Insulin Resistance, Hyperinsulinemia - Diabetes Care

Insulin Resistance,Hyperinsulinemia,Hypertriglyceridemia,and HypertensionParallels Between HumanDisease and Rodent Models

Gerald M. Reaven, MD

There is considerable evidence that abnormalities ofglucose, insulin, and lipoprotein metabolism occurmore frequently in untreated hypertensive patientsthan in normotensive control subjects. More recently,it has also become apparent that similar metabolicabnormalities occur in rodent models of hypertension.One purpose of this article is to review the experimentaldata that have led to the above generalizations. Thesecond goal is to address the significance of thesefindings, which is certainly not clear. For example, itcould be argued that the relationship between highblood pressure and the associated metabolic defects isincidental. On the other hand, there is evidence that thechanges in glucose, insulin, and lipoprotein metabolismmay play a role in the etiology and/or clinical courseof patients with high blood pressure. Although it isimpossible at this point to definitively choose betweenthese possibilities, an effort is made to marshal theevidence in support of the latter alternative. DiabetesCare 14:195-202, 1991

INSULIN RESISTANCE, HYPERINSULINEMIA, ANDHYPERTRIGLYCERIDEMIA IN HYPERTENSIVE PATIENTS

Plasma insulin concentration. Perhaps the earliestpublication demonstrating the presence of higher-than-normal plasma insulin concentration in patients withhigh blood pressure was that of Welborn et al. (1) in1966. They studied 19 patients diagnosed as havingessential hypertension, 10 of whom were not beingtreated. Although there was overlap between plasma

From the Department of Medicine, Stanford University School of Medicine, andGeriatric Research, Education and Clinical Center, Veterans AdministrationMedical Center, Palo Alto, California.

Address correspondence and reprint requests to Gerald M. Reaven, MD, GRECC(182-B), VA Medical Center, 3801 Miranda Avenue, Palo Alto, CA 94304.

insulin concentrations in those with hypertension com-pared with the control population, the group with highblood pressure also had significantly higher plasma in-sulin concentrations. The hyperinsulinemia was notedbefore and at every time point after an oral glucose loadand was true of both the treated and the untreated pa-tients with high blood pressure.

Although of obvious interest, there appeared to belittle attention directed toward the relationship betweenhyperinsulinemia and hypertension over the next twodecades. However, in the past few years, several articles(2-6) have confirmed the original observation of Wel-born et al. (1). A typical example of these recent obser-vations can be seen in Fig. 1. Several points can bemade from these data. First, the data show that plasmainsulin concentrations are higher in untreated patientswith high blood pressure than in healthy individuals (Fig.1, right). Furthermore, lowering high blood pressure withantihypertensive drugs does not necessarily decreaseplasma insulin concentration to normal. Indeed, it ispossible that treatment may actually accentuate the de-gree of hyperinsulinemia. Finally, the results suggest thathypertension and/or its treatment may also be associ-ated with glucose intolerance, an observation that hasbeen made previously (7-9; Fig. 1, left).Resistance to insulin-stimulated glucose uptake. Thecombination of glucose intolerance and hyperinsulin-emia seen in Fig. 1 strongly suggests that a defect ininsulin-stimulated glucose uptake exists in some patientswith hypertension; there is now evidence that this is thecase (4-6). In addition, as in the case of the glucoseintolerance and hyperinsulinemia (Fig. 1), insulin re-sistance has also been shown to persist in patients whoseblood pressure had been successfully lowered by phar-macological intervention (5,6). This point is demon-strated in Fig. 2, which illustrates the ability of insulin

DIABETES CARE, VOL. 14, NO. 3, MARCH 1991

Dow

nloaded from http://diabetesjournals.org/care/article-pdf/14/3/195/440207/14-3-195.pdf by guest on 04 February 2022

INSULIN RESISTANCE AND HYPERTENSION

250

200

150

100

50

Glucose (mg/dl) Insulin (uU/ml)

30 60 90 120 0

Time (min)

30 60 90 120

FIG. 1. Mean ± SE plasma glucose and insulin concen-tration in response to 75-g oral glucose challenge in healthymen (0) , men with untreated hypertension (•), and menreceiving treatment for hypertension (O). From Shen et al.(5). © 1988 by Journal of Clinical Endocrinology and Me-tabolism.

to dispose of an infused glucose load during a period ofphysiological hyperinsulinemia. Details of this approachhave been published previously (5,6), but it can be sum-marized briefly as follows. Individuals are infused for 3h with somatostatin (350 y^gfh), insulin (25 mU • m"2

body surface area • min"1), and glucose (240 mmol •rrr2 body surface area • min"1). Under these conditions,endogenous insulin is suppressed, similar steady-stateplasma concentrations of exogenous insulin (SSPI) areachieved in all individuals, and the steady-state plasmaglucose (SSPG) concentration reached at the end of the

