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Effect of Dietary Sodium on Insulin Sensitivity in Older, Obese, Sedentary Hypertensives
AJH
1997;10:964 –970
Effect of Dietary Sodium on Insulin Sensitivity in Older, Obese, Sedentary Hypertensives Donald R. Dengel, Ronaldo S. Mayuga, Gretchen M. Kairis, Andrew P. Goldberg, and Matthew R. Weir
Increased dietary sodium intake has been associated with an increase in blood pressure as well as a decrease in insulin-mediated glucose disposal in young healthy adults. The purpose of this study was to determine whether dietary sodium intake is associated with changes in oral glucose tolerance, insulin sensitivity, and blood pressure in older, sedentary, overweight hypertensives. Eight older (70.0 6 1.4 years, mean 6 SEM), overweight (40.2 6 3.1% body fat), mildly hypertensive (151 6 8/82 6 2 mm Hg) patients with a fasting plasma glucose < 7.8 mmol/ L were studied after 2 weeks on low (3 g/day) and 2 weeks on high (10 g/day) sodium diets. To examine carbohydrate metabolism we performed a 2 h oral glucose tolerance test and a two-dose (240 and 600 pmol/m 2/min) hyperinsulinemiceuglycemic clamp at the end of each sodium diet. High sodium intake was associated with a significantly greater urinary sodium excretion (364 6 45 mmol/day v 112 6 21 mmol/day; P < .0001). The increase in dietary sodium from low to
high did not result in significant differences in fasting plasma glucose (6.0 6 0.2 v 5.8 6 0.1 mmol/ L, P 5 .20) or insulin (72.5 6 7.8 v 69.9 6 12.4 pmol/L, P 5 0.71) levels or in the glucose (374.0 6 50.8 v 493.2 6 45.0 mmol/min/L, P 5 .12) and insulin (43,783 6 10,278 v 44,110 6 12,392 pmol/ min/L, P 5 .96) areas determined during the oral glucose tolerance test. Similarly, there was no effect of dietary sodium on insulin-mediated glucose disposal at low (5.87 6 1.02 v 5.60 6 0.94 mg/kg LBM/min, P 5 .36) or high (12.15 6 1.49 v 11.91 6 1.49 mg/kg LBM/min, P 5 .64) insulin infusion rates. Our findings suggest that, in insulin resistant hypertensives, increased dietary sodium does not affect either glucose or insulin responses during an oral glucose tolerance test or glucose disposal during a hyperinsulinemic euglycemic clamp. Am J Hypertens 1997;10:964 –970 © 1997 American Journal of Hypertension, Ltd.
Received October 21, 1996; accepted February 25, 1997. From the Department of Medicine, Division of Gerontology (DRD, APG), and Division of Nephrology (MRW), University of Maryland School of Medicine; and Geriatric Service and Geriatric Research, Education, and Clinical Center, Baltimore Veterans Administration Medical Center (DRD, APG), Baltimore, Maryland. Supported by American Heart Association grant-in-aid, Maryland affiliate (MRW), a grant from the Fraternal Order of Eagles,
Maryland (MRW), National Institutes of Health Research Scientist Development Award in Aging KO1 AG0072301 (DRD), and the Department of Veterans Affairs Geriatric Research, Education and Clinical Center at Baltimore, University of Maryland, Claude D. Pepper Older Americans Independence Center (P60AG12583) and K07Ag00608 (APG). Address correspondence and reprint requests to Donald R. Dengel, PhD, Ann Arbor VA Medical Center, GRECC (11G), 2215 Fuller Road, Ann Arbor, MI 48105; e-mail:[email protected].
© 1997 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
KEY WORDS:
Insulin resistance, dietary sodium, glucose clamp.
0895-7061/97/$17.00 PII S0895-7061(97)00159-3
AJH–SEPTEMBER 1997–VOL. 10, NO. 9, PART 1
R
ecent studies suggest that there may be a relationship between sodium sensitivity, blood pressure, and insulin resistance.1– 8 Moreover, insulin resistance and glucose intolerance frequently coexist in obese hypertensive individuals.9,10 These observations suggest that high dietary sodium may worsen insulin resistance and glucose homeostasis in hypertensive individuals. A prior study by Donovan et al1 demonstrated that increasing dietary sodium intake worsened insulin sensitivity in young, healthy, normotensive, nondiabetic white men. These subjects were studied after 5 days on a high (200 mmol/day) sodium diet and after 5 days on a low (10 mmol/day) sodium diet. They showed that insulin mediated glucose disposal during a hyperinsulinemic-euglycemic clamp was significantly reduced on the high versus the low sodium diet. They concluded that increasing dietary sodium intake may worsen insulin resistance in young, healthy normotensives, and that these observations may be more important in more insulin resistant individuals. A hyperinsulinemic response to oral glucose loading was observed in sodium sensitive normotensive subjects, but not in sodium resistant normotensive subjects in another clinical study.5 In contrast, in another study, impaired glucose tolerance was associated with a low sodium diet (34 mmol/day) rather than a high sodium (340 mmol/day) diet in hypertensive subjects.11 The problem with the latter study is that the oral glucose tolerance test is not a sensitive means of assessing tissue sensitivity to the effects of insulin. Moreover, both of these studies were conducted with specialized diets with at least a 10-fold variation for dietary sodium intake. However, these results suggest there is a difference in tissue sensitivity to insulin between normotensive and hypertensive subjects, depending on sodium intake. Such studies have not been conducted in older, overweight, sedentary hypertensives, who are more insulin resistant and might be at greater risk for dietary sodium exacerbated changes in glucose homeostasis. This study was designed to determine the influence of a threefold increase in dietary sodium intake on glucose and insulin responses to an oral glucose challenge and on insulin-mediated glucose disposal in older, overweight, deconditioned, hypertensive subjects. This range of dietary sodium consumption was chosen because it reflects a range of sodium intake that would be observed in clinical practice. METHODS Subjects Three male and 5 female overweight, sedentary, older subjects with mild hypertension were recruited for study. Prior to being enrolled in the study the subjects needed to give voluntary informed, written consent as approved by the Human Volun-
