Klin Wochenschr (1988) 66: 724-728
Klinische
The Effect of Low and High NaC1 Diets
on Oral Glucose Tolerance
T. Iwaoka, T. Umeda, M. Ohno, J. Inoue, S. Naomi, T. Sato, and I. Kawakami
Third Department of Internal Medicine and Dietetic Department, Kumamoto University Medical School, Kumamoto, Japan
Summary. The effects of low and high NaC1 diets
on plasma glucose and insulin responses to glucose
ingestion were investigated in 15 patients with es-
sential hypertension. Oral glucose (75 g) tolerance
tests were carried out while patients were taking
diets with low (2 g/day) and high (20 g/day) NaC1
content. Fasting plasma glucose and insulin levels
were both significantly lower during ingestion of
the high NaC1 diet (p < 0.05). After glucose inges-
tion, the incremental areas under the two hour
plasma glucose and insulin curves were significant-
ly smaller during ingestion of the high NaC1 diet
(glucose p < 0.005 and insulin p < 0.025). These
findings that low NaC1 diets increase the glycemic
response to glucose loads suggest that use of NaC1
restriction for the treatment of essential hyperten-
sion may not always be desirable.
Key words: NaC1 intake - Glucose tolerance - Na +
dependent glucose absorption - Intracellular Na +
concentration - Plasma Na +, K +-ATPase inhibi-
tor
Restriction of dietary sodium chloride (NaC1) is
regarded by some physicians as an important fea-
ture in the treatment of patients with hypertension
[13, 15, 19]. In some studies blood pressure has
been reported to be lowered in approximately half
of patients with essential hypertension with a re-
striction of dietary NaC1 for periods as short as
7 days [7, 14]. While NaC1 restriction may be effec-
tive in lowering blood pressure in a subset of pa-
tients with essential hypertension, its effect on car-
bohydrate metabolism has not been examined.
Abbreviations: Na +, K +-ATPase = sodium, potassium adeno-
sinetriphosphatase; SEM = standard error of the mean
Wochen-
schrift
© Springer-Verlag 1988
Since hypertension is known to be commonly asso-
ciated with glucose intolerance [l, 12, 20], it may
be important to examine the effect of low NaC1
diets on glucose metabolism. We examined the ef-
fect on the glycemic response to glucose of diets
containing small and large amounts of NaC1 in
patients with essential hypertension.
Subjects and Methods
Fifteen untreated hypertensive patients partici-
pated in the study. They had their blood pressures
taken in the sitting position at Hypertension Clinic
of Kumamoto University Hospital. Hypertension
was defined as a systolic pressure greater than
160 m m H g and/or a diastolic pressure greater than
95 m m H g on the last two visits. After admission,
each patient underwent a thorough evaluation in-
cluding a history and physical examination, urina-
lysis, chest roentgenogram, electrocardiogram, ra-
pid sequence intravenous pyelogram, blood studies
for electrolytes, plasma renin activity and aldoster-
one and the measurement of urinary 17-hydroxy-
corticosteroids, 17-ketosteroids, epinephrine and
norepinephrine on a normal (11 g per day) NaC1
diet. None were found to have an identifiable cause
for hypertension. Nine were men and six were
women. Their ages ranged from 37 to 67 years
(52 + 2, m e a n _ SEM) and body mass indexes were
18.2 to 27.0 (23.3 _ 0.5). All subjects gave informed
consent to the tests which were performed.
Each patient was studied for 8 days on two dif-
ferent diets (cross over design). The patients were
randomly assigned to low (2 g per day) and high
(20 g per day) NaC1 diets. This resulted in 7 pa-
tients starting with the low NaC1 diet. N o NaC1
was added in cooking or at the table in the low
NaC1 diet. In the high NaC1 diet, 9 g of NaC1 was
added in cooking and another 9 g of NaC1 was
T. Iwaoka et al. : Dietary NaCI and Glucose Tolerance 725