100

80

60

40

20

SSPI (uU/ml)

I

250

200

150

100

50

SSPG (mg/dl)

HT+Rx HT HT+Rx

FIG. 2. Mean steady-state exogenous plasma insulin (SSPI)and steady-state plasma glucose (SSPG) concentrationsduring last 60 min of 180-min infusion of somatostatin (350fig/h), insulin (25 mU • rrr2 body surface area • min1) , andglucose (6 mg • kg"1 • min"1). N, healthy men; HT, hyper-tensive men; HT + Rx, hypertensive men receiving treat-ment. From Shen et al. (5). © 1988 by Journal of ClinicalEndocrinology and Metabolism.

study provides an estimate of insulin-mediated glucosedisposal. It is apparent from the data in Fig. 2 that similarSSPI concentrations were achieved in normal healthyindividuals, untreated patients with hypertension, andpatients with hypertension whose blood pressure hadbeen lowered by antihypertensive drugs. In contrast, theSSPG concentrations were significantly higher in bothgroups of patients with high blood pressure. In otherwords, patients with high blood pressure are resistant toinsulin-mediated glucose uptake, and treatment of highblood pressure does not necessarily lead to any im-provement in this defect in insulin action. Note that allthree groups were nonobese and were matched for allother relevant experimental variables.Plasma triglyceride (TG) concentration. Figure 3 dis-plays the fasting plasma TG concentration of four ex-perimental groups—a population of healthy individuals,patients with high blood pressure without any evidenceof coronary heart disease (CHD) and not receiving an-tihypertensive medication, patients with CHD diag-nosed by coronary angiography without hypertension,and a group of patients who have both high blood pres-sure and CHD diagnosed by angiography (10). Bothgroups of patients with hypertension had significantlyhigher plasma TG concentrations than the control pop-ulation. Parenthetically, hypertriglyceridemia was alsopresent in the nonhypertensive patients with CHD, em-phasizing the ubiquitous presence of this abnormality oflipoprotein metabolism in the syndrome of CHD. Notethat the four patient groups were nonobese and werecomparable in terms of age and other relevant environ-mental variables. The conclusion that patients with un-treated hypertension as a group are hypertriglyceridemicis supported by the results of a much larger epidemio-logical survey from Australia (11). These data also pointed

200

150

100

50

TT

CHD CHD+ HT

HT

FIG. 3. Mean ± SE plasma triglyceride concentration in 4patient groups. N, healthy subjects; CHD, symptomaticcoronary heart disease (determined by abnormal coronaryangiogram); CHD + HT, symptomatic coronary heart dis-ease (determined by abnormal coronary anteriogram andhypertension); HT, hypertension without clinical evidenceof CHD. From Shieh et al. (10).

1 % DIABETES CARE, VOL. 14, NO. 3, MARCH 1991

Dow


C M . REAVEN

out that the plasma TG concentration was even higherin patients with high blood pressure when they weretreated with antihypertensive medication, an importantissue that will be discussed in detail subsequently.

INSULIN RESISTANCE, HYPERINSULINEMIA,AND HYPERTRIGLYCERIDEMIA IN RODENTMODELS OF HYPERTENSION

Several years ago, we showed that substituting fructosefor the carbohydrate conventionally present in rat chowled to insulin resistance, hyperinsulinemia, and hyper-triglyceridemia in Sprague-Dawley rats (12). Thesechanges could be seen within 1 wk and were not as-sociated with obesity. More recently, we have shownthat this dietary manipulation leads to a consistent in-crease in blood pressure between 20 and 30 mmHg(13). The increase in blood pressure will develop within10 days, last for as long as 3 mo, and disappear oncethe fructose-enriched diet is removed (unpublished ob-servations).

The fact that a form of dietary manipulation knownto cause insulin resistance and hyperinsulinemia alsoresults in hypertension raises the possibility that thechanges in insulin metabolism may play a role in theincrease in blood pressure. To evaluate this possibility,we conducted two additional studies in fructose-fed rats.In one of these studies, we took advantage of our pre-vious observation that fructose-induced insulin resist-ance, hyperinsulinemia, and hypertriglyceridemia inSprague-Dawley rats can be greatly attenuated by ex-ercise training (14). The results of these experiments in-dicated that the ability of fructose-enriched diets to in-crease blood pressure was also significantly decreasedin exercise-trained rats (15). Our other effort to evaluatethe role of insulin resistance and hyperinsulinemia inthe genesis of fructose-induced hypertension was basedon the use of somatostatin to inhibit the hyperinsulin-emia that ensues when Sprague-Dawley rats consumethe fructose-enriched diet (16). The results of this studydemonstrated that infusing somatostatin into fructose-fed rats significantly reduced the increase in plasma in-sulin concentration, plasma TG concentration, and bloodpressure associated with this dietary manipulation.