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teers Research Committee of the University of Maryland School of Medicine. Individuals were eligible for the study if their sitting diastolic blood pressure on an ad libitum sodium diet was $ 85 mm Hg and # 105 mm Hg after being off all antihypertensive medication for 4 weeks. Individuals were excluded from the study if they had clinically significant concomitant medical illness such as cardiac, renal (serum creatinine greater than 135 mmol/L), hepatic, or gastrointestinal disease, or required concomitant medications. Also excluded were individuals with a recent history of smoking or drug or alcohol abuse, or clinically relevant mental disorders, and concomitant use of medications that might affect glucose metabolism, blood pressure, or renal function. Procedures Individuals were screened prior to participation with a medical history, physical exam, a fasting plasma glucose, and routine blood chemistries. Individuals were excluded from participation if they exceeded 140% (body mass index . 35 kg/m2) of ideal body weight or had a fasting plasma glucose . 7.8 mmol/L or the presence of underlying illness based on screening medical history and examination of baseline laboratory biochemical analyses. Prior to metabolic studies, measurements of maximal oxygen consumption (VO2max) and body composition (percent body fat, lean body mass) were performed in the subjects who met the criteria for study entry. Prior to the study, all subjects were taught the principles of an American Heart Association (AHA) step I diet12 over an 8 week period prior to metabolic testing. This diet consisted of 50% to 55% of calories as carbohydrate; 30% to 35% as fat; 15% to 20% as protein; 300 to 350 mg/day of cholesterol; and 3 g/day of sodium. Patients were weight stable on this diet for 4 weeks prior to research testing. Registered dietitians monitored adherence by reviewing weekly food records and body weight, and calculating dietary composition from biweekly 7 day food records (Nutritionist III, N-Squared Computing, Salem, OR). Study Design After completion of the weight stable, 8 week AHA step I diet, the subjects were placed on a constant isocaloric 3 g sodium diet. At the end of the 2 week sodium diet, subjects received a 2 h oral glucose tolerance test (OGTT) followed 24 h later by a two dose hyperinsulinemic-euglycemic clamp (240 and 600 pmol/m2/min insulin infusion rates). Compliance with the diet was monitored by urine samples (24 h) for sodium. After completion of the metabolic tests the subjects consumed their own diet for a 1 week period. The subjects were then switched to a 10 g sodium diet having the same caloric constituents as the 3 g sodium diet for a period of 2 weeks, prior to being retested again with an OGTT and a two-dose hyperinsulinemic-euglycemic clamp.
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Measurement of Body Composition Body weight was measured prior to all testing to the nearest 0.1 kg using a medical beam balance (Detecto, Webb City, MO) and height was measured to the nearest 0.5 cm. Body mass index was calculated by weight (in kilograms) by height (in meters) squared. Body fat, lean body mass (LBM), and percent body fat were determined by dual energy x-ray absorptiometry (DXA, Model DPX-L Lunar Radiation Corporation, Madison, WI). Measurement of Maximal Oxygen Consumption (VO2max) A treadmill VO2 max test was performed in each subject on at least 2 separate days, as previously described.13 A true VO2 max was considered to be attained if two of the following three criteria were met: 1) respiratory exchange ratio at maximal exercise . 1.10; 2) maximal heart rate . 90% of age predicted maximum (220 2 age); and 3) a plateau in VO2 (, 200 mL/min change in VO2 during the last stages of exercise. If a true VO2 max was not attained on the second test or the VO2 max results for the two exercise tests differed by . 200 mL/min, additional VO2 max tests were performed until these criteria were met. Hyperinsulinemic-Euglycemic Clamp Protocol Insulin sensitivity and maximal responsiveness were measured using a modification of the hyperinsulinemic-euglycemic glucose clamp technique of DeFronzo et al.14 Briefly, an intravenous catheter was inserted into an antecubital vein for infusion of insulin, glucose, and potassium and a second catheter was inserted into a dorsal hand vein for blood sampling. The hand was then placed in a warming box thermostatically controlled at 70°C to arterialize the blood and allowed to equilibrate for 30 min before baseline samples for glucose and insulin were obtained. Insulin (Humulin-R, Eli Lilly Inc., Indianapolis, IN) was administered at two sequential primed infusions at rates of 240 pmol/m2 min for 120 min (low dose), and 600 pmol/m2/min for 120 min (high dose). During the clamp, plasma glucose levels were measured at 5 min intervals using the glucose oxidase method (Beckman Instruments, Fullerton, CA) and maintained at basal levels with a variable infusion of 20% glucose, which was adjusted according to a computerized algorithm. Samples were obtained at 10 min intervals during the clamp for subsequent measurement of plasma insulin levels by radioimmunoassay.15 Mean glucose infusion rates were normalized for LBM and averaged over the last 30 min of each insulin dose. Steady state plasma insulin levels were calculated over the same interval. Oral Glucose Tolerance Test Subjects were weight stable and eating a diet containing . 250 g carbohydrate for 3 days prior to all metabolic testing. After a 12 h overnight fast, patients had an intravenous cath-
AJH–SEPTEMBER 1997–VOL. 10, NO. 9, PART 1
eter placed in an antecubital vein. Two fasting samples were drawn at baseline prior to ingesting of 75 g of glucose. Blood samples were drawn at 30 min intervals for 2 h. Plasma glucose was measured by a glucose oxidase method (Beckman Instruments, Fullerton, CA) and plasma insulin by radioimmunoassay.15 The areas under the curves for glucose and insulin responses during the 2 h OGTT were calculated above the fasting basal level using a trapezoidal model. Statistical Analysis Data were analyzed using a standard statistical software package (Statview, Abacus Concepts, Inc., Berkeley, CA). An alpha level of 0.05 was accepted for statistical significance. Differences in variables resulting from the sodium diet were examined for significance using Student’s paired t tests. All data are reported as the mean 6 standard error of the mean (SEM). RESULTS Physical Characteristics of Subjects Eight subjects (three men, five women; four black, four white) with essential hypertension and normal renal function as determined by serum creatinine concentration (99 6 9 mmol/L) were studied. The subjects had a mean age of 70 6 1.4 years and were sedentary (maximal oxygen consumption: 19.2 6 1.4 mL/kg/min). Body weight of these subjects ranged from 63 to 105 kg with an average BMI of 30.2 6 1.1 kg/m2 and percent body fat of 40.2% 6 3.1%. The change in dietary sodium intake from low to high resulted in a significant increase in urinary sodium levels (252.4 6 38.3 mmol/day, P 5 .0003) (Table 1).
