Medical Management of Diabetes and Heart Disease - part 6 pdf

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27 Karter, AJ, Mayer-Davis EJ, Selby JV, D’Agostino Jr RB, Haffner SM, Sholinsky

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a new factor of the metabolic syndrome: a population-based study Diabetes Care1998; 21:649–654

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Ho-45 Haffner SM, Miettinen H, Stern MP The homeostasis model in the San AntonioHeart Study Diabetes Care 1997; 20(7):1087–1092

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sensitiv-49 Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW,Neifing JL, Ward WK, Beard JC, Palmer JP, Porte D Quantification of the relation-ship between insulin sensitivity andβ cell function in human subjects: evidence for

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52 The Diabetes Prevention Program Research Group The Diabetes Prevention

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53 National Cholesterol Education Program Expert Panel Third report on detection,evaluation and treatment of high blood cholesterol in adults (adult treatment panel3) NIH publication 2000; 01–3670

54 Adler AI, Stratton IM, Neil HAW, Yudkin JS, Matthews DR, Cull CA, et al ation of systolic blood pressure with macrovascular and microvascular complications

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Polycystic Ovary Syndrome, Insulin

Resistance, and Cardiovascular

Disease

Matthew C Corcoran and David A Ehrmann

University of Chicago Pritzker School of Medicine, Chicago, Illinois

I INTRODUCTION

Polycystic ovary syndrome (PCOS) affects up to 10% of women of reproductiveage (1,2), making it one of the most common endocrine disorders in this agegroup Insulin resistance and hyperinsulinemia appear to be central to the patho-genesis of both the reproductive and metabolic aberrations that characterize thesyndrome This chapter focuses on the metabolic components of PCOS, particu-larly those which may impart risk for development of cardiovascular disease:obesity, impaired glucose tolerance and type 2 diabetes mellitus, hypertension,dyslipidemia, and obstructive sleep apnea

II OBESITY

Obesity is observed in 30 to 50% of women with PCOS (3,4) and was present

in most of the patients originally described by Stein and Leventhal in 1935 (5)

In addition, women with PCOS typically have an ‘‘android’’ pattern of obesity,indicative of a relative increase in visceral adiposity The finding of an increasedwaist-to-hip ratio or other more sophisticated imaging measure of body fat distri-bution can serve as a surrogate measure of increased visceral fat depots Thispattern of distribution of body fat has been associated with elevated androgen

149

levels as well as with abnormalities in glucose tolerance, insulin secretion, andlipoprotein profiles (6,7).

Obesity contributes to the insulin resistance in PCOS However, the tude of insulin resistance exceeds that which would be predicted on the basis oftotal or even fat-free body mass (8) The cause of obesity in PCOS remains enig-matic One possible explanation is that hyperinsulinemia exerts a lipogenic effect.Another possibility is that the anovulatory lack of progesterone predisposes toabdominal obesity and a change in muscle fiber type, both of which have deleteri-ous metabolic consequences (9)

magni-It has been reported that relative to controls matched for weight and bodyfat distribution, postprandial thermogenesis is reduced in women with PCOS and

is associated with increased insulin resistance (10) However, the magnitude ofthe reduction in postprandial thermogenesis appears to be insufficient to accountfor the degree of the obesity in most PCOS patients Insulin resistance has alsobeen implicated in retarding the ability to reduce weight in response to a hypoca-loric diet A recent report (11), however, has documented that differences ininsulin resistance do not predict weight loss in response to hypocaloric diets inhealthy obese women Whether this finding is applicable to women with PCOSremains unanswered

Nonetheless, it has been clearly documented that attenuation of insulin sistance, whether by weight loss or pharmacologically with diazoxide, metformin,

re-or troglitazone, amelire-orates many of the metabolic aberrations in women withPCOS (12)