administered by tablets (Slow Sodium, Ciba, UK). Table 1. Blood pressures (mean-+SEM) during the low (2 g/
The daily amount of potassium intake during the day) and high (20 g/day) NaC1 diets after admission
period of one week was not significantly different NaC1 intake low high p
between the low and high NaC1 diets (2.28_+ 0.08
vs 2.41 + 0.06 g/day, p > 0.05). Neither were those SBP ( m m H g ) 137.8-+3.4 150.4-+4.4 <0.01
of the calories, carbohydrates, proteins, nor fats DBP (mmHg) 84.5-+2.3 88.2_+3.5 NS
intake. The daily calorie intake of each patient was MBP (mmHg) 102.2_+2.4 108.8__3.5 <0.02
adjusted to 1500 or 1800 kcal diet according to SBP=systolic blood pressure, DBP=diastolic blood pressure,
their body weight. On the 6th to 8th day of the MBP = mean blood pressure
low and high daily dietary NaC1 diets, blood pres-
sure in the right arm was measured at 8, 12, 16,
20 and 24 o'clock using an automatic sphygmo- Table 2. Laboratory data (mean-+SEM) during the low (2 g/
manometer (Colin, Japan) in the supine position. day) and high (20 g/day) NaC1 diets
Mean blood pressure was calculated as the diastol-
ic pressure plus one-third of the pulse pressure. NaC1 intake low high p
The means of mean blood pressure at five points Urinary Na output 28.9 _+2.8 315.5 _+19.2 <0.001
during each of the two diets were compared. On (mEq/day)
the same day, venous blood was drawn in the fast- Urinary Koutput 39.9 +_3.3 41.7 + 2.0 NS
ing state for the measurement of serum sodium (mEq/day)
and potassium concentrations. Urine was also col- Serum Na (mEq/1) 139.9 +0.7 142.9 -+ 0.8 <0.01
lected for the measurement of daily sodium and
Serum K (mEq/1) 4.40_+0.08 4.27+ 0.10 NS
potassium output. On one other day during 6th
to 8th day of each diet, 75 g oral glucose tolerance RBCNa(mEq/1) 8.2 _+0.3 8.7 _+ 0.7 NS
tests were carried out. Venous blood samples for RBC K (mEq/1) 94.4 _+1.3 95.1 _+ 1.2 NS
the measurement of glucose and insulin concentra-
tions were drawn in the fasting state at 9 A M and RBC Na=intraerythrocyte sodium concentration, RBC K=
intraerythrocyte potassium concentration
30, 60 and 120 min after the ingestion of 225 ml
of water containing 75 g of glucose. Plasma glucose
concentrations were measured with a glucose oxi-
insulin curves above fasting values were calculated
dase method (Glucose A U T O and STAT, K y o t o
using the trapezoidal area. Mean values were com-
Daiichi Kagaku, Japan). Plasma insulin concentra-
pared with paired t-tests.
tions were measured using a double antibody ra-
dioimmunoassay kit (Pharmacia Diagnostics, Swe-
den). Patients received no antihypertensive drugs
Results
for at least two weeks before the study.
In 14 patients, intraerythrocyte sodium and po- The mean of ambulatory blood pressure was
tassium concentrations were determined on the 6th 173.3 +2.3/104.1 +_ 1.8 mmHg, which was sponta-
to 8th day of the low and high NaC1 diets. One neously decreased after admission. Mean blood
ml of heparinized blood was drawn in the fasting pressure during the low NaC1 diet period was sig-
state and centrifuged at 6000 g for 3 min. After nificantly lower than that during the high NaC1
removal of the supernatant and buffy coat, the diet period (Table 1). In 6 of 15 patients, however,
sediment was washed three times with i ml of mean blood pressure was not lower during the low
l l 0 m M magnesium chloride (MgC12) at 4°C. NaC1 diet period.
After the final centrifugation, the cell pellet was The labolatory data during the tow and high
suspended in 0.4 ml of the MgC12 solution. Fol- NaC1 diets are shown in Table 2. Both urinary Na
lowing hematocrit determination, 0.1 ml of the sus- output and serum Na levels during the high NaC1
pension was hemolyzed with 9.9 ml of distilled diet were higher than those during the low NaC1
water. The sodium and potassium concentrations diet. However, neither urinary K output nor serum
were determined with a flame photometry (Atomic K levels were significantly different between two
Absorption Spectrophotometer 2380, Perkin Elmer, diets.
USA). Intraerythrocyte sodium and potassium Both plasma glucose and plasma insulin con-
concentrations were calculated after correcting for centrations in the fasting state were slightly but
the hematocrit. significantly lower during the high NaCI diet peri-
Data are shown as the mean_+ SEM. Incremen- od (plasma glucose concentration 96.2-t-4.2 vs
tal areas under the two hour plasma glucose and 91.4 _+3.3 mg/dl, p < 0.05, and plasma insulin con-
726 T. Iwaoka et al.: Dietary NaC1 and GlucoseTolerance

