Hypertension in Patients With Diabetes Mellitus Jay S. Skyler, Jennifer B. Marks, and Neil Schneiderman Diabetes mellitus and hypertension each confer increased cardiovascular risk. That risk is much greater when the diseases coexist and is further magnified by their frequent association with dyslipidemia and central obesity. Insulin resistance appears to be an important common component to these four entities, whether or not the relationship is truly cause and effect. Increased renal tubule absorption of sodium and increased sympathetic nervous system stimulation from insulin have been said to be the mechanisms by which elevated levels of insulin cause hypertension. However, animal experiments suggest that these are short-term effects only and that long-term insulin may actually increase peripheral blood flow and reduce blood pressure. Experiments in humans suggest that the insulin resistant state in obese patients
and type II diabetics is associated with a decrease of the usual vasodilatory effect of insulin. Antihypertensive drugs have differing effects on insulin resistance. Angiotensin converting enzyme inhibitors, o~-adrenergic blockers, and dihydropyridines appear to improve insulin sensitivity. Other calcium channel blockers appear to be neutral, as is furosemide. Thiazide diuretics, spironolactone, and ~-adrenergic blockers impair insulin sensitivity. The drugs that increase insulin sensitivity also tend to improve dyslipidemia or remain lipid neutral. In contrast, those drugs that tend to impair insulin sensitivity also tend to worsen dyslipidemia. Am J Hypertens 1995;8;1005-1055
ypertension and diabetes mellitus are two c o m m o n conditions which confer increased risk of cardiovascular disease. Because they are both common, they frequently coexist. When they occur together, there is even greater increased risk of cardiovascular disease and mortality. Yet these two entities, along with dyslipidemia and central obesity, each of which also confers increased risk of cardiovascular disease, may actually be components of a common syndrome which has been called "Syndrome X," the Insulin Resistance Syndrome, the Insulin Metabolic Syndrome, the Metabolic or Pluri-Metabolic Syndrome, the New World
Syndrome, or the Deadly Quartet. 1-9 The concert master of this deadly quartet--hypertension, glucose intolerance (or diabetes), central obesity, and dyslipidemia--is insulin resistance and associated hyperinsulinemia. Insulin resistance and hyperinsulinemia have been commonly associated with each of the components of the deadly quartet. The relationship between insulin resistance as an underlying feature of type II diabetes mellitus is well-establishedJ °'n It has also long been demonstrated that obese people are insulin resistant. 11"12 A variety of studies have shown that insulin resistance is a common feature of hypertension and that there is an inverse correlation between level of systolic or diastolic blood pressure and insulin sensitivity (decreased insulin sensitivity is the same as insulin resistance). 13-15 Dyslipidemia is c o m m o n l y associated with insulin resistance as well. 16-19 Moreover, recent studies have demonstrated that coronary artery disease itself is an insulin-resistant state. 2°
From the Departments of Medicine (JSS, ]BM, NS), Pediatrics (JSS), and Psychology (JSS, NS), University of Miami, Miami, Florida. This study was supported by grant #PO1-HL 36588 from the National Institutes of Health. Address correspondence and reprint requests to Jay S. Skyler, MD, University of Miami (D-110), 1500 NW 12th Avenue, 14th Floor West, Miami, FL 33136.
© 1995 by the American Journal ~t Hypertension1, Ltd.
KEY WORDS: Insulin sensitivity, diabetes mellitus, cardiovascular risk, hypertension, dyslipidemia, Syndrome X.