TABLE 1. PHYSICAL AND BIOCHEMICAL RESPONSES TO SODIUM INTAKE Diet Variable Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Mean arterial blood pressure (mm Hg) Weight (kg) Urine sodium (mmol/day) Fasting plasma glucose (mmol/L) Fasting plasma insulin (pmol/L) Values are means 6 SEM. * P , .05 v low sodium. † P , 0.01 v low sodium.
Low Sodium
High Sodium
158 6 8
165 6 6
83 6 2
87 6 3
108 6 4 113 6 3 83.9 6 5.5 84.0 6 5.4 111.6 6 21.0 363.9 6 45.2† 6.0 6 0.2
5.8 6 0.1
72.5 6 7.8
69.9 6 12.4
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However, the increase in dietary sodium intake did not result in a significant change in systolic (7 6 4 mm Hg, P 5 .13), diastolic (4 6 2 mm Hg, P 5 .15), or mean arterial (5 6 3 mm Hg, P 5 .09) blood pressures (Table 1). Hyperinsulinemic-Euglycemic Clamp (Figure 1) There were no differences in the mean plasma insulin levels during the hyperinsulinemic-euglycemic clamp on the low or high sodium diets at either the low (424 6 57 v 393 6 53 pmol/L, P 5 .40) or high (1176 6 109 v 1149 6 80 pmol/L, P 5 .77) insulin infusion rates. The change in dietary sodium intake did not alter insulin-mediated glucose disposal at the low (5.87 6 1.02 v 5.60 6 0.94 mg/kgLBM/min, P 5 .36) or high (12.15 6 1.49 v 11.91 6 1.49 mg/kgLBM/min, P 5 .64) insulin infusion rates. Oral Glucose Tolerance Test (Figure 2) The oral glucose tolerance test performed on the AHA Step I diet showed that four subjects had normal OGTT, one was impaired, and three were diabetic.16 Changes in dietary sodium from low to high did not result in significant changes in fasting plasma glucoses (6.0 6 0.2 v 5.8 6 0.1 mmol/L, P 5 .20) or glucose responses to the oral glucose challenge. As a result there was no significant difference in the glucose area (374.0 6 50.8 v 493.2 6 45.0 mmol/min/L, P 5 .12) due to a change in dietary sodium. The glucose tolerance of three subjects was affected by the increase in dietary sodium. One normal subject became impaired, one impaired subject became normal, and one impaired subject became diabetic. The change from low to high sodium intake did not change the fasting insulin (72.5 6 7.8 v 69.9 6 12.4 pmol/L, P 5 .71) levels or insulin responses to an oral glucose challenge. The insulin area on the low and high sodium diets was also not significantly different (43,783 6 10,278 v 44,110 6 12,392 pmol/min/L, P 5 .96). DISCUSSION The results of our study demonstrate that greater dietary sodium intake, in the physiologic range for ad libitum sodium consumption, does not worsen oral glucose tolerance or insulin sensitivity, as determined with oral glucose tolerance tests and hyperinsulinemic-euglycemic clamp techniques, in older insulin resistant hypertensives. Although Sharma et al6 reported similar findings, it should be noted that these observations were made in young, lean, normotensive individuals, who underwent a 10-fold increase in dietary sodium. In addition, Sharma et al6 used the insulin suppression test17,18 to determine insulin sensitivity. Although this methodology has been correlated to the hyperinsulinemic-euglycemic clamp technique, it does have limitations in that hyperglycemia
FIGURE 1. Insulin-mediated glucose disposal rate at low (240 pmol/m2/min: Panel A) and high (600 pmol/m2/min: Panel B) insulin infusion rates on low (3 g/day) and high (10 g/day) sodium diets. Open circles, mean 1 SEM insulin-mediated glucose disposal rate.
and hypoglycemia, which are often observed with this technique, can result in either an over- or an underestimation of insulin sensitivity.19 In contrast to Sharma et al,6 we studied an older, hypertensive population, with a threefold increase in dietary sodium, which is more in the physiologic range for sodium consump-
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FIGURE 2. Plasma glucose (Panel A) and insulin (Panel B) responses to an oral 75 g of glucose challenge on low (3 g/day; open circles) and high (10 g/day; closed circles) sodium intake.
