Kidney International, Vol. 43 (1993), pp. 1402—1417 NEPHROLOGY FORUM

Hyperinsulinemia: A link between and ?

Principal discussant: JOHN E. HALL

University of Mississippi Medical Center, Jackson, Mississippi

serum glucose of 101 mg/dl; triglycerides, 1142 mgldl; total cholesterol, 222 mg/dl; and HDL cholesterol, 43 mg/dl. Repeat fasting blood glucose Editors was 101 mg/dl, and plasma concentration was 42 U/ml; 2 hours JORDAN J. COHEN after a standard oral glucose load, the serum glucose was 116 mg/dl and JOHN T. HARRINOTON plasma insulin concentration was 230 U/m1. Other laboratory mea- surements revealed a serum sodium concentration of 139 mEq/liter; NIcoLAos E. MADIAS potassium, 4.9 mEq/liter; creatinine, 1.3 mg/dl; BUN, 18 mg/dl; and plasma renin activity, 1.0 ng Al/mi/hr. Managing Editor A diagnosis of obesity, hyperinsulinemia, , and CHERYL J. ZUSMAN hypertension was made. The impotence was thought to be related to his antihypertensive medications. These medications were tapered during a one-week period, and he began a diet restricted in sodium chloride, calories, and , as well as an program. At one-month State University of New York at Stony Brook followup, his blood pressure off medication was 128—136/84—88 mm Hg and in both arms. Blood pressure monitoring at home had revealed similar Tufts University School of Medicine values. Normal sexual function had returned within 2 weeks after he discontinued taking the medications. After 2 months of followup, his weight was 270 lbs (122.7 kg), his blood pressure off medication was 124/86 mm Hg, and laboratory studies revealed a fasting blood glucose of 129 mg/dl, a fasting plasma insulin of 40 MU/mi, and fasting triglycerides of 1042 mg/dl. Case presentation Discussion A 45-year-old white man was referred for evaluation of hypertension and sexual impotence. His hypertension was first noted at age 23. DR. JOHN E. HALL (Professor and Chairman, Department of Before treatment, his systolic blood pressure was 164 mm Hg; the diastolic pressure was 96 mm Hg. He had taken antihypertensive agents Physiology and Biophysics, University of Mississippi Medical intermittently for several years, and for the immediate preceding 10 Center, Jackson, Mississippi): An association between obesity years had taken clonidine, 0.15 mg daily, and chlorthalidone, 37.5 mgand hypertension has been recognized for more than 50 years daily. He was overweight in high school, and he had gradually gained [1—6]. A resurgence of interest in this field has recently occurred weight during the ensuing years. On at least three occasions, he had lost because of the realization that weight gain might significantly as much as 25 pounds through a weight-reduction diet and exercise over a several-month period. However, he had regained this weight within contribute to increased blood pressure in many patients with one year each time. He had been told 3 years earlier that he hadessential hypertension. Weight gain is also an important cause elevated lipid levels and took gemfibrozil for approximately one year. of age-related increases in blood pressure [7]. For the previous year, he had experienced significant problems with Population studies have shown correlations between body impotence. Physical examination revealed an obese white man who appearedweight and blood pressure in normotensive as well as in otherwise healthy. His height was 5 ft 9 in (175 cm) and weight 277 lb hypertensive individuals [3, 5, 61, and weight gain, even over a (125.9 kg). While he was taking antihypertensive medications, hisrelatively short period (several weeks), elevates blood pressure systolic blood pressure was 138—142 mm Hg, the diastolic bloodin humans and in experimental animals [7—11]. In many hyper- pressure was 84—88 mm Hg, measured in both arms, and the pulse rate tensive patients, weight loss significantly decreases blood pres- was 69 beats/mm. The fundi revealed no arterial narrowing, arterio- venous nicking, hemorrhages, or exudates. His chest was clear. Car- sure [11—131 and this decrease can be dissociated from reduced diac examination revealed no murmur, rub, or gallop. The jugularsodium intake [10]. Despite the recognition that obesity and venous pressure was normal, and no peripheral edema was present. The hypertension are closely associated, the mechanisms responsi- abdomen revealed no organomegaly, tenderness, or masses. He had ble for weight-related increases in blood pressure are still significant truncal obesity, The neurologic examination was unremark- unclear. Elucidation of the causes of obesity-associated hyper- able. Laboratory measurements made after overnight fasting included a tension has been hampered by the lack of clinical and animal studies in which sequential changes in renal, endocrine, and cardiovascular function have been examined during the devel- Presentation of this Forum is made possible by grants from Merckopment of hypertension or after blockade of one or more of the Sharp & Dohme International; Amgen, Incorporated; Dialysis Clinic, feedback systems suspected to be responsible for elevating Incorporated; Parke-Davis, Incorporated; and Marion Merrell Dow, blood pressure. Most of our current evidence in this area comes Incorporated. from anecdotal observations, as illustrated in the case presen- © 1993 by the International Society of Nephrology tation, and from studies showing correlations between one or

