Hypertension as a disease of carbohydrate and lipoprotein metabolism

Hypertension 1 as a Disease of -carDonyarate 1 1 1 A ana1 Lipoprotein Metabolism GERALD

M. RENEN, M.D., BRIAN B. HOFFMAN, M.D. Pa/o

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bnormalities in glucose and insulin metabolism A are commonly found in patients with high blood pressure U-91. It is well recognized that some anti-

Patients with untreated hypertension have been shown to be resistant to insulin-stimulated glucose uptake and both hyperinsulinemic and hypertriglyceridemic when compared w.ith matched control groups with normal blood pressure. In addition, insulin resistance, hyperinsulinemia, and hypertriglyceridemia have been demonstrated in rat models of hypertension, including spontaneously hypertensive rats and Sprague-Dawley rats fed a fructose-enriched diet, and the defect in insulin-stimulated glucose uptake in these experimental models can also be shown at the cellular level. Furthermore, experimental interventions that prevent insulin resistance and/or hyperinsulinemia from developing in fructose-fed rats also greatly attenuate the increase in blood pressure. Finally, endogenous hyperinsulinemia and hypertriglyceridemia have been identified as factors that increase the risk of coronary artery disease, and may contribute to the increased prevalence of ischemic heart disease in patients with high blood pressure. The fact that past antihypertensive treatment has not focused on these metabolic abnormalities, and, indeed, may have exacerbated them, could help explain why it has been difficult to show that lowering blood pressure decreases risk of coronary artery disease. These observations raise the possibility that abnormalities of carbohydrate and lipoprotein metabolism may play a role in both the etiology and the clinical course of hypertension.

hypertensive medications are associated with a deterioration in glucose tolerance [lo]. More recently it has been demonstrated that abnormalities of glucose and insulin metabolism may occur more frequently in untreated patients with hypertension than in normotensive controls [6-g]. It is possible that the relationship between high blood pressure and defects in glucose and insulin metabolism is incidental, and the circulatory and metabolic changes are not related in a causal fashion. On the other hand there is evidence suggesting that defects in glucose and insulin metabolism may pIay a role mboth the origin and the natural history of high blood pressure.

From the Department of Medicine, Stanford University School of Medicine, and Gerlatric Research, Education and Clinical Center, Veterans Administration Medical Center, Palo Alto, California. This study was supported by Research grant (HL-08506) from the National Institutes of Health. Dr. Hoffman is an Established Investigator of the American Heart Association. Requests for reprints should be addressed to Dr. Gerald M. Reaven, Geriatric Research, Education, and Clinical Center, Veterans Administration Medlcal Center, 3801 Miranda Avenue, Palo Alto, California 94303. I

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INSULIN RESlSTAiCE AS A BASIC DEFECT IN PATIENTS WITH HYPERTENSION Several reports have indicated that patients with high blood pressure are relatively glucose intolerant compared with normotensive persons [l-5]. Indeed, it has been shown that untreated patients with high blood pressure are hyperinsulinemic compared with normotensive persons [6-91. An example of this change is shown in Figure 1, which summarizes ambient plasma glucose and insulin concentration from 8 A.M. to 4 P.M. in a series of normal volunteers and patients with untreated hypertension. The combination of glucose intolerance and hyperinsulinemia strongly suggests that a defect in insulin-stimulated glucose uptake exists in some patients with hypertension, leading to an impairment in glucose tolerance. As a result, the glasma glucose concentration tends to rise, stimulating beta-cells to secrete more insulin. This causes hyperinsulinemia, which prevents further decompensation of glucose tolerance. There is strong evidence that this series of events occurs in a number of clinical situations, e.g., noninsulin-dependent diabetes, obesity, renal failure, and glucocorticoid administration [ll]. Indeed, there is now evidence indicating that similar changes also occur in patients with hypertension [12,13]. In both of these studies, it was shown that the ability of insulin to stimulate glucose uptake was reduced in non-obese patients with untreated hypertension. In addition, evidence of glucose intolerance, hyperinsulinemia, and insulin resistance persisted in a group of patients whose blood pressure had been successfully lowered with combined beta-blocker and thiazide treatment [13]. Thus, it is reasonabIe to conclude that resistance to insulin-stimulated glucose uptake, glucose intolerance, and hyperinsulinemia are characteristic of a certain proportion of patients with hypertension. Furthermore, abnormalities of glucose and insulin metabolism do not necessarily improve when hypertension is treated pharmacologically.