AIH-DECEMBER 1995-VOL. 8, NO. 12, PART 2
Many of the early studies of this syndrome noted that hyperinsulinemia was a risk factor for coronary artery events. In his description of "Syndrome X" Reaven proposed that hyperinsulinemia itself may be responsible for the lipid abnormalities, elevated blood pressure, and adiposity that are associated with this syndrome. ] He noted that hyperinsulinemia is a compensatory phenomenon in the setting of insulin resistance. The insulin resistance, as usually measured, is resistance to insulin mediated glucose uptake. This is demonstrated by a variety of techniques, including the hyperinsulinemic euglycemic clamp technique, the frequently sampled intravenous glucose tolerance test with minimal modeling, or the insulin suppression test. Each of these techniques demonstrates that there is reduced insulin action in terms of glucose metabolism per se. Reaven and others have contended that the reduction of insulin sensitivity for glucose metabolism may not be accompanied by a corresponding reduction of insulin sensitivity in terms of lipid metabolism, blood pressure regulation, or fat accretion. 1-2 If some tissues retain insulin sensitivity, whereas others are resistant to the action of insulin, then the compensatory hyperinsulinemia which arises as a consequence of resistance to insulin-mediated glucose uptake could very well be responsible for some of the other components of the plurimetabolic syndrome. A scheme by which this might occur is shown in Figure 1. Alternatively, it could be argued that the dyslipidemia and blood pressure elevation might arise directly as a consequence of insulin resistance and not as a consequence of hyperinsulinemia, although the latter may still beget adiposity. This alternative scheme is shown in Figure 2. This then poses a crucial question: which is the culprit--hyperinsulinemia or insulin resistance? The reason this question is important is that it may have profound therapeutic implications. Therefore, it will be discussed in some detail.
I INSULINRESISTANCE HYPERINSULINEMIA
i OSLPOEMAI I HPETENSO"I I OBESTI I GLUCOSEINTOLERANCE]
SKYLER ET AL 101S
I I I
I DYSL'P'OEM'AI I HYPERTENSIONI I OBESITYI I GLUCOSEINTOLERANCEI FIGURE 2. Scheme outlining the evolution of the various components of the insulin metabolic syndrome, with insulin resistance playing the central role. INSULIN RESISTANCE AND DYSLIPIDEMIA
It has long been noted that there is a correlation between hyperinsulinemia and increased hepatic triglyceride synthesis and very low density lipoproteins (VLDL) secretion. 21 A consequence of the combination of increased hepatic triglyceride synthesis and VLDL secretion is a dyslipidemia characterized by increased VLDL resulting in elevated circulating triglycerides and decreased HDL cholesterol. 22 Given the correlation b e t w e e n hyperinsulinemia and these other components, it could be argued that the hyperinsulinemia stimulates hepatic triglyceride synthesis resulting in increased VLDL secretion and dyslipidemia (Figure 3). This would suggest that hyperinsulinemia begets the dyslipidemia. It should be noted that although the stimulation of triglyceride synthesis is an important effect of insulin, there are other crucial effects of insulin on lipid metabolism that might very well work in the opposite direction. 23"24 One of insulin's important biological effects is to inhibit lipolysis and thus prevent the release of free fatty acids
I HYPERINSULINEMIA HEPATICTRIGLYCERIDESYNTHESIS]
[VLDLSECRETIONiI I DYSLIPIDEMIA I
FIGURE 1. Scheme outlining the evolution of the various components of the insulin metabolic syndrome, with hyperinsulinemia playing the central role.
FIGURE 3. Putative effects of hyperinsulinemia in causing increased lipid production, thereby promoting dyslipidemia.
AJH-DECEMBER 1995-VOL. 8, NO. 12, PART 2
HYPERTENSION IN DIABETICS
(FFA) into the circulation. Insulin is also important in activating lipoprotein lipase, which is responsible for triglyceride removal. 25 In isolated hepatocytes insulin actually inhibits, rather than stimulates, VLDL secretion. 23'26 Taking these things into consideration, an alternative scenario to that shown in Figure 3 is depicted in Figure 4. In this situation, insulin resistance would result in less inhibition of lipolysis and therefore an excessive rate of lipolysis leading to increased FFA availability and consequent increased hepatic FFA delivery and uptake. It is the increased substrate availability that would drive hepatic triglyceride synthesis and consequent VLDL secretion. The usual effect of insulin to inhibit VLDL secretion (as demonstrated in isolated hepatocytes) would be less energetic because of insulin resistance, and thus contribute to dyslipidemia. Moreover, the failure of insulin to activate lipoprotein lipase would result in decreased triglyceride removal and this, too, leads to triglyceride accumulation. That this latter sequence is likely to be the case is evidenced by a number of studies that demonstrate marked lowering of hypertriglyceridemia, with concomitant decrease in total cholesterol and increase in HDL cholesterol during intensive insulin therapy of type II diabetes mellitus (Figure 5). 27-29 In this circumstance, the insulin resistance is overcome with increased amounts of insulin. If insulin were the culprit driving hepatic triglyceride synthesis and VLDL secretion to create hypertriglyceridemia, one would expect that during intensive insulin therapy there would be an increase in hypertriglyceridemia. In contrast, the marked decrease in triglyceride levels (Figure 5) is more consistent with the sequence outlined in Figure 4, in which insulin resistance is responsible for hypertriglyceridemia, and insulin, w h e n given in sufficient amounts to o v e r c o m e the i n s u l i n r e s i s t a n c e , corrects the abnormality.