1402 Nephrology Forum: Hyperinsulinemia, obesity, and hypertension 1403 more variables and increased blood pressure in obese individ-that even though obese subjects had higher plasma insulin uals. levels, a good correlation did not exist between hypertension One possible link between weight gain and hypertension thatand hyperinsulinemia; in fact, they found a tendency toward a has recently received considerable attention is the insulinnegative correlation between plasma insulin and blood pressure resistance and compensatory hyperinsulinemia frequently ob-[29]. Grugni et al also noted no correlation between insulin and served in obese patients [14—22]. Support for the insulin resis-blood pressure in a study of 100 obese hypertensive patients tance-hyperinsulinemia concept of hypertension comes mainlyand 78 obese normotensive subjects [30]. Asch et al found that, from two types of observations. First, hyperinsulinemia, insulinafter stratification for obesity and glucose intolerance, no resistance, and blood pressure have been correlated in obesesignificant difference existed between the mean age-adjusted and lean hypertensive patients in several studies [16—24]. Sec-fasting or post-challenge insulin levels of normotensive and ond, insulin has been shown in multiple studies to have acutehypertensive subjects [31]. Others also have reported that the actions on the sympathetic nervous system, the kidneys, andrelationship between plasma insulin concentration and blood the cardiovascular system that could lead to hypertension ifpressure is weak [32—341 or nonexistent [35]. these effects were sustained [15, 18, 25, 26]. However, there is A dissociation between hyperinsulinemia and hypertension still considerable debate about the quantitative importance ofalso has been demonstrated in large-scale epidemiologic studies insulin in contributing to hypertension, and only recently have[36, 37]. In Pima Indians and Mexican Americans in the United experimental studies directly tested the importance of hyperin-States, and hyperinsulinemia are common, sulinemia as a cause of hypertension. but hypertension is rare [26, 28, 36]. Also, an inconsistent relationship was found between insulin and blood pressure in Correlations among insulin resistance, hyperinsulinemia, three different Pacific island populations [37]. and hypertension Thus, considerable controversy remains about whether hy- pertension is even correlated with plasma insulin concentration Multiple studies have demonstrated a positive correlationor insulin resistance, The fact that the relationship among these between blood pressure and plasma insulin concentration invariables has not always been consistent suggests that a reas- obese [14, 17, 18, 20, 23] as well as in lean hypertensive patientssessment of their interactions is warranted. Certainly, if hyper- [24, 26]. Plasma insulin levels are elevated in patients withtension and hyperinsulinemia or insulin resistance are related, , compared with normotensive controlsthe relationship is not a straightforward one. Moreover, the [27], although differences in body weight and age often are notpresence or absence of an association does not prove or taken into consideration. Berglund et al found that untreateddisprove causality. hypertensive individuals tended to have a higher body mass Because hypertension affects many organ systems and cell index, higher fasting insulin levels, and greater glucose intoler-functions that might or might not be involved in raising blood ance than did normotensive controls and that serum insulinpressure, it is possible that hyperinsulinemia and insulin resis- concentrations were higher in hypertensive individuals eventance occur via the multiple changes that develop secondary to after correction for body weight [14]. Manicardi et al found inhypertension. Thus, correlations among hyperinsulinemia, in- age- and weight-matched obese, non-diabetic individuals withsulin resistance, and hypertension could have several explana- and without hypertension that insulin resistance was greater intions: (1) hyperinsulinemia and insulin resistance could be obese hypertensive subjects than in obese normotensive indi-secondary to other abnormalities associated with hypertension; viduals; in these studies, the plasma insulin response to an oral(2) insulin resistance and hyperinsulinemia could cause hyper- glucose tolerance test was correlated with blood pressure in thetension; and (3) insulin resistance, hyperinsulinemia, and hy- obese hypertensive group [231. pertension might occur through parallel but unlinked mecha- Correlations between hypertension and plasma insulin con-nisms. Regardless of whether insulin and blood pressure are centration after an oral glucose load may be independent ofcorrelated, the quantitative importance of hyperinsulinemia and obesity, glucose intolerance, and age [20]. Ferrannini andinsulin resistance in causing hypertension clearly cannot be colleagues reported that insulin-mediated whole-body glucoseestablished solely from correlational studies. uptake was reduced by 30% to 40% in lean hypertensive patients, compared with normotensive controls, thereby sug- Are insulin resistance and hyperinsulinemia gesting an association between insulin resistance and blood secondary to hypertension? pressure even in non-obese individuals [24]. The severity of hypertension in these studies was correlated with the degree of Recently, insulin resistance and compensatory hyperinsulin- insulin resistance as determined by the glucose infusion ratesemia in hypertension have been postulated to be due to vascular needed to maintain euglycemia during insulin infusion. Theserarefaction and increased peripheral vascular resistance, which and other studies demonstrating a positive association amongare believed to reduce the delivery of glucose and insulin and to hyperinsulinemia, insulin resistance, and hypertension have ledimpair skeletal muscle uptake of glucose [38, 39]. At first to considerable speculation about cause-and-effect relation-glance, this concept is intuitively pleasing when considered ships among these variables. only at the microcirculatory level. Hypertension almost invari- Not all hypertensive patients, however, are insulin resistant,ably is associated with increased total peripheral resistance, and many individuals with hyperinsulinemia and insulin resis-and vascular rarefaction is common with longstanding hyper- tance do not have high blood pressure [28, 29]. For example,tension [40—44]. Also, it is almost certain that altered blood flow Mbanya and coworkers found that insulin levels were similar inand substrate delivery are important determinants of glucose nondiabetic hypertensive and nondiabetic normal subjects anduptake under acute conditions, such as during transients of 1404 NephrologyForum: Hyperinsulinemia, obesity, and hypertension glucose disposal after a meal or during a glucosesion per se could induce these abnormalities is difficult. Recent tolerance test. However, it is important that we keep in mindstudies investigating several forms of hypertension associated the chronic nature of hypertension and insulin resistance,with increased peripheral vascular resistance and vascular entities that are found under long-term steady-state conditions,rarefaction, such as renovascular or mineralocorticoid hyper- not simply when the system is challenged acutely. For thistension, found no evidence of insulin resistance [50—53]. These hypothesis of insulin resistance to be valid, at least two condi-observations suggest that, in most instances, hyperinsulinemia tions must be met: (1) tissue blood flow must be reducedand insulin resistance are not a consequence of hypertension chronically at the principal site at which insulin resistanceand its associated increases in total peripheral vascular resis- occurs, likely skeletal muscle [45, 46], and (2) sustained de-tance and blood vessel rarefaction. This conclusion agrees with creases in tissue (skeletal muscle) blood flow must impairrecent observations by Capaldo and colleagues, who found that glucose uptake. insulin resistance occurred in skeletal muscle of patients with The question of whether tissue blood flow is reduced inessential hypertension even though blood flow was not reduced hypertension has generated considerable controversy. Al-[54]. though vascular resistance usually is elevated in hypertension, it does not necessarily follow that tissue blood flow is reduced. Does hyperinsulinernia cause hypertension? In fact, vascular rarefaction and other regulatory adjustments that raise peripheral vascular resistance might be compensatory Given that correlations among insulin resistance, hyperten- responses that prevent overperfusion of the tissues in hyper-sion, and hyperinsulinemia do not appear to be explained by tension [40, 47]. According to this concept, increased peripheralhypothesizing that hypertension causes insulin resistance, we vascular resistance maintains substrate supply to the tissues atmust consider the possibility that insulin resistance and com- a level that matches metabolic demands, even in the presence ofpensatory hyperinsulinemia cause hypertension. increased blood pressure, which tends to raise tissue blood Acute effects of insulin on renal, sympathetic, and cardio- flow. vascular function. One line of evidence that supports a role for The literature supports this concept; most hypertensive sub-insulin in causing hypertension is that insulin has acute effects jects have normal cardiac output and normal blood flow in theon the kidneys, sympathetic nervous system, and cardiovascu- tissues that have been studied, including skeletal muscle [40,lar system, which, if sustained, could lead to high blood 47]. Also, in many of the experimental studies in which vascularpressure. Hyperinsulinemia is widely believed to occur as a rarefaction has been demonstrated, abnormalities of renal func-compensation for insulin resistance in peripheral tissues, espe- tion precede the hypertension and are associated with eithercially skeletal muscle. Normal sensitivity to insulin, however, blood volume expansion or reductions in venous compliancecan be present in certain tissues, such as the kidneys and and accompanying increases in "effective" blood volume [40,sympathetic nervous system, in which insulin has been postu- 47, 48]. In these instances, vascular rarefaction might be alated to exert effects that could increase blood pressure [55, compensation for an initial overperfusion of the tissues. As58—62]. Two mechanisms are often suggested by which hyper- Cowley recently noted, structural rarefaction is often precededinsulinemia might raise blood pressure: (1) by directly causing by functional changes that lead to increased vasomotion, de-renal sodium retention, and (2) by increasing sympathetic creased luminal diameter, and decreased maximal vasodilation,nervous system activity [15, 55, 59—62]. all of which cause a functional rarefaction [40]. These functional Several studies have shown that insulin reduces sodium and anatomic changes in vascular resistance, however, do notexcretion when administered to intact animals and humans. As result in underperfusion of tissues but instead protect thefar back as the 1930s, Atchley and coworkers reported a tissues from excessive blood flow or increased wall tension [40,marked reduction in sodium excretion during reinstitution of 47, 48]. insulin therapy in diabetic subjects and that withdrawal of The second assumption of the hemodynamic hypothesis ofinsulin therapy increased sodium excretion [63]. Other investi- insulin resistance is that reductions in tissue blood flow impairgators have reported antinatriuresis after insulin administration insulin's action on glucose uptake. But experimental evidencein diabetics as well as in