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Figure 1. Mean (FSEM) plasma glucose and insulin concentrations in normal subjects (open circles) and subjects with hypertension (solid circles) in response to a control diet containing (as percentage of calones) 19 percent protein, 41 percent fat, and 40 percent carbohydrate. Breakfast was eaten at 8 A.M. (20 percent of daily calories), and lunch was eaten at 12 P.M. (40 percent of total calories). Blood was drawn before breakfast and every hour thereafter until 4 P.M. Reproduced from [53] with permission.

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ROLE OF INSULIN RESISTANCE AND HYPERINSULINEMIA IN THE ORIGIN OF HYPERTENSION In the vast majority of cases, the cause of systemic hypertension is not known. Secondary forms of hypertension, such as pheochromocytoma and Cushing’s syndrome, are rare. Although not widely appreciated, there is considerable indirect evidence that is compatible with the hypothesis that insulin resistance and hyperinsulinemia may play a role in the origin of hypertension in certain patients. For example, it has been suggested that hypertension is more common in obese persons perhaps because they are hyperinsulinemic 114,151. Similarly, the decline in blood pressure associated with exercise training programs seems to be limited to persons who were initially hyperinsulinemic and had the greatest decrease in plasma insulin level as a result of the training program [14]. Furthermore, it has been possible in recent studies to define a highly significant relationship between plasma insulin concentration and height of blood pressure [6,9]. It is obvious that the correlations between insulin and blood pressure described earlier do not prove that the relationship is causal. On the other hand, if one postulates that insulin resistance and hyperinsulinemia are involved in the origin of hypertension, it is possible to find experimental data that provide possible mechanisms to account for this putative relationship. For example, two reports in human volunteers indicate that elevations of plasma insulin concentration are associated with significant increases in plasma catecholamine concentration, and this relationship is independent of any change in plasma glucose concentration [16,17]. The potential importance of excessive sympathetic activity in the genesis -of experimental hypertension has also been emphasized in sucrose-fed rats with spontaneous hypertension [18]. Sucrose feeding enhances sympathetic nervous system activity [HI. Interestingly, insulin resistance and hyperinsulinemia also develop in sucrose-fed rats [19]. The extent to which insulin resistance and hyperinsulinemia could contribute to the etiology of hypertension by stimulating sympathetic activity remains to be determined. December

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The kidney is another possible site at which hyperinsulinemia might act to raise blood pressure. There is evidence that insulin can act on the isolated toad bladder [20], as well as in intact dogs [21] and humans [22], to promote renal tubular sodium resorption. More recently, evidence has been published indicating that insulin acts at the level of the proximal tubule to increase volume reabsorption [23]. The fact that insulin has been shown to acutely regulate renal sodium and water metabolism in a manner that could raise blood pressure does not prove that these phenomena occur chronically, or that they play a role in the origin of hypertension. On the other hand, as in the case of the relationship between insulin and sympathetic activity, available data provide a testable hypothesis to account for a possible causal relationship between hyperinsulinemia and high blood pressure in certain persons. It should be emphasized that an assumption underlying the earlier discussion is that an elevated plasma insulin concentration, secondary to resistance to insulinstimulated glucose uptake, can have increased action on the sympathetic nervous system and the kidney. In other words, a defect involving one facet of insulin action does not necessarily mean that all of its effeets are equally blunted. In an attempt to provide more direct evidence of a link between insulin resistance, hyperinsulinemia, and hypertension, we have taken advantage of results of previous studies from our laboratory that demonstrated that insulin resistance and hyperinsulinemia develop when normal rats are fed diets with high levels of sucrose [19,24] or fructose [25]. Consequently, we evaluated the effects of fructose-rich diets on blood pressure in normal rats. The results shown in Figure 2 demonstrate that significant hypertension developed within two weeks in fructose-fed rats, without differences noted in the weight gain of the fructosefed and control rats. The increase in blood pressure was associated with insulin resistance and hyperinsulinemia [261. All of these variables were maintained constant in chow-fed control rats. Furthermore, the fructose-induced increase in blood pressure will persist for as long as three months if the rats continue to eat the fructose-enriched diet (unpublished observations) . In an effort to further evaluate the role of insulin 8, 1989

