Medical Management of Diabetes and Heart Disease - part 2 pps

Their data indicated that theinsulin resistance syndrome preceded the development of type 2 diabetes by manyyears and that impaired glucose tolerance was associated with the insulin resi

higher in the women than in the normal population Their data indicated that theinsulin resistance syndrome preceded the development of type 2 diabetes by manyyears and that impaired glucose tolerance was associated with the insulin resis-tance syndrome Recently, they have further analyzed their prediabetic cohort bydefining insulin resistance at baseline by the HOMA model and insulin secretion

by the incremental increase in plasma insulin 30 min after an oral glucose loaddivided by the incremental increase in plasma glucose Of 195 individuals whodeveloped diabetes, 161 were insulin resistant at baseline and 34 were insulinsensitive The components of the insulin resistance syndrome were present only

in those with insulin resistance as determined by HOMA (36)

Insulin resistance occurs very commonly in societies that have acquiredwestern cultural patterns In Europe, it is estimated that 16% of the adult popula-tion has the insulin resistance syndrome In a recent analysis of the Botnia popula-tion in Finland, the prevalence of the metabolic syndrome as defined by WHOwas assessed in individuals with normal glucose tolerance, impaired glucose tol-erance, or impaired fasting plasma glucose (IFG), and type 2 diabetes (37) TheWHO definition of the metabolic syndrome is (1) hypertension (BP ⬎160/90mmHg or treatment for hypertension); (2) dyslipidemia, defined as plasma tri-glycerideⱖ1.7 mmol/L (150 mg/dL) and/or HDL cholesterol ⬍0.9 mmol/L (35mg/dL) in men or⬍1.0 mmol/L (38.5 mg/dL) in women; (3) obesity, defined

as BMI ⱖ30 kg/m2

and/or WHR ⬎0.90 in men or ⬎0.85 in women; and (4)microalbuminuria (urinary albumin excretion ⱖ20 µg/min) Fifteen (10%) ofnormal glucose-tolerant men and women aged 35 to 70 years had the metabolicsyndrome as compared to 64 (42%) of those with IFG/IGT and 84 (78%) ofthose with type 2 diabetes

A routine health examination of 2113 middle-aged men and women inTokyo in the early 1990s revealed the following prevalence of components ofthe insulin resistance syndrome: obesity 20.9%; hypertension 23.1%; hyperinsuli-nemia 11.0%; hypertriglyceridemia 24.4%; low HDL cholesterol 23.0% (38) Theindividuals with hyperinsulinemia had higher plasma triglycerides, lower plasmaHDL cholesterol, higher systolic and diastolic blood pressure, and higher area-under-the-plasma glucose curve during the oral glucose tolerance than those withnormoinsulinemia matched for age, sex, and BMI Individuals with glucose intol-erance (defined as 2-h plasma glucoseⱖ133 mg/dL after a 100-g oral glucoseload) had higher plasma triglycerides, higher systolic and diastolic blood pres-sures, and higher area-under-the-2-h plasma glucose curve during the OGTT ascompared to the normal glucose-tolerant individuals matched for age, sex, andBMI

As noted previously, fasting plasma glucose as well as lenge plasma glucose predicts the future development of type 2 diabetes Thiswas the reason for the definition of the new category of glucose intolerance called

post-glucose-chal-impaired fasting glucose IFG is defined as a fasting plasma glucoseⱖ110 mg/

dL (6.2 mmol/dL) and ⬍126 mg/dL (7.0 mmol/dL) The introduction of thiscategory has created much controversy Many analyses of data bases, includingthose in the DECODE study, have shown that IFG consists of some who would

be diagnosed as type 2 diabetics by the 2-h post-glucose-challenge plasma coseⱖ200 mg/dL (11.1 mmol/L), some who have IGT, and a small subset whohave only IFG (39,40) Some series show that IFG predicts CV disease whileothers show little or no predictive value (41) In studies where IFG predicts futureCVD (as in the CARE secondary prevention study employing pravastatin in pa-tients post myocardial infarction), the IFG cohort has the insulin resistance syn-drome with increased BMI and waist circumference, increased systolic bloodpressure, and the characteristic dyslipidemia (42)

glu-Insulin resistance can occur very early in life Data from an ongoing spective study of low-birth-weight infants in India indicate that these childrencan develop the insulin resistance syndrome as early as 8 years of age Manystudies have found insulin resistance in young adults who are first degree relatives

pro-of individuals who have type 2 diabetes Insulin resistance is a characteristic pro-ofindividuals who have visceral obesity Individuals who are obese as assessed byBMI are not necessarily insulin resistant nor do they have the insulin resistancesyndrome Brochu et al examined the metabolic characteristics of 43 obese, sed-entary, postmenopausal women (44) Despite comparable BMI (31.5 vs 34.7 kg/