III IMPAIRED GLUCOSE TOLERANCE

AND TYPE 2 DIABETES

Obesity is a well-recognized risk-factor for development of type 2 diabetes, butalone is insufficient to cause glucose intolerance Thus, while it is generally ac-cepted that women with PCOS are predisposed to type 2 diabetes (13,14), thedevelopment of diabetes cannot be attributed solely to the obesity that typicallyaccompanies PCOS

Initial studies placed the prevalence of diabetes in PCOS at approximately20% (8) More recent data have established that the prevalence of impaired glu-cose tolerance and type 2 diabetes mellitus among women with PCOS is evenhigher, with consistency across populations of varied ethnic and racial back-grounds (14,15) In two recent, large prospective studies, the prevalence of IGTwas between 30 to 40% and that of type 2 diabetes between 5 to 10% (14,15).These prevalences approximate those in Pima Indians who have one of the highestrates of diabetes in the world (16) Evidence for an enhanced rate of development

of diabetes is also evident from long-term follow-up of women with PCOS (17)

More recently, we have found a nearly five- to tenfold increase in the expectedconversion rate from IGT to type 2 diabetes in PCOS (14,18).

What factors underlie this predisposition to type 2 diabetes in PCOS? There

is much to support a key role for insulin resistance As noted, the magnitude ofinsulin resistance is greater in women with PCOS than in carefully matched con-trols (19–21) A distinct, and possibly selective (22), form of insulin resistancemay account for these findings Fibroblasts isolated from women with PCOSexhibit decreased insulin receptor autophosphorylation, both basally and in re-sponse to insulin stimulation (23) Phosphoaminoacid analysis has revealed adecrease in insulin-dependent receptor tyrosine phosphorylation and increasedinsulin-dependent receptor serine phosphorylation (23) The relative increase inserine phosphorylation could account, at least in part, for the post-receptor defect

in insulin action since it has been shown that insulin receptor serine tion decreases the receptor’s tyrosine kinase activity (24) In addition, it has beenproposed that the presence of such defects in ex vivo cell culture of fibroblastssupports a genetic, rather than acquired, basis for insulin resistance (21).Even though a substantial proportion of women with PCOS develop glu-cose intolerance, the majority do not, thus making it reasonable to ask whetherthe defects in insulin action described above are sufficient to account for the highprevalence of diabetes in this population Specifically, what factors distinguishinsulin-resistant women with PCOS who develop glucose intolerance from thosewho are able to maintain normoglycemia?

phosphoryla-Insulin secretory defects play an important role in the propensity to developdiabetes in PCOS Initial evidence forβ-cell dysfunction in PCOS was derivedfrom analyses of basal and postprandial insulin secretory responses in womenwith PCOS relative to weight-matched controls with normal androgen levels (25).The incremental insulin secretory response to meals was markedly reduced inwomen with PCOS, resulting from a reduction in the relative amplitude of meal-related secretory pulses rather than from a reduction in the number of pulsespresent This pattern, which resembled that of type 2 diabetes more than that ofsimple obesity (26,27), was striking in that it was evident in these nondiabeticwomen with PCOS

It was subsequently reported that women with PCOS had similar, or evenexaggerated (28), acute insulin responses during a modified IVGTT, leading some

to conclude thatβ-cell function was normal in PCOS However, insulin secretion

is most appropriately expressed in relation to the magnitude of ambient insulinresistance The product of these measures can be quantitated (the so-called ‘‘dis-position index’’) and related as a percentile to the hyperbolic relationship forthese measures established in normal subjects (29) In so doing, we (13), as well

as others (30), have found that a subset of PCOS subjects has β-cell secretorydysfunction In absolute terms, women with PCOS had normal first-phase insulinsecretion compared to controls In contrast, when first-phase insulin secretion

was analyzed in relation to the degree of insulin resistance, women with PCOSexhibited a significant impairment inβ-cell function This reduction was particu-larly marked in women with PCOS who had a first-degree relative with type 2diabetes: the mean disposition index of women with PCOS and a family history

of type 2 diabetes was in the eighth percentile, while that of those without such a

family history was in the thirty-third percentile ( p⬍ 0.05) We have additionallyquantitatedβ-cell function in PCOS by examining the insulin secretory response

to a graded increase in plasma glucose and by the ability of theβ-cell to adjustand respond to induced oscillations in the plasma glucose level (13) Results fromboth provocative stimuli were consistent: when expressed in relation to the degree

of insulin resistance, insulin secretion was impaired in PCOS subjects with afamily history of type 2 diabetes when compared to controls