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Figure 2. Mean (ISEM) body weight and blood pressure in rats fed either chow or high-fructose diet. Measurements were made before (6) and after (A) the introductron of the fructose diet. The number of animals in each group is shown in parentheses. The blood pressure increased in the rats fed the high-fructose diet (p
resistance and hyperinsulinemia in blood pressure regulation, we have taken advantage of the fact that insulin sensitivity is enhanced in exercise-trained rats [27]. Consequently, we initiated studies in which two groups of normal rats were fed fructose-enriched diets-one group was maintained in conventional laboratory cages, whereas the other was allowed to run spontaneously. Insulin resistance, hyperinsulinemia, and hypertension developed as before in the sedentary fructose-fed rats, whereas all three of these changes were significantly attenuated in the exercisetrained rats [28]. In a third study, we evaluated the ability of somatostatin, a potent suppressor of beta-cell function, to modulate the circulatory and metabolic effects of fructose-enriched diets 1291. The results indicated that somatostatin was capable of attenuating the hyperinsulinemia that occurs when normal rats eat a highfructose diet, as well as preventing the increase in blood pressure and plasma triglyceride concentration associated with fructose feeding. Finally, it should be noted that insulin resistance and hyperinsulinemia are also seen in spontaneously hypertensive rats [30]. Insulin-stimulated glucose uptake is lower in adipocytes isolated from spontaneously hypertensive rats than in Wistar-Kyoto rats [31]. Thus, abnormalities of insulin metabolism can be seen in genetic, as well as in dietary-induced, rat models of hypertension. Observations that insulin resistance and hyperinsulinemia are seen in two rat models of hypertension [26,30] are certainly intriguing. In view of the fact that hypertension can be produced in normal rats by experimental manipulation known to induce insulin resistance and hyperinsulinemia, it is difficult not to wonder if the relationship between the three variables may be more than coincidental. Additional evidence for a causal relationship between the defects in insulin action and high blood pressure can be derived from the observation that prevention of fructose-induced hyperinsulinemia also significantly reduced the increase in blood pressure associated with the highcarbohydrate diet [28,29]. On the other hand, great care should be exercised in the extrapolation of results from studies with normal rats to human beings with hypertension. The results of studies on experimental 6A4