Plasma glucose 1-a Plasma insulin 1-b

concentration concentration
(mg/dl) (/~U/ml)
200 IO0

100 50 Fig. 1. Plasma glucose (l-a) and insulin (l-b)

concentrations before and after ingestion of 75 g of
glucose on the 6th to 8th day of low and high NaCI
diets. Open and closed circles indicate those values
~4 P<0.05 /I NaCI intake during the low and high NaC1 diets, respectively.
' ~ P<0,025 {// 2 g/day Bars indicate 1 SEM. Asterisks mark mean values
~ '~ P<0.005 ~' - - - - 20 g/day which were significantlydifferentbetweengroups
I f t (* p < 0.05, ** p < 0.025, *** p < 0.005)
0 60 120 0 60 120
Time (minute) Time (minute)

Incremental area of 2-a Incremental area of 2-b

plasma glucose plasma insulin
(rag, h/dl) (/zU-h/ml)
p<0.005
300 , 300 r
p<0.025

2OO 200

100

Fig. 2. Incremental areas under two hour plasma glucose

(2-a) and insulin (2-b) curves after 75 g of glucose on the
0 I I 0 1 I 6th to 8th day of ingestion of low and high NaC1 diets
2 20 2 2O
NaCI intake (g/day) NaCI intake (g/day)