normal and obese subjects [64, 65]. and theoretical reasons suggest that changes in tissue blood Although the exact mechanisms of insulin-mediated antina- flow are not the primary mechanism by which chronic insulintriuresis are not entirely clear, several studies suggest that resistance occurs. First, considerable evidence indicates thatinsulin directly increases renal tubular sodium reabsorption. insulin resistance is due mainly to postreceptor abnormalities inFirst, insulin infusion reduces sodium excretion in isolated obese hypertensive patients [49]. Although insulin-receptorkidneys with no change in glomerular filtration rate (GFR) [66]. binding can be altered in some pathophysiologic conditions,Also, intrarenal insulin infusions at rates that do not markedly reduced numbers of receptors or decreased receptor affinity foralter systemic plasma insulin concentration reduce sodium insulin probably do not play a major role in most cases of insulinexcretion without altering GFR [67, 68]. Micropuncture studies resistance [49]. The primary reason for this is that only a smallsuggest that insulin increases sodium reabsorption at a site fraction of the total number of insulin receptors normallybeyond the proximal tubule, possibly in the ioop of Henle [69]. available is required to exert a near-maximal effect of insulin onInsulin also has been reported to stimulate fluid reabsorption in glucose transport [49]. isolated proximal tubules, however [70]. Because abnormalities of insulin sensitivity associated with If insulin's antinatriuretic effect were maintained chronically, hypertension and type-Il are likely to be caused byblood pressure would rise because of renal sodium retention postreceptor alterations of intracellular signaling, envisioning aand extracellular fluid volume expansion. As arterial blood mechanism by which changes in tissue blood flow or hyperten-pressure increased, the antinatriuretic effects of insulin would Nephrology Forum: Hyperinsulinemia, obesity, and hypertension 1405 be offset by pressure natriuresis and, under steady-state condi-effect on arterial pressure, although sympathetic nerve activity tions, sodium balance would be maintained at the expense ofcan increase. Whether sympathetic activity is stimulated with volume expansion and hypertension. Although this conceptchronic hyperinsulinemia, however, has not been reported. offers an attractive explanation for the link between insulin and Thus, acute hyperinsulinemia reduces urinary sodium excre- blood pressure, evidence supporting it is derived mainly fromtion and activates the sympathetic nervous system, and these acute studies. Until recently, it was not clear whether insulineffects, if sustained, could influence the cardiovascular system could cause sustained reductions in renal excretory capabilityand blood pressure regulation. Insulin also has important va- sufficient to elevate blood pressure, or whether other compen-sodilatory actions that tend to lower blood pressure, however. satory mechanisms might override the antinatriuretic effect ofThe net effect of insulin on these various systems acutely raises insulin in the absence of hypertension. Several recent studies inblood pressure only with supraphysiologic concentrations in our laboratory suggest, however, that insulin's antinatriureticnormal animals and humans. More important, the relevance of effects on the kidney are not sufficient to elevate blood pressurethese observations (made during short-term insulin administra- chronically [71]. I will return to these studies in a moment. tion) to the problem of chronic obesity-induced hypertension is Another mechanism by which insulin might elevate blooddifficult to ascertain because the data do not indicate the pressure is by activation of the sympathetic nervous system [18,time-dependence of these various actions and whether the 25, 59—61]. Troisi et al reported that total caloric intake wasalterations are sustained sufficiently to cause chronic hyperten- independently correlated with 24-hour urinary norepinephrinesion. excretion in 572 men in the Normative Aging Study [72]. Chronic hyperinsulinemia and blood pressure regulation. Increased caloric intake in rats raises sympathetic nervousEven though multiple studies have examined the acute renal system activity and plasma insulin concentration in parallel,and cardiovascular actions of insulin, only a few studies have whereas caloric restriction lowers plasma insulin and sympa-looked at the chronic effects of insulin on blood pressure. thetic activity as assessed by indirect methods such as tissueBecause hypertension is a disturbance of long-term blood norepinephrine turnover [18, 25]. Experimental hypertension inpressure regulation, the importance of various neurohumoral rats, caused by feeding a high sucrose diet, also is associatedmechanisms cannot always be extrapolated from the results of with increased catecholamine secretion and hyperinsulinemiaacute experiments. A pertinent example of this problem comes [73]. It is difficult to determine from these "overfeeding"from extrapolation of acute studies with vasoconstrictors such studies, however, whether hyperinsulinemia is the key factor inas vasopressin to the problem of chronic hypertension. Vaso- elevating blood pressure and adrenergic activity, or whetherpressin, one of the most powerful vasoconstrictors in the body, other mechanisms are more important. has been demonstrated to be important in the acute regulation Only a few studies have directly examined the acute effects ofof blood pressure, particularly in circumstances such as hem- hyperinsulinemia on blood pressure and adrenergic activity.orrhage [79]. But chronic increases in plasma vasopressin Acute insulin infusion has been reported to elevate plasmaconcentrations cause only small elevations in blood pressure as norepinephrine even when plasma glucose concentration waslong as renal function is not impaired [80, 81]. Thus, the acute held constant [74, 75], and blockade of adrenergic activityeffects of this on blood pressure regulation do not attenuated the rise in blood pressure associated with insulinaccurately predict its role in chronic hypertension. Likewise, an injection [76]. The relevance of these observations to theunderstanding of the quantitative importance of insulin in problem of chronic hypertension is difficult to assess, however,hypertension will likely come from long-term, rather than as large pharmacologic doses of insulin were used and only theacute, studies. acute changes in blood pressure were studied. Recently we performed a series of studies in dogs and rats to Anderson and colleagues recently studied the short-termtest directly whether a cause-and-effect relationship exists effects of pathophysiologic levels of insulin on sympatheticbetween hyperinsulinemia and hypertension. These experi- nervous system activity, blood pressure, and vascular resis-ments were designed to determine whether chronic increases in tance in humans. An increase in insulin concentration from 8 toplasma insulin concentration, comparable to those found in 72—144 sU/ml in these studies increased skeletal muscle sym-obese hypertensive patients, would cause sustained increases in pathetic activity and plasma norepinephrine concentration butblood pressure or sustained alterations in renal function [82— decreased forearm vascular resistance and failed to increase85]. In one series of experiments (Fig. 1), we infused insulin into blood pressure [77]. This study indicates that in normal hu-dogs for 7 days at a rate that increased plasma insulin concen- mans, acute (60-minute) elevations in plasma insulin exert bothtration approximately five- to sixfold; plasma glucose concen- pressor (increased sympathetic nervous system activity) andtration was maintained relatively constant with a glucose-clamp depressor (vasodilator) actions, but cause little change in bloodprocedure [83]. Insulin infusion transiently reduced sodium pressure. Rooney et al also found that acute insulin infusion atexcretion and urine volume for 2 to 3 days, but these variables rates that raised plasma insulin concentration from 5 to approx-returned toward control during the next few days; after 7 days imately 31 and 55 U/ml increased plasma renin activity,of insulin infusion, we noted a net retention of approximately plasma angiotensin II, and norepinephrine concentration, but120 mEq of sodium. Consistent with the results from acute caused only small (2—4 mm Hg) increases in systolic bloodstudies, the sodium retention observed during hyperinsulinemia pressure; diastolic blood pressure was not significantly alteredwas clearly due to increased tubular reabsorption, since GFR by insulin infusion and, although mean arterial pressure was notand filtered sodium load, as well as effective renal plasma flow, reported in the study, it is unlikely that it changed significantlyactually increased by approximately 15% to 20%. Despite the [78]. Thus, human studies indicate that relatively large in-transient sodium retention, mean arterial pressure fell by ap- creases in plasma insulin concentration have little or no acuteproximately 10 mm Hg during chronic hyperinsulinemia (Fig. other antinatriuretic ,suchasaldosterone, ismark- with anelevatedintakeofsodium [82].Hypertensioncausedby circumstances associatedwith impairmentofrenalfunctionor bility thathyperinsulinemiamight contributetohypertensionin raise bloodpressureinnormal dogs,weconsideredthepossi- impairment ofrena/function. Althoughinsulininfusiondidnot normal dogs[83,84]. chronic hyperinsulinemiadidnotelevatebloodpressure in important findinginthisgroupofstudies,however,is that creased metabolicrateinskeletalmuscle[77,86].Themost infusion causesperipheralvasodilationassociatedwith in- mechanisms. Studiesinhumansalsosuggestthatacuteinsulin metabolic rateandsubsequentactivationoflocalvasodilator lation, possiblyduetostimulationoftissueglucoseuptake and plasma insulinconcentrationcausedmarkedperipheralvasodi- cardiac output30%to40%[841.Thus,sustainedincreases in dogs markedlyreducedtotalvascularresistanceandraised peripheral vasodilation.Infusionofinsulinfor7daysinnormal might beoue,inpart,tothefallbloodpressurecausedby 1). Thesodiumretentionassociatedwithhyperinsulinemia sodium Mean arterial mm 1406 Blood pressureresponsesto chronic hyperinsulinemiaafter Urinary excretion, mEq/day pressure, Hg o 0r' 0a 0a 0 0o 0 0CO I I I I I w Nephrology Forum: Hyperinsulineinia,obesity,andhypertension function duetolossofnephrons[47,48].Thispossibilityhas in part,tothefall inrenalperfusionpressure. Thefactthatthere bly asaresultofsodiumand waterretentionthatmightbedue, mia, bloodpressuregradually increasedtowardcontrol,possi- observed innormaldogs.After 2to3weeksofhyperinsuline- during insulininfusion;the changesweresimilartothose fact, arterialpressuredecreased approximately10mmHg decreased sodiumexcretion, arterialpressuredidnotrise;in cose-clamp procedure.Althoughinsulininfusiontransiently Plasma glucoseconcentrationwasheldconstantwiththe glu- sufficient timeforinsulintoexertahypertensiveeffect [82], tration wasincreasedfour-tosixfoldfor28daysallow tial hypertensiveeffectsofinsulin,andplasmainsulinconcen- a high-sodiumdiettoincreasetheirsusceptibilityanypoten- mately 30%ofnormal.Intheseexperiments,thedogswere fed dogs inwhichrenalmasswasreducedsurgicallytoapproxi- gradually decreaseswithaging,particularlyafterage40[87]. are alsoelderlyandbecausethenumberoffunctionalnephrons clinical relevancebecausemanyobesehypertensivepatients edly exacerbatedbyhighsodiumintakeordecreasedrenal I.' Figure 2depictstheeffectsofchronichyperinsulinemia in k H (Adapted withpermissionfromRef.83.) kg/mm, Fig. 1.Theeffectsofinsulininfusion(1.0U/ iv) for 7 daysinnormaldogs. Nephrology Forum: Hyperinsulinemia, obesity, and hypertension 1407

