultrasound of ovaries. In order to minimize costs, I suggest the following androgen measurements: total testosterone, DHEAS and androstanediol glucuronide. Total testosterone is useful in helping to exclude androgen producing neoplasm of ovary or adrenal as a cause. In PCOS, total testosterone is expected to be high normal or slightly elevated (normal 6 - 68ng/dl) while androgen producing neoplasm may be suspected with values over 200. DHEAS is a product of the adrenal cortex and measurement gives an indication to the contribution of adrenal sources to total androgens. This information may be relevant to alternative treatments, discussed later. Androstanediol glucuronide (AG) is an end product of dihydrotestosterone (DHT) production. Testosterone itself is metabolized to DHT, which is returned to blood or metabolized within cells of AG. AG is expected to be highly elevated in PCOS and androgen tumors and corresponds to the clinical evaluation of androgen effects. Treatment of insulin resistance in PCOS results in decreased androgen production and increased rate of ovulation and pregnancy. Ortega-Gonzalez et al.  recently, published results of treatment of 52 obese, insulin resistant women with PCOS randomly assigned to either; pioglitazone (30mg/day) or metformin (850 mg TID). Both medications were equally effective in decreasing serum androgen’s and increasing insulin sensitivity, and were associated with occurrences of pregnancies. Pioglitazone, while as effective as metformin, was associated with an increase in body weight, increase in BMI, and increase in waist to hip ratio. Rosiglitazone (4mg/day) has also been shown to be effective in normalizing serum androgens, increasing insulin sensitivity and restoring spontaneous ovulation in POCS (24). Because of these adverse effects and because of the greater cost of glitazones over metformin, metformin is recommended as initial treatment in PCOS. Metformin is usually associated with weight reduction, decrease appetite as well as increased insulin sensitively, decreased androgen production, and increase ovulation. If osilizone is selected as treatment it should be discontinued when or if pregnancy occurs, for its safety during pregnancy is unknown. An alternative treatment consists of treatment with Flutamide (an antiandrogen) with metformin, ( (Flu) - metformin) with an oral contraceptive (ethinly - estradiol + dropirenone). This combination in several studies has been shown to result in increased lean body mass, decrease in abdominal fat, decreased serum androgens & decreased 1L – 6, a marker of atherogenesis. Metformin was a key ingredient in this combined treatment; the combination with metformin was more effective than flutamide with the oral contraceptives. Orlistat is a potent and irreversible inhibitor of gastric & pancreatic carboxylestor lipase, which thus inhibits the digestion of dietary triglycerides & decreases absorption of lipids. Orlistat has been shown to also be effective in treatment of PCOS.

Patients with acne & hirsuitism with elevated DHEAS, indicating a major adrenal source of hyperandrogonism, may be considered for very low dose dexamethasone suppression of adrenal androgen production. I initiate therapy with 0.5mg. Dexamethasone given at 10:00PM nightly. This is the most sensitive time to suppress ACTH secretion & permits much lower effective doses of glucocorticoids than does of glucocorticoids than does daytime treatment. Side effects of this dose are uncommon but can include increased appetite & making the patient aware of this possible effect will limit weight effects. After 4-6 weeks with 0.5 mg. Measurement of DHEAS should show suppression to very low levels (<20ug/dl).At this time dexamethasone dose can be reduced to 0.25mg. Nightly. On this low dose no side effects are expected and AM cortisol is usually normal while DHEAS remains suppressed. This treatment is associated with decrease in acne, usually in 3-4 weeks & decrease in other androgen effects in several months. Increased ovulation & pregnancy occurs also. If the treatment is unsuccessful in reducing an-ovulation, or fails to result in desired  pregnancy, addition of clomiphene citrate to either metformin or thiazolidinedione is likely to induce ovulation. It is a safe oral therapy & has few side effects other than increased multiple pregnancies. Ovulation rates after the first cycle have been stated to be about 70% although pregnancy rates are lower. Ultrasound monitoring of follicle development & blood measurement of progesterone are recommended 14-18 days after initiation of treatment. Clomiphene is usually started at 50mg/day given for 5 days, & if ovulation does not occur after 2-3 cycles, increasing doses of 100mg/day & 200mg/'day can be used.