I INSULIN RESISTANCE I I INCREASED LIPOLYSIS
I .E AT,C
LIPID CHANGES DURING INTENSIVEINSULINTHERAPYOF TYPE II DIABETES 7 6 5 4 BBASELINE u3 MONTHS E 3 E36 MONTHS 2 1
0 TRIGLYCERIDES LDL CHOL CHOL HDL CHOL FIGURE 5. Changes in plasma lipid levels during intensive therapy of type II diabetes. (Adapted from data in Henry et al. 27) INSULIN RESISTANCE AND BLOOD PRESSURE
It has been contended that hyperinsulinemia is responsible for blood pressure elevation in subjects with insulin resistance. There are two possible ways that insulin may elevate blood pressure. It has been demonstrated in both dogs and humans that hyperinsulinemia results in increased sodium reabsorption and consequent decreased sodium excretion. 3°-33 It also has been demonstrated that very high levels of insulin, during a euglycemic hyperinsulinemic clamp, increase sympathetic nervous system activity as evidenced by a rise in circulating levels of catecholamines. 34 Thus, the scheme has arisen that hyperinsulinemia, by increasing sodium reabsorption and sympathetic activation, may result in hypertension (Figure 6). Yet, in a remarkable series of experiments, Hall and colleagues have demonstrated that the effects of insulin on increasing sodium reabsorption are transient. 3~-36 When infusing insulin into dogs and maintaining the hyperinsulinemic state for 1 week, Hall et al found that decreased urinary sodium excretion occurred in the first day or two and then equilibrated. 37 This was seen even when the insulin was injected directly into the renal artery. 38 Moreover, Hall and associates noted that the mean arterial pressure actually declined during chronic insulin infu-
I HYPERINSULINEMIA ]
ISODtUMREABSORPTIONI ISYMPATHETICACTIVATIONj I VLDL SECRETION I
I °YsLIP'°EM'A I
FIGURE 4. Mechanism ~ which insulin resistance leads to increased lipid production and dyslipidemia.
FIGURE 6. Putative effects of hyperinsulinemia in the evolution of hypertension.