These results suggest that the risk imparted by insulin resistance to thedevelopment of type 2 diabetes in PCOS is enhanced by defects in insulin secre-tion Further, a history of type 2 diabetes in a first-degree relative appears todefine a subset of PCOS subjects with the most profound defects inβ-cell func-tion Taken together, these findings are in accord with studies showing a highdegree of heritability ofβ-cell function, particularly when examined in relation

to insulin sensitivity (31), and among nondiabetic members of familial type 2diabetic kindreds (32)

IV HYPERTENSION

Women with PCOS would appear to be highly predisposed to the development

of hypertension by virtue of their characteristic obesity and insulin resistance.However, the presence of systolic and/or diastolic elevations in blood pressureare not a uniform feature of PCOS during the reproductive years In one study(33), women with PCOS and controls were compared using 24-h ambulatoryblood pressure monitoring and echocardiography Despite the fact that the PCOSwomen were significantly more insulin resistant than their matched controls, therewas no difference in systolic or diastolic blood pressure levels or in left ventricu-lar mass between groups It is possible, however, that measurement of ambulatoryblood pressures or left ventricular mass are not sufficiently sensitive to detectsubtle effects, direct or indirect, of hyperinsulinemia upon the resistance vessels.With age, insulin resistance and secondary hyperinsulinemia may play a centralrole in the development of hypertension and atherosclerotic vascular disease Datasuggest that later in life sustained hypertension is three times more likely inwomen with PCOS compared to normal women (17,34)

The pathogenesis of hypertension in PCOS and other insulin-resistant states

is complex Insulin acts as a vasodilator through the induction of endothelialnitric oxide production (35) Nitric oxide, in turn, causes an increase in the con-

centration of cyclic GMP, which acts as a potent vasodilator Thus, resistance

to insulin action at the level of the vascular endothelium may contribute to thedevelopment of arterial hypertension In both animals and normal humans, theinfusion of insulin induces vasodilation However, vasoconstriction predominates

in the presence of insulin resistance The hyperinsulinemia may also result insustained hypertension via insulin’s stimulatory effect on the sympathetic nervoussystem, resulting in an increased cardiac output, vasoconstriction, and increasedsodium resorption by the kidneys Additional effects of nitric oxide, includinginhibition of growth and migration of vascular smooth muscle cells and attenua-tion of the vascular inflammatory reaction (36), may be decreased in the insulin-resistant state Nitric oxide also inhibits thrombosis by preventing platelet adhe-sion and enhancing the ability of prostacyclin to inhibit platelet aggregation.Thus, the insulin-resistant state may mediate a cascade of events predisposingwomen with PCOS to hypertension and atherosclerosis

V MACROVASCULAR DISEASE AND THROMBOSIS:

ROLE OF INHIBIN AND PAI-1 IN PCOS

Endogenous fibrinolysis is modulated intravascularly by endothelial cell–derivedtissue plasminogen activator (tPA), resulting in the activation of plasminogenand subsequent plasmin formation Plasminogen activator inhibitor-1(PAI-1) is

a serine protease that is produced by liver and endothelial cells It is capable ofbinding to tPA and neutralizing its activity Over 90% of the immunoreactivePAI-1 in the bloodstream is stored in platelets; with platelet activation, PAI-1 isreleased along with other physiological mediators that inhibit the lysis of nascentclots (37) A homeostatic balance exists between the levels and activity of tPAand PAI-1, controlling net local fibrinolytic activity on the luminal surface ofblood vessels The homeostatic balance prevents the development of thrombosisand vascular occlusion, as PAI-1 regulates the removal of fibrin deposits fromblood vessels An imbalance favoring the relative excess of PAI-1 will result indecreased fibrinolytic activity and a predisposition to the formation of thrombus,placing patients at risk for recurrent thrombotic disease