It is obvious from the results of our studies of fructose-fed Sprague-Dawley rats that high blood pressure in thisdiet-induced rodent model is associated with the samechanges in insulin and triglyceride metabolism seen inpatients with untreated hypertension. It is also apparentthat our efforts to decrease insulin resistance and/orhyperinsulinemia in fructose-fed rats led to results con-sistent with the hypothesis that the changes in insulinmetabolism were related to the hypertension. An ob-vious next question is how insulin resistance and hyper-insulinemia might increase blood pressure in fructose-fed rats. To address this issue, plasma concentrations ofrenin activity, angiotensin, aldosterone, and atrial na-

triuretic peptide were measured in fructose-fed rats (17).We could not discern any change in either plasma reninactivity or angiotensin concentration. However, plasmaaldosterone levels were lower and atrial natriuretic pep-tide concentrations were higher in fructose-fed rats. Theseresults are consistent with the conclusion that fructose-induced hypertension in rats is associated with volumeoverload. In this context, it is important to note thathyperinsulinemia has been shown to increase renal so-dium and/or volume reabsorption in a series of exper-imental situations (18-20). The issue of the relationshipbetween hyperinsulinemia and high blood pressure isan important one and is discussed in detail subse-quently. At this juncture, the hypothesis that fructose-induced hypertension is secondary to increased insulinaction at the level of the kidney is worth further evalu-ation.

Although the spontaneously hypertensive rat (SHR) hasbeen studied extensively since its introduction, it hasonly recently been shown that these rats are insulin re-sistant and hyperinsulinemic compared with its control,the WKY rat (21). In addition, plasma TG concentrationsare significantly higher in SHRs (Fig. 4).

In an attempt to further evaluate resistance to insulin-stimulated glucose uptake in SHRs, we have turned tothe isolated adipocyte (22). The results of these effortsindicate insulin-stimulated glucose uptake is lower inadipocytes isolated from SHRs compared with WKY rats(Fig. 5). Insulin resistance at the level of the adipocytedid not seem related to a decrease in number of insulinreceptors or the ability of insulin to stimulate insulin-receptor autophosphorylation or insulin-receptor tyro-sine kinase activity. Thus, we do not know why fat cellsfrom SHRs do not transport glucose normally in re-sponse to insulin. On the other hand, the defect seemsto be specific to insulin-stimulated glucose transport,because it appears that the ability of insulin to inhibitcatecholamine-induced lipolysis is similar in adipocytesfrom SHRs and WKY rats (22).

E. 90

Group I Group II Group III

SHR SHR

FIG. 4. Mean ± SE plasma triglyceride concentration in 3groups of WKY and spontaneously hypertensive rats (SHR)ranging in weight from 140 to 300 g. Number of rats pergroup is given in parentheses.

DIABETES CARE, VOL. 14, NO. 3, MARCH 1991 197

Dow



l/se

l/cel

c

isp

o

2h-0)CO

oo

400

350

300

250

200

150

100

100 1000 10000 100000

Insulin (pM)

FIG. 5. Glucose transport in absence or presence of vary-ing amounts of insulin by adipocytes isolated from WKY(#) or spontaneously hypertensive (D) rats. Results aremeans ± SE of 8 experiments. From Reaven et al. (22). ©1989 by the American Diabetes Association.

To this point in the article, the implication has beenthat insulin resistance and hyperinsulinemia may play arole in the etiology of hypertension. Alternatively, it couldbe argued that high blood pressure causes the defectsin insulin action and concentration. To address this is-sue, we have quantified insulin resistance in isolated fatcells as SHR rats grow from ~6 wk to 3 mo of age (23).During this time, systolic blood pressure increased by—60 mmHg, whereas insulin-stimulated glucose uptakeby isolated adipocytes did not change (Fig. 6). Althoughthese observations do not rule out the possibility thathypertension causes insulin resistance, they do indicatethat insulin resistance at the tissue level can be detectedearly in the course of hypertension, and insulin resist-ance remains unchanged in response to a significantincrease in blood pressure.

