Medical Management of Diabetes and Heart Disease - part 3 ppt

Among those subjects who manifested insulin resistanceand components of the syndrome i.e., excess body weight, increased WHR, hy-pertension, and elevated lipids, treatment of insulin res

Insulin has also been found not to potentiate the blood pressure or kidney effects

of other vasoactive substances, such as norepinephrine or angiotensin-II(102,103) Further, in obese subjects who are resistant to the metabolic and vaso-dilator effects of insulin, elevated insulin did not appear to increase arterial pres-sure (104) Therefore, the results of several clinical research studies stronglysuggest that hyperinsulinemia does not explain the increased renal tubular NaClreabsorption, shifts of pressure natriuesis, or the hypertension associated withobesity in both animals and humans (101)

In contrast to the above, results from rodent studies suggest that long-termelevated insulin levels may result in significant elevations in arterial pressure.This effect may be mediated through interactions with the RAS and thromboxane(101) Studies have suggested that inhibition of thromboxane synthesis or ACEinhibition did indeed abolish the insulin-induced rise in arterial pressure in ro-dents (105,106) Further, blockade of endothelial-derived NO synthesis appears

to enhance insulin-induced hypertension in rodents (107) It is unclear whetherthese findings in rodents are relevant to the hypertension noted in obese humans,but summation of the currently available studies does suggest that chronic ele-vated insulin levels cannot account for obesity-induced increases in blood pres-sure Therefore, the very close correlation between hyperinsulinemia and hyper-tension in obese subjects may be because obesity itself not only elevates arterialpressure but also induces peripheral insulin resistance in hyperinsulinemiathrough parallel but independent mechanisms (101)

The question that remains, therefore, is the mechanism by which obesitycontributes to hypertension A recent review by Hall et al (101) outlines a sum-mary of mechanisms by which obesity may cause hypertension and glomerulo-sclerosis by activation of the renin-angiotensin and sympathetic nervous systems,including metabolic abnormalities and compression of the renal medulla A sum-mary of these mechanisms is outlined in Figure 4 (101)

F Prothrombotic Activity

An additional mechanism proposed to explain the accelerated atherosclerosis served with insulin resistance and type 2 diabetes is a hypercoagulable state.The body’s fibrinolytic system normally limits vascular thrombosis and appearsresponsible for dissolution of thrombi after vascular repair has occurred How-ever, a disturbance of the fibrinolytic system favors the development of vasculardamage and the final occlusion event in the progress of coronary heart disease(108–113)

ob-A balance normally exists between plasminogen activators and inhibitors,and diminished fibrinolysis secondary to elevated concentrations of plasminogenactivator inhibitors may help to explain the exacerbation and persistence ofthrombosis observed in acute events A diminished release of tissue plasminogen

Figure 4 Schematic outlining postulated mechanisms by which obesity contributes tohypertension (Adapted from Ref 101; used with permission.)

activator (t-PA) or increased levels of PAI-1 (Fig 5) may both contribute toimpaired fibrinolysis (108–112) PAI-1, a major regulator of the fibrinolytic sys-tem, is a serine protease inhibitor and binds to and inhibits t-PA and u-PA (uroki-nase plasminogen activator) Sources of PAI-1 include hepatocytes, endothelialcells, adipocytes, and smooth muscle cells PAI-1 is also present in the alphagranules of platelets

Elevated PAI-1 activity or reduced t-PA resulting in defective fibrinolysismay predispose individuals to sequela from thrombotic events and contribute tothe development and progression of atherosclerosis (108–114) PAI-1 appears tomodulate vessel wall proteolysis, and increased production of PAI-1 has beenobserved in components of the atherosclerotic plaque and the vessel wall (111).Diminished vessel wall proteolysis may predispose to accumulation of extracellu-lar matrix Further, cell migration is dependent on cell surface expression of u-

PA Thus, overexpression of PAI-1 in the vessel wall may limit migration ofsmooth muscle cells into the neointima This limitation of migration may predis-pose to the development of a thin cap overlying the lipid core, a feature associatedwith increased risk of evolution of vulnerable plaque rupture, when acute eventstrigger proteolysis (112,113)

The fibrinolytic variables (PAI-1 and t-PA antigen) are strongly associatedwith components of the insulin resistance syndrome in cross-sectional studies

Figure 5 Schematic demonstrating components of the fibrinolytic system (Reprintedwith permission from Ref 117.)