tion.20 In addition, we utilized the hyperinsulinemiceuglycemic clamp technique to measure insulin sensitivity instead of the insulin suppression test. Using the same hyperinsulinemic-euglycemic clamp technique to measure insulin sensitivity as the present study, Donovan et al1 demonstrated that a 10-fold increase in dietary sodium in young healthy normotensive resulted in a 16% decrease in insulin sensitivity. Using the same insulin infusion level (240 pmol/m2/min) as Donovan et al1 and a higher insulin infusion level (600 pmol/m2/min) we did not observe
AJH–SEPTEMBER 1997–VOL. 10, NO. 9, PART 1
any difference in insulin due to the change in dietary sodium intake at either insulin infusion level. Differences between our results and those of Donovan et al1 may be due to differences in subject populations. Our subjects were older, sedentary, overweight, and hypertensive, whereas their population was younger, healthier, and normotensive. These differences in age and body composition are evident by the large differences in insulin-mediated glucose disposal rates reported by Donovan et al1 from those observed in the present study. Utilizing an insulin infusion rate of 240 pmol/m2/min during the hyperinsulinemic-euglycemic clamp, Donovan et al1 reported an insulin mediated glucose disposal rate of 279 6 19 v 334 6 24 mg/m2/min for his subjects on low and high sodium intakes. If we express our insulin-mediated glucose disposal rate in mg/m2/min during the 240 pmol/ m2/min insulin infusion rate our older, overweight hypertensives had a mean insulin-mediated glucose disposal rate (147 6 21 v 140 6 18 mg/m2/min: low v high sodium intake), half of that reported by Donovan et al.1 Only at the high insulin infusion rate of 600 pmol/m2/min used in the present study does the mean insulin mediated glucose disposal rate (309 6 32 v 301 6 28 mg/m2/min: low v high sodium intake) of our subjects approach of that reported by Donovan et al.1 This twofold difference in insulin mediated glucose disposal rates might explain the differences in results between those reported by Donovan et al1 and those of the present study. Another possible explanation as to the differences between these two studies may be due to the sodium content and length of the diets utilized in these two studies. Our subjects consumed dietary sodium in a range consistent with an ad libitum sodium diet, whereas the Donovan group examined a dietary sodium range that is not what is customarily achieved on an outpatient basis. Had Donovan et al1 studied young, healthy normotensives in the dietary sodium range that we examined, their results may have been different. Differences in the length of time that the subjects consumed the sodium diet also exist between our study and that of Donovan et al,1 and may also contribute to the differences in the results. In the present study, the subjects consumed each diet over a 12 to 14 day period, whereas in the study by Donovan et al1 the subjects consumed the sodium diets for a 5 day period. Recently, Fliser et al21 examined the effect of a high (200 mmol/day) and low (20 mmol/day) sodium diet consumed over 3 days versus 7 days on insulin-mediated glucose disposal in young healthy normotensive subjects. The authors observed that there was a significant increase in insulin-mediated glucose disposal on the high compared with low sodium diet after 3 days. However, in another group that underwent the same sodium diets for a 7 day
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period, there was no difference in insulin-mediated glucose disposal rates between the two sodium diets. The results of Fliser et al21 suggest that the worsening of tissue sensitivity to insulin by dietary sodium is an acute event, and that studies examining the effect of dietary sodium on glucose metabolism need to be carried out over a longer period of time. Previous studies5,8,11,22 examining the effect of dietary sodium on glucose and insulin responses to an oral glucose challenge have produced varied results. Iwaoka et al11 reported that high sodium intake (340 mmol/day) for 8 days resulted in significantly lower glucose and insulin response to an oral glucose challenge than low sodium intake (34 mmol/day). However, Egan et al22 reported that 7 days of high (200 mmol/day) and low (20 mmol/day) sodium diets had no significant effect on either glucose or insulin responses to an oral glucose load. The results of our study are in agreement with those of Egan et al,22 as threefold increase in dietary sodium did not change the glucose or insulin responses to an oral glucose challenge. The difference between the results of our present study and those of Iwaoka et al11 may be related to the age and physical characteristics of the subjects studied and to the 10-fold variation in dietary sodium intake. Unfortunately, Iwaoka et al11 did not report these details in their article, so a comparison between subject populations is not possible. Sodium sensitivity could be a confounding variable and might explain some of the differences in the effects of dietary sodium on glucose tolerance. Sharma et al5 studied 25 healthy, young (age range, 23 to 29 years) normotensive men. Subjects received both a high (260 mmol/day) and low (20 mmol/day) sodium diet. Using a criteria of a 3 mm Hg drop in mean arterial blood pressure on the low sodium diet, 10 of the subjects were classified as sodium sensitive. The authors reported a significant increase in glucose and insulin responses to an oral glucose challenge in sodium sensitive, normotensive individuals on a high sodium diet. However, the sodium resistant individuals had a decrease in insulin responses to the high sodium diet. If we apply the blood pressure sodium sensitivity criteria of Sharma et al5 to our subjects, six were sodium sensitive and two were sodium resistant. We observed no consistent effect of dietary sodium on insulin-mediated glucose disposal or in glucose and insulin responses to an oral glucose challenge, at either the low or high insulin infusion rates in our six sodium sensitive subjects. The results of this study combined with previous studies suggest that there are differences in the effects of dietary sodium on glucose metabolism between young normotensives and older hypertensives. This difference may be due to the fact that hypertensive individuals in our study were older, more insulin
resistant, and more obese than were the normotensive subjects evaluated in other studies. In conclusion, although our results are limited by a relatively small number of subjects, increased dietary sodium intake did not affect glucose homeostasis in this group of older hypertensives. It is possible that the sodium sensitivity status of an individual may result in differences in the effects of dietary sodium intake on glucose metabolism. ACKNOWLEDGMENTS We thank all the subjects who volunteered; the nursing staffs at the Geriatrics Service at the Baltimore VA Medical Center and at the Division of Nephrology, University of Maryland Hospital for assistance with the research studies, and the dietitians for their nutrition instruction and dietary evaluations.
REFERENCES 1.
Donovan DS, Soloman CG, Seely EW, et al: Effect of sodium intake on insulin sensitivity. Am J Physiol 1993; E730 –E734.
2.
Egan BM, Stepniakowski K, Nazzaro P: Insulin levels are similar in obese salt-sensitive and salt-resistant hypertensive subjects. Hypertension 1994;23(suppl I):I1– I7.
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Meland E, Laerum E, Aakvaag A, et al: Salt restriction and increased insulin production in hypertensive patients. Scand J Clin Lab Invest 1994;54:405– 409.
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Ruppert M, Diehl J, Kolloch R, et al: Short-term dietary sodium restriction increases serum lipids and insulin in salt-sensitive and salt-resistant normotensive adults. Klin Wochenschr 1991;69(suppl 25):51–57.
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Sharma AM, Ruland K, Spies KP, et al: Salt sensitivity in young normotensive subjects is associated with a hyperinsulinemic response to oral glucose. J Hypertens 1991;9:329 –335.
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Sharma AM, Schorr U, Distler A: Insulin resistance in young salt-sensitive normotensive subjects. Hypertension 1993;21:273–279.
7.
Thorburn AW, Brand JC, Truswell AS: Salt and the glycaemic response. Br Med J 1986;292:1697–1699.
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Zavaroni I, Coruzzi P, Bonini L, et al: Association between salt sensitivity and insulin concentrations in patients with hypertension. Am J Hypertens 1995;8:855– 858.
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DeFronzo RA, Ferrannini E: Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991;14:173–194.
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Reaven GM: Relationship between insulin resistance and hypertension. Diabetes Care 1991;14(suppl 4):33– 38.
11.