Many conditions that are associated with PCOS have been associated withdecreased fibrinolytic activity, including obesity, diabetes, and hyperlipidemia(38) PAI-1 concentrations in PCOS may be as high, or even higher, than thosetypically seen in patients with type 2 diabetes (39) This increase in PAI-1 islikely to be one of several factors that place women with PCOS at risk for macro-vascular disease (40–42) Consistently, the decreased fibrinolytic activity in theseconditions has been associated with elevated PAI-1 protein and increased func-tional PAI-1 activity Less consistently have there been altered concentrations oftPA protein in plasma Several recent studies have documented elevated PAI-1

levels in women with PCOS In one study (43), significantly higher PAI-1 levelswere observed in lean women with polycystic ovaries and extreme menstrualdisturbance compared to women with polycystic ovaries and normal menstrualcycles This latter observation makes it tempting to speculate that a commonfactor, possibly hyperinsulinemia, could account for the ovulatory dysfunctionand elevation in PAI-1 levels seen in PCOS.

Insulin and proinsulin both play a regulatory role in PAI-1 production byhepatic and endothelial cells (44) and a strong direct association between insulinlevels and PAI-1 activity has been demonstrated in normals, obese women, andpatients with type 2 diabetes (44) IGF-1 plays a synergistic role in the regulation

of PAI-1 production (37)

Reduction in insulin levels by fasting, or the administration of either formin (45,46) or troglitazone (39), results in lower PAI-1 levels/activity Treat-ment of women with PCOS with troglitazone led to a 31% decrease in the concen-tration of PAI-1 protein in the blood and a 50% reduction in the functional activity

met-of PAI-1 (39) that was significantly correlated with the decline in insulin levelsduring an oral glucose tolerance test This finding is consistent with the proposeddirect role of insulin in modulating expression of PAI-1 A modest reduction intPA antigen levels (15%) was seen; however, fibrinolytic activity attributable

to tPA in blood did not change after treatment with troglitazone An improvedfibrinolytic response to thrombosis might be anticipated as a result of the substan-tial decrease in the level and activity of PAI-1 after treatment with insulin-sensi-tizing agents

VI DYSLIPIDEMIA

Women with PCOS are frequently characterized as having hypertriglyceridemia,increased levels of VLDL and LDL, and a lower HDL cholesterol (47,48), a lipidpattern similar to that seen in patients with type 2 diabetes

Various lipid subfractions may possess a greater atherogenic potential due

to alterations in their lipid and apolipoprotein composition Rajkhowa et al (49)have reported that the HDL composition in obese PCOS subjects is modified bythe depletion of lipid relative to protein, with significant reductions in both theHDL cholesterol and phospholipids to apoA-1 This suggests a reduced capacityfor cholesterol removal from tissue with diminished antiatherogenic potential.Both insulin resistance and hyperandrogenemia have been implicated inthe pathogenesis of the lipid abnormalities in PCOS Testosterone decreases lipo-protein lipase activity in abdominal fat cells, while insulin resistance impairs theability of insulin to exert its antilipolytic effects and leads to altered activity oflipoprotein and hepatic lipases These abnormalities are coupled with a decreasedcholesterol ester transfer protein activity

Evidence supporting an important role for insulin resistance in the

patho-genesis of these lipid abnormalities includes the findings of Wild et al (50),who noted that, among hyperandrogenic women, suppression of estradiol andtestosterone levels with a GnRH agonist did not result in alteration of baselinelipid abnormalities Rather, the lipid profiles remained aberrant and correlatedwith the degree of insulin resistance Slowinska-Srzednicka (51) subsequentlyfound that, after adjustment for age, BMI, and androgen levels, fasting insulinwas a significant explanatory variable for triglyceride and apoA-1 levels in PCOS.Although it is reasonable to predict that these lipid abnormalities in PCOSconvey an increased risk for cardiovascular morbidity and mortality, little dataexist to confirm this Using a predictive, cohort model, Dahlgren and colleagues(34) have estimated that myocardial infarction would be seven times more com-mon in women with PCOS than in the general population The risk function wasage-dependent, with an estimated risk ratio of 4.2 to develop ischemic heart dis-ease for PCOS women 40 to 49 years of age, and a risk ratio of 11.0 for those