AJH-DECEMBER 1995-VOL. 8, NO. 12, PART 2
sion, suggesting that insulin causes a lowering of blood pressure rather than elevation of blood pressure. To further study this, these investigators did a series of experiments where the insulin infusion was accompanied by other maneuvers that were designed to try to increase blood pressure in an attempt to unmask an effect of insulin in raising the blood pressure. What they found was that when there was concomitant infusion of either norepinephrine or angiotensin II or when there was a high sodium diet and decreased kidney mass, there was still no effect of insulin in raising blood pressure. If anything, blood pressure depression might be blunted, but certainly no elevation of blood pressure was seen. In addition, when these investigators measured the effects of insulin on cardiac output and total peripheral resistance, they found that insulin caused a decrease in peripheral resistance and compensatory increase in cardiac output to help maintain blood pressure. 39 Thus, these investigators found that insulin had a tendency to lower, and not raise, blood pressure. Anderson, Mark, and their colleagues studied the effects of hyperinsulinemia during the euglycemic clamp in two populations of people, healthy volunteers 4° and individuals with hypertension. 41 They did demonstrate, by direct measurement of sympathetic activity at the muscle level, that there was an effect of insulin in stimulating the sympathetic nervous system. However, this was not accompanied by a blood pressure elevation. Rather, it was accompanied by a decrease in mean arterial pressure although there was a slight increase in heart rate. Forearm blood flow increased and peripheral vascular resistance decreased during their experiments. In a series of experiments in human volunteers, Baron and colleagues have also demonstrated that insulin has profound effects of increasing blood flow and causing a decrease in vascular resistance. 42'43 Moreover, these investigators found that the insulin resistant state of obesity, 44 and more so the more profound insulin resistance of type II diabetes, 4s were associated with shifts to the right of the dose response curve for insulin effects on increasing leg blood flow. Thus, they directly observed that the insulin resistant state was associated with a decrease of the usual vasodilatory effect of insulin. Moreover, the increment in leg blood flow in response to insulin was inversely proportional to the height of the baseline mean arterial pressure. 43 They demonstrated a blunted effect of insulin on lowering vascular resistance and in reducing mean arterial pressure in insulin resistant individuals. 46 Interestingly, the insulin resistance of obesity is associated with augmented pressor sensitivity to norepinephrine and decreased norepinephrine metabolic clearance. 47 Our own studies have also demonstrated that there is an inverse correlation between insulin sensitivity and change in
SKYLER ET AL
total peripheral resistance such that the more insulin resistant individuals also have increased peripheral resistance. 4s All of these observations are consistent with the notion that blood pressure elevation arises as a consequence of resistance to the action of insulin in terms of its usual effect of vasodilatation (Figure 7). Thus, we would argue that it is insulin resistance per se, not hyperinsulinemia, which is responsible for both the dyslipidemia and the blood pressure elevation that characterize the insulin resistance syndrome. This means that insulin therapy itself does not aggravate the lipid or blood pressure disturbances of this syndrome and may effectively be used in patients with type II diabetes to control glycemia. One would expect that sufficient insulin would overcome the insulin resistance and correct the other abnormalities created by that insulin resistance. In the future, therapies which directly correct insulin resistance, such as troglitazone or the vanadium compounds, might very well be used to overcome the insulin resistant state. I M P L I C A T I O N S FOR THE S E L E C T I O N OF ANTIHYPERTENSIVES
The effects of a number of different antihypertensive agents on insulin sensitivity have been directly studled. 49'5° Improvement in insulin sensitivity has been seen with a number of angiotensin converting enzyme inhibitors (captopril, enalapril, a n d ramipril), 51-~s with ~-adrenergic blockers (prazosin, doxazosin), 56'57 and with one of the dihydropyridine class of calcium channel blockers (nifedipine). 58 It is interesting to note that other classes of calcium channel blockers (diltiazem and verapamil) were neutral in terms of effects of insulin sensitivity. 49'5°'s9 A common feature of the angiotensin converting enzyme inhibitors, c~-adrenergic blockers, and dihydropyridine calcium channel blockers is that they all work to create peripheral vasodilatation, which is impaired as a consequence of insulin resistance. In contrast to the beneficial effects on insulin sensitivity of these classes of antihypertensives, an impairment of insulin sensitivity or aggravation of insulin resistance has been
I INSULINRESISTANCEI I LACKOFVASODILATIONI
IHYPERTENSION I FIGURE 7. Mechanism by which insulin resistance leads to hypertension.
