R e v i e w P a p e r

Relationships Among Insulin Resistance, Type 2Diabetes, Essential Hypertension, andCardiovascular Disease: Similarities andDifferences

Gerald M. Reaven, MD

Insulin resistance plays a major role in thepathogenesis and clinical course of patients withtype 2 diabetes (2DM) and essential hypertension.However, the syndromes differ in prevalence ofinsulin resistance, and associated insulin secretoryresponse. Essentially all patients with type 2diabetes are insulin resistant, whereas onlyapproximately 50% of those with essential hyper-tension are insulin resistant. Furthermore, 2DMdevelops when the pancreatic b-cell can no longermaintain the degree of compensatory hyper-insulinemia needed to prevent hyperglycemia. Incontrast, the compensatory hyperinsulinemia thatprevents most insulin resistant individuals fromdeveloping 2DM acts on normally insulin sensitivetissues in a manner that predisposes to the devel-opment of essential hypertension. This review willdiscuss these similarities and differences in somedetail, as well as exploring the relationship amonginsulin resistance and related metabolic abnormal-ities in the pathogenesis of cardiovascular diseasein patients with 2DM and essential hypertension.

J Clin Hypertens (Greenwich). 2011;13:238243.2011 Wiley Periodicals, Inc.

Insulin-mediated glucose uptake by muscle var-ies more than 6-fold in apparently healthy indi-viduals,1 with approximately 50% of thevariability in insulin action2 resulting from differ-ences in degree of adiposity (25%) and physicalfitness (25%). The remaining 50% is likely to beof genetic origin, with powerful familial and eth-nic influences.3,4 Type 2 diabetes develops wheninsulin-resistant individuals cannot secrete theincreased amounts of insulin needed to compen-sate for the insulin resistance.57 However, themajority of insulin-resistant individuals are ableto maintain the degree of hyperinsulinemiarequired to prevent manifest decompensation ofglucose homeostasis. Although compensatoryhyperinsulinemia prevents the development offrank hyperglycemia in insulin-resistant persons,insulin-resistant hyperinsulinemic individuals areat greatly increased risk of being somewhatglucose-intolerant, with dyslipidemia character-ized by a high plasma triglyceride (TG) andlow high-density lipoprotein cholesterol (HDL-C) concentration and an increase in bloodpressure (BP).5,8 Glucose intolerance, the dyslipi-demia associated with insulin resistance, andessential hypertension represent important riskfactors for cardiovascular disease (CVD). Thegoal of this overview is to summarize the rolethat insulin resistance plays in the pathogenesisof type 2 diabetes and essential hypertension, as

From the Division of Cardiovascular Medicine,Stanford University School of MedicineAddress for correspondence:Gerald M. Reaven, MD, Division of CardiovascularMedicine, Stanford University School of Medicine, FalkCVRC, Stanford Medical Center, 300 Pasteur Drive,Stanford, CA 94305E-mail: greaven@stanford.eduManuscript received November 30, 2010; accepted January21, 2011

doi: 10.1111/j.1751-7176.2011.00439.x

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well as demonstrate the link between them andCVD. In the process, the similarities and the dif-ferences between these relationships will beemphasized.

INSULIN RESISTANCE IN THEPATHOGENESIS OF TYPE 2 DIABETES ANDESSENTIAL HYPERTENSIONType 2 DiabetesAlthough the role of insulin resistance in the patho-genesis of diabetes was initially demonstrated priorto World War II by Himsworth and colleagues,911

it was not until approximately 45 years later that itbecame generally recognized that the majority ofpatients with impaired glucose tolerance or type 2diabetes were insulin-resistant.12,13 In addition, itwas shown that insulin resistance existed in nondia-betic first-degree relatives of patients with type 2diabetes14 and that insulin resistance predicted theonset of frank type 2 diabetes.6,7

