Chidarnoyo, a rural area 383 km north of Harare,. Zimbabwe. Subjects. Twenty-seven rural volunteers (16 women,. 11 men). Outcome measures. Systolic and ...
SAMJ Endocrinology, Metabolism and Diabetes
Salt sensitivity is not associated with hyperinsuli naemia in a sam pie of rural black Zimbabweans J MufUrlda, J Chifarnba, N Chitate, PM Vengesa Objectives. To investigate the relationship between salt sensitivity and hyperinsulinaemia in rural black African sUbjects. Design. An intervention study where 27 subjects were divided into two groups; group 1 was initially salt loaded (300 mmol Na'/day) while group 2 was salt restricted (25 mmol Na'/day), each for 4 days, after which a cross-over study was done. Setting. Chidarnoyo, a rural area 383 km north of Harare, Zimbabwe. Subjects. Twenty-seven rural volunteers (16 women, 11 men). Outcome measures. Systolic and diastolic blood pressures, salt sensitivi~, insulin and glucose levels, body mass index and mean arterial pressure. Results. Mean arterial pressure, which was 91 ± 2 mmHg on a low-salt diet, increased significantly (P < 0.01) to 105!: 3 mmHg on a high-salt diet in the salt-sensitive sUbjects. In the same salt-sensitive subjects, the fasting insulin level was 8.4 !: 0.8 ~Ulml on a low-salt and 6.1 :to 1.0 IJUlml on a high-salt diet. The difference was not statistically signiiicant. Conclusions. Althoug 11 salt pressor sensitivity was demonstrated in the subjects, there was no accompanying increase but rather a decrease in fasting insulin levels, suggesting that in the short term, salt sensitivity and hyperinsulinaemja are not linked in raising blood pressure in this sample of' rural Zimbabwean SUbjects. S Atr Med J
1998;~:
361-364.
Various lines o' evidence point to essential hypertension as having a multifaciorial pathophysiological basis.' Insulin resistance' and salt sensitivity' are two of the key factors to have been implicated in the pathogenesis of essential
Department of Physiology, University of Zimbabwe, Harare. Zimbabwe
J Mufunda.
MB ChB P.,o
J Chifamba. BSc Hch
hypertension. Salt sensitivity has been associated with increased renal sodium retention: while acute hyperinsulinaemia has been reported to cause renal sodium retention,' thus raising the possibility that hyperinsulinaemia and salt sensitivity may be linked. Hyperinsulinaemia has been reported to be associated with increased sympathetic nerve activity" while salt-sensitive subjects also exhibit increased sympathetic activity.' Hyperglycaemic and hyperinsulinaemic responses were found in young saltsensitive normotensive white subjects.' However, it is well known that the pathophysiological mechanisms of essential hypertension in whites and blacks are different 8 Although previous findings shed light on the mechanisms in white subjects. little is known about the link between hyperinsulinaemia and salt sensitivity in blacks, particularly in rural Africa where blood pressures are known to be relatively low. In this study we investigated the relationship between salt sensitivity and hyperinsulinaemia in rural black African SUbjects.
Methods After a blood pressure survey similar to one preViously described by Mufunda et al.,9 30 subjects who were Willing to participate in the diet intervention were recruited. However, 3 of the subjects did not turn up on the first day of the study and were excluded. The remaining 27 normotensive volunteers with no personal or family history of hypertension were recruited from Chidamoyo, a rural area 383 km from Harare. Subjects were randomly placed into two groups. Group 1 subjects were put on a high-salt diet (300 mEq Na-/day) and group 2 subjects on a low-salt diet (25 mEq Na-/day) each for 4 days as previously described. 9 A cross-over in the dietary treatment was effected at the end of the initial diet intervention. A 3-day period. which had preViously been shown to effect recovery,'0 was allowed between the two treatment periods, during which time the subjects had free access to salted food. The baseline salt intake of this community had previously been reported as 130 ± 15 mEq Na-/day.9 Blood pressure, pulse, weight and height were measured at the beginning of the study when subjects had free access to salt and at the end of the first and second dietary treatments. Oral glucose tolerance tests were done after overnight fasting. Bloed samples were taken by venepuncture before and 2 hours after the consumption of 75 g oral glucose. The blood collections were made at 08hOO on the fifth day after commencement of each diet. Smoking and alcohol intake were prohibited during the period of the study. We used Sullivan's definition of salt sensitivity, viz. an increase in mean arterial pressure of ;:. 5 mmHg with salt loading." The study was approved by the Medical Research Council of Zimbabwe and all subjects signed informed consent forms before commencement.