seen w i t h thiazide diuretics (eg, h y d r o c h l o r t h i a z ide), 49-51 and spironolactone, 49 but not furosemide, 49 which is neutral in terms of effects of insulin sensitivity. In addition, dramatic reductions of insulin sensitivity and aggravation of insulin resistance have been seen with a n u m b e r of [3-adrenergic blockers (atenolol, metoprolol, propranolol, and pindolol). 49'5°'59"6° One should note that the two classes of a n t i h y p e r t e n s i v e agents that have effects of aggravating insulin resistance, ie, thiazide diuretics and ~-adrenergic blockers, are those classes associated with w o r s e n i n g of dyslipidemia. In contrast, those classes which are either neutral or beneficial in terms of insulin sensitivity are also either neutral (calcium channel blockers, angiotensin converting e n z y m e inhibitors) or beneficial (cx-adrenergic blockers) in terms of dyslipidemia. O n e might predict that the angiotensin receptor blockers will have effects similar to the angiotensin converting e n z y m e inhibitors in terms of insulin sensitivity, but direct studies of this are not yet available. In addition, studies examining the effects of central adrenergic blockers on insulin sensitivity are notable by their absence. Thus, from the s t a n d p o i n t of i m p r o v i n g insulin sensitivity, o n e m i g h t favor use of c~-adrenergic blockers, angiotensin converting e n z y m e inhibitors, or d i h y d r o p y r i d i n e calcium channel blockers. Therefore, these w o u l d be the agents of choice in the mana g e m e n t of h y p e r t e n s i o n in diabetic patients w h o clearly have insulin resistance. To the extent that insulin resistance u n d e r l i e s h y p e r t e n s i o n itself, and contributes to associated abnormalities (eg, dyslipidemia) that aggravate the risk of coronary artery disease, it might also be reasonable to argue that these classes of agents should be the preferred treatment of essential h y p e r t e n s i o n in general. REFERENCES 1. Reaven GM: Role of insulin resistance in human disease: Banting Lecture. Diabetes 1988;37:1595-1607 2. DeFronzo RA, Ferrannini E: A multifaceted svndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991;14:173-194 3. Julius S: Sympathetic hyperactivity and coronary risk in hypertension: Corcoran Lecture. Hypertension 1993;21:886-893 4. Modan M, Halkin H, Almog S, et al: Hyperinsulinemia: a link between hypertension, obesity and glucose intolerance. J Clin Invest 1985;75:809-817 5. Ferrannini E, Haffner SM, Mitchell DB, Stern MP: Hyperinsulinaemia: the key feature of a cardiovascular and metabolic syndrome. Diabetologia 1991;34:416-422 6. Landsberg L: Hyperinsulinemia: possible role in obesity-induced hypertension. Hypertension 1992;19 (suppl):I-61-I-55 7. Zimmet P: Hyperinsulinemia--how innocent a bystander? Diabetes Care 1993;16(suppl 3):56-77.
AJH-DECEMBER 1995-VOL. 8, NO. 12, PART 2
Zimmet P: Kelly West Lecture 1991. Challenges in diabetes epidemiology--from West to the rest. Diabetes Care 1992;15:232-252. Kaplan NM: The deadly quartet: upper-body obesity, glucose intolerance, hypertriglyceridemia and hypertension. Arch Intern Med 1989;149:1514-1520. Bonadonna R, Groop L, Kraemer N, DeFronzo RA: Obesity and insulin resistance in man: a dose response study. Metabolism 1990;39:452-459. Olefsky JM, Kolterman OG, Scarlett JA: Insulin action and resistance in obesity and noninsulin-dependent type II diabetes mellitus. Am J Physiol 1982;243:E15E30. DeFronzo RA: Lilly lecture 1987: The triumvirate: f~-cell, muscle, liver: a collusion responsible for NIDDM. Diabetes 1988;37:667-687. Fournier AM, Gadia MT, Kubrusly DB, et ah Blood pressure, insulin, and glycemia in nondiabetic subjects. Am J Med 1986;80:861-864. Ferrannini E, Buzzigoli G, Bonadonna R, et al: Insulin resistance