(115,116) Further, the observed association between insulin resistance and

PAI-1 or t-PA antigen levels has also been confirmed in intervention studies aimed

at reducing insulin resistance (113) The improvement in insulin resistance isparalleled by improvement of the metabolic abnormalities altering the concentra-tions of these moieties Among those subjects who manifested insulin resistanceand components of the syndrome (i.e., excess body weight, increased WHR, hy-pertension, and elevated lipids), treatment of insulin resistance was associatedwith a decrease in PAI-1 and improvement of the fibrinolytic activity in the ma-jority of these studies

VI CLINICAL INTERVENTIONS IN THE MANAGEMENT

OF THE INSULIN RESISTANCE SYNDROME

On the basis of convincing clinical studies, it is no longer questioned that theinsulin resistance syndrome is associated with an increased morbidity and mortal-ity A more relevant question is whether improvement of insulin resistance witheffective clinical interventions will decrease mortality and morbidity associatedwith the syndrome Addressing the question will be problematic, as a clinicallypractical and reliable test to assess insulin resistance, or a way to serially measureclinical resistance with less invasive techniques for large-scale studies, is notwell established (5) We do know, however, that there are a number of clinical

interventions that increase insulin sensitivity These interventions include a rie-restricted diet, weight reduction, exercise, and pharmacological interventionwith agents such as metformin and glitazones (5) Most clinicians will readilyagree that, in those subjects who do comply, a calorie-restricted diet will mark-edly ameliorate insulin resistance Insulin sensitivity, in these cases, is signifi-cantly increased very early after initiating the calorie-restricted diet and this re-duction is observed even before significant weight loss has occurred Clinically,

calo-a reduction in insulin resistcalo-ance is reflected by calo-an improvement in glycemic trol or a marked decrease in the need for exogenous insulin or higher doses oforal antidiabetic medications to maintain glycemic control It has also been firmlyestablished that weight reduction over a longer time frame continues to improveinsulin sensitivity Should a patient not be able to lose weight, the most efficientmeans of preventing insulin resistance and worsening morbidity may be to avoidadditional weight gain (5) A current controversy regarding nutritional recom-mendations for weight loss is whether caloric distribution among carbohydratesand the various fats is a critical parameter A general consensus is that totalcalorie intake is the critical parameter responsible for the weight loss However,others would argue that the distribution of calories is the key Unfortunately,comparison trials evaluating such diets have not been done (5)

con-Exercise is an effective intervention in the management of the resistant syndrome, as vigorous exercise has been demonstrated to improveinsulin sensitivity, even in elderly patients Unfortunately, the effect on insulinsensitivity is known to diminish quickly (within 3 to 5 days) after stopping theexercise Exercise should be considered a necessary adjunct to diet, as long-termexercise would result in little weight reduction unless caloric restriction is alsopart of the regimen

insulin-Pharmacological treatment of insulin resistance is an area of active gation Two specific pharmacological approaches in the treatment of insulin resis-tance have been made available over the past several years A class of compoundscalled biguanides, as represented by the agent metformin, has been available for

investi-a number of yeinvesti-ars investi-and hinvesti-as investi-a predomininvesti-ant effect of diminishing hepinvesti-atic glucoseproduction The biguanides also have a moderate effect on skeletal muscle insulinresistance On the other hand, drugs referred to as thiazolidinediones, represented

by agents such as troglitazone, rosiglitazone, and pioglitazone, represent a class

of drugs considered true insulin sensitizers, as insulin-stimulated glucose disposal

is enhanced in insulin-sensitive tissues Although both classes of drugs are rently available in the United States for treatment of the type 2 diabetic condition,neither class is approved to treat insulin resistance in the absence of the type 2diabetic state

cur-Both classes of drugs have been postulated to be beneficial in either laying or preventing the progression to type 2 diabetes In particular, the DiabetesPrevention Program, sponsored by the National Institutes of Health, is designed

de-to determine if any treatment (nutrition, exercise, or pharmacological) is effective

in the primary prevention of type 2 diabetes in people who have been diagnosedwith impaired glucose tolerance (13) As originally designed, there was to be acontrol group that employed intensive lifestyle changes to effect an approxi-mately 7% reduction in body weight through caloric restriction and exercise Thesecond and third groups were to consist of pharmacological treatments to reduceinsulin resistance, mainly metformin and troglitazone The troglitazone arm wasdropped from study due to an adverse event involving the liver Because of thehepatic concern, troglitazone was removed from the market in March 2000