Essential HypertensionIn 1966, Welborn and colleagues15 demonstratedthat 19 individuals with essential hypertension hadsignificantly higher plasma insulin concentrationsthan a control population, but approximately ano-ther 20 years elapsed before there was confirmationof this finding.16 During the next few years, itbecame clear that patients with essential hyperten-sion, as a group, were insulin-resistant, that insulinresistance predicted the development of essentialhypertension, and that normotensive first-degreerelatives of patents with essential hypertension wereinsulin-resistant.1719

On the other hand, there is a fundamental differ-ence in the relationship between insulin resistanceand the development of type 2 diabetes as com-pared with its role in the pathogenesis of essentialhypertension. Namely, the overwhelming majorityof patients with type 2 diabetes are insulin-resistantand this is not the case as regards essential hyper-tension. There is no absolute definition of insulinresistance, but prospective studies in which theinsulin suppression test (IST) was used to quantifyinsulin-mediated glucose uptake indicated that onethird of apparently healthy individuals who weremost insulin-resistant developed an adverse clinicaloutcome.20 Insulin action as quantified by the ISTis based on determining the steady-state plasma glu-cose (SSPG) concentration in response to a continu-ous infusion of glucose, insulin, and octreotidethehigher the SSPG, the more insulin-resistant the indi-vidual. Insulin action was quantified with thismethod in 126 patients with essential hypertension,21

treated (n=70) or untreated (n=56), using SSPGconcentration cut-points derived from earlier studiesto divide patients into tertiles. The two groups werenot different in demographic characteristics, andthe data in Figure 1 indicate that they also had asimilar distribution of SSPG concentrations. Thus,approximately 15% of patients with essentialhypertension, treated or untreated, were insulin-sen-sitive (SSPG concentration 180 mg dL). Thus,the prevalence of insulin resistance in patients withessential hypertension is much lower than is thecase in patients with type 2 diabetes, in whichessentially all patients are insulin-resistant.

WHAT IS THE SECOND HIT?Type 2 DiabetesAlthough the vast majority of patients with type 2diabetes are insulin-resistant, insulin resistance, perse, does not explain why fasting hyperglycemiadevelops. The magnitude of insulin resistance variesdramatically in nondiabetic individuals over a nar-row range of fasting plasma glucose concentra-tions,1,22 and the most insulin-resistant nondiabeticindividuals have values that overlap those ofpatients with frank type 2 diabetes. Whatever it isthat protects the majority of insulin-resistant indi-viduals from developing type 2 diabetes remains amystery, but it is clear that failure of the pancreaticb-cell to maintain the degree of compensatoryhyperinsulinemia required to overcome the insulinresistance is what leads to gross decompensation ofglucose homeostasis. It is this inability of the insulinsecretory mechanism to compensate for insulinresistance that provides the second hit that

Figure 1. Comparison of the proportion (percent) ofuntreated and treated patients with essentialhypertension in the 3 SSPG categories:180 mg dL=most insulin-resistant. Reprinted with permission.21

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renders insulin-resistant individuals frankly diabetic.This statement should not be interpreted to meanthat absolute insulin deficiency characterizespatients with type 2 diabetes, and plasma insulinconcentrations in patients with type 2 diabetes areoften as high, or higher, than those of glucose-toler-ant individuals.23

Essential HypertensionIdentifying the second hit that explains why normo-tensive, insulin-resistant individuals develop ele-vated BP is much more elusive, at least partlybecause probably no more than half of patientswith essential hypertension are insulin-resistant.21

However, there is information that may helpexplain some of the mechanistic links between insu-lin resistance and an increase in BP. For example, anumber of relevant variables were compared in 19healthy individuals in response to 5-day periods ofhigh (200 mmol d) and low (25 mmol d) sodiumdiets.24 Mean changes found with a high-sodiumdiet were not surprising and included an increase inweight, sodium excretion, and plasma concentra-tions of atrial natriuretic peptide (ANP) and plasmarenin activity (PRA), and a decrease in plasmaaldosterone concentration. The dramatic differencein salt intake did not affect either insulin action orthe insulin response to an oral glucose challenge,but there was an increase in urinary nitrate excre-tion on the high-salt diet of marginal statistical sig-nificance (P=.06).