lipoprotein (VLDL)-TG secretion, and hypertriglyceri-demia. Extensive evidence supporting this formulationhas been published from this laboratory over the past—25 yr, and only some of it will be summarized at thispoint. To begin with, in individuals who retain insulinsecretory function, particularly nondiabetic subjects, thereis a relatively linear relationship between measures ofinsulin resistance and plasma insulin concentration, i.e.,the more resistant, the greater the magnitude of hyper-insulinemia (24,25). In addition, there is substantial evi-dence that significant correlations exist between resist-ance to insulin-stimulated glucose uptake, plasma insulinconcentration, VLDL-TG secretion rate, and plasma TGconcentration in healthy humans and patients with hy-pertriglyceridemia (25,26). Furthermore, experimentalmanipulations that modify insulin action and/or plasmainsulin concentration have led to predictable changesin VLDL-TG secretion rate and plasma TG concentra-tion. For example, weight loss, which results in en-hanced insulin action, was associated with a commen-surate decrease in plasma insulin concentration, hepaticVLDL-TG secretion, and plasma TG concentration (27).In contrast, feeding patients a high-carbohydrate dietleads to increases in ambient plasma insulin and TGconcentrations, and the increment in plasma TG con-centration is significantly correlated with the carbohy-drate-induced hyperinsulinemia (25). Similar relation-ships have been described in experiments carried out inSprague-Dawley rats. Thus, feeding such animals dietsin which the carbohydrate normally present in rat chowhas been replaced with either sucrose or fructose is as-sociated with the development of insulin resistance,hyperinsulinemia, and hypertriglyceridemia (12,28). Thissequence of events can be prevented if animals fed suchdiets are exercise trained, a manipulation that attenuatesthe development of the insulin resistance in rats fed dietsenriched with sucrose (28) or fructose (29) or given a

RELATIONSHIP BETWEEN INSULINRESISTANCE, HYPERINSULINEMIA, ANDHYPERTRIGLYCERIDEMIA IN HYPERTENSION

The data presented so far have shown that patients withhigh blood pressure and three rat models of hyperten-sion share certain metabolic abnormalities—resistanceto insulin-stimulated glucose uptake, hyperinsulinemia,and hypertriglyceridemia. Demonstration that the samecluster of changes occurs in association with multipleforms of hypertension suggests that the relationship notedis more than coincidental. Furthermore, there are manypublished data derived from the results of experimentsin both humans and rats that provide support for a hy-pothesis to account for the observed phenomena. Spe-cifically, it is suggested that the most fundamental defectis resistance to insulin-stimulated glucose uptake, whichin turn leads to a compensatory increase in plasma in-sulin concentration, enhanced hepatic very-low-density

IJ 400

85 200

FIG. 6. Mean ± SE glucose transport in absence ( - ) orpresence ( + ) of maximal insulin concentration (8000 pM)by adipocytes isolated from 3 groups of WKY and spon-taneously hypertensive rats (SHR) varying in weight from140 to 300 g. Group I, -140 g; group II, -200 g; group III,—300 g. Number of adipocyte preparations studied fromeach group is given in parentheses.

198 DIABETES CARE, VOL. 14, NO. 3, MARCH 1991

Dow


C M . HEAVEN

disaccharidase inhibitor (30), which prevents hyperin-sulinemia from developing in rats fed a high-carbohy-drate diet.

It is apparent that much evidence supports the generalhypothesis outlined at the beginning of this section.Consequently, it is concluded that the hyperinsulin-emia and hypertriglyceridemia present in untreatedpatients with high blood pressure and in two rodentmodels of hypertension are secondary to the resistanceto insulin-stimulated glucose uptake present in all threesituations.

RELATIONSHIP BETWEEN INSULIN RESISTANCE,HYPERINSULINEMIA, HYPERTRIGLYCERIDEMIAAND REGULATION OF BLOOD PRESSURE

Because a triad of metabolic abnormalities has beenshown to cluster in patients with high blood pressureand both dietary-induced and genetic models of hyper-tension, it seems only reasonable to ask what relation-ship, if any, exists between the changes noted and reg-ulation of blood pressure. In this context, there are atleast three general ways to respond to this question. Atthe simplest, the changes in insulin and lipid metabo-lism associated with hypertension may be epiphenom-enal and may be unrelated to the change in blood pres-sure. Although this formulation may be true, there is nopositive evidence to support it. A second theoreticalpossibility is that high blood pressure is the cause of theinsulin resistance, hyperinsulinemia, and hypertrigly-ceridemia. There are experimental data in humans thatshow that lowering of blood pressure in hypertensivepatients need not be associated with any improvementin insulin resistance or hyperinsulinemia (5,6,31). Onthe other hand, decreased blood pressure associated withantihypertensive treatment has also been accompaniedby improved insulin-stimulated glucose uptake and de-creased plasma insulin concentrations (31,32). Unfor-tunately, it is difficult to distinguish between the effectsof blood pressure reduction per se on the metabolicvariables involved, as contrasted with the potentialmetabolic effects of the drugs used to lower blood pres-sure. Perhaps the most relevant data are those describedearlier in the SHRs. It was pointed out that a significantdefect can be seen in the ability of insulin to stimulateglucose uptake by isolated adipocytes when hyperten-sion is barely detectable, which gets no worse as bloodpressure continues to increase (23). There is no une-quivocal answer to the question posed, but it appearsthat the evidence is consistent with the view that highblood pressure by itself does not cause the changes ininsulin and lipid metabolism associated with both hu-man and experimental hypertension.