It is not currently recommended that providers prescribe pharmacologicaltreatment to their patients who are felt to be insulin resistant before the diagnosis

is established for type 2 diabetes Depending on the outcome of the current vention trials, this may be a recommendation in the future However, until theongoing prevention trials are completed and the results made available, a non-pharmacological approach is probably the most reasonable option the cliniciancan offer to the patient in order to achieve a reduction in insulin resistance andprevent the development of type 2 diabetes Appropriate candidates for such ther-apy include those who are centrally obese, have a strong family history of diabetes

pre-or gestational diabetes, demonstrate impaired fasting glucose on testing, pre-or fest other clinical symptoms associated with insulin resistance (e.g., hypertension,dyslipidemia)

mani-VII SUMMARY

This chapter has summarized current concepts regarding insulin resistance andits associated clinical risk factors Insulin resistance is very much a part of thenatural history of type 2 diabetes and may precede the clinical diagnosis by manyyears The responsible cellular mechanisms that contribute to insulin resistanceare not clearly defined, yet it is well established that cardiovascular risk factorsare strongly related to insulin resistance Whether specific treatment of insulinresistance will delay or prevent development of type 2 diabetes and reduce mor-bidity and mortality from cardiovascular disease will need to be answered inwell-defined clinical studies

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Hypertension, Diabetes,

and the Heart

Tevfik Ecder, Melinda L Hockensmith, Didem Korular,

and Robert W Schrier

University of Colorado School of Medicine, Denver, Colorado

I INTRODUCTION

Diabetes mellitus is a common health problem throughout the world According

to the World Health Organization statistics, the global prevalence of diabetesmellitus is approximately 155 million, which is expected to increase to 300 mil-lion in the year 2025 (1) The prevalence of diabetes is increasing significantly

in the United States (2) According to the Third National Health and NutritionExamination Survey (NHANES III), which was conducted between 1988 and

1994, there are 10.2 million diagnosed and 5.4 million undiagnosed diabetic adultpatients in the United States based on American Diabetes Association criteria(3) Diabetes is even more common in certain ethnic groups African Americans,Native Americans, and Hispanic Americans have a two- to sixfold greater preva-lence of diabetes when compared with white non-Hispanic Americans (3,4).Type 1 diabetes comprises 5 to 10% of diagnosed cases, whereas type 2diabetes accounts for 90 to 95% of the cases in the United States (5) Bothtype 1 and type 2 diabetes are associated with vascular complications leading tocoronary heart disease, peripheral vascular disease, nephropathy, retinopathy, andneuropathy These complications adversely affect the morbidity and mortality ofdiabetic patients, in addition to causing an enormous economic burden Cardio-vascular complications are the most common cause of death, accounting for 60

to 70% of all deaths in patients with diabetes mellitus (6,7) Moreover, diabetes

is the most common cause of renal failure, adult blindness, and amputations in

65

the United States (7) Thus, patients with diabetes mellitus should be carefullymanaged both for the prevention and treatment of these complications.

II PREVALENCE OF HYPERTENSION AND

CARDIOVASCULAR COMPLICATIONS IN DIABETES

Diabetes plays a powerful role in the development of cardiovascular diseases (8–10) The incidence of cardiovascular disease is two times higher in men withdiabetes and three times higher in women with diabetes than nondiabetic subjects(10) Haffner et al (11) reported that the risk of developing a myocardial in-farction in type 2 diabetic patients without a previous history of myocardial in-farction is similar to that of nondiabetic patients who have had a prior myocardialinfarction

Diabetic patients have a twofold increase in the prevalence of hypertensioncompared with nondiabetic subjects (5) Hypertension is even more common incertain ethnic groups with type 2 diabetes Almost twice as many African Ameri-cans and three times as many Hispanic Americans as compared with white non-Hispanic subjects have coexistent diabetes and hypertension (5) The coexistinghypertension and diabetes continue to rise dramatically in western countries asthe overall population ages and as obesity and sedentary lifestyles become moreprevalent

The coexistence of diabetes and hypertension causes a very high risk forthe development of macrovascular and microvascular complications In patientswith diabetes, 30 to 75% of complications can be attributed to hypertension (12).Risk for cardiovascular disease increases significantly when hypertension co-exists with diabetes mellitus (13,14) Moreover, hypertension has a greater impact

on cardiovascular diseases in diabetic as compared with nondiabetic subjects (15).Diabetic patients have a higher incidence of coronary artery disease, congestiveheart failure, and left ventricular hypertrophy when hypertension is present Theincidence of other macrovascular complications, such as stroke and peripheralvascular disease, also increases significantly when hypertension exists in diabeticpatients Moreover, in addition to macrovascular complications, hypertension ac-celerates the risk of microvascular complications Diabetic nephropathy (16,17),retinopathy (18–20), and neuropathy (21) are much more common when hyper-tension is found in association with diabetes

The prevalence and natural history of hypertension differ markedly tween patients with type 1 and type 2 diabetes mellitus The prevalence of hyper-tension in patients with type 1 diabetes mellitus is similar to that of the generalpopulation until the onset of diabetic nephropathy Hypertension not only devel-ops with the onset of renal disease in these patients but also worsens with theprogression of nephropathy The hypertension in this setting is characterized by