m2

) and fat mass (37.3 vs 39.0 kg), 17 individuals had normal insulin sensitivityand 26 were insulin resistant as assessed by the euglycemic hyperinsulinemicclamp The obese individuals with normal insulin sensitivity had 49% less vis-ceral adipose tissue than the resistant individuals, and had normal fasting andpost-glucose-challenge plasma glucose and insulin and mean plasma triglycerides

of 1.50 mmol/L (133 mg/dL) and plasma HDL cholesterol of 1.16 mmol/L (45mg/dL) The insulin-resistant individuals had hyperinsulinemia and the classicdyslipidemia of insulin resistance as well as borderline increases in fasting andpost-glucose-challenge plasma glucose levels

The evidence suggesting that the insulin resistance syndrome plays a centralrole in the development of macrovascular disease in type 2 diabetic patientscomes from many sources In 1989, Banerji and Lebovitz described two variants

of type 2 diabetes: one with impaired insulin action (insulin-resistance variant)and one with normal insulin action (insulin-sensitive variant) (6) Their insulin-sensitive patients had none of the components of the insulin resistance syndrome,while the insulin-resistant patients had the classic insulin resistance syndrome(17) These observations were extended by Haffner et al., who showed that insu-lin-sensitive type 2 diabetic patients had lower BMI and waist circumference,lower plasma triglyceride and higher plasma HDL cholesterol levels and larger,more buoyant, LDL particles, and lower plasma fibrinogen and plasminogen

activator inhibitor 1 (PAI-1) levels than insulin-resistant type 2 patients(45) In essence, the insulin-sensitive type 2 diabetic patients had none of thecharacteristics of the insulin resistance syndrome In the United Kingdom Pro-spective Diabetes Study (UKPDS), newly diagnosed type 2 diabetic Caucasian,Asian, Indian, and Afro-Caribbean patients were randomized to either intensive

or conventional glucose control treatment programs and the effects on clinicaldiabetic complications were assessed over a mean of 11 years At baseline, theAfro-Caribbean population had less insulin resistance and insulin resistance com-ponents and more beta-cell deficiency than the Caucasian population (46) Therelative risk of the Afro-Caribbean patients developing a fatal or nonfatal myocar-dial infarction over the 11-year follow-up was 0.4 that of the Caucasian popula-tion (47)

Two large, long-term prospective studies from Finland have examined therelationship between the insulin resistance syndrome and the development ofcoronary heart events in nondiabetic men An analysis of 22-year follow-up datafrom the Helsinki Policemen Study (48) showed that a factor analysis includingsix risk factor variables that are considered to be components of the insulinresistance syndrome (BMI, subscapular skinfold, areas under the plasma glucoseand insulin curves during the oral glucose tolerance test, mean blood pressure,and plasma triglyceride) independently predict the risk of CHD (hazard ratio1.48) and stroke (hazard ratio 2.02) A 7-year follow-up study of 1069 subjectsaged 65 to 74 years from eastern Finland assessed the relationship of variousclusters of risk factors to predict CHD events in men and women (49) An insulinresistance factor (BMI, WHR, fasting plasma glucose, insulin, and triglycerides)predicted CHD events in elderly men (hazard ratio 1.33), but not in elderlywomen

In the Botnia population, cardiovascular outcomes were assessed in 2401subjects The adjusted relative risk of developing CHD was 2.96 and of stroke2.27 in those whom at baseline had the metabolic syndrome as defined byWHO Cardiac mortality in 3606 subjects with a mean follow-up of 6.9 yearswas 12.0% in those who had the metabolic syndrome and 2.2% in those who didnot (37)

Outcome studies indicate a statistical relationship between CVD events andeach of the various components of the insulin resistance syndrome (37,50–56).The extensive interrelationships among the various components of the insulinresistance syndrome (9,10,37,48) have prevented identifying with certaintywhether certain independent individual components underlie the syndrome or,more importantly, whether specific major components are responsible for theaccelerated atherosclerosis and increased macrovascular disease