High sodium + L kidney mass

120 - I 110 LI I11 [I

100

90 -

Fig.2. The effects of insulin infusion (1.0 jU/ 80 - kg/mm, iv) for 28 days in dogs with reduced renal mass maintained on a high sodium 24 28 intake of approximately 319 mEqiday. (Adapted with permission from Ref. 82.) was a transient overshoot of blood pressure after the insulinduring chronic hyperinsulinemia in normal dogs as long as infusion was stopped suggests that insulin might have beenplasma glucose concentration was held constant [83]. In addi- exerting a depressor effect throughout the 28 days of thetion, we found no indication that insulin potentiates the chronic infusion (Fig. 2). Thus, chronic hyperinsulinemia, lasting athypertensive effect of norepinephrine [83]. However, we did least 4 weeks, does not elevate blood pressure in dogs evenobserve increases in heart rate during chronic hyperinsulinemia when renal mass is reduced and a high-sodium intake isin dogs [83, 84]; our findings are consistent with the possibility maintained. that insulin increases sympathetic activity. Yet the mechanisms Does insulin interact with other pressor stimuli to causeresponsible for the tachycardia during hyperinsulinemia are still hypertension? Although the studies I have cited provide nounclear and could be related to a direct chronotropic effect on evidence that hyperinsulinemia per se causes hypertension, it isthe heart, withdrawal of parasympathetic tone, or increased possible that insulin could increase the blood pressure actionssympathetic activity. Further studies are needed to explore of other pressor stimuli, such as increased angiotensin II (All)these possibilities. The most important conclusion from these or elevated adrenergic activity. Previous acute studies in dogsstudies, however, is that hyperinsulinemia does not appear to suggested that insulin potentiates the blood pressure- andpotentiate the chronic blood pressure effects of other pressor aldosterone-stimulating effects of All [88], although studies instimuli such as All or catecholaminés. humans have not confirmed this observation [89]. In addition, Can chronic hyperinsulinemia cause hypertension by stimu- evidence points to increased activity of the renin-angiotensinlating vascular smooth muscle growth? Chronic hyperinsuline- system and increased sympathetic activity in obese patients andmia also might have a mitogenic action on vascular smooth in obese dogs [18, 25, 90, 91]. muscle [46, 55]. High levels of insulin induce proliferation of Figure 3 illustrates results from experiments designed to testcultured smooth muscle cells [93, 94]. Whether insulin, at the possibility that hyperinsulinemia might exacerbate theconcentrations similar to those found in obese hypertensives, chronic blood pressure effects of All. In these studies, renalcan stimulate blood vessel growth in vivo is still not clear, mass was reduced to approximately 30% of normal, the dogshowever. Also, for insulin to stimulate vascular smooth muscle were maintained on a high sodium intake, and All was infusedgrowth in insulin-resistant subjects, the blood vessels would at a rate that produced mild hypertension for several dayshave to remain sensitive to the effects of insulin on cell growth before the insulin infusion was started. Subsequent infusion ofor proliferation. More important, stimulation of blood vessel insulin for 28 days, while maintaining All infusion constant, didgrowth in peripheral tissues probably is not by itself an impor- not change arterial pressure further [82]. These studies suggesttant cause of chronic hypertension, because increased total that insulin does not potentiate the chronic hypertensive effectperipheral resistance does not appear to be a sufficient stimulus of All. for chronic hypertension. Although previous acute studies suggest that hyperinsuline- Increased peripheral vascular resistance probably occurs mia increases plasma catecholamines, we found no indication ofsecondary to increased blood pressure in many forms of hyper- increased plasma norepinèphrine or epinephrine concentrationtension [47, 48]. Numerous theoretical and experimental studies 1408 NephrologyForum: Hyperinsulinemia, obesity, and hypertension

High sodium + kidney mass Angiotensin II

180

II 140

100

60 Fig. 3. The effects of insulin infusion (1.0 pill kg/mm, iv) for 28 days in dogs with reduced renal mass maintained on a high sodium intake of 300 mEqiday and infused with 20 angiotensmn II (2.0 ng/kg/,nmn). Angiotensin II infusion was started several days before insulin infusion was begun and was continued —4 0 4 8 12 16 20 24 28 32 throughout the experiment. (Adapted with permission from Ref. 82.) suggest that chronic hypertension can occur only if renalfindings in obesity-associated hypertension, which is character- function is abnormal and a shift of the renal pressure-natriuresisized by marked sodium retention and increased plasma renin relationship occurs [46, 47]. In the absence of altered pressureactivity [11, 62, 90—92]. In addition, rats with insulin-induced natriuresis, increased peripheral vascular resistance leads onlyhypertension are not sensitive to changes in sodium intake [96] to a transient increase in blood pressure, as the rise in pressure(Fig. 4), whereas obese humans with hypertension are sensitive is associated with increased urinary sodium excretion, a pro-to alterations in soaium intake [11, 62]. Thus, insulin elevates gressive reduction in extracellular fluid volume and, eventually,blood pressure in rats via mechanisms that are still unclear, but a return of arterial pressure toward normal [47, 481. Forseveral important differences exist between this model of hy- hypertension to occur and for sodium balance to be maintained,pertension in rats and obesity-induced hypertension in humans. a requirement that is essential for life, there must be a shift of It is still unclear whether the human blood pressure response renal pressure natriuresis so that normal rates of sodiumto insulin is more closely related to that in dogs or in rats. Acute excretion can be maintained at elevated arterial pressures [47,insulin infusion in humans causes many of the same changes 48]. Thus, stimulation of smooth muscle growth could cause hypertension only if it also increased renal vascular resistanceobserved during insulin infusion in dogs, including peripheral vasodilation, increased heart rate, increased plasma renin ac- and shifted pressure natriuresis to higher levels. An important tivity, and little or no change in arterial pressure. Although observation that argues against this possibility is the finding that renal blood flow is increased rather than reduced in obese,long-term insulin infusion studies in humans have not been reported, the chronic hyperinsulinemia and insulin resistance insulin-resistant subjects [90, 95]. Thus, even though the long- term effects of hyperinsulinemia on blood vessel growth haveassociated with insulinoma do not elevate blood pressure in not been adequately studied (comparable to that found in obese,humans [97—99]. insulin-resistant subjects), it seems unlikely that this action is a Several population studies have shown a poor correlation major cause of hypertension. between blood pressure and plasma insulin concentration in Species variations in blood pressure responses to chronicnormal humans [26, 28—30]. In a study of more than 2000 hyperinsulinemia. Although several chronic studies in dogs dosubjects, Ferrannini et al reported that, after adjustment for not support the concept that hyperinsulinemia is a primaryage, sex, body-mass index, and waist:hip circumference ratio, cause of obesity-induced hypertension, it might be premature tothe slope of the regression line for blood pressure versus insulin rule out a role for insulin; species might vary in their bloodconcentration predicted that a 200 U/ml increase in insulin pressure responses to hyperinsulinemia. Recent studies bycould account for only a 1 mm Hg rise in blood pressure (Fig. 5) Brands et al in our laboratory have shown that hyperinsuline-[26]. Considering the fact that fasting plasma insulin concentra- mia increases blood pressure in rats [85, 961, In these studies,tion is usually elevated by less than 20 U/ml in obese hyper- arterial pressure was monitored 24 hours a day, and plasmatensive subjects compared with normal subjects [11, 16, 17, 28], glucose concentration was held constant using the glucose-these observations call into question the quantitative impor- clamp procedure [96]. Chronic hyperinsulinemia significantlytance of hyperinsulinemia in human hypertension. Although raised mean arterial pressure. The increased blood pressurethese findings do not completely rule out the possibility that was not associated with sodium retention or activation of thehyperinsulinemia could interact with another, as yet unknown, renin-angiotensin system [96]. These observations contrast withabnormality to increase blood pressure in obesity, these results Nephrology Forum: Hyperinsulinemia, obesity, and hypertension 1409