50 to 61 years of age as compared to age-matched referents This calculated riskwas not evident in a retrospective analysis of 30 years follow-up on 786 womendiagnosed with PCOS between 1930 and 1979 (52) Of interest, there was asignificant excess of deaths in which diabetes was listed as a contributing cause.Finally, Wild and colleagues (53) evaluated 102 women presenting for cor-onary artery catheterization for the signs and symptoms of androgen excess, andfound that hirsutism was more common in those women with confirmed coronaryartery disease In addition, women with polycystic ovaries by ultrasonographywho were undergoing coronary arteriography have been found to have more ex-tensive coronary artery disease compared to women with normal ovaries (54).Finally, carotid intima-media thickness was found to be significantly greater forwomen in their forties with a diagnosis of PCOS than for controls (55), suggesting

an increased risk of subclinical atherosclerosis in women with PCOS

VII OBSTRUCTIVE SLEEP APNEA

Obese women with PCOS are at increased risk for obstructive sleep apnea (OSA)(56) Based on the increased prevalence of OSA in men, and recent evidencethat androgens may play a role in the male predominance, overnight polysomnog-raphy was performed in obese women with PCOS and age/weight-matched con-trols (56) Women with PCOS had a significantly higher apnea-hypopnea index(AHI), and were more likely to suffer from symptomatic OSA syndrome TheAHI correlated with waist–hip ratio, as well as total and free testosterone levels.Vgontzas et al (57) also reported that sleep-disordered breathing (SDB) and ex-cessive daytime sleepiness are more frequent in women with PCOS than in pre-menopausal controls Insulin resistance appeared to be a risk factor for SDB inwomen with PCOS

Whether there is a causal relationship between OSA and cardiovascular

morbidity and mortality is uncertain However, recent evidence suggests thatOSA may indirectly increase the risk of cardiovascular morbidity and mortality.The Wisconsin Sleep Cohort Study documented that an apnea index of five ormore events per hour resulted in significantly higher systemic pressures than insnorers or normals (58) Lavie et al (59) demonstrated a similar association be-tween an increased apnea–hypopnea index and systolic and diastolic blood pres-sures during waketime hours Furthermore, a 10% decrement in oxygen saturationduring sleep was linearly associated with an increased risk of systemic hyperten-sion (59) Several recent studies have demonstrated that OSA alone is not suffi-cient to cause persistently elevated pulmonary arterial pressures Daytime hy-poxia, resulting from obesity or underlying lung disease, is also necessary forthe development of sustained pulmonary hypertension The most common andsignificant cardiac rhythm abnormalities associated with OSA are severe brady-cardia and ventricular asystole greater than 10 s (60) The physiological abnor-malities associated with OSA, including hypoventilation, hypoxemia, respiratoryacidosis, and vigorous inspiratory effort against a closed airway, result in para-sympathetic stimulation and the resultant rhythm disturbances Finally, there islittle direct evidence to support the hypothesis that OSA contributes to vascularmorbidity including myocardial infarction and stroke It thus appears that obesewomen with PCOS are at increased risk for OSA, and that they should be ques-tioned carefully regarding potential symptoms of sleep-disordered breathing Itremains speculative as to whether obstructive sleep apnea predisposes womenwith PCOS to a higher risk of systemic hypertension, and subsequent cardiovas-cular morbidity and mortality.