The mechanism by which insulin resistance is created and the quences of insulin resistance that contribute to macrovascular and perhaps mi-

conse-crovascular disease have been the subjects of intensive investigations andnumerous speculations Considerable new data have suggested that insulin resis-tance and its dyslipidemia are related to the metabolic consequences of visceraladiposity (8,26,28,30,44,57) It is likely that adipose tissue releases circulatingfactors that both facilitate and inhibit insulin action (58–61) Free fatty acids(62) and tumor necrosis factor-α (63) inhibit insulin action by blocking activa-tion of the insulin receptor substrate (IRS) phosphoinositide-3 kinase (PI-3 ki-nase) pathway This limb of the intracellular insulin action cascade is responsiblefor regulating insulin’s action on glucose transport and lipid metabolism (64).The other limb of the intracellular insulin action cascade is the MAP kinase path-way, which regulates insulin’s mitogenic and growth activities (64) This path-way is not inhibited in the insulin resistance syndrome (37,65) Insulin acts onendothelial cells to regulate vascular tone and other aspects of endothelial func-tion (66) Insulin action on endothelial cells is mediated by the intracellular IRSPI-3 kinase pathway and this action is inhibited in the insulin resistance syn-drome just as are the intermediary metabolism effects (67–69) The ability ofinsulin to generate nitric oxide by activating endothelial cell nitric oxide syn-thase is markedly decreased (67) The result is that endothelial dysfunction is acharacteristic finding in the insulin resistance syndrome (66,68–70) The distur-bance of endothelial function results in increased synthesis of growth factors andadhesion molecules, proliferation of matrix and smooth muscle cell, and in-creased expression of PAI-1 gene (66) Increased peripheral resistance and in-creases in mean arterial blood pressure are probably due in part to an imbalance

of the angiotensin-2 and endothelin actions on the endothelial cells nating over those of insulin and other vasodilators (68–69) The procoagulantand antifibrinolytic state results from abnormalities of the coagulation cascadeand the increase in PAI-1 activity (54,71–73) Associated with, and probablypart of, the insulin resistance syndrome is an increase in arterial inflammatoryprocesses that are marked by elevated levels of fibrinogen and plasma CRP lev-els as measured by a highly sensitive assay (74–76)

predomi-Many studies have documented the association between insulin resistanceand endothelial dysfunction (66,69), the dyslipidemia of high plasma triglycer-ides, low plasma HDL cholesterol, and a pattern of small dense LDL particles(77–79), the procoagulant state, the low-grade inflammatory state, and, in somepopulations, increased blood pressure and microalbuminuria (80) These samemetabolic abnormalities have all been shown to increase CVD morbidity andmortality risk (37,42,48,49,80) Thus insulin resistance is a metabolic abnor-mality that increases cardiovascular disease risk In the type 2 diabetic, cardiovas-cular risks are due to two factors, the insulin resistance syndrome and poorlycontrolled hyperglycemia (Fig 6) In contrast to type 1 diabetic patients, type 2diabetic patients require treatment of both abnormalities from the onset of theillness

Figure 6 A hypothesis for the pathogenesis of macrovascular disease in type 2 diabeticpatients Visceral obesity leads to the development of insulin resistance and the othercomponents of the insulin resistance syndrome The insulin resistance syndrome itselfcauses accelerated atherosclerosis, which increases clinical macrovascular disease events.

In those individuals with the genetic predisposition for type 2 diabetes, the insulin tance, which increases the requirement for insulin secretion, accelerates beta-cell func-tional failure and this eventually results in first postprandial and later fasting hyperglyce-mia The hyperglycemia further contributes to atherogenesis and macrovascular disease

resis-by the mechanisms shown in the figure (Adapted from Ref 8.)

III CONCLUSIONS AND THERAPEUTIC IMPLICATIONS

From the point of view of understanding and preventing or treating the cular complications of diabetes mellitus, it is important to differentiate whetherthe diabetes is or is not associated with insulin resistance If it is not initiallyassociated with insulin resistance, as in type 1 or insulin-sensitive type 2 diabetes,then the primary goal should be to treat to and maintain the fasting and postpran-dial plasma glucose as close to normal as possible, while minimizing the develop-ment of visceral obesity Such a strategy, if it can be implemented, should main-tain atherosclerosis progression at the prediabetic level

macrovas-If, however, insulin resistance is the early event, it should be treated asaggressively as possible in order to prevent accelerated atherosclerosis and the

possible progression to type 2 diabetes The rate of development of sis varies in different populations depending on their genetic background andlifestyle (3,81) The acquisition of insulin resistance or diabetes mellitus increasesthe intrinsic rate of atherosclerosis (82) Populations such as the Pima Indians,who have a low rate of CHD, increase the prevalence two- to threefold with thedevelopment of IGT or type 2 diabetes The absolute prevalence, however, isstill significantly lower than that in most nondiabetic populations who have rela-tively high intrinsic rates of CHD (83).