Regression analysis of the whole group, how-ever, showed that the more insulin-resistant the per-son, the less the natriuretic response to the high-sodium diet ()0.50, P=.04), and the greater thesodium-induced weight gain (r=0.54, P=.03). Ofinterest, changes in PRA, ANP, and aldosteronewere not significantly related to either sodiumexcretion or weight gain. Finally, the only two vari-ables significantly associated with a sodium-inducedincrease in mean arterial BP were weight gain(r=0.51, P

insulin sensitivity, favoring vasoconstriction aswell as sodium retention.27,28 Thus, the pancre-atic b-cell response mounted in an effort to main-tain normal glucose homeostasis in an individualwith adipose tissue and muscle insulin resistanceincreases the likelihood of that person developingessential hypertension.

INSULIN RESISTANCE AND CVDType 2 DiabetesAlthough there is general agreement that CVD isthe major cause of morbidity and morality in type2 diabetes, controversy remains as to why this isthe case. An obvious contender is hyperglycemia,accounting for the many studies in which effortshave been made to decrease CVD by achieving bet-ter glycemic control. Although the results of thesestudies could best be described as mixed, a patternseems to emerge when a number of studies are sub-jected to a meta-analysis.29 With this approach, itappears that there is a modest reduction in majormacrovascular events with greater glucose lower-ing. The greatest benefit was seen in nonfatalmyocardial infarction, with no significant effect onstroke. These findings are not surprising. The CVDrisk factors that are present in insulin-resistant,nondiabetic individuals5,8 do not disappear whenfasting hyperglycemia ensues. Consequently, it isalso not surprising that the multifactorial approachused in the Steno-2 Study30 was shown to decreaseboth cardiovascular mortality and cardiovascularevents in patients with type 2 diabetes. It shouldalso be noted that there was less emphasis on anaggressive improvement of glycemia in this study,and the decrease in hemoglobin A1c concentrationswas not as great as in the studies focused only onintensive control of glucose concentrations. Thus,there appear to be a number of CVD risk factorsthat are operating in increasing risk of CVD inpatients with type 2 diabetes.

Essential HypertensionThe link between essential hypertension and vascu-lar disease differs in two important ways from therelationship seen in patients with type 2 diabetes.

Just as the focus in prevention of CVD inpatients with type 2 diabetes has been on loweringglucose concentrations, efforts to improve vascularoutcomes in patients with hypertension havefocused on lowering BP. However, in contrast tothe results of studies in type 2 diabetes, it appearsthat the clinical benefit of lowering BP has beenmuch more dramatic in decreasing risk of strokeas compared with CVD.31 There is no current

consensus for this discordance (CVD vs stroke) inthe effects of lowering BP on vascular outcome,and several different explanations have been pro-posed to account for this finding. For example, ithas been argued that stroke is more directly relatedto BP than is myocardial infarction, and or that theapparent difference in outcome is a function of therelatively short duration of the intervention trials.Another suggestion has been that thiazide diureticsand or b-receptor antagonists, drugs used in manyof the controlled clinical trials, are associated withadverse changes in carbohydrate and lipid meta-bolism that tended to mitigate their beneficialeffect on BP. Both of these possibilities maycontribute to this apparent paradox, but there is asimpler explanation for the observation that thebeneficial effect of lowering BP on CVD risk is lessthan might have been anticipated, one that isrelated to the heterogeneity of the essential hyper-tension phenotype.