The final alternative that must be considered is thatinsulin resistance, hyperinsulinemia, or hypertriglycer-idemia might play a role in regulating blood pressure.Indeed, as indicated earlier, there is evidence that this

might be the case regarding fructose-induced hyperten-sion. Our laboratory has shown that experimental in-terventions that decrease fructose-induced insulin re-sistance and hyperinsulinemia in Sprague-Dawley ratsalso attenuate the increase in blood pressure associatedwith consumption of the fructose-enriched diet (15,16).Circumstantial evidence is also present, consistent witha causal re'e for insulin resistance and hyperinsulinemiain human hypertension. For example, statistically sig-nificant correlations between plasma insulin concentra-tion and blood pressure have been described (2,33). Inaddition, the relationship between obesity and hyper-tension may be best understood in the light of the hy-pothesis that blood pressure can be regulated by changesin insulin metabolism. Certainly, this point of view mayhelp explain why weight loss, which enhances insulinsensitivity and lowers plasma insulin concentrations (27),can also decrease blood pressure in patients with hy-pertension (34). Perhaps more direct evidence for therole that insulin resistance and hyperinsulinemia mayplay in regulating blood pressure can be derived fromthe study by Krotkiewski et al. (35) of the effect of ex-ercise training on blood pressure in obese patients withhypertension. Krotkiewski et al. demonstrated that bloodpressure could be lowered in obese individuals by phys-ical training without any change in weight but only inthose individuals who were hyperinsulinemic andhypertriglyceridemic before the training program wasstarted. Because there is also evidence that insulin sen-sitivity is directly related to level of habitual physicalactivity (36), it seems reasonable to conclude that thefall in blood pressure was associated with an improve-ment in insulin-stimulated glucose uptake. Similarly, theobservation that blood pressure decreased when insulindose was reduced in obese patients with non-insulin-dependent diabetes and hypertension lends support tothe view that ambient insulin concentration modulatesblood pressure (37).

If the possibility that insulin resistance and hyper-insulinemia play a role in blood pressure regula-tion is accepted, it is obviously necessary to ask howthis is accomplished. In the case of obese individualswith high blood pressure, the link between insulinresistance, hyperinsulinemia, and hypertension maybe the sympathetic nervous system. In this con-text, Landsberg and Krieger (38) have suggested thatheightened sympathetic nervous system activity isthe expected consequence of the increased calorieintake seen in obese individuals, possibly secondaryto hyperinsulinemia. Although the insulin-mediatedsympathetic stimulation may represent a compensatorymechanism aimed at limiting weight gain by increas-ing thermogenesis, the effects of hyperinsulinemia andincreased sympathetic activity on the kidney and cardio-vascular system tend to raise blood pressure. It is ob-vious that the relationship between insulin resistance,hyperinsulinemia, and increased sympathetic activityneed not be limited to obese patients with hyperten-sion, and there is evidence that acute hyperinsulin-


Dow



emia can increase plasma catecholamine concentrationin nonobese individuals (39).

Another possible link between insulin resistance,hyperinsulinemia, and blood pressure regulation in-volves the effect of insulin on the handling of sodiumand water by the kidney. As mentioned earlier, fructose-induced hypertension is associated with a series ofchanges that suggest that the increased blood pressureassociated with this dietary manipulation may be relatedto volume overload (17). This possibility is consistentwith evidence that insulin can act on the isolated toadbladder (18) and in the intact dog (40) and humans (19)to promote renal tubular sodium resorption. More re-cently, it has been shown that insulin acts at the levelof the proximal tubule to increase volume reabsorption(20). The fact that insulin has been shown to acutelyregulate renal sodium and water metabolism in a man-ner that could raise blood pressure does not prove thatthese phenomena occur chronically or that they play arole in the etiology of hypertension. On the other hand,as in the case of the relationship between insulin andsympathetic activity, available data provide a testablehypothesis to account for a possible causal relationshipbetween hyperinsulinemia and high blood pressure incertain individuals. Note that an assumption underlyingthe above discussion is that an elevated plasma insulinconcentration, secondary to resistance to insulin-stim-ulated glucose uptake, can have increased action on thesympathetic nervous system and/or kidney. In otherwords, a defect involving one facet of insulin actiondoes not necessarily mean that all of its effects are equallyblunted.