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models of hypertension in rats are consistent with the speculation that abnormalities in insulin metabolism may play some role in the origin of high blood pressure in humans. RELATIONSHIP BETWEEN INSULIN RESISTANCE, HYPERINSULINEMIA, AND ABNORMAL LIPOPROTEIN METABOLISM IN PATIENTS WITH HYPERTENSIQN It has been frequently demonstrated that abnormalities of lipid metabolism are common in patients receiving antihypertensive drugs such as beta-blockers and thiazide diuretics [32,33]. Lipid abnormalities have also been described in untreated patients with high blood pressure [34,35]. A common finding in such patients is an elevation in plasma triglyceride concentration. Hypertriglyceridemia represents a change in lipid metabolism that also appears to be secondary to insulin resistance and hyperinsulinemia [36-381. Specifically, highly significant correlations have been documented between resistance to insulin-stimulated glucose uptake, hyperinsulinemia, increased very lowdensity lipoprotein secretion rate, and hypertriglyceridemia in normal humans and patients with hypertriglyceridemia [36-381. Similar relationships have also been described in rats with various forms of carbohydrate-induced hypertriglyceridemia [25,39,40]. Furthermore, when insulin-stimulated glucose uptake is enhanced, either by weight reduction in humans 1411 or exercise training in rats [28], plasma insulin and triglyceride levels decline. Finally, direct evidence from experiments on perfused rat liver indicate that hepatic very low-density lipoprotein-triglyceride secretion is directly related to ambient insulin concentration [42]. Thus, there is considerable evidence to support the hypothesis that hypertriglyceridemia is secondary to hyperinsulinemia and insulin resistance. This mechanism may well account for the appearance of elevated plasma triglyceride concentrations in patients with hypertension. The results from a recent study in which multiple metabolic variables were measured in a group of untreated hypertensive patients support the view that carbohydrate and lipoprotein metabolism abnormalities are related in persons with high blood pressure [43]. This population was glucose-intolerant and hyperinsulinemic, and was compared with a matched group of normal persons. Direct correlations were noted between degree of both hyperglycemia and hyperinsulinemia and increased in plasma triglyceride concentration. In addition, an inverse correlation was observed between high-density lipoprotein cholesterol concentration, glucose intolerance, and hyperinsulinemia. These data re-emphasize the fact that abnormalities of carbohydrate and lipoprotein metabolism are present in patients with hypertension, and that significant relationships exist between the various metabolic variables. None of the patients in this study received antihypertensive medication, which strengthens the observation that multiple and related abnormalities of carbohydrate and lipid metabolism exist in persons with essential hypertension. Indeed, these data provide further evidence that abnormalities of both carbohydrate and lipoprotein metabolism are prominent in patients with high blood pressure, and these metabolic changes, which are seen in both treated and untreated patients, are likely to be related to each other.

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INSULIN RESISTANCE, GLUCOSE INTOLERANCE, AND HYPERINSULINEMIA AS RISK FACTORS FOR CAD IN HYPERTENSION Although high blood pressure is a well-recognized risk factor for CAD [44], it is difficult to demonstrate that treating hypertension leads to lower morbidity and mortality from CAD [45-471. This paradox has received a good deal of recent attention, most of which has focused on the fact that conventional treatment for hypertension is often associated with changes in lipid metabolism thought to increase the risk of CAD [32,33]. What has been overlooked is the possibility that the abnormalities of carbohydrate metabolism that are common in hypertensive patients may contribute to an increased incidence of CAD. For example, observations have suggested that relatively minor degrees of glucose intolerance, comparable with that described in many persons with high blood pressure, significantly increase the risk of developing CAD [48,49]. More recently, three prospective epidemiologic studies have indicated that hyperinsulinemia is a risk factor for CAD [49-511. The mechanisms by which hyperglycemia or hyperinsulinemia increase the risk of developing CAD are far from clear, and it is possible that neither function as primary risk factors. On the other hand, given current uncertainty as to why morbidity and mortality from CAD have not decreased with anti-hypertensive treatment, it is necessary to seriously consider the possibility that the defects in carbohydrate metabolism associated with high blood pressure are to some degree responsible for this disappointing clinical situation. Considering there is no evidence that conventional treatment improves these defects, and the fact that they can be worsened by certain drugs [ 10,131, this hypothesis deserves further evaluation. SUMMARY AND CONCLUSIONS There is considerable evidence that insulin resistance, glucose intolerance, and hyperinsulinemia exist in people with high blood pressure. The challenge at this point is to better define the potential mechanism or clinical importance, if any, of these changes. An argument has been developed that insulin resistance and hyperinsulinemia may be of great importance in the origin of hypertension and its ultimate clinical course. Of interest is the recent observation that persons with normal glucose tolerance, selected on the basis of hyperinsulinemia, had higher blood pressures than did a group of matched persons with normoinsulinemia [52]. The importance of insulin resistance and hyperinsulinemia is based upon a series of observed correlations, none of which may be causally related. However, we are not aware of any data that refute the general formulation put forward here. More importantly, all of the postulated series of events are subject to experimental evaluation. Given the unsatisfactory situation that currently exists in the effort to reduce the risk of CAD from high blood pressure, we believe that the issues raised in this presentation deserve consideration. REFERENCES 1. Stamler J, Rhomberg P, Schoenberg JA, et ai: Multrvariate analysis of the relatronship of seven variables to blood pressure: findings of the Chicago Heart Association detection project in industry, 1967-1972. J Chron DIS 1975; 28: 527-548. 2. Florey C, Du V, Uppal S, Lowry C: Relatronshlp between blood pressure, werght, and