120 150

130 E T I Systolic P<0.0001 E E 100 a) 110 (I) a) N=2241

a) ta) 80 Diastolic P<0.0001 C a) a)

— ___ I 0 100 200 300 400 500 600 0 2 4 6 8 10 12 Two-hourplasma insulin, iU/ml Sodiumintake, mEq/day Fig.5. Graph shows systolic and diastolic blood pressure as afunction Fig.4. Chronic relationship between sodium intake and mean arterial of post-load plasma insulin concentrations in normotensive, non- pressure in rats during control conditions (•) and during insulindiabetic subjects (n =2241)after adjustment for age, gender, body infusion (1.5 jU/kg/min, i.v.; U).Controlvalues represent the average mass index, and weight:hip circumference ratio. (Adapted with permis- of 4 control days, and insulin values are the average of days 5—7 of sion from Ref. 27.) insulin infusion. (Adapted with permission from Ref. 96.) do suggest that the independent effects of insulin on bloodhypertensive actions of insulin to be expressed, one would pressure are minimal in humans. predict that hyperinsulinemia would cause hypertension in circumstances in which the peripheral vasodilatory actions of Possible role of insulin resistance in hypertension insulin are absent. To test this hypothesis, we investigated the Although hyperinsulinemia per Se, comparable with thateffects of chronic insulin infusion into the renal artery of found in obese individuals, does not appear to elevate bloodconscious dogs to determine whether the direct renal actions of pressure in dogs or in humans with insulinoma, it is possibleinsulin could cause hypertension in the absence of any periph- that insulin resistance elevates blood pressure by facilitating aeral vasodilatory effects [101]. In these experiments, we calcu- hypertensive action of insulin or by mechanisms that arelated insulin infusion rates to increase intrarenal, but not independent of hyperinsulinemia. Several investigators havesystemic, insulin concentrations to levels comparable to those postulated that resistance to the metabolic and cell-membranefound in obese hypertensive subjects [loll. Presumably, if the effects of insulin is a key element in linking obesity anddirect renal actions of insulin can cause chronic hypertension, hypertension. then raising intrarenal levels should elevate blood pressure in Because normal humans and dogs are sensitive to the effectsthe absence of marked increases in systemic insulin concentra- of insulin on glucose uptake, insulin infusion would be expectedtions. However, intrarenal insulin infusion for 7 days failed to to increase peripheral glucose uptake and metabolic rate,significantly alter mean arterial pressure and caused only tran- changes that cause peripheral vasodilation via local blood flowsient, mild sodium retention [loll. These observations indicate control mechanisms. Recent studies in our laboratory bythat the direct renal actions of hyperinsulinemia, in the absence Brands et al have demonstrated that chronic hyperinsulinemiaof a peripheral vasodilatory effect, cannot cause sustained in normal dogs markedly reduces total peripheral vascularhypertension in conscious dogs. resistance and increases cardiac output [84]. In normal humans To further test the importance of insulin resistance as a and in patients with borderline hypertension, hyperinsulinemiadeterminant of whether insulin can elevate blood pressure, we also reduces forearm vascular resistance and increases bloodexamined the effects of chronic hyperinsulinemia in obese dogs flow [77, 100]; this response is substantially attenuated in obese,that were resistant to the metabolic effects of insulin [102]. In insulin-resistant subjects [861. Therefore, some investigatorsthese experiments, we gave dogs a high-fat diet for 6 weeks to have suggested that the failure of chronic hyperinsulinemia tocause obesity, increased blood pressure, and insulin resistance. elevate blood pressure in normal animals and humans could beSubsequent infusion of insulin for 7 days in obese dogs pro- due to offsetting effects of peripheral vasodilation, which wouldduced no significant changes in cardiac output or total periph- tend to lower blood pressure, and other actions of insulin (foreral vascular resistance. This finding contrasts with the re- example, antinatriuresis and sympathetic activation), whichsponse of normal dogs, in which total peripheral resistance would tend to elevate blood pressure. decreased and cardiac output increased markedly [841. Thus, If, by preventing the peripheral vasodilatory actions of insu-compared with normal dogs, obese dogs are resistant to the lin, insulin resistance were important in allowing the putativeperipheral vasodilatory and metabolic actions of insulin. Yet, 1410 NephrologyForum: Hyperinsulinemia, obesity, and hypertension despite insulin resistance, blood pressure did not increaseincrease markedly in obese, insulin-resistant dogs [90]. These significantly in obese dogs infused with insulin [1021. In fact,observations suggest that increased peripheral vascular resis- insulin infusion caused a small decrease in blood pressure, antance mediated by insulin resistance probably is not a primary alteration similar to that found in normal dogs. Thus, thefactor in causing hypertension in obese individuals. presence of insulin resistance does not appear to markedly alter the blood pressure responses to chronic hyperinsulinemia in Abnormal renal function in obesity-induced hypertension dogs. Rocchini et al reported that the pressure-natriuresis curve Insulin resistance has been postulated to play a key role inwas altered in obese adolescents [11]. Figure 6 shows the hypertension not only by causing compensatory hyperinsuline-steady-state relationships between blood pressure and sodium mia, but also by other, as yet unidentified, mechanisms thatexcretion for normal individuals, obese adolescents, and the increase peripheral vascular resistance [58, 59,103,104]. Forsame subjects after they lost weight. In normal subjects, the example, insulin resistance might elevate intracellular calciumrelationship is extremely steep, whereas in obese individuals concentration in vascular smooth muscle, thereby causingthe slope of the curve is reduced, an abnormality corrected by peripheral vasoconstriction and increased blood pressure [103].weight loss. Although the mechanisms responsible for altered This notion is based on the observation that insulin blockspressure natriuresis in obese subjects have not been elucidated, calcium currents, shortens calcium-driven action potentials,increased tubular sodium reabsorption or an inability to sup- and causes cell membrane depolarization and relaxation inpress All formation in response to volume expansion appears to normal vascular smooth muscle [103]. Insulin also might atten-initiate elevated blood pressure in many forms of hypertension uate the contractile response of vascular smooth muscle toassociated with a reduced slope of the pressure-natriuresis constrictor agents and stimulate calcium-ATPase activity [103],relationship. Obesity-induced hypertension thus might be in turn lowering intracellular calcium concentration. Presum-caused by factors that increase renal tubular sodium reabsorp- ably, in tissues that are insulin resistant, these actions of insulintion or prevent All formation from being suppressed in re- are blunted, causing increased intracellular calcium concentra-sponse to volume expansion. tion. In support of this possibility are recent studies showing We found in preliminary studies that obesity-induced hyper- that intracellular calcium concentration is elevated in vasculartension in dogs was associated with increased sodium reabsorp- smooth muscle of insulin-resistant animals such as the Zuckertion at a nephron site beyond the proximal tubule [90, 109]. The obese rat [103]. We should remember, however, that correla-increased reabsorption was accompanied by marked sodium tions between insulin resistance in these models of obesity andretention, large increases in GFR and renal plasma flow, cell transport abnormalities do not prove cause-and-effect rela-expansion of extracellular fluid volume, and a failure to sup- tionships. It is still not clear to what extent insulin resistancepress plasma renin activity [90, 109]. Although hyperinsuline- contributes to these changes or whether alterations in ion flux atmia cannot account for these changes in obese dogs, the basic the cell membrane may be caused by other cellular defectsmechanisms responsible for increased sodium reabsorption and unrelated to insulin resistance. hypertension in obesity are still unclear. Two factors that might An observation that argues against the hypothesis that acontribute to increased tubular reabsorption of sodium in obe- primary increase in total peripheral resistance, initiated bysity include activation of the renin-angiotensin system and insulin resistance, is a major factor in causing obesity-inducedincreased renal sympathetic activity [90, 91, 109]. Preliminary hypertension is the finding that cardiac output is elevated andstudies in our laboratory indicate that plasma renin activity is that in many tissues blood flow is increased, rather thanincreased approximately twofold in obese dogs and that acute reduced, in obese hypertensive patients [105, 106]. Experimen-or chronic sympathetic blockade produces a much greater tal models of hypertension associated with vasoconstrictionreduction in blood pressure in obese than in normal dogs usually are characterized by normal or reduced cardiac output(unpublished observations). The quantitative importance of and tissue blood flow [47, 48], rather than by increases, as inthese changes in contributing to increased sodium reabsorption obesity [105, 106]. and to the rise in blood pressure associated with weight gain is Other theoretical considerations and experimental observa-still unclear and is an important area for further investigation. In tions also argue against an increase in total peripheral vascularaddition, the mechanisms responsible for activation of the resistance as a primary cause of hypertension. Although in-renin-angiotensin system and sympathetic nervous system in creased total peripheral resistance is a hallmark of most formsobese patients also will require further study. of established hypertension, numerous studies have suggested Another factor that could contribute to increased tubular that increased peripheral vascular resistance is unlikely toreabsorption in obesity is altered intrarenal physical forces initiate the hypertension unless the constriction also occurs inassociated with histologic changes. Preliminary histologic stud- renal vessels and shifts pressure natriuresis to higher bloodies in kidneys from obese dogs reveal striking changes in the pressures [47]. A key element in all experimental forms ofrenal medulla: marked increases in the number of cells, and hypertension studied thus far, including human essential hyper-especially non-cellular matrix material between the tubules, tension, is an abnormality of renal function that shifts pressurewhich appear to compress the tubules [109]. The matrix mate- natriuresis to higher blood pressures [47, 107, 108]. rial between the tubules stains with alcian blue and periodic If insulin resistance also caused vasoconstriction in renalacid-Schiff (PAS), suggesting increased glycoprotein content. vessels and shifted pressure natriuresis to higher levels, hyper-These changes were observed only in the renal medulla, not in tension would result [47, 107]. Recent studies indicate, how-the renal cortex. Since the kidney is surrounded by a tight ever, that obesity and insulin resistance are not associated withcapsule with a low compliance, cell proliferation or matrix renal vasoconstriction [90]. In fact, renal blood flow and GFRdeposition between the tubules could raise interstitial fluid Nephrology Forum: Hyperinsulinemia, obesity, and hypertension 1411 300