ROLE OF INSULIN RESISTANCE, HYPERINSULINEMIA,AND HYPERTRIGLYCERIDEMIA IN CLINICALCOURSE OF HYPERTENSION

Although high blood pressure is a well-recognized riskfactor (41) for CHD, it has been difficult to demonstratethat treatment of hypertension leads to improved mor-bidity and mortality from CHD (42). This apparent par-adox has received a good deal of recent attention, mostof which has focused on the fact that conventional treat-ment of hypertension is often associated with changesin lipid metabolism thought to increase the risk for CHD.However, with recognition that patients with high bloodpressure have abnormalities of carbohydrate and lipidmetabolism before hypertensive treatment is initiated, ithas become necessary to consider the role these changesmay have in the development of CHD. Perhaps the mostclear-cut issue in this context involves the evidence thathyperinsulinemia has been identified as a primary riskfactor for CHD in three prospective epidemiologicalstudies (43-45). An extensive discussion of the mech-anism by which hyperinsulinemia may contribute to thedevelopment of CHD would be inappropriate within thisarticle. However, it is worth pointing out that this couldbe related to various direct effects of insulin at the cel-

lular level (46) and the role played by insulin in regu-lation of lipoprotein metabolism (47). As discussed indetail earlier, there is substantial evidence that resist-ance to insulin-stimulated glucose uptake and compen-satory hyperinsulinemia are responsible for the hyper-triglyceridemia in patients with high blood pressure.Although controversy continues as to whether an in-crease in plasma TG concentration is a primary risk fac-tor for CHD (48), there is little question about the ob-servation that hypertriglyceridemia occurs quitecommonly in patients with CHD (48,49). More recently,emphasis has been placed on the importance of thecombination of a high plasma TG and a low high-den-sity lipoprotein cholesterol (HDL-chol) concentration inincreasing risk of CHD (50). Although a low HDL-cholconcentration has not been shown to be consistentlydecreased in patients with hypertension, there is evi-dence of the presence of relationships between plasmainsulin and TG (direct) and HDL-chol (inverse) concen-tration (51). Thus, the dyslipidemia of patients with highblood pressure may include both a high plasma TG anda low HDL-chol concentration. Furthermore, there isample evidence that any tendency for these changes todevelop in patients with high blood pressure can beaccentuated by the treatment used (31,52,53). Giventhe uncertainty as to why morbidity and mortality fromCHD have not been improved with antihypertensivetreatment, it seems necessary to consider the possibilitythat the abnormalities in carbohydrate and lipoproteinmetabolism associated with high blood pressure are re-sponsible to some degree for this disappointing clinicalsituation. In this context, observations that some anti-hypertensive treatment may actually be associated withan improvement in several of these abnormalities is ofconsiderable interest (31,32).

CONCLUSIONS

There is evidence that insulin resistance, hyperinsulin-emia, and dyslipidemia occur commonly in patients withhigh blood pressure, and similar abnormalities have beendescribed in several rodent models of hypertension. Thechallenge at this point is to define the potential mech-anism and/or clinical importance, if any, of these changes.An argument has been developed that insulin resistanceand hyperinsulinemia may play a role in both the etiol-ogy of hypertension and its ultimate clinical course. Theimportance of insulin resistance and hyperinsulinemiais based on a series of observed correlations in bothhumans and rats, none of which may be causally re-lated. However, there do not appear to be data thatrefute the general formulation advanced. More impor-tant, all of the postulated series of events are subject toexperimental evaluation. Given the unsatisfactory situ-ation that exists in the effort to reduce the risk of CHDfrom high blood pressure, issues raised in this articleseem to deserve continued consideration.


Dow


C M . REAVEN

REFERENCES

1. Welborn TA, Breckenridge A, Rubinstein AH, Dollery CT,Fraser TR: Serum-insulin in essential hypertension and inperipheral vascular disease. Lancet 1:1336-37, 1966

2. Lucas CP, Estigarribia JA, Darga LL, Reaven CM: Insulinand blood pressure in obesity. Hypertension 7:702-706,1985

3. Modan M, Halkin H, Almog S, Lusky A, Eshkil A, ShefiM, Shitrit A, Fuchs A: Hyperinsulinemia: a link betweenhypertension, obesity and glucose intolerance. / Clin In-vest 75:809-17, 1985

4. Ferrannini E, Buzzigoli G, Bonadona R: Insulin resistancein essential hypertension. N Engl I Med 317:350-57,1987

5. Shen D-C, Shieh S-M, Fuh M, Wu D-A, Chen Y-DI, ReavenCM: Resistance to insulin-stimulated glucose uptake inpatients with hypertension, ) Clin Endocrinol Metab 66:580-83, 1988

6. Swislocki ALM, Hoffman BB, Reaven GM: Insulin resist-ance, glucose intolerance and hyperinsulinemia in pa-tients with hypertension. Am j Hypertens 2:419-23, 1989

7. Jarrett RJ, Keen H, McCartney M, Fulley JH, HamiltonPJS, Reid DD, Rose G: Glucose tolerance and blood pres-sure in two population samples: their relation to diabetesmellitus and hypertension. Int I Epidemiol 7:15-24, 1978