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Krotkiewski M, Mandroukas K, Sjostrom L, Sulkvan L, Wetteraurst H, Biorntorp P: Effects of long-term physical training on body fat, metabolism, and blood pressure rn obesity. Metabolism 1979; 68: 650-658. 15. Sims EAH, Berchtold P: Obesity and hypertension: mechanisms and implications for management. JAMA 1982; 247: 49-52. 16. Rowe JW, Young JB, Minaker KL, Stevens AL, Pallotta J, Landsberg L: Effect of insulin and glucose infusions on sympathetic nervous system actrvity in normal man. Diabetes 1981; 30: 219. 17. Chrrstensen NJ, Gundersen HJG, Hegedus L, et a/: Acute effect of insulrn on plasma noradrenaline and the cardiovascular system. Metabolism 1980; 29: 1138-1145. 18. Landsberg L, Young JB Dret and the sympathetic nervous system: relationshrp to hypertension. Int J Obesrty 1981; 5: 79-91. 19. Wright DW, Hansen RI, Mondon CE, Reaven GM: Sucrose-induced insulin resistance in the rat: modulatron by exercise and dret. Am J Clin Nutr 1983; 38: 879-883. 20. Andres R, Crabbe J: Stimulation by insulin of active sodium transport across toadskrn: influence of aldosterone and vasopressin. Arch Int Physiol Biochim 1966; 74: 538-540. 21. Defronzo RA, Goldberg M, Agus Z: The effects of glucose and insulin on renal electrolfle transport. J Clin invest 1976; 58: 83-90. 22. Defronzo RA, Cooke C, Andres R, Faloona GR, Davrs PJ: The effect of Insulin In renal handling of sodium, potassium, calcium, and phosphate in man. J Clan Invest 1975; 55: 845-855. 23. Baum M: Insulin strmulates volume absorpbon in the rabbit proximal convoluted tubule. J Clin Invest 1987; 79: 1104-1109, 24. Reaven GM, Risser TR, Chen Y-Di, Reaven EP: Characterization of a model of dietary induced hypertriglycerrdemia rn young, non-obese rats. J Lrpid Res 1970: 20: 371-378. 25. Zavaroni I, Sander S, Scott S, Reaven GM: Effect of fructose feedrng on Insulin secretion and Insulin action in the rat. Metabolism 1980; 29: 970-973. 26. Hwang IS, Ho H, Hoffman BB, Reaven GM: Fructose-induced insulin and hypertension in rats. Hypertension 1987; 10: 512-516. 27. Mondon CE, Dolkas CB, Reaven GM: Site of enhanced insulin sensitrvity rn exercise trained rats at rest. Am J Physiol 1980; 239 (Endo Metab 2): E169-El77 28. Reaven GM, Ho H, Hoffman BB: Attenuation of fructose-Induced hypertension rn rats by exercrse training. Hypertension 1988; 12: 129-132. 29. Reaven GM, Ho H, Hoffman BB: Somatostatin inhibition of fructose.induced hypertension. Hypertension 1989; 14: 117-120. 30. Mondon CE, Reaven GM: Evidence of abnormalities of insulin metabolrsm in rats with spontaneous hypertension. Metabolism 1988; 37: 303-305. 31. Reaven GM, Chang H, Hoffman BB, Azhar S: Resistance to rnsulrn-stimulated glucose uptake in adipocytes Isolated from spontaneously hypertensive rats. Diabetes 1989; 38: 1155-1160. 32. Rohlflng JJ, Brunzell JD: The effects of druretics and adrenergrc-blockrng agents on plasma lipids. 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Tobey TA, Greenfield M, Kraemer F, Reaven GM: Relationship between insulin resistance, Insulin secretion, very low density lipoprotein kinetics and plasma tnglycende levels rn normotnglyceridemic man. Metabolism 1981; 30: 165-171.