Iwaoka T, Umeda T, Ohno M, et al: The effect of low and high NaCl diets on oral glucose tolerance. Klin Wochenschr 1988;66:724 –728.
12.
American Heart Association Steering Committee: Dietary guidelines for healthy American adults: a statement for physicians and health professionals by the
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Nutrition Committee of the American Heart Association. Circulation 1988;77:721A–724A.
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Greenfield MS, Doberne L, Kraemer F, et al: Assessment of insulin resistance with the insulin suppression test and the euglycemic clamp. Diabetes 1981;30:387– 392.
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Dengel DR, Pratley RE, Hagberg JM, et al: Impaired insulin sensitivity and maximal responsiveness in older hypertensive men. Hypertension 1994;23:320 –324.
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DeFronzo RA, Tobin JD, Andres R: Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979;237:E214 –E223.
Bergman RN, Finegood DT, Ader M: Assessment of insulin sensitivity in vivo. Endocr Rev 1985;6:45– 86.
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Zaharko DS, Beck LV: Studies of a simplified plasma insulin immunoassay using cellulose powder. Diabetes 1968;17:444 – 447.
Intersalt Cooperative Research Group: An international study of electrolyte excretion and blood pressure: results for 24 hour urinary sodium and potassium excretion. Br Med J 1988;297:319 –328.
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World Health Organization: WHO expert committee on diabetes mellitus, in World Health Organization Technical Report Series 646. Geneva, World Health Organization, 1980, pp 6 – 80.
21.
Fliser D, Fode P, Arnold U, et al: The effect of dietary salt on insulin sensitivity. Eur J Clin Invest 1995;25:39 – 43.
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Egan BM, Stepniakowski K, Goodfriend TL: Renin and aldosterone are higher and the hyperinsulinemic effect of salt restriction greater in subjects with risk factors clustering. Am J Hypertens 1994;7:886 – 893.
17. Harano Y, Hidaka H, Takatsuki K, et al: Glucose, insulin, and somatostatin infusion for the determination of insulin sensitivity in vivo. Metabolism 1978;27:1449 –1452.
1997;10:964 –970
Effect of Dietary Sodium on Insulin Sensitivity in Older, Obese, Sedentary Hypertensives Donald R. Dengel, Ronaldo S. Mayuga, Gretchen M. Kairis, Andrew P. Goldberg, and Matthew R. Weir
Increased dietary sodium intake has been associated with an increase in blood pressure as well as a decrease in insulin-mediated glucose disposal in young healthy adults. The purpose of this study was to determine whether dietary sodium intake is associated with changes in oral glucose tolerance, insulin sensitivity, and blood pressure in older, sedentary, overweight hypertensives. Eight older (70.0 6 1.4 years, mean 6 SEM), overweight (40.2 6 3.1% body fat), mildly hypertensive (151 6 8/82 6 2 mm Hg) patients with a fasting plasma glucose < 7.8 mmol/ L were studied after 2 weeks on low (3 g/day) and 2 weeks on high (10 g/day) sodium diets. To examine carbohydrate metabolism we performed a 2 h oral glucose tolerance test and a two-dose (240 and 600 pmol/m 2/min) hyperinsulinemiceuglycemic clamp at the end of each sodium diet. High sodium intake was associated with a significantly greater urinary sodium excretion (364 6 45 mmol/day v 112 6 21 mmol/day; P < .0001). The increase in dietary sodium from low to
high did not result in significant differences in fasting plasma glucose (6.0 6 0.2 v 5.8 6 0.1 mmol/ L, P 5 .20) or insulin (72.5 6 7.8 v 69.9 6 12.4 pmol/L, P 5 0.71) levels or in the glucose (374.0 6 50.8 v 493.2 6 45.0 mmol/min/L, P 5 .12) and insulin (43,783 6 10,278 v 44,110 6 12,392 pmol/ min/L, P 5 .96) areas determined during the oral glucose tolerance test. Similarly, there was no effect of dietary sodium on insulin-mediated glucose disposal at low (5.87 6 1.02 v 5.60 6 0.94 mg/kg LBM/min, P 5 .36) or high (12.15 6 1.49 v 11.91 6 1.49 mg/kg LBM/min, P 5 .64) insulin infusion rates. Our findings suggest that, in insulin resistant hypertensives, increased dietary sodium does not affect either glucose or insulin responses during an oral glucose tolerance test or glucose disposal during a hyperinsulinemic euglycemic clamp. Am J Hypertens 1997;10:964 –970 © 1997 American Journal of Hypertension, Ltd.
Received October 21, 1996; accepted February 25, 1997. From the Department of Medicine, Division of Gerontology (DRD, APG), and Division of Nephrology (MRW), University of Maryland School of Medicine; and Geriatric Service and Geriatric Research, Education, and Clinical Center, Baltimore Veterans Administration Medical Center (DRD, APG), Baltimore, Maryland. Supported by American Heart Association grant-in-aid, Maryland affiliate (MRW), a grant from the Fraternal Order of Eagles,
Maryland (MRW), National Institutes of Health Research Scientist Development Award in Aging KO1 AG0072301 (DRD), and the Department of Veterans Affairs Geriatric Research, Education and Clinical Center at Baltimore, University of Maryland, Claude D. Pepper Older Americans Independence Center (P60AG12583) and K07Ag00608 (APG). Address correspondence and reprint requests to Donald R. Dengel, PhD, Ann Arbor VA Medical Center, GRECC (11G), 2215 Fuller Road, Ann Arbor, MI 48105; e-mail:[email protected].
© 1997 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
KEY WORDS:
Insulin resistance, dietary sodium, glucose clamp.