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Mean arterial pressure, mm Hg Fig.6. Steady-state relationship between mean arterial pressure and urinary sodium excretion for non-obese adolescents (U,n=18),obese adolescents (, n =60),and obese adolescentsafter weight loss (0,n =36).(Adapted with permission from Ref. 11.) hydrostatic pressure and cause tubular compression (Fig. 7). Indeed, preliminary observations indicate that renal interstitial fluid hydrostatic pressure is approximately 10 mm Hg higher in kidneys of obese compared with normal dogs [1091. Although small increases in renal interstitial hydrostatic pressure might reduce tubular reabsorption, large increases could cause tubu- lar compression which, in turn, could reduce tubular flow rate, Fig. 7. Possible mechanisms by which altered renal medullary histol- increase tubular transit time, and increase tubular reabsorptionogy associated with obesity could lead to increased total tissue pressure [110]. A tendency toward tubular collapse would especially bein the kidney, increased tubular reabsorption, and chronic hyperten- expected in the loop of Henle, which normally is very disten- sion. sible. Because we found that renal interstitial hydrostatic pres-(Herrera G, personal communication), additional studies are sure is elevated to approximately 19 mm Hg in the kidneys ofneeded in humans to further document these abnormalities and obese dogs, the tubular pressure in the loop of Henle also mustto determine their quantitative importance in causing hyperten- be increased to this level to maintain flow in the tubule. sion. Increased pressure in the loop of Henle could occur as a In summary, although plasma insulin and blood pressure result of increased delivery to this site secondary to an increasemight be correlated in some individuals, a cause-and-effect in GFR or to a reduction in proximal tubule reabsorption.relationship among insulin resistance, hyperinsulinemia, and Preliminary studies indicate that proximal fractional reabsorp-hypertension has not been clearly established. Only a few tion, estimated with the lithium clearance technique, is notstudies of the long-term effects of insulin on blood pressure markedly altered in kidneys of obese dogs [109]. However,regulation have been published, and most of these reports have GFR is increased by approximately 35% to 50% via mecha-suggested that hyperinsulinemia per se cannot account for nisms that are not currently understood. One possible explana-obesity-induced hypertension. Further studies on the quantita- tion is that initial changes in renal medullary histology couldtive importance of insulin resistance and hyperinsulinemia on increase reabsorption in the ioop of Henle and that theselong-term blood pressure regulation in humans are needed. In alterations in turn would reduce sodium chloride delivery to theaddition, other mechanisms that alter renal function and blood macula densa. This reduction would initiate compensatorypressure in obesity should be examined, particularly those that renal vasodilation, as well as increased renin secretion, both ofcause a chronic increase in renal tubular sodium reabsorption which have been observed in obese dogs [109]. Thus, obesity-and shift of pressure natriuresis to higher blood pressures. induced hypertension might be due, in part, to histologic changes in the renal medulla that increase intrarenal pressures Questions and answers and necessitate increased arterial pressure to maintain sodium Ms. CAROL STOLLAR (Dietitian, Frances Stern Nutrition balance. Although preliminary studies suggest that similarCenter, New England Medical Center, Boston, Massachu- histologic changes occur in the renal medulla of obese humanssetts): You used the term "high-fat" diet throughout your talk. 1412 NephrologyForum: Hyperinsulinemia, obesity, and hypertension