centration 7.8 _+1.0 vs 6.2_ 0.5 pU/ml, p < 0.05).
Mean plasma glucose concentrations were lower
30, 60 and 120 rain after glucose ingestion during
the high NaC1 diet than during the low NaC1 diet
period (p<0.005-0.025) (Fig. ]-a). Mean plasma
insulin concentrations were also lower 30, 60 and
120 min after glucose ingestion during the high
NaC1 diet period (p <0.025-0.05) (Fig. l-b). Thir-
teen of the 15 patients had smaller incremental ar-
eas under the glucose curves while taking the high
NaC1 diet (Fig. 2-a). The mean of the incremental
areas under the two hour plasma glucose curves
and plasma insulin curves were also significantly
smaller during the high NaC1 diet period than dur-
ing the low NaC1 diet period (incremental areas
of glucose 153.4_+16.7 vs 110.3_+11.5mg-h/dl,
p<0.005, and those of insulin 97.1_+18.4 vs
69.2 _+12.1 pU" h/ml, p < 0.025) (Fig. 2-a, and 2-b).
The coefficients of intraassay and interassay
variance for the measurement of intraerythrocyte
sodium concentrations were 3.7% (n = 8) and 5.5%
(n = 6), respectively. Those for intraerythrocyte po-
tassium concentrations were 3.3% ( n = 8 ) and
5.3% (n= 6). Eleven of t4 patients showed an ele-
vation of intraerythrocyte sodium concentration
with increase of NaC1 intake. However, the differ-
ence of mean intraerythrocyte sodium concentra-
tions during the low NaC1 diet and the high NaC1
diet periods was not statistically significant
(8.2_+0.3 vs 8.7_+0.3 m Eq/1, p>0.05). The mean
intraerythrocyte potassium concentrations were
unchanged with increase of dietary NaC1 intake
(Table 2).
Discussion
We found that blood pressure in patients with es-
sential hypertension was lowered while the patients
T. Iwaoka et al. : Dietary NaC1 and Glucose Tolerance
were taking a tow NaC1 diet. H o w e v e r , i m p a i r e d
glucose tolerance was o b s e r v e d at the s a m e time.
A c c o r d i n g to the h y p o t h e s i s by C r a n e [3] a n d
the review b y G r a y [9], in active glucose t r a n s p o r t ,
glucose binds to a carrier a l o n g with N a ÷ at a
different b i n d i n g site a n d is carried into the intesti-
nal wall cells. Since intracellular N a ÷ c o n c e n t r a -
tions are low, N a ÷ can m o v e d o w n a c o n c e n t r a t i o n
gradient into the cell a n d glucose a c c o m p a n i e s
N a ÷ o n the carrier. Therefore, one factor deter-
m i n i n g the a b s o r p t i o n o f glucose f r o m the intesti-
nal l u m e n is the g r a d i e n t o f N a ÷ c o n c e n t r a t i o n
between the intestinal l u m e n a n d the interior o f
the intestinal epithelium. W h e n N a ÷ c o n c e n t r a t i o n
in the intestinal l u m e n is elevated, the a b s o r p t i o n
o f glucose is facilitated because o f the i n c r e m e n t
o f the l u m e n to tissue N a ÷ c o n c e n t r a t i o n gradient.
In fact, it was p r o v e d b y F e r r a n n i n i et al. in glu-
cose tolerance test with or w i t h o u t addition o f
NaC1 [6]. O n the other hand, an i n c r e m e n t o f the
intracellular N a ÷ c o n c e n t r a t i o n w o u l d be expected
to suppress the a b s o r p t i o n o f glucose. This w o u l d
decrease the glycemic r e s p o n s e to an oral glucose
toad.
We measured intraerythrocyte Na ÷ concentra-
tions instead o f using intestinal epithelium a n d
f o u n d t h e m to be higher in 11 out o f 14 w h e n they
were taking the high NaC1 diet. H o w e v e r , the dif-
ference was n o t statistically significant. M e a n -
while, C o s t a et al. [2] treated b o r d e r l i n e h y p e r t e n -
sive patients with a low NaC1 diet (3 g/day) a n d
f o u n d a significant decrease o f i n t r a l y m p h o c y t i c
sodium.
W e a n d s o m e investigators [5, 10, 11, 16] h a v e
suggested t h a t a natriuretic f a c t o r could be r e s p o n -
sible f o r elevating intracellular N a ÷ c o n c e n t r a t i o n
in patients with essential hypertension. This f a c t o r
is t h o u g h t to suppress the extrusion o f N a ÷ f r o m
cells by inhibiting N a t, K ÷ - A T P a s e a n d in this
w a y to elevate intracellular N a ÷ c o n c e n t r a t i o n . I n
fact, excessive NaC1 intake was s h o w n to increase
secretion o f this natriuretic f a c t o r [4, 8, 18]. I f the
natriuetic f a c t o r elevates N a ÷ c o n c e n t r a t i o n inside
intestinal epithelium, the efficiency o f glucose ab-
s o r p t i o n t h r o u g h intestinal wall coupling with N a +
w o u l d be decreased.
T h o r b u r n et al. [17] r e c o m m e n d that diabetics,