in essential hypertension. N Eng J Med 1987;317:350-357. Pollare T, Lithell H, Berne C: Insulin resistance is a characteristic feature of primary hypertension independent of obesity. Metabolism 1990;39:169-174. Orchard TJ, Becker DJ, Bates M: Plasma insulin and lipoprotein cholesterol concentrations: an atherogenic association? Am J Epidemiol 1983;118:326-327. Zavaroni I, Dall'Aglio E, Alpi O, et al: Evidence for an independent relationship between plasma insulin and concentration of high density lipoprotein cholesterol and triglyceride. Atherosclerosis 1985;55:259-266. Abbott WGH, Lillioja S, Young AA: Relationships between plasma lipoprotein concentrations and insulin action in an obese hyperinsulinemic population. Diabetes 1987;36:897-904. Garg A, Helderman JH, Koffler M: Relationship between lipoprotein levels and in vivo insulin action in normal young white men. Metabolism 1988;37:982-987. Bressler P, Bailey S, Saad R, DeFronzo RA: Insulin resistance and coronary artery disease: the missing link (abst). Diabetes 1992;41(suppl 1):24A. Olefsky J, Reaven GM, Farquhar JW: Effects of weight reduction on obesity. Studies of lipid and carbohydrate metabolism in normal and hyperlipoproteinemic subjects. J Clin Invest 1974;53:64-76. Howard BV: Lipoprotein metabolism in diabetes mellitus. J Lipid Res 1987;28:613-628. Brindley DN, McCann BS, Niaura R, et ah Stress and lipoprotein metabolism: modulators and mechanism. Metabolism 1993;42(suppl):3-15. Howard BV, Schneiderman N, Falkner B, et al: Insulin, health behaviors, and lipid metabolism. Metabolism 1993;42(suppl) :25-35. Taskinen MR: Lipoprotein lipase in diabetes. Diabetes Metab Rev 1987;3:551-570. Sparks CE, Sparks JD, Bolognino M: Insulin effects on apolipoprotein B lipoprotein synthesis and secretion by primary cultures of rat hepatocytes. Metabolism 1986;35:1128-1136. Henry RR, Gumbiner B, Ditz|er T, et ah Intensive con-
SKYLER ET AL 105S
AJH-DECEMBER 1995-VOL. 8, NO. 12, PART 2
ventional insulin therapy for type II diabetes, metabolic effects during a six month out-patient trial. Diabetes Care 1993;16:21-31. Taskinen MR, Kuusi T, Helve E, et al: Insulin therapy induces antiatherogenic changes of serum lipoproteins in non-insulin dependent diabetes. Arteriosclerosis 1988;8:168-177.
Lindstrom T, Olsson AG, Von Schneck H, et ah Insulin treatment improves microalbuminuria and other cardiovascular risk factors in patients with type 2 diabetes mellitus. J Intern Med 1994;235:253-261.
DeFronzo RA, Cooke CR, Andres R, et al: The effect of insulin on renal handling of sodium, potassium, calcium and phosphate in man. J Clin Invest 1975;55:845855. DeFronzo RA: The effect of insulin on renal sodium metabolism. Diabetologia 1981;21:165--171. Skott P, Hother-Nielsen O, Bruun NE, et al: Effects of insulin on kidney function and sodium excretion in healthy subjects. Diabetologia 1989;32:694-699. Endre T, Mattiasson I, Berglund G, Hulthen UL: Insulin and renal sodium retention in hypertensionprone men. Hypertension 1994;23:313-319.
Rowe JW, Young JB, Minaker KL, et al: Effect of insulin and glucose infusions on sympathetic nervous system activity in normal man. Diabetes 1981;30:219225.
Hall JE, Brands MW, Hildebrandt DA, Mizelle HL: Obesity-associated hypertension: hyperinsulinemia and renal mechanisms. Hypertension 1992;19(suppl I):I-45-I-55.
Hall JE: Renal and cardiovascular mechanisms of hypertension in obesity. Hypertension 1994;23:381-394.
Laakso M, Edelman SV, Brechtel G, Baron AD: Effects of epinephrine on insulin-mediated glucose uptake in whole body and leg muscle in humans: role of blood flow. Am J Physiol 1992;263:E199-E204.
Baron AD, Brechtel G, Johnson A, et al: Interactions between insulin and norepinephrine on blood pressure and insulin sensitivity. Studies in lean and obese men. J Clin Invest 1994;93:2453-2462.