You used beef tallow, which is a fairly saturated fat. Do youabsence of tubuloglomerular feedback, did not know whether other behave the same way? Have you triedraise the GFR [113]. To get back to the obesity model, there are others? some similarities with type-I diabetes. One possible explanation DR. HALL: We have not had the opportunity to do thosefor the high GFR in obese animals is an increase in reabsorption studies. There is some evidence from rat studies that highin the loop of Henle prior to the macula densa. caloric intake in the form of fructose or sucrose causes hyper- DR. NICOLAOS E. MADLAS (Chief, Division of Nephrology, tension [111, 112]. However, we have not studied other high-fatNew England Medical Center): In many situations in which or high-carbohydrate diets in dogs. there is interaction of various systems with opposing effects, DR. ANDREW KING (Division of Nephrology, New Englandone is able to demonstrate the possible pathophysiologic role of Medical Center): I'm intrigued by the histologic changes in thea given system through the use of inhibitors. I was wondering medulla. Is there any evidence that obese individuals havewhether somatostatin could be used in chronically obese ani- concentrating and diluting disorders or other evidence of med-mals—dogs and rats—to probe whether insulin might have a ullary dysfunction? hypertensive role, an effect that might be masked because of the DR. HALL: Not that I am aware of. The obese dogs that weconcomitant activation of other systems. studied concentrated their urine, but not to a maximal level. DR. HALL: We've tried that in preliminary studies in obese Their average urine osmolality was approximately equal to thatdogs. We gave somatostatin for 24 hours; we limited adminis- of normal dogs. But if we subject them to 24 hours of vasopres-tration to 24 hours because somatostatin is very expensive. We sin infusion to quantitate maximal concentrating ability, they dofound no change in blood pressure (unpublished observations). not concentrate their urine as well as normal dogs do (unpub-Some work has been done recently in insulin-resistant humans lished observations). I don't know whether similar studies haveand rats. In one study by Carretta et al, somatostatin was given been done in obese humans. for several hours to obese hypertensive patients; their blood DR. RICHARD LAFAYETTE (Division of Nephrology, Newpressure decreased a few mm Hg [114]. However, because England Medical Center): Hyperlipidemia is a frequent compo-somatostatin has many other effects besides inhibiting insulin nent of this syndrome. Have you examined this dyslipidemicsecretion, the results are not convincing. I know of no studies component in terms of its association with changing the hor-that have examined the long-term effects of somatostatin on monal milieu or directly causing vascular injury within theblood pressure in obese hypertensive patients; if somatostatin medulla? does chronically reduce blood pressure, it is important to DR. HALL: No, we have not. That is a good suggestion. demonstrate that insulin replacement reverses the effect of DR. JOHN T. HARRINGTON (Chief of Medicine, Newton-somatostatin. Wellesley Hospital, Newton, Massachusetts): In the early part DR. MADIAS: The plasma concentration of insulin that you of your talk, you commented on the use of the glucose clampobtained in your infusion studies is more than sufficient to technique. In those studies, you're obviously giving lots ofenhance translocation of potassium into cells—muscle, liver, glucose. Does the increase in glucose trafficking through theand . The resultant hypokalemia could then affect body have anything to do with the observed decrease in bloodplasma renin activity, vascular resistance, and renal sodium pressure? reabsorption. Was hypokalemia observed in your studies? DR. HALL: I think it does. The increased uptake of glucose, DR. HALL: Insulin can shift potassium from extracellular to by activating local vasodilatory mechanisms, might be respon-intracellular fluid. However, there were no major changes in sible for the peripheral vasodilation and the transient fall inplasma potassium in our studies [82, 83]. Although plasma blood pressure with insulin and glucose infusions. However,potassium tended to decrease in some experiments, the changes there is also evidence that insulin dilates isolated blood vessels.were small. I agree, however, that some of the renal changes At present, it's difficult to quantitatively assess the contributionobserved during insulin infusion could be related to transloca- of the increased glucose uptake and of direct vascular actions oftion of potassium into the cells. insulin in mediating the decrease in blood pressure associated DR. AJAY SINGH (Division of Nephrology, New England with chronic insulin infusion. Medical Center): I'd like to ask you questions about the DR. HARRINGTON: I have a second, unrelated question. Areepidemiology of this syndrome. First, does this syndrome of there good measurements of total-body sodium in type-I dia-hyperinsulinemia, obesity, and hypertension cluster in families? betics soon after the diagnosis has been made—when the GFRSecond, is there any evidence in twin studies of increased risk is supranormal? Is total-body sodium balance positive? Myfor the syndrome? Third, are racial factors important? understanding is that these patients are not sodium overloaded. DR. HALL: Yes, racial factors should be considered. For Could you comment on this? example, in Mexican Americans, hyperinsulinemia and insulin DR. HALL: We have been talking about type-Il diabetics, whoresistance often are not associated with hypertension. The tend to have high GFRs and sodium retention, as we observedincidence of type-I! diabetes in Mexican Americans is very in these obese dogs. Type-I diabetics also have increased GFRshigh, and yet the incidence of hypertension is low. In contrast, in the early phase, but as the GFR starts decreasing, they maythe relationship might be stronger in Caucasoids. Obviously, retain sodium. Obviously, if they have an increase in GFR, theythese differences imply that genetic factors might be important. also must have an increase in tubular reabsorption. A few years I'm not aware of twin studies, but the abnormalities would be ago, we studied the effects of hyperglycemia per se as aexpected to cluster in families because obesity clusters for mechanism for increased GFR in type-I diabetes [113]. Ourgenetic and environmental reasons. studies suggested that hyperglycemia might increase GFR, in DR. RONALD D. PERRONE (Division of Nephrology, New part, by a tubuloglomerular feedback mechanism [113]. In theEngland Medical Center): I have two questions relating to the Nephrology Forum: Hyperinsulinemia, obesity, and hypertension 1413 interstitial changes that you demonstrated. Are these changestotal peripheral resistance with obesity. With insulin infusion, it reversible with reduction of the high-fat diet? appears to be due to increased metabolic rate. Is the cause the DR. HALL: Yes, they appear to be reversible if the animalssame in obese dogs? Second, is there renal vasodilation? return to their normal body weight. However, it took much DR. HALL: Yes, there is renal vasodilation. Rocchini also has longer for them to return to normal body weight than for themshown that obesity is associated with forearm vasodilation in to become obese. humans [105], and we found that renal blood flow is elevated DR. PERRONE:Mysecond question relates to this model: are35% to 50% in obese dogs [90, 109]. My guess is that coronary there other models of increased interstitial pressure? Is this ablood flow also is elevated because of a greater work load on the known mechanism of hypertension? For example, interstitialheart. Although we have not studied the mechanisms responsi- nephritis or nephrotic syndrome might cause interstitial edemable for the increased cardiac output in obese dogs, the increased and tubular compression. metabolic rate of various tissues could play an important role. DR. HALL: That's a good question and one that we would like DR. LEVEY: A followup question is, could the decline in renal to examine. We have one case, Dr. Guillermo Herrera's pa-vascular resistance cause the increased sodium reabsorption? tient, in whom an interstitial cell tumor was associated with DR. HALL: Renal vasodilation and increased GFR would not severe hypertension (personal communication). However, Ilead to sodium retention and increased fractional sodium reab- know of no published studies that have directly tested whethersorption, as we observed in obese dogs [90, 109]. In fact, renal renomedullary compression and increased interstitial fluid hy-vasodilation, as a primary change, should cause natriuresis and drostatic pressure can cause chronic hypertension. sodium loss. The sodium retention observed in obese dogs, DR. HARRINGTON: Could you tell us precisely how youdespite renal vasodilation, can be explained, however, if the measure renal interstitial pressure? What is the coefficient ofrenal vasodilation and increased GFR occur as a compensation variability? Did you measure it acutely only? Can you measurefor a primary increase in tubular reabsorption. it chronically? Do you have any simultaneous measurements of Da. ANDREW KING (Division of Nephrology, New England intratubular pressure? Medical Center): If there is a decrease in total peripheral DR. HALL: We measured renal interstitial fluid hydrostaticresistance, is the mechanism of hypertension related to an pressure using the implanted capsule technique designed byincrease in cardiac output due to volume expansion? Cobern Ott at the University of Mississippi and later micro- DR. HALL: The cardiac output increases in obese dogs. If you adapted by Frank Knox's group at the Mayo Clinic. We haveindex cardiac output according to body weight, it is not ele- not measured renal interstitial fluid pressure chronically duringvated. However, indexing cardiac output to body weight might the development of the hypertension, only