Glucose and insulin measurement Plasma glucose values were determined by glucose oxidase method (Glucose PAP kit; Roche Diagnostic Products, UK)
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and insulin levels were measured with a commercial radioimmunoassay kit supplied by Kodak Clinical Diagnostics, UK, as previously described."·13
Blood pressure, hip and waist circumference measurement Systolic and diastolic blood pressures as well as pulse rate were measured with a Dinamap 8100 blood pressure monitor supplied by Critikon Inc., UK, according to a previous report." Each subject was seated quietly and relaxed for 5 minutes. Five consecutive blood pressure readings, at 2-minute intervals, were then taken; the average of the closest three readings was taken as the subject's blood pressure. The hips were measured at the widest part of the buttocks and the waist at the umbilicus.
Statistical analysis Results are given as mean ± standard error of mean. For analyses of difference between groups, Student's Hest was used. Statistical significance was considered for P-values < 0.05. We measured the treatment effect (Iow-salt or highsalt) and the period effect with ANOVA. In both cases the treatment and period effect did not have any significance for the result.
Table I. Characteristics of the study population (mean ± SEM)
Salt-resistant Parameter
Women (N: 9)
Salt-sensitive
Men (N:4)
Women (N: 7)
Men (N: 7)
Age (yrs)
39.3 ± 3.7
42.5 ± 3.8
BMI (kg/m')
21.0 ± 1.0
21.5 ± 0.7
41 ± 5.9 21.7±0.7
36.6 ± 4.0 21.6 ± 0.8
Hip/waist ratio
1.2 ± 0.02
1.1 ± 0.01
1.2±0.02
1.2 ± 0.01
Table 11. Characteristics of the study population (mean ± SEM)
Salt-resistant
Salt-sensitive
Women (N: 9)
(N:4)
11.24 ± 1.9
9.80 ± 1.6
13.36 ± 1.5 11.83±2.3
Fasting high-salt insulin (~U/ml)
7.46 ± 1.4
8.07 ± 1.4
6.94±1.4
5.27 ± 1.4
Fasting low-salt insulin (~U/ml)
9.51 ± 1.5
7.35 ± 1.9
7.1 ± 0.9
9.7 ± 1.3
Fasting glucose (mmoll1)
3.64 ± 0.15 3.55 ± 0.04 3.52 ± 0.41
High-salt glucose (mmol/l)
4.26 ± 0.78 4.14 ± 0.22 4.50 ± 0.17 4.53 ± 0.14
Low-salt glucose (mmol/l)
4.26 ± 0.36 4.93 ± 0.35 4.17 ± 0.13 4.52 ± 0.36
Parameter Fasting insulin
Men
Women (N: 7)
Men (N:7)
(~U/ml)
3.12 ± 0.29
Results Salt-sensitive subjects v, salt-resistant subjects Tables I and 11 summarise the characteristics of the saltsensitive and salt-resistant subjects. No differences were found in age, body mass index and hip/waist ratio. However, there was a significant difference in their blood pressures (by definition). There was also no significant difference in their fasting insulin and glucose levels during baseline, low-salt and high-salt dietary treatments (Table 11). No significant gender difference was noted between and within groups, although baseline insulin levels tended to be higher in women. In both groups and both sexes glucose levels were significantly higher on low-salt and high-salt diets, compared with baseline values. There was no significant difference in weight between the two groups and sexes. Baseline blood pressures were not significantly different between salt-sensitive and salt-resistant subjects, although all tended to be higher in the salt-sensitive. Mean arterial pressure was significantly (P < 0.0065) higher in saltsensitive subjects on high-salt diets than in salt-resistant subjects. The higher mean arterial pressure was almost
Table Ill. Comparison of salt-sensitive subjects on different diets (mean ± SEM)
MAP (mmHg) SBP (mmHg) DBP (mmHg) Fasting insulin (~U/ml) 2-hour insulin (~U/ml) Fasting glucose (mmol/dl) 2-hour glucose (mmol/dl)
SAMl
Low-salt
High-salt
103 ± 3§' 134 ± 5' 78 ± 3 12.7 ± 1.3* 19.9 ± 4 3.3 ± 0.3§~ 3.8 ± 0.3§*
91 ± 2§t 122 ± 3§t 72 ± 3 8.4 ± 0.8 24.4 ± 3.6 4.3 ± 0.2 4.8 ± 0.3
105 ± 3 138 ± 5 80 ± 3 6.1 ± 1.0*11 19.1 ±2.8 4.5 ± 0.1*11 4.5 ± 0.3
.. Baseline v. Iow salt. t Low sa~ v. high salt. Baseline v. high sa . P < 0.05. §P< 0.01. 11 P < 0.001. MAP; mean arterial pressure; SBP ; systolic blood pressure; DBP ; diastolic blood pressure.