0895-7061/97/$17.00 PII S0895-7061(97)00159-3
AJH–SEPTEMBER 1997–VOL. 10, NO. 9, PART 1
R
ecent studies suggest that there may be a relationship between sodium sensitivity, blood pressure, and insulin resistance.1– 8 Moreover, insulin resistance and glucose intolerance frequently coexist in obese hypertensive individuals.9,10 These observations suggest that high dietary sodium may worsen insulin resistance and glucose homeostasis in hypertensive individuals. A prior study by Donovan et al1 demonstrated that increasing dietary sodium intake worsened insulin sensitivity in young, healthy, normotensive, nondiabetic white men. These subjects were studied after 5 days on a high (200 mmol/day) sodium diet and after 5 days on a low (10 mmol/day) sodium diet. They showed that insulin mediated glucose disposal during a hyperinsulinemic-euglycemic clamp was significantly reduced on the high versus the low sodium diet. They concluded that increasing dietary sodium intake may worsen insulin resistance in young, healthy normotensives, and that these observations may be more important in more insulin resistant individuals. A hyperinsulinemic response to oral glucose loading was observed in sodium sensitive normotensive subjects, but not in sodium resistant normotensive subjects in another clinical study.5 In contrast, in another study, impaired glucose tolerance was associated with a low sodium diet (34 mmol/day) rather than a high sodium (340 mmol/day) diet in hypertensive subjects.11 The problem with the latter study is that the oral glucose tolerance test is not a sensitive means of assessing tissue sensitivity to the effects of insulin. Moreover, both of these studies were conducted with specialized diets with at least a 10-fold variation for dietary sodium intake. However, these results suggest there is a difference in tissue sensitivity to insulin between normotensive and hypertensive subjects, depending on sodium intake. Such studies have not been conducted in older, overweight, sedentary hypertensives, who are more insulin resistant and might be at greater risk for dietary sodium exacerbated changes in glucose homeostasis. This study was designed to determine the influence of a threefold increase in dietary sodium intake on glucose and insulin responses to an oral glucose challenge and on insulin-mediated glucose disposal in older, overweight, deconditioned, hypertensive subjects. This range of dietary sodium consumption was chosen because it reflects a range of sodium intake that would be observed in clinical practice. METHODS Subjects Three male and 5 female overweight, sedentary, older subjects with mild hypertension were recruited for study. Prior to being enrolled in the study the subjects needed to give voluntary informed, written consent as approved by the Human Volun-
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teers Research Committee of the University of Maryland School of Medicine. Individuals were eligible for the study if their sitting diastolic blood pressure on an ad libitum sodium diet was $ 85 mm Hg and # 105 mm Hg after being off all antihypertensive medication for 4 weeks. Individuals were excluded from the study if they had clinically significant concomitant medical illness such as cardiac, renal (serum creatinine greater than 135 mmol/L), hepatic, or gastrointestinal disease, or required concomitant medications. Also excluded were individuals with a recent history of smoking or drug or alcohol abuse, or clinically relevant mental disorders, and concomitant use of medications that might affect glucose metabolism, blood pressure, or renal function. Procedures Individuals were screened prior to participation with a medical history, physical exam, a fasting plasma glucose, and routine blood chemistries. Individuals were excluded from participation if they exceeded 140% (body mass index . 35 kg/m2) of ideal body weight or had a fasting plasma glucose . 7.8 mmol/L or the presence of underlying illness based on screening medical history and examination of baseline laboratory biochemical analyses. Prior to metabolic studies, measurements of maximal oxygen consumption (VO2max) and body composition (percent body fat, lean body mass) were performed in the subjects who met the criteria for study entry. Prior to the study, all subjects were taught the principles of an American Heart Association (AHA) step I diet12 over an 8 week period prior to metabolic testing. This diet consisted of 50% to 55% of calories as carbohydrate; 30% to 35% as fat; 15% to 20% as protein; 300 to 350 mg/day of cholesterol; and 3 g/day of sodium. Patients were weight stable on this diet for 4 weeks prior to research testing. Registered dietitians monitored adherence by reviewing weekly food records and body weight, and calculating dietary composition from biweekly 7 day food records (Nutritionist III, N-Squared Computing, Salem, OR). Study Design After completion of the weight stable, 8 week AHA step I diet, the subjects were placed on a constant isocaloric 3 g sodium diet. At the end of the 2 week sodium diet, subjects received a 2 h oral glucose tolerance test (OGTT) followed 24 h later by a two dose hyperinsulinemic-euglycemic clamp (240 and 600 pmol/m2/min insulin infusion rates). Compliance with the diet was monitored by urine samples (24 h) for sodium. After completion of the metabolic tests the subjects consumed their own diet for a 1 week period. The subjects were then switched to a 10 g sodium diet having the same caloric constituents as the 3 g sodium diet for a period of 2 weeks, prior to being retested again with an OGTT and a two-dose hyperinsulinemic-euglycemic clamp.