atherosclero-Insulin resistance usually starts and has been accelerating atherosclerosisyears before glucose intolerance and type 2 diabetes become evident By thetime IGT or type 2 diabetes is diagnosed, individuals already have advancedatherosclerosis and are on their way to developing clinical macrovascular disease.This likely explains the observations that a diabetic without any preceding clinicalCVD has the same likelihood of having a myocardial infarction in a 7-yearfollow-up as a nondiabetic individuals who already has had a myocardial in-farction (84) The suggestion has been made that all type 2 diabetic patientsshould be treated to prevent progression of their atherosclerosis and that thiswould be comparable to secondary intervention rather than primary prevention.There are data to suggest that such a strategy, while probably good, may not

be good enough The results of the 6.4-year mean follow-up of the CardiovascularHealth Study indicated ‘‘that most of the traditional cardiovascular risk factorswere not significant predictors of the risk of CVD among diabetics after adjustingfor the extent of subclinical disease’’ (Table 6) (85) Subclinical disease wasdefined as an ankle-arm indexⱕ0.9; internal carotid artery wall thickness ⬎80thpercentile; carotid stenosis⬎25%; major ECG abnormalities (based on Minne-

Table 6 Multivariate Analysis of Clinical Endpoints as a Function

of Subclinical Disease and CVD Risk Factors in Diabetic Participants

Without a History of Baseline Clinical Disease

Outcomea

Serum creatinine (per 1 mg/dL) 2.15

Fasting plasma glucose (per 20 mg/dL) 1.06

sota code); and a Rose Questionnaire positive for claudication or angina pectoris

in the absence of clinical diagnosis of angina pectoris or claudication Subclinicaldisease was present in 60% of participants with IGT One can interpret thesetypes of data to provide the following chronology The insulin resistance syn-drome starts at a relatively young age (young adulthood) and causes acceleratedatherosclerosis By middle age, subclinical macrovascular disease is present Inthose individuals with the genetic propensity, beta-cell insulin secretory functiondecreases and impaired glucose tolerance and finally type 2 diabetes develop Bythe time type 2 diabetes does develop, subclinical and, in some cases, clinicalmacrovascular disease is well established and will continue to progress Poorlycontrolled hyperglycemia even further accelerates the rate of atherosclerosis.The implications of this hypothesis have far-reaching clinical implications

It means that accelerated atherosclerosis starts at a relatively young age, longbefore there is any clinical disease and before we would traditionally intervene.This is the stage at which treatment of insulin resistance and cardiovascular riskfactors are likely to be most effective in reducing macrovascular disease At thetime of diagnosis of type 2 diabetes, many or perhaps most patients will alreadyhave moderately advanced subclinical or even clinical cardiovascular disease.Intervention strategies to reduce cardiovascular risk factors in type 2 diabeticpatients will be of value but may have somewhat limited effectiveness since thesubclinical cardiovascular abnormalities may be more important in determiningthe future course of the CVD than the risk factors themselves

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SM LDL particle size in relation to insulin, proinsulin, and insulin sensitivity betes Care 1999; 22:1688–1693

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82 Laakso M, Ro¨nnemaa T, Lehto S, Puukka P, Kallio V, Pyo¨ra¨la¨ K Does NIDDM

increase the risk for coronary heart disease similarly in both low- and high-risk lations? Diabetologia 1995; 38:487–493.

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85 Kuller LH, Velentgas P, Barzilay J, Beauchamp NJ, O’Leary DH, Savage PJ tes mellitus: Subclinical cardiovascular disease and risk of incident cardiovasculardisease and all-cause mortality Arterioscler Thromb Vasc Biol 2000; 20:823–829

be maintained for many years Once pancreaticβ-cell dysfunction occurs, ever, inability to compensate for the increased insulin resistance results in clinicalhyperglycemia and the diagnosis of type 2 diabetes is then apparent and can bemade on clinical grounds As such, insulin resistance can be considered an initialpathophysiological event leading to, and premonitory of, type 2 diabetes (3–5).Intensive research has been aimed at identifying the cellular mechanisms respon-sible for insulin resistance and providing a framework for designing pharmaco-logical therapies to alleviate the condition This chapter will review basic researchstudies evaluating the cellular defects contributing to insulin resistance, describemethods to clinically assess this variable, discuss associated clinical risk factors,and provide an overview of management options.

how-The concept of ‘‘insulin resistance’’ originated well over 50 years ago andthe understanding of this condition has continued to evolve, as outlined from ahistorical perspective by Hunter and Garvey (6) Specifically, early observationsnoted with the clinical use of insulin therapy for treatment of diabetes suggestedthat there were two groups of diabetic patients, roughly divided by their glycemicresponse to exogenously administered insulin (6) Using present-day terms, these

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