Marks JB, Hurwitz BE, Ansley J, et al: Effects of induced hyperinsulinemia on blood pressure & sympathetic tone in healthy volunteers (abst). Diabetes 1991;40(suppl 1):367A. Lithell HO: Effect of antihypertensive drugs on insulin, glucose, and lipid metabolism. Diabetes Care 1991;14:203-209. Lithell HO, Pollare T, Berne C: Insulin sensitivity in newly detected hypertensive patients: influence of captopril and other antihypertensive agents on insulin sensitivity and related biological parameters. J Cardiovas Pharm 1990;15(suppl 5):$46-$52.
Pollare T, Lithell H, Berne C: A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension. N Engl J Med 1989;321:868-873. Torlone E, Rambotti AM, Perriello G, et al: ACEinhibition increases hepatic and extrahepatic sensitivity to insulin in patients with type 2 (non-insulindependent) diabetes mellitus and arterial hypertension. Diabetologia 1991;34:119-125.
Hall JE, Coleman TG, Mizelle HL: Does chronic hyperinsulinemia cause hypertension? Am J Hypertens 1989;2:171-173.
Totterman K, Groop L, Groop P-H, et al: Effect of beta-blocking drugs on beta-cell function and insulin sensitivity in hypertensive non-diabetic patients. Eur J Clin Pharmacol 1984;26:13-17.
Hall JE, Brands MW, Mizelle HL, et ah Chronic intrarenal hyperinsulinemia does not cause hypertension. Am J Physiol 1991;260:F663-F669.
Dietze G, Rett K, Jauch K, et ah Captopril in hypertensive patients with non-insulin dependent diabetes mellitus (NIDDM). Hertz 1987;12:16-21.
Jauch KW, Hartl W, Guenther B, et al: Captopril enhances insulin responsiveness of forearm muscle tissue in non-insulin-dependent diabetes mellitus. Eur J Clin Invest 1987;17:448-454.
Pollare T, Lithell H, Selinus I, Berne C: Application of prazosin is associated with an increase of insulin sensitivity in obese patients with hypertension. Diabetologia 1988;31:415-420.
Lehtonen A: Doxazosin effects on insulin and glucose in hypertensive patients. The Finnish Multicenter Study Group. Am Heart J 1991;121:1307-1311. Sheu WHH, Swislocki ALM, Hoffman B, et al: Comparison of the effects of atenolol and nifedipiine on glucose, insulin, and lipid metabolism in patients with hypertension. Am J Hypertens 1991;4:199-205. Pollare T, Lithell H, Morlin C, et ah Metabolic effects of diltiazem and atenolol: results from a randomized, double blind study with parallel groups. J Hypertens 1989;7:551-559. Pollare T, Lithell H, Selinus I Berne C: Sensitivity to insulin during treatment with atenolol and metoprolo1: a randomized, double blind study of effects on carbohydrate and lipoprotein metabolism in hypertensive patients. Br Med J 1989;298:1152-1157.
Hall JE, Brands MW, Dixon WN, Smith MJ, Jr.: Obesity-induced hypertension--renal function and systemic hemodynamics. Hypertension 1993;22:292-299. Anderson EA, Hoffman RP, Balon TW, et ah Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. J Clin Invest 1991;87:2246-2252. Anderson EA, Balon TW, Hoffman RP, Sinkey MA: Insulin increases sympathetic activity but not blood pressure in borderline hypertensive humans. Hypertension 1992;19:621-627. Baron AD: Cardiovascular actions of insulin. Balli6re's Clin Endocrinol Metab 1993;7:961-987.
Baron AD, Brechtel-Hook G, Johnson A, Hardin D: Skeletal muscle blood flow. A possible link between insulin resistance and blood pressure. Hypertension 1993;21:129-35 Laakso M, Edelman SV, Brechtel G, Baron AD: Decreased effect of insulin to stimulate skeletal muscle blood flow in obese men. J Clin Invest 1990;85:1844-1852. Laakso M, Edelman SV, Brechtel G, Baron AD: Im-
paired insulin-mediated skeletal muscle blood flow in patients with NIDDM. Diabetes 1992;41:1076-1083.