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Measurement of Body Composition Body weight was measured prior to all testing to the nearest 0.1 kg using a medical beam balance (Detecto, Webb City, MO) and height was measured to the nearest 0.5 cm. Body mass index was calculated by weight (in kilograms) by height (in meters) squared. Body fat, lean body mass (LBM), and percent body fat were determined by dual energy x-ray absorptiometry (DXA, Model DPX-L Lunar Radiation Corporation, Madison, WI). Measurement of Maximal Oxygen Consumption (VO2max) A treadmill VO2 max test was performed in each subject on at least 2 separate days, as previously described.13 A true VO2 max was considered to be attained if two of the following three criteria were met: 1) respiratory exchange ratio at maximal exercise . 1.10; 2) maximal heart rate . 90% of age predicted maximum (220 2 age); and 3) a plateau in VO2 (, 200 mL/min change in VO2 during the last stages of exercise. If a true VO2 max was not attained on the second test or the VO2 max results for the two exercise tests differed by . 200 mL/min, additional VO2 max tests were performed until these criteria were met. Hyperinsulinemic-Euglycemic Clamp Protocol Insulin sensitivity and maximal responsiveness were measured using a modification of the hyperinsulinemic-euglycemic glucose clamp technique of DeFronzo et al.14 Briefly, an intravenous catheter was inserted into an antecubital vein for infusion of insulin, glucose, and potassium and a second catheter was inserted into a dorsal hand vein for blood sampling. The hand was then placed in a warming box thermostatically controlled at 70°C to arterialize the blood and allowed to equilibrate for 30 min before baseline samples for glucose and insulin were obtained. Insulin (Humulin-R, Eli Lilly Inc., Indianapolis, IN) was administered at two sequential primed infusions at rates of 240 pmol/m2 min for 120 min (low dose), and 600 pmol/m2/min for 120 min (high dose). During the clamp, plasma glucose levels were measured at 5 min intervals using the glucose oxidase method (Beckman Instruments, Fullerton, CA) and maintained at basal levels with a variable infusion of 20% glucose, which was adjusted according to a computerized algorithm. Samples were obtained at 10 min intervals during the clamp for subsequent measurement of plasma insulin levels by radioimmunoassay.15 Mean glucose infusion rates were normalized for LBM and averaged over the last 30 min of each insulin dose. Steady state plasma insulin levels were calculated over the same interval. Oral Glucose Tolerance Test Subjects were weight stable and eating a diet containing . 250 g carbohydrate for 3 days prior to all metabolic testing. After a 12 h overnight fast, patients had an intravenous cath-
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eter placed in an antecubital vein. Two fasting samples were drawn at baseline prior to ingesting of 75 g of glucose. Blood samples were drawn at 30 min intervals for 2 h. Plasma glucose was measured by a glucose oxidase method (Beckman Instruments, Fullerton, CA) and plasma insulin by radioimmunoassay.15 The areas under the curves for glucose and insulin responses during the 2 h OGTT were calculated above the fasting basal level using a trapezoidal model. Statistical Analysis Data were analyzed using a standard statistical software package (Statview, Abacus Concepts, Inc., Berkeley, CA). An alpha level of 0.05 was accepted for statistical significance. Differences in variables resulting from the sodium diet were examined for significance using Student’s paired t tests. All data are reported as the mean 6 standard error of the mean (SEM). RESULTS Physical Characteristics of Subjects Eight subjects (three men, five women; four black, four white) with essential hypertension and normal renal function as determined by serum creatinine concentration (99 6 9 mmol/L) were studied. The subjects had a mean age of 70 6 1.4 years and were sedentary (maximal oxygen consumption: 19.2 6 1.4 mL/kg/min). Body weight of these subjects ranged from 63 to 105 kg with an average BMI of 30.2 6 1.1 kg/m2 and percent body fat of 40.2% 6 3.1%. The change in dietary sodium intake from low to high resulted in a significant increase in urinary sodium levels (252.4 6 38.3 mmol/day, P 5 .0003) (Table 1).
TABLE 1. PHYSICAL AND BIOCHEMICAL RESPONSES TO SODIUM INTAKE Diet Variable Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Mean arterial blood pressure (mm Hg) Weight (kg) Urine sodium (mmol/day) Fasting plasma glucose (mmol/L) Fasting plasma insulin (pmol/L) Values are means 6 SEM. * P , .05 v low sodium. † P , 0.01 v low sodium.
Low Sodium
High Sodium
158 6 8
165 6 6
83 6 2
87 6 3
108 6 4 113 6 3 83.9 6 5.5 84.0 6 5.4 111.6 6 21.0 363.9 6 45.2† 6.0 6 0.2
5.8 6 0.1
72.5 6 7.8
69.9 6 12.4
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However, the increase in dietary sodium intake did not result in a significant change in systolic (7 6 4 mm Hg, P 5 .13), diastolic (4 6 2 mm Hg, P 5 .15), or mean arterial (5 6 3 mm Hg, P 5 .09) blood pressures (Table 1). Hyperinsulinemic-Euglycemic Clamp (Figure 1) There were no differences in the mean plasma insulin levels during the hyperinsulinemic-euglycemic clamp on the low or high sodium diets at either the low (424 6 57 v 393 6 53 pmol/L, P 5 .40) or high (1176 6 109 v 1149 6 80 pmol/L, P 5 .77) insulin infusion rates. The change in dietary sodium intake did not alter insulin-mediated glucose disposal at the low (5.87 6 1.02 v 5.60 6 0.94 mg/kgLBM/min, P 5 .36) or high (12.15 6 1.49 v 11.91 6 1.49 mg/kgLBM/min, P 5 .64) insulin infusion rates. Oral Glucose Tolerance Test (Figure 2) The oral glucose tolerance test performed on the AHA Step I diet showed that four subjects had normal OGTT, one was impaired, and three were diabetic.16 Changes in dietary sodium from low to high did not result in significant changes in fasting plasma glucoses (6.0 6 0.2 v 5.8 6 0.1 mmol/L, P 5 .20) or glucose responses to the oral glucose challenge. As a result there was no significant difference in the glucose area (374.0 6 50.8 v 493.2 6 45.0 mmol/min/L, P 5 .12) due to a change in dietary sodium. The glucose tolerance of three subjects was affected by the increase in dietary sodium. One normal subject became impaired, one impaired subject became normal, and one impaired subject became diabetic. The change from low to high sodium intake did not change the fasting insulin (72.5 6 7.8 v 69.9 6 12.4 pmol/L, P 5 .71) levels or insulin responses to an oral glucose challenge. The insulin area on the low and high sodium diets was also not significantly different (43,783 6 10,278 v 44,110 6 12,392 pmol/min/L, P 5 .96). DISCUSSION The results of our study demonstrate that greater dietary sodium intake, in the physiologic range for ad libitum sodium consumption, does not worsen oral glucose tolerance or insulin sensitivity, as determined with oral glucose tolerance tests and hyperinsulinemic-euglycemic clamp techniques, in older insulin resistant hypertensives. Although Sharma et al6 reported similar findings, it should be noted that these observations were made in young, lean, normotensive individuals, who underwent a 10-fold increase in dietary sodium. In addition, Sharma et al6 used the insulin suppression test17,18 to determine insulin sensitivity. Although this methodology has been correlated to the hyperinsulinemic-euglycemic clamp technique, it does have limitations in that hyperglycemia
FIGURE 1. Insulin-mediated glucose disposal rate at low (240 pmol/m2/min: Panel A) and high (600 pmol/m2/min: Panel B) insulin infusion rates on low (3 g/day) and high (10 g/day) sodium diets. Open circles, mean 1 SEM insulin-mediated glucose disposal rate.
and hypoglycemia, which are often observed with this technique, can result in either an over- or an underestimation of insulin sensitivity.19 In contrast to Sharma et al,6 we studied an older, hypertensive population, with a threefold increase in dietary sodium, which is more in the physiologic range for sodium consump-
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FIGURE 2. Plasma glucose (Panel A) and insulin (Panel B) responses to an oral 75 g of glucose challenge on low (3 g/day; open circles) and high (10 g/day; closed circles) sodium intake.