Insulin resistance is present in the vast majorityof patients with type 2 diabetes, whereas manypatients with essential hypertension are insulin-sensitive.21,32 It is only the approximately 50% ofpatients with essential hypertension who are insulin-resistant hyperinsulinemic who are likely to havesome degree of glucose intolerance, an atherogeniclipoprotein phenotype characterized by high triglyce-rides (TGs) and low high-density lipoprotein choles-terol (HDL-C) concentrations, smaller and denserlow-density lipoprotein (LDL) particles, and an exag-gerated degree of postprandial lipemia,21,31,32 andevidence of endothelial dysfunction.25

An example of the impact of differences in insu-lin action on CVD risk factors is given in theTable,21 in which the 126 patients described inFigure 1 were divided into two groups: IR (the50% who were most insulin-resistant; SSPG con-centration >180 mg dL) vs non-IR patients (theinsulin-sensitive and intermediate tertiles; SSPGconcentrations

criteria, were insulin-resistant (significantly higherSSPG concentrations during the IST, P

address all of the CVD risk factors associated withinsulin resistance compensatory hyperinsulinemiathat occur in patients with type 2 diabetes and in thesubset of patients with hypertension who are alsoinsulin-resistant.

REFERENCES1 Yeni-Komshian H, Carantoni M, Abbasi F, et al. Rela-

tionship between several surrogate estimates of insulinresistance and quantification of insulin-mediated glucosedisposal in 490 healthy, nondiabetic volunteers. DiabetesCare. 2000;23:71175.

2 Bogardus C, Lillioja S, Mott DM, et al. Relationshipbetween degree of obesity and in vivo insulin action inman. Am J Physiol. 1985;248(Endocrinol Metab 11):E286E291.

3 Lillioja S, Mott DM, Zawadzki J, et al. In vivo insulinaction is a familial characteristic in nondiabetic Pima Indi-ans. Diabetes. 1987;36:13291335.

4 Zoratti R, Godsland IF, Chaturvedi N, et al. Relation ofplasma lipids to insulin resistance, nonesterified fattyacids, and body fat in men from three ethnic groups: rele-vance to variations in risk of diabetes and coronary arterydisease. Metabolism. 2000;49:245252.

5 Reaven G. Role of insulin resistance in human disease.Diabetes. 1988;37:15951607.

6 Warram JH, Martin BC, Krolewski AS, et al. Slow glu-cose removal rate and hyperinsulinemia precede the devel-opment of type II diabetes in the offspring of the diabeticparents. Ann Intern Med. 1990;113:909912.

7 Lillioja S, Mott DM, Spraul M, et al. Insulin resistanceand insulin secretory dysfunction as precursors ofnon-insulin-dependent diabetes mellitus. N Engl J Med.1993;329:19881992.

8 Zavaroni I, Bonora E, Pagliara M, et al. Risk factors forcoronary artery disease in healthy persons with hyperinsu-linemia and normal glucose tolerance. N Engl J Med.1989;320:702706.

9 Himsworth HP. The mechanism of diabetes mellitus. I.Lancet. 1939;2:16.

10 Himsworth HP. The mechanism of diabetes mellitus. II.The control of the blood sugar level. Lancet. 1939;2:6568.

11 Himsworth HP. The mechanism of diabetes mellitus. III.Human diabetes mellitus. Lancet. 1939;2:171175.

12 Ginsberg H, Olefsky JM, Reaven GM. Further evidencethat insulin resistance exists in patients with chemical dia-betes. Diabetes. 1974;23:674678.

13 Ginsberg H, Kimmerling G, Olefsky JM, et al. Demon-stration of insulin resistance in untreated adult onset dia-betic subjects with fasting hyperglycemia. J Clin Invest.1975;55:454461.

14 Laws A, Stefanick ML, Reaven GM. Insulin resistance innon-diabetic relatives of patients with non-insulin depen-dent diabetes mellitus. J Clin Endocrinol Metab. 1989;69:343347.

15 Welborn TA, Breckenridge A, Rubinstein AH, et al.Serum-insulin in essential hypertension and in peripheralvascular disease. Lancet. 1966;1:11361137.