8. Stamler J, Rhomberg P, SchoenbergJA, Shekelle RB, DyerA, Shekelle S, Stamler R, Wannamaker J: Multivariateanalysis of the relationship of seven variables to bloodpressure: findings of the Chicago Heart Association de-tection project in industry, 1967-1972. / Chronic Dis28:527-48, 1975

9. Voors AW, Radhakrishnamurthy B, Srinavasan SE, Web-ber LS, Berenson GS: Plasma glucose level related to bloodpressure in 272 children, ages 7-15 years, sampled froma total biracial population. Am I Epidemiol 113:347-56,1981

10. Shieh S-M, Shen M, Fuh MM-T, Chen Y-DI, Reaven GM:Plasma lipid and lipoprotein concentrations in Chinesemales with coronary artery disease, with and without hy-pertension. Atherosclerosis 67:49-55, 1987

11. MacMahon SW, Macdonald GJ, Blacket RB: Plasma li-poprotein levels in treated and untreated hypertensive menand women. Arteriosclerosis 5:391-96, 1985

12. Zavaroni I, Sander S, Scott S, Reaven GM: Effect of fruc-tose feeding on insulin secretion and insulin action in therat. Metabolism 29:970-73, 1980

13. Hwang I-S, Ho H, Hoffman BB, Reaven GM: Fructose-induced insulin and hypertension in rats. Hypertension10:512-16, 1987

14. Mondon CE, Dolkas CB, Reaven GM: Site of enhancedinsulin sensitivity in exercise trained rats at rest. Am IPhvs/o/239:E169-77, 1980

15. Reaven GM, Ho H, Hoffman BB: Attenuation of fruc-tose induced hypertension in rats by exercise training.Hypertension 12:129-32, 1988

16. Reaven GM, Ho H, Hoffman BB: Somatostatin inhibitionof fructose induced hypertension. Hypertension 14:117-20, 1989

17. Hwang I-S, Huang W-C, Wu J-N, Shian LR, Reaven GM:Effect of fructose-induced hypertension on the renin-an-giotensin-aldosterone system and atrial natriuretic factor.Am I Hypertens 2:424-27, 1989

18. Andres R, Crabbe J: Stimulation by insulin of active so-

dium transport across toadskin: influence of aldosteroneand vasopressin. Arch Int Physio! Biochim 74:538-40,1966

19. DeFronzo RA, Cooke C, Andres R, Faloona GR, DavisPJ: The effect of insulin in renal handling of sodium, po-tassium, calcium, and phosphate in man. J Clin Invest55:845-55, 1975

20. Baum M: Insulin stimulates volume absorption in the rab-bit proximal convoluted tubule. / Clin Invest 79:1104-109, 1987

21. Mondon CE, Reaven GM: Evidence of abnormalities ofinsulin metabolism in rats with spontaneous hyperten-sion. Metabolism 37:303-305, 1988

22. Reaven GM, Chang H, Hoffman BB, Azhar S: Resistanceto insulin-stimulated glucose uptake in adipocytes iso-lated from spontaneously hypertensive rats. Diabetes38:1155-60, 1989

23. Reaven GM, Change H: Relationship between bloodpressure, insulin concentration, and insulin action in SHRand WKY rats. Am ) Hypertens. In press

24. Reaven GM: Banting Lecture 1988: role of insulin resist-ance in human disease. Diabetes 37:1595-607, 1988

25. Reaven GM, Lerner RL, Stern MP, Farquhar JW: Role ofinsulin in endogenous hypertriglyceridemia. / Clin Invest46:1756-67, 1967

26. Tobey TA, Greenfield M, Kraemer F, Reaven GM: Rela-tionship between insulin resistance, insulin secretion, verylow density lipoprotein kinetics and plasma triglyceridelevels in normotriglyceridemic man. Metabolism 30:165-71, 1981

27. Olefsky JM, Reaven GM, Farquhar JW: Effects of weightreduction on obesity: studies of carbohydrate and lipidmetabolism. / Clin Invest 53:64-76, 1974

28. Wright DW, Hansen Rl, Mondon CE, Reaven GM: Su-crose-induced insulin resistance in the rat: modulation byexercise and diet. Am J Clin Nutr 38:879-83, 1983

29. Zavaroni I, Chen Y-DI, Mondon CE, Reaven GM: Abilityof exercise to inhibit carbohydrate induced hypertriglyc-eridemia in rats. Metabolism 30:476-80, 1981

30. Zavaroni I, Reaven GM: Inhibition of carbohydrate-in-duced hypertriglyceridemia by a disaccharidase inhibitor.Metabolism 30:417-20, 1981