*
Table IV. Comparison of salt-resistant subjects on different diets (mean ± SEM)
MAP (mmHg) SBP (mmHg) DBP (mmHg) Fasting insulin (~U/ml) 2-hour insulin (~U/ml) Fasting glucose (mmol/dl) 2-hour glucose (mmol/dl)
Baseline
Low-salt
High-salt
94 ± 4 125 ± 3 73 ± 3 10.5±1.5 29.4 ± 6.7 3.6 ± 0.1 *§ 3.9 ± 0,2*,
94 ± 2 121 ± 3 72 ± 2 9.1 ± 1.3 29.9 ± 7.2 4.5 ± 0.2 4.8 ± 0.3
93 ± 2 122 ± 3 75 ± 3 7.2 ± 1.0 26.1 ± 7.7 4.3 ± 0.2§* 4.4 ± 0.4
Baseline v. Iow salt. Low salt v. high salt. Baseline v. high sa~. ~ P < 0.05. § P < 0.01. 11 P < 0.001. MAP; mean arterial pressure; SBP ; systolic blood pressure; DBP ; diastolic blood pressure. *
Volume 88 SO.3 March 1998
Baseline
*
solely due to the significantly (P < 0.0053) higher systolic blood pressure in salt-sensitive subjects on high-salt diets, as there was no significant difference in diastolic blood pressure between the two groups.
Discussion Subjects from a rural setting in Zimbabwe with a low hypertension prevalence underwent an acute dietary intervention study to elicit salt pressor sensitivity and examine glucose tolerance. The results of the present study showed that insulin and glucose levels were not linked to any dietary intervention in both salt-sensitive and salt-resistant groups. We expected insulin levels in salt-sensitive subjects to be higher, as previously noted by Sharma et al.,' who observed an increase in insulin levels on a high-salt diet only in the saltsensitive but not in the salt-resistant. There is no immediate explanation for this variance, but we speculate that this could be a result of a possible genetic difference between blacks and whites in respect of the aetiology of hypertension and diabetes. Rubenstein et al., in a study on metabolic responses to oral glucose load in healthy South Africans, found differences between blacks and whites, despite similar glucose values at all times during the test, where the blacks had lower serum insulin levels." Joffe et al. proposed that malnutrition in black South Africans may lead to diabetes mellitus given their reduced beta-cell mass per se and, because of the increased demand placed on them by the development of peripheral insulin resistance, thus induce receptor downregulation, a transient phase of compensatory relative hyperinsulinaemia and accelerated decline in betacell function. 15 The result of this would be increased glucose levels. Swai et al. also reported a low incidence of hyperinsulinaemia in a Tanzanian rural community.'s All these studies indicate that it is possible to get a different response in black subjects. Glucose values were also independent of salt sensitivity or salt resistance, but in both groups glucose levels were lower at baseline than when on the low- or high-salt diet. These rural subjects were fed on a diet obtained from an urban environment, and we noticed that fasting glucose levels in both low- and high-salt diet groups reached those previously found in urban sUbjects. 13 This may be a reflection of increased salt intake rather than impairment of control, and may possibly be one of the explanations for urbanisation-related higher blood pressures, given that excessive caloric intake has been associated with obesity and obesity in turn with hypertension." The higher fasting glucose levels would raise the fasting insulin levels, a phenomenon associated with urbanisation-related hypertension. 13 Fasting insulin levels tended to be higher in women, although no significant levels were reached. Urban women have been found to have higher fasting insulin levels,"'· suggesting an inherent genetic gender difference which may be heightened by urbanisation. Despite the attractiveness of a possible synergistic relationship between hyperinsulinaemia and salt sensitivity with regard to the raising of blood pressure, this study is not