16 Lucas CP, Estigarribia JA. Darga LL, Reaven GM. Insulinand blood pressure in obesity. Hypertension. 1985;7:702706.

17 Pollare T, Lithell H, Berne C. Insulin resistance is a char-acteristic feature of primary hypertension independent ofobesity. Metabolism. 1990;39:167174.

18 Raitakari OT, Porkka KVK, Ronnemaa T, et al. The roleof insulin in clustering of serum lipids and blood pressurein children and adolescents. Diabetologia. 1995;38:10421050.

19 Allemann Y, Horber FF, Colombo M, et al. Insulinsensitivity and body fat distribution in normotensiveoffspring of hypertensive parents. Lancet. 1993;341:327331.

20 Facchini FS, Hua N, Abbas F, et al. Insulin resistance as apredictor of age-related diseases. J Clin Endocrinol Metab.2001;86:35743578.

21 Lima NKC, Abbasi F, Lamendola C, et al. Prevalence ofinsulin resistance and related risk factors for cardiovascu-lar disease in patients with essential hypertension. Am JHypertens. 2009;22:106111.

22 Reaven GM, Hollenbeck CB, Chen Y-DI. Relationshipbetween glucose tolerance, insulin secretion, and insulinaction in non-obese individuals with varying degrees ofglucose tolerance. Diabetologia. 1989;32:5255.

23 Reaven GM, Chen Y-DI, Hollenbeck CB, et al. Plasmainsulin, C-peptide, and proinsulin concentrations in obeseand nonobese individuals with varying degrees of glucosetolerance. J Clin Endocrinol Metab. 1993;76:4448.

24 Facchini FS, DoNascimento C, Reaven GM, et al. Bloodpressure, nsulin resistance, and urinary nitrate excretion.Hypertension. 1999;33:10081012.

25 Stuhlinger MC, Abbasi F, Chu JW, et al. Relationshipbetween insulin resistance and an endogenous nitiric oxidesynthase inhibitor. JAMA. 2002;287:14201426.

26 Abbasi F, McLaughlin T, Lamendola C, et al. The rela-tionship between glucose disposal in response to physio-logical hyperinsulinemia and basal glucose and free fattyacid concentrations in healthy volunteers. J Clin Endocri-nol Metab. 2000;85:12511254.

27 Reaven GM, Lithell H, Landsberg L. Hypertension andassociated metabolic abnormalities the role of insulinresistance and the sympathoadrenal system. N Engl JMed. 1996;334:374381.

28 Reaven GM. The kidney: an unwilling accomplice in syn-drome X. Am J Kidney Dis. 1997;30:928931.

29 Turnbull FM, Abraira C, Anderson RJ, et al. Intensiveglucose control and macrovascular outcomes in type 2diabetes. Diabetologia. 2009;52:22882298.

30 Gaede P, Lund-Andersen H, Parving H-H, et al. Effect ofa multifactorial intervention on mortality in type 2 diabe-tes. N Engl J Med. 2008;358:580591.

31 Reaven GM. Insulin resistance compensatory hyperinsu-linemia, essential hypertension, and cardiovascular dis-ease. J Clin Endocrinol Metab. 2003;88:23992403.

32 Zavaroni I, Mazza S, DallAglio E, et al. Prevalence ofhyperinsulinaemia in patients with high blood pressure.J Intern Med. 1992;231:235240.

33 Sheuh WH-H, Jeng C-Y, Shieh S-M, et al. Insulin resis-tance and abnormal electrocardiograms in patients withhigh blood pressure. Am J Hypertens. 1992;5:444448.

34 Gaziano JM, Sesso HD, Breslow JL, et al. Relationsbetween systemic hypertension and blood lipids on risk ofmyocardial infarction. Am J Cardiol. 1999;84:768773.

35 Jeppesen J, Hein HO, Suadicani P, et al. Low triglycerides-high high-density lipoprotein cholesterol and risk of ische-mic heart disease. Arch Intern Med. 2001;161:361366.

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