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39. Sleder J, Chen Y-DI, Gully MD, Reaven GM: Hyperinsuiinemia in fructose-induced hypertriglyceridemia in the rat. Metabolism 1980; 29: 303-305. 40. Zavaroni I, Chen Y-DI, Mondon CE, Reaven GM: Ability of exercise to inhibit carbohydrate-induced hypertnglyceridemia in rats. Metabolism 1981; 30: 476-480. 41. Olefsky JM, Reaven GM, Farquhar JW: Effects of weight reduction on obesity: studies of carbohydrate and lipld metabolism. J Clin Invest 1974; 53: 64-76. 42. Topping DL, Mayes PA: The immediate effects of insulin and fructose on the metabolism of the perfused liver. Biochem J 1972; 1X 295-311. 43. Fuh MM-T, Shieh S-M, Wu D-A, Chen Y-DI, Reaven GM: Abnormalities of carbohydrate and lipid metabolism in patients with hypertension. Arch intern Med 1987; 147: 10351038. 44. Stamler J, Stamler R, Liu K: High blood pressure: role in coronary heart diseases and implications for prevention and control. In: Connor W, Bristow D, eds. Coronary heart disease. Philadelphia: JB Lippincott, 1985; 85-109. 45. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension. Il. Results in patients with diastolic blood pressure averaging 90 through 114 mmHg. JAMA 1970; 213: 1143-1152. 46. Korner PI, Bauer GE, Doyle AE, et a/. Untreated mild hypertension: a report by the

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management commIttee of the Australian therapeutic trial in mild hypettension. Lancet 1982; I: 185-191. 47. MultIpIe Risk Factor Intervention Trial Research Group: Multiple Risk Factor Interven tion Trial: risk factor changes and mortality results. JAMA 1982; 248: 1465-1477. 48. Fuller JH, Shipley MJ, Rose G, Jarrett J, Keen H: Coronary-heart-disease risk and impaired glucose tolerance. Lancet 1980; I: 373-376. 49. Pyorala K: Relationship of glucose tolerance and plasma insulin to the incidence of coronary heart disease: results from two population studies in Finland. Diabetes Care 1979; 2: 131-141. 50. Ducimetiere P, Eschwege E, Papoz L, Richard JL, Claude JR, Rosselln G: Relationship of plasma insulin levels to the incidence of myocardial infarctlon and coronary heart disease mortality in a middle-aged population. Diabetologia 1980; 19: 205-210. 51. Welborn TA, Wearne K: Coronary heart disease Incidence and cardiovascular mortality in Busselton with reference to glucose and insulin concentrations. Diabetes Care 1979; 2: 154-160. 52. Zavaroni I, Bonora E, Pagliara M, ef ai: Risk factors for coronary artery disease in healthy persons with hyperinsulinemia and normal glucose tolerance. N Engl J Med 1989; 320: 702-706.

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