tion.20 In addition, we utilized the hyperinsulinemiceuglycemic clamp technique to measure insulin sensitivity instead of the insulin suppression test. Using the same hyperinsulinemic-euglycemic clamp technique to measure insulin sensitivity as the present study, Donovan et al1 demonstrated that a 10-fold increase in dietary sodium in young healthy normotensive resulted in a 16% decrease in insulin sensitivity. Using the same insulin infusion level (240 pmol/m2/min) as Donovan et al1 and a higher insulin infusion level (600 pmol/m2/min) we did not observe
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any difference in insulin due to the change in dietary sodium intake at either insulin infusion level. Differences between our results and those of Donovan et al1 may be due to differences in subject populations. Our subjects were older, sedentary, overweight, and hypertensive, whereas their population was younger, healthier, and normotensive. These differences in age and body composition are evident by the large differences in insulin-mediated glucose disposal rates reported by Donovan et al1 from those observed in the present study. Utilizing an insulin infusion rate of 240 pmol/m2/min during the hyperinsulinemic-euglycemic clamp, Donovan et al1 reported an insulin mediated glucose disposal rate of 279 6 19 v 334 6 24 mg/m2/min for his subjects on low and high sodium intakes. If we express our insulin-mediated glucose disposal rate in mg/m2/min during the 240 pmol/ m2/min insulin infusion rate our older, overweight hypertensives had a mean insulin-mediated glucose disposal rate (147 6 21 v 140 6 18 mg/m2/min: low v high sodium intake), half of that reported by Donovan et al.1 Only at the high insulin infusion rate of 600 pmol/m2/min used in the present study does the mean insulin mediated glucose disposal rate (309 6 32 v 301 6 28 mg/m2/min: low v high sodium intake) of our subjects approach of that reported by Donovan et al.1 This twofold difference in insulin mediated glucose disposal rates might explain the differences in results between those reported by Donovan et al1 and those of the present study. Another possible explanation as to the differences between these two studies may be due to the sodium content and length of the diets utilized in these two studies. Our subjects consumed dietary sodium in a range consistent with an ad libitum sodium diet, whereas the Donovan group examined a dietary sodium range that is not what is customarily achieved on an outpatient basis. Had Donovan et al1 studied young, healthy normotensives in the dietary sodium range that we examined, their results may have been different. Differences in the length of time that the subjects consumed the sodium diet also exist between our study and that of Donovan et al,1 and may also contribute to the differences in the results. In the present study, the subjects consumed each diet over a 12 to 14 day period, whereas in the study by Donovan et al1 the subjects consumed the sodium diets for a 5 day period. Recently, Fliser et al21 examined the effect of a high (200 mmol/day) and low (20 mmol/day) sodium diet consumed over 3 days versus 7 days on insulin-mediated glucose disposal in young healthy normotensive subjects. The authors observed that there was a significant increase in insulin-mediated glucose disposal on the high compared with low sodium diet after 3 days. However, in another group that underwent the same sodium diets for a 7 day
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period, there was no difference in insulin-mediated glucose disposal rates between the two sodium diets. The results of Fliser et al21 suggest that the worsening of tissue sensitivity to insulin by dietary sodium is an acute event, and that studies examining the effect of dietary sodium on glucose metabolism need to be carried out over a longer period of time. Previous studies5,8,11,22 examining the effect of dietary sodium on glucose and insulin responses to an oral glucose challenge have produced varied results. Iwaoka et al11 reported that high sodium intake (340 mmol/day) for 8 days resulted in significantly lower glucose and insulin response to an oral glucose challenge than low sodium intake (34 mmol/day). However, Egan et al22 reported that 7 days of high (200 mmol/day) and low (20 mmol/day) sodium diets had no significant effect on either glucose or insulin responses to an oral glucose load. The results of our study are in agreement with those of Egan et al,22 as threefold increase in dietary sodium did not change the glucose or insulin responses to an oral glucose challenge. The difference between the results of our present study and those of Iwaoka et al11 may be related to the age and physical characteristics of the subjects studied and to the 10-fold variation in dietary sodium intake. Unfortunately, Iwaoka et al11 did not report these details in their article, so a comparison between subject populations is not possible. Sodium sensitivity could be a confounding variable and might explain some of the differences in the effects of dietary sodium on glucose tolerance. Sharma et al5 studied 25 healthy, young (age range, 23 to 29 years) normotensive men. Subjects received both a high (260 mmol/day) and low (20 mmol/day) sodium diet. Using a criteria of a 3 mm Hg drop in mean arterial blood pressure on the low sodium diet, 10 of the subjects were classified as sodium sensitive. The authors reported a significant increase in glucose and insulin responses to an oral glucose challenge in sodium sensitive, normotensive individuals on a high sodium diet. However, the sodium resistant individuals had a decrease in insulin responses to the high sodium diet. If we apply the blood pressure sodium sensitivity criteria of Sharma et al5 to our subjects, six were sodium sensitive and two were sodium resistant. We observed no consistent effect of dietary sodium on insulin-mediated glucose disposal or in glucose and insulin responses to an oral glucose challenge, at either the low or high insulin infusion rates in our six sodium sensitive subjects. The results of this study combined with previous studies suggest that there are differences in the effects of dietary sodium on glucose metabolism between young normotensives and older hypertensives. This difference may be due to the fact that hypertensive individuals in our study were older, more insulin
resistant, and more obese than were the normotensive subjects evaluated in other studies. In conclusion, although our results are limited by a relatively small number of subjects, increased dietary sodium intake did not affect glucose homeostasis in this group of older hypertensives. It is possible that the sodium sensitivity status of an individual may result in differences in the effects of dietary sodium intake on glucose metabolism. ACKNOWLEDGMENTS We thank all the subjects who volunteered; the nursing staffs at the Geriatrics Service at the Baltimore VA Medical Center and at the Division of Nephrology, University of Maryland Hospital for assistance with the research studies, and the dietitians for their nutrition instruction and dietary evaluations.
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