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supportive of this thesis. This suggests possible racial differences, given that a previous report' reported an association between the two phenomena in whites. In conclusion, this study of rural normotensive Zimbabweans ascertained that salt sensitivity was not associated with hyperinsulinaemia in these subjects. The authors are grateful to the University of Zimbabwe Research Board for funding the project. We are also grateful for the help we received from Sister Kathy McCarty of Chidamoyo Hospital, Mr P Juma, Mr 0 J Fluck, Mr C Mugoni and all the subjects who participated. We acknowledge the help with statistical analysis that we received from Or S Siziya of the Department of Community Medicine, University of Zimbabwe. REFERENCES 1. Frohlich EO. Essential hypertension - multifactorial pathophysiological and therapeutic clinical problem. Med Cfin North Am 1987; 71(5): xiii-xviii. 2. Modan M, Halkin H, Almog S, et al. Hyperinsulinemla: a link between hypertension, obeSity. and glucose intolerance. J Clin Invest 1985; 75: 809-817. 3. Mufunda J, Sparks HV jun. Salt sensitivity and hypertension in African blacks. In: Fray JC. Douglas JG. eds. Pachophysiology of Hypercenslon In Blacks. New York: Oxford niversity Press, 1992: 143-165. 4. Dustan HP. Valdes G. Bravo E. Tarazi RC. Excessive sodium retention as a characteristic of salt-sensitive hypertension. Am J Med 1986; 292: 67-74. 5. DeFronzo RA, Cooke CR. Andres R, Faloona GR, Oavis PJ. The effect of Insulin on renal handling of sodium. potassium, calcium and phosphate in man. J Clin
Invest 1975; 55: 845·855. 6. Anderson EA. Hoffman RP. Balon TW, Sinkey CA, Mark AL. Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. J Clin Invest 1991; 87: 2246-2252. 7. Sharma AM, Ruland K, Spies K. Oistler A. Salt sensitivity in young normotensive subjects IS associated with hyperinsulinemic response to oral glucose. J Hypenens 1991; 9: 329-335. 8. Fray JCS. Hypertension in blacks: Physiological. psychosocial, theoretical and therapeutIc challenges. In: Fray JCS, Douglas JG. eds. Pachophysiologyof Hypenension in Blacks. New York: Oxford UniverSIty Press, 1992: 3-22. 9. Mufunda J, Fink GO, Sparks HV jun. Blood pressure responses to dietary salt in rural and urban African men. Echnicity and Disease 1993; 3: 546-858. 10. Luft FC. Rankin 1I. Sloch AE. er al. Cardiovascular and humoral responses to extremes of sodium intake in normotensive black and White men. Circulation
1979; 60: 697 -705. 11. Sullivan JM, Prewirt RL, Ratts TE, Josephs JA, Connor MJ. Hemodynamic characteristics of sodium-sensitive human subjects. Hypertension 1987; 9: 398406. 12. Mufunda J, Sigola LB, Chifamba J, Vengesa PM. Aspects of insulin resistance in urbanisation-related hypertension in Zimbabwe: a preliminary report. J Hum Hypenens 1994; 8: 481 -484. 13. Mufunda J. Chifamba J, Chitate N. Sigola LB, Vengesa PM. Hyperinsulinemia: Possible cause of high blood pressure in unemployed urban black women. High Blood Pressure 1995; 4: 137-140. 14. Rubenstein AH, Settel He, Miller K, Bersohn I, Wright AD. Metabolic response to oral glucose in healthy South Af(lcan whIte, Indian. and African subjects. BMJ
1969; 1: 748-751. 15. Joffe 81, Panz VA, Wing JR, Aaal FG, Settel HC. Pathogenesls of non-insulindependent diabetes mellitus In the black populatIon of southern Africa. Lancet
1992; 340: 460-462. 16. Swai ABM, Kitange H, Masuki G, et al. Is diabetes mellitus related to undernutrition in ,..:ral Tanzania? BMJ 1992; 305: 1057-1062. 17. Viskoper JR. Risk factors for cardiovascular disease and their control. In: Viskoper JR, ed. Manual of Nonpharmacological Control of Hypertension. Berlin: Springer-Verlag, 1990. 18. Falkner B. Hulman 5, Kushner H. Insulin-stimulated glucose utilisation and borderline hypertension in young adult blacks. Hypenension 1992; 10: suppl,
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