            In summary, treatment of polycystic ovary syndrome is initiated with weight reduction & exercise program if the subject is obese. Even small amounts of weight reduction & modest exercise are helpful. Medical treatment, in my opinion should start with metformin starting at 500mg. BID & gradually increasing to 500 mg. QID as tolerated. This treatment should be  continued indefinitely. If pregnancy is desired,  ovulation as suggested by regularization of menses may occur & pregnancy may be achieved. If, after 6 months to 1 year of treatment, pregnancy has not occurred, treatment with clomiphene is a good choice. Alternatively,  addition of a thiazolidinedione to metformin may be selected. In women with bothersome androgen side effects and elevated DHEAS, low dose androgen suppression with dexamethasone has been effective in reducing androgen effects & increasing ovulation in my experience.

            Type II diabetes mellitus: A discussion of treatment of type II diabetes mellitus could occupy an entire textbook, and is beyond the purpose of this discussion of three insulin resistance syndromes. Several recent discussions are available for example. Initial physical examination must include thorough neurological examination for proprioception changes & alteration in light touch sensory perception, fundascopic examination for diabetic retinopathy, status of peripheral pulses as well as cardiovascular examination &  full assessment of mean blood pressure  (discussed  previously) Optimally intense education of nutrition principles & diet instruction  are  given to the patient by a qualified nutritionist. In addition, education is given in home glucose monitoring techniques. Treatment    of diabetes thus requires a team approach for optimal result. Laboratory should Include fasting lipids, fasting glucose, Haemoglobin A1c and urinary micro-albumin. Treatment of any of these diabetes complications should be given along with the treatment of the hyperglycemia, and won't be discussed further. For discussion of treatment of micro or macro – albumin excretion. For treatment of lipid disorder.

There are many options available for treatment of hyperglycemia. The initial treatment, as was true for obese patients with PCOS is education and institution of an exercise and weight reduction program. If mild hypertension and increased micro-albumin excretion are present, treatment with angiotensin converting enzyme inhibitor (ACE inhibitors) is advisable. Initial treatment with sulfonylureas is recommended. These drugs act by closure of ATP-sensitive potassium channels in beta cell membranes, thereby leading to influx of calcium and an increase in insulin secretion. In some, slender subjects with mild Type II diabetes this treatment is adequate for months to years. The goal is to achieve normal fasting blood glucose and normal HbA1c. Eventually resistance to sulfonylureas is expected and additional medications are required. Since there are several which act by expected and additional medications are required. Since there are several which act by very different mechanisms, one can add these in sequence.

           

            A good second choice is metformin, which acts to decrease hepatic glucose production, probably by inhibiting gluconeogenesis. Metformin can be added to sulfonylureas and has good efficacy. If this combination is not sufficient to decrease fasting glucose to normal, addition of a thiazolidinedione to two drugs is possible and often helpful. Thiazolidinediones act predominantly on muscle and adipose tissues to decrease insulin resistance. They bind to Peroxisome-Proliferator-Activated Receptors (PPAR), one member of nuclear receptors which regulate gene expression in response to ligand binding. They consistently lower fasting glucose, post-prandial glucose and free fatty acid concentrations. They are associated with weight gain, which require explanation to the patient and careful diet control. Use of these drugs is expensive, which is often a limitation in multidrug treatment. Roziglitazone, in addition to reducing insulin resistance may also reduce beta cell dysfunction, a principle underlying cause of type II diabetes. A fourth class of drugs which act quite differently from the previous three are alpha-glucosidase inhibitors. Treatment with combinations of drugs may adequately control diabetes for some time and may delay the necessity of treatment with insulin. When oral agents in combination are not adequate, treatment with insulin is instituted. A new, very long acting insulin is Glargine. Glargine has an onset of action in 1.5 hours and a duration of action of 30 to 90 hours. It has no peak of action and serves as an excellent therapy for reducing fasting insulin to normal. For some type II diabetes, post-prandial secretion of endogenous may be adequate to control glucose in fasting glucose are reduced by Glargine. If postprandial in sulin required, the very short acting synthetic insulins (Lispro insulin and Insulin as part) can be used at onset of a meal. They have onset of action in 15-30 minutes, and peak action in 2-3 hours. For type II diabetes, the goals of treatment are normal fasting glucoses and normal HbA1c.

            Treatment of the Metabolic Syndrome, uses the same drugs and principles discussed for PCOA and Type II diabetes. Weight reduction and an exercise program are again initial treatments to be continued life-long. Initial drug treatment is with metformin, which should be continued indefinitely. If glucose is not controlled, additional drugs and insulin are used as discussed for type II diabetes. Since lipid abnormalities are very commonly part of this syndrome they must also be treated aggressively.