31. Pollare T, Lithell H, Berne C: A comparison of the effectsof hydrochlorothiazide and captopril on glucose and lipidmetabolism in patients with hypertension. N Engl / Med321:868-73, 1989

32. Swislocki ALM, Hoffman BB, Sheu WH-H, Chen Y-DI,Reaven GM: Effect of prazosin treatment on carbohydrateand lipoprotein metabolism in patients with hypertension.Am )Med 86:14-18, 1989

33. Manicardi V, Camellini L, Bellodi G, Coscelli C, Ferran-nini E: Evidence for an association of high blood pressureand hyperinsulinemia in obese man. / Clin EndocrinolMetab 62:1302-304, 1986

34. Reisin E, Abel R, Modan M, Silverberg DS, Eliahou HE,Modan B: Effect of weight loss without salt restriction onthe reduction of blood pressure in overweight hyperten-sive patients. N Engl I Med 298:1-6, 1978

35. Krotkiewski M, Mandroukas K, Sjostrom L, Sullivan L,Wetterqvist H, Bjorntorp P: Effects of long-term physicaltraining on body fat, metabolism, and blood pressure inobesity. Metabolism 28:650-58, 1979

36. Rosenthal M, Haskell WL, Solomon R, Widstrom A, ReavenGM: Demonstration of a relationship between level ofphysical training and insulin-stimulated glucose utiliza-


Dow



tion in normal humans. Diabetes 32:408-11, 198337. Tedde R, Sechi LA, Marigliano A, Pala A, Scano L:

Antihypertensive effect of insulin reduction in diabetic- 45.hypertensive patients. Am j Hypertens 2:163-70,1989

38. Landsberg L, Krieger DR: Obesity, metabolism, and thesympathetic nervous system. Am ) Hypertens 2:1255- 46.325, 1989

39. Rowe JW, Young JB, Minaker KL, Stevens AL, Pallotta J, 47.Landsberg L: Effect of insulin and glucose infusions onsympathetic nervous system activity in normal man. Di-abetes 30:219-25, 1981 48.

40. DeFronzo RA, Goldberg M, Agus Z: The effects of glucoseand insulin on renal electrolyte transport. ) Clin Invest58:83-90, 1976 49.

41. Stamler J, Stamler R, Liu K: High blood pressure: role incoronary heart diseases and implications for preventionand control. In Coronary Heart Disease. Connor W, Bris-tow D, Eds. Philadelphia, PA, Lippincott, 1985, p. 85-109 50.

42. MacMahon SW, Cutler JA, Furberg CD, Payne GH: Theeffects of drug treatment for hypertension on morbidity 51.and mortality from cardiovascular disease: a review ofrandomized controlled trials. Prog Cardiovasc Dis 29:99-118, 1986

43. Pyorala K: Relationship of glucose tolerance and plasmainsulin to the incidence of coronary heart disease: results 52.from two population studies in Finland. Diabetes Care2:131-41, 1979

44. Ducimetiere P, Eschwege E, Papoz L, Richard JL, Claude 53.JR, Rosselin G: Relationship of plasma insulin levels tothe incidence of myocardial infarction and coronary heart

disease mortality in a middle-aged population. Diabeto-logia 19:205-10, 1980Welborn TA, Wearne K: Coronary heart disease incidenceand cardiovascular mortality in Busselton with referenceto glucose and insulin concentrations. Diabetes Care2:154-60, 1979Stout RW: Insulin and atheroma—an update. Lancet1:1077-79, 1987Reaven GM, Chen Y-DI: Role of insulin in regulation oflipoprotein metabolism in diabetes. Diabetes Metab Rev4:639-52, 1988Austin MA: Plasma triglyceride as a risk factor for coro-nary heart disease: the epidemiologic evidence and be-yond. Am J Epidemiol 129:249-59, 1989Cambien F, Jaqueson A, Richard JL, Warnet JM, Duci-metiere P, Claude JR: Is the level of serum triglyceride asignificant predictor of coronary death in "normocholes-terolemic" subjects? The Paris Prospective Study. Am )Epidemiol 124:624-32, 1986Castelli WP: The triglyceride issue: a view from Fram-ingham. Am Heart) 112:432-40, 1986Zavaroni I, Dall'Aglio E, Alpi O, Bruschi F, Bonora E,Pezzarossa A, Butturini U: Evidence for an independentrelationship between plasma insulin and concentration ofhigh density lipoprotein cholesterol and triglyceride.Atherosclerosis 55:259-66, 1985Rohlfing JJ, Brunzell JD: The effects of diuretics and ad-renergic-blocking agents on plasma lipids. West I Med145:210-18, 1986Weinberger MH: Antihypertensive therapy and lipids:paradoxical influences on cardiovascular disease risk. AmJ Med 80:64-70, 1986


Dow


Documents

Insulin Resistance, Hyperinsulinemia - Diabetes Care