at the terminal phasenot be appropriate because much of the increased weight is fat, after the animals have established hypertension. We implantedand blood flow in fat is not as great as flow in many other the capsules and measured the interstitial fluid pressure acutely.tissues. Blood flow in skeletal muscle, kidneys, and cardiac Measurements in different dogs vary, as you might expect,tissue is likely to be increased. In addition, there is expansion of because some dogs gain more weight and become more hyper-extracellular fluid volume and marked renal sodium retention, tensive than others. We do not yet have measurements ofwhich we believe play an important role in causing obesity- intratubular pressures. induced hypertension. Da. MADIAS: You suggested that the intratubular pressure DR. KING: I'm intrigued by the renal findings of increased might be greater than 20 mm Hg in these animals. Shouldn't thisGFR and renal plasma flow in these patients. These findings are change affect glomerular filtration? If I understood you, GFR isnot the footprints of either norepinephrine or angiotensin II. increased from normal in these animals. You believe that this glomerular hemodynamic profile is due to DR. HALL: We have not measured intratubular pressure, buta decrease in tubuloglomerular feedback. Have you done any it must be at least 20 mm Hg for the tubules to remain open ifstop-flow studies or assessed the activity of TGF in these renal interstitial fluid hydrostatic pressure is approximately 20animals? mm Hg. Tubular pressure could increase because of increased DR. HALL: No, we have not done those studies. We believe resistance to flow in the tubule and increased GFR. As I saidthat tubuloglomerular feedback is a possible explanation for the earlier, the increase in GFR could be a compensation forincreased GFR. Reduced distal tubular sodium chloride deliv- increased tubular reabsorption. There are two ways by whichery, caused by increased reabsorption at a site prior to the tubular flow rate could be reestablished if there is an increase inmacula densa, would be expected to cause a compensatory rise reabsorption in the loop of Henle: by increasing GFR or byin GFR. Increased GFR also could occur via a change in decreasing proximal reabsorption. Our preliminary data do notsensitivity of the macula densa mechanism. We haven't had the indicate an inhibition of proximal reabsorption. I would suggestopportunity to test this hypothesis yet. Micropuncture is diffi- that a rise in tubular pressure could result from increased GFRcult in the dog, but we do plan to do these experiments. in combination with the increased resistance to tubular flow. DR. MADIAS: I was intrigued by the fact that in your studies, DR. MADIAS: I was wondering whether the histologic changesinsulin infusion in rats increased systemic blood pressure sig- that you observed in the renal medulla of obese dogs are presentnificantly. It is of interest that the spontaneously hypertensive in the obese Zucker rat. rat (SHR) displays insulin resistance [115] and that the stimu- DR. HALL: The obese Zucker rat has multiple renal abnor-latory effect of insulin on the proximal tubule Na/H ex- malities, including glomerular damage. I'm not aware of de-changer is greater in the SHR compared with the Wistar-Kyoto tailed studies of the renal medulla in obese Zucker rats. rat, the normotensive counterpart [116]. Studies show that DR. ANDREW S. LEVEY (Division of Nephrology, New Eng-some antihypertensive medications might affect insulin resis- land Medical Center): I'm interested in the cause of decline intance. Thiazides and beta blockers have been shown to worsen 1414 NephrologyForum: Hyperinsulinemia, obesity, and hypertension insulin resistance, whereas angiotensin-converting enzyme in-blockers for 7 days in obese dogs, we did not find any changes hibitors and alpha1 blockers improve insulin sensitivity [117].in plasma renin activity (unpublished observations). This ob- Could you comment on the possible mechanism of theseservation suggests that another stimulus for increased renin effects? secretion, other than the sympathetic nervous system, might Da. HALL: I don't have a good explanation. Several conceptsexist. One possibility is that renin secretion is increased by a have been proposed. Dr. Stevo Julius has suggested that insulinmacula densa mechanism that, in turn, is activated by increased resistance might be caused by increased peripheral vascularsodium chloride reabsorption in the loop of Henle. resistance and vascular rarefaction, which reduce tissue deliv- DR. LAFAYETFE: Vasodilation in this model could be due to ery of insulin and glucose, and impair glucose uptake, espe-some other circulating factor not yet examined. Is there an cially in skeletal muscle [38]. If that concept were correct,increased metabolic activity present in skeletal or heart muscle you'd expect blood flow in peripheral tissues to be reduced inor in the kidney that might be responsible for "work-load" these insulin-resistant individuals; this is not the case. In obese,vasodilation? Have you or other investigators looked at total- insulin-resistant dogs and in obese humans, skeletal musclebody metabolic rate in the study animal or obese humans? blood flow is elevated [1051. If the enhancement of insulin DR. HALL: We haven't done that in these animals. Oxygen sensitivity by converting enzyme inhibitors is as simple asconsumption and cardiac output are both elevated in obesity, vasodilation, other vasodilators should work as well as convert-suggesting increased metabolic rate. It is likely that increased ing enzyme inhibitors; this does not seem to be the case. Wemetabolic rate is a stimulus for vasodilation in some tissues, don't have a good explanation for why converting enzymesuch as skeletal muscle. However, it is also possible that inhibitors improve insulin sensitivity. circulating factors could contribute to peripheral vasodilation. DR. MADIAS: Did I understand you to say that in obeseAtrial natriuretic factor tends to be elevated, but it is not a very individuals, insulin doesn't have as much of a vasodilatorygood vasodilator in the kidney. As I said before, the macula effect on peripheral tissues? To what extent might this defectdensa feedback could contribute to renal vasodilation and contribute to insulin resistance and compensatory hyperinsu-increased GFR. linemia? Also, is this defect present in hypertensive, non-obese individuals? Acknowledgments DR. HALL: Yes. The vasodilatory effect of insulin is attenu- The case presentation was kindly supplied by Dr. Daniel W. Jones, ated in obese, insulin-resistant patients and in obese dogs [1021.Director, Clinical Hypertension Program, University of Mississippi The role of this defect in contributing to insulin resistance isMedical Center. The renal histologic studies were done by Dr. Guill- unknown. It is possible that insulin resistance (for example,ermo Herrera, The author greatly appreciates the excellent secretarial assistance of impaired insulin-stimulated glucose uptake in skeletal muscle)Ms. Susie Araysi and Mrs. Ivadelle Heidke. The author's research is responsible for the impaired vasodilatory effect of insulin. Ifdescribed herein was supported by National Institutes of Health grants the peripheral vasodilatory effect of insulin is linked to stimu-HL 39399, HL 23502, and HL 11678. lation of tissue glucose uptake and increased tissue metabolism, then insulin resistance should be associated with an impaired Reprint requests to Dr. J. Hall, Chairman, Department of Physiology vasodilatory response to insulin. There is evidence that someand Biophysics, University of Mississippi Medical Center, 2500 North lean hypertensive patients are insulin resistant [24], but theState Street, Jackson, Mississippi 39216-4505, USA vasodilatory action of insulin in these individuals has not been References extensively studied. DR. HARRTNGTON: Your studies on salt-induced hypertension 1. Woor JE, CASH JR: Obesity and hypertension: clinical and experimental observations. Ann Intern Med 13:81—90, 1939 were done in your obese dog model. What percentage weight 2. CHIANG BW, PERLMAN LV, EPSTEIN FH: Overweight and hyper- loss is required to achieve eradication of salt-induced hyperten- tension: a review. Circulation 39:403—421, 1969 sion? 3. DUSTAN HP: Mechanisms of hypertension associated with obe- DR. HALL: We have not done that in the dog. Salt-sensitivity sity. Ann Intern Med 98:860—864, 1983 of blood pressure has been studied in obese humans by Roe- 4. PRIOR lAM, EVANS JG, HARVEY HPB, DAVIDSON F, LINDSEY M: Sodium intake and blood pressure in two Polynesian populations. chini et a! [11]. In that study, salt sensitivity of blood pressure N Engi J Med 279:515—520, 1968 was reversed by weight loss, even though the patients did not 5. HAVLIK RJ, HUBERT HB, FABSITZ RR, FEINLE!B M: Weight and return to ideal body weight. hypertension. Ann Intern Med 98:855—859, 1983 DR. LEVEY: Did the change in blood pressure parallel the 6. STAMLER RA, STAMLER J, RIEDLINGER, WF, ALGERA G, ROB- ERTS RH: Weight and blood pressure findings in hypertension change in dietary intake or the change in weight? screening of I million Americans. JAMA 240:1607—1610, 1978 DR. HALL: In our obese dogs, blood pressure paralleled the 7. ALEXANDER J, DUSTAN HP, SIMS EAH, TARAZI R: Report of the increase in body weight. Hypertension Task Force (vol 9). DHEW Publication No. 70-1631 DR. KING: In your studies, plasma renin activity and norepi- (NIH), 1979, pp 61—77 nephrine are increased, and vasodilation occurs. Do these dogs 8. RoccHINI AP, MOOREHEAD CP, DEREMER S, BONDIE D: Patho- genesis of weight related changes in blood pressure in dogs. manifest a resistance to All? For instance, ii you infuse All in Hypertension 13:922—928, 1989 these animals, do they show an equivalent hypertensive re- 9. RoccHiNi AP, MOOREHEAD CP, WENTZ E, DEREMER S: Obesity- sponse? Is there evidence of decreased receptors? induced hypertension in the dog. 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