In conclusion, the metabolic alterations seen in PCOS appear to impart anincrease in risk for the development of glucose intolerance and diabetes as well

as lipid abnormalities and macrovascular disease Advances in our understanding

of the pathogenesis of the insulin resistance that underlies the development ofthese complications has provided the impetus for use of novel therapies, chiefamong them the insulin-lowering medications The ultimate role of these agents

in the treatment of PCOS and its metabolic sequelae remains to be determined

VIII CLINICAL AND THERAPEUTIC IMPLICATIONS

The evidence suggests that the metabolic syndrome of PCOS is placing youngwomen at risk for premature macrovascular disease Accordingly, management

of PCOS in the future may shift from solely the control of symptoms to theprimary prevention of chronic disease through management of cardiovascularrisk factors Women with PCOS should be carefully evaluated for the presence

of obesity, hypertension, dyslipidemia, insulin resistance, and glucose ance Some authorities advocate screening for impaired glucose tolerance and

intoler-diabetes in all women with PCOS It is probably prudent to utilize the standardoral glucose tolerance test in women with PCOS that are obese, display signs ofinsulin resistance (acanthosis nigricans), or have a significant family history oftype 2 diabetes mellitus Fasting plasma glucose levels do not correlate well withthe results of glucose tolerance testing in this patient population Therefore, theyshould not be relied upon for screening in women felt to be at significant riskfor impaired glucose tolerance and diabetes Screening for dyslipidemia is alsoimportant; fasting lipid subfractions, to include triglyceride levels, should be de-termined A total cholesterol may be less sensitive for detecting atherogenic ab-normalities that are common in women with PCOS Women with PCOS should

be counseled on lifestyle modification, including weight management, nutritionand exercise counseling, and smoking cessation, if appropriate Weight reduction

in obese women with PCOS should be encouraged Adherence to necessarychanges may result in a lessening of insulin resistance, insulin levels, and reversesome of the metabolic aberrations Furthermore, moderate weight loss has beendemonstrated to result in improvements in menstrual function and fertility.Management of hypertension and cardiovascular risk factors might bestfollow the strategies utilized in diabetes management given the similar clinicaldeterminants of cardiovascular risk Due to cost and side-effect profiles, the phy-sician must emphasize the protective benefits of antihypertensive therapy overthe long term in those patients who require treatment The selection of an antihy-pertensive agent may initially involve the use of an angiotensin converting en-zyme inhibitor, which decreases the progression of microalbuminuria and ne-phropathy in patients with type 2 diabetes Spironolactone is also a reasonableagent to utilize in hirsute patients that will benefit from androgenic receptorblockade In considering other agents, thought should be given to the ability ofthe medication to adversely affect lipid profiles and/or insulin sensitivity.There is no objective evidence that the daily use of aspirin therapy inwomen with PCOS has a beneficial role in retarding the evolution of macrovascu-lar disease, although this prophylactic strategy is utilized by many physicians inthe management of patients with type 2 diabetes In a recent meta-analysis of

145 randomized assignment studies including 4500 patients with diabetes, aspirinuse in moderate dosage reduced cardiovascular morbidity and mortality Withrespect to the dyslipidemia and potential cardiovascular risk, many believe thatwomen with PCOS should be considered similar to those with disorders of insulinresistance and diabetes Accordingly, appropriate lifestyle and nutritional modi-fications, as well as pharmacological interventions, should be employed toachieve target values set forth by the NCEP As current research unfolds, wemay find that the quality, as well as the quantity, of certain lipoprotein subclassesshould be addressed to achieve a healthier lipid profile

Insulin-sensitizing agents, such as metformin and the thiazolidinediones,may gain a greater role in the management of these patients in the future The

insulin sensitizers have many potential beneficial effects on the metabolic profileand subsequent cardiovascular risk, including the attenuation of peripheral insulinresistance and a subsequent lowering of plasma insulin levels Furthermore, theyhave beneficial effects on triglyceride and HDL subfractions, as well as PAI-1levels The ultimate role of these agents in the treatment of PCOS and its meta-bolic sequelae remains to be determined.

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