as well as the general p o p u l a t i o n , should reduce
their intake o f NaC1 because o f the e n h a n c e m e n t
o f glycemic r e s p o n s e to c a r b o h y d r a t e b y the addi-
t o n o f NaC1 at the time o f c a r b o h y d r a t e loading.
O u r results do n o t s u p p o r t their r e c o m m e n d a t i o n .
A l t h o u g h further studies are required to e x a m i n e
the effect o f NaC1 restriction for long periods o n
glucose m e t a b o l i s m , m o r e c a u t i o n is needed in re-
727
c o m m e n d i n g low NaC1 diets to patients with essen-
tial h y p e r t e n s i o n w h o s e b l o o d pressures are n o t
lowered b y NaC1 restriction, a n d in patients with
i m p a i r e d glucose tolerance.
Acknowledgment: The authors thank C.A. Nugent, M.D., Uni-
versity of Arizona College of Medicine, for revising the manu-
script.
References
1. Barrett-Corner E, Criqui MH, Klauber MR, Holdbrook
M (t981) Diabetes and hypertension in a community of
older adults. Am J Epidemiol 113 :276-284
2. Costa FV, Ambrosioni E, Montebugnoli L, Paccaloni L,
Vasconi L, Magnani B (1981) Effects of a low-salt diet and
acute salt loading on blood pressure and intralymphocytic
sodium concentration in young subjects with borderline hy-
pertension. Clin Sci 6i : 21s-23s
3. Crane PK (1965) Na+-dependent transport in the intestine
and other animal tissue. Fed Proc 24:100~1006
4. de Wardener HE, MacGregor GA, Clarkson EM, Alagh-
band-Zadeh J, Bitensky L, Chayen J (1981) Effect of sodium
intake on ability of human plasma to inhibit renal Na ÷-K +-
adenosine triphosphatase in vitro. Lancet 1:411 412
5. de Wardener HE, MacGregor GA (1983) The role of a
circulating inhibitor of Na +-K ÷-ATPase in essential hyper-
tension. Am J Nephrol 3 : 88-91
6. Ferrannini E, Barrett E, Bevilacqua S, Dupre J, Defronzo
RA (1982) Sodium elevates the plasma glucose response
to glucose ingestion in man. J Clin Endocrinol Metab
54:455-458
7. Fujita T, Henry WL, Bartter CF, Lake CR, Delea CS (1980)
Factors influencing blood pressure in salt-sensitive patients
with hypertension. Am J Med 69 : 334-344
8. Gault MH, Vasdev SC, Longerich LL, Fernandez P, Prab-
hakaran V, Dave M, Maillet C (1983) Plasma digitalis-like
factor(s) increase with salt loading. N Engl J Med 309:1459
9. Gray GM (1975) Carbohydrate digestion and absorption.
Role of smatl intestine. N Engl J Med 292:1225-t230
10. Hamlyn JM, Ringel R, Schaeffer J, Levinson PD, Hamilton
BP, Kowarski AA, Blaustein MP (1982) A circulating inhib-
itor of (Na ÷+ K +)ATPase associated with essential hyper-
tension. Nature 300:650-652
11. Iwaoka T, Nugent CA, Umeda T, Sato T (1987) (Na ÷ +
K ÷) ATPase inhibitors and intracellular electrolytes in es-
sential hypertension. Jpn Heart J 28 : 695-705
12. Jarett RJ, Keen H, McCartney M, Fuller JH, Hamilton
PJS, Reid DD, Rose G (1978) Glucose tolerance and hyper-
tension. Int J Epidemiol 7:15-24
13. Kaplan NM (1985) Non-drug treatment of hypertension.
Ann Intern Med 102:359-373
14. Kawasaki T, Delea CS, Bartter CF, Smith H (1978) The
effect of Ngh-sodium and low-sodium intakes on blood
pressure and other related variables in human subjects with
idiopathic hypertension. Am J Med 64:193-t98
15. MacGregor GA, Markandu ND, Best FE, Elder DM, Cam
JM, Sagnella GA (1982) Double-blind randomised cross-
over trial of moderate sodium restriction in essential hyper-
tension. Lancet 1:351-355
t6. Poston L, Sewell RB, Wilkinson SP, Richardson PJ, Wil-
liams R, Clarkson EM, MacGregor GA, de Wardener H
(1981) Evidence for a circulating sodium transport inhibitor
in essential hypertension. Br Med J 282:842849
728
17. Thorburn AW, Brand JC, Truswell AS (1986) Salt and the
glycemic response. Br Med J 292:1697-1699
18. Umeda T, Hamasaki S, Naomi S, Inoue J, Miura F, Ohno
M, Iwaoka T, Sato T (1986) Evidence for reduced central
dopaminergic activity in salt-sensitive essential hyperten-
sion. In: Nakamura K (ed) Brain and blood pressure con-
trol. Elsevier Science Publishers, New York, pp 353-
358
19. Watt GCM, Edwards C, Hart JT, Hart M, Walton P, Foy
CJW (1983) Dietary sodium restriction for mild hyperten-
sion in general practice. Br Med J 286:432-436
T. Iwaoka et al. : Dietary NaC1 and Glucose Tolerance
20. Zimmet P (1982) Type 2 (non-insulin-dependent) diabetes:
an epidemiological overview. Diabetologia 22: 399-411
Received: January 8, 1988
Returned for revision: February 26, 1988
Accepted: June 7, 1988
Taisuke Iwaoka, MD
The Third Department of Internal Medicine,
Kumamoto University Medical School,
Honjyo 1-1-1, Kumamoto 860, Japan