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Dietary Sodium Restriction Impairs Insulin Sensitivity in Noninsulin-Dependent Diabetes Mellitus¹

Department of Medicine and Therapeutics (J.R.P., K.M., H.L.E., J.McC.), West Glasgow Hospitals University NHS Trust, University of Glasgow, Glasgow G11 6NT; Department of Medicine (A.D.M.), Ninewells Hospital and Medical School, University of Dundee, Dundee 001954; Department of Clinical Physics and Bio-Engineering (T.E.H.), West Glasgow Hospitals University National Health Service Trust, Glasgow G11 6NT; Diabetes Centre (M.S.), West Glasgow Hospitals University NHS Trust, Glasgow G120YN, United Kingdom

Address all correspondence and requests for reprints to: Dr. John R. Petrie, Department of Medicine and Therapeutics, Western Infirmary, Glasgow G11 6NT, United Kingdom. E-mail: jrp1s{at}clinmed.gla.ac.uk

	Abstract

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Dietary sodium restriction has a variety of effects on metabolism, including activation of the renin-angiotensin system. Angiotensin II has complex metabolic and cardiovascular effects, and these may be relevant to the effects of both nonpharmacological and pharmacological interventions in noninsulin-dependent diabetes mellitus (NIDDM). We have assessed the effect of dietary sodium restriction on insulin sensitivity and endogenous glucose production in eight normotensive patients with diet-controlled NIDDM who underwent hyperinsulinemic clamp studies in a randomized, double-blind, placebo-controlled cross-over protocol after two 4-day periods on sodium replete (160 mmol/day) and sodium deplete (40 mmol/day) diets. Mean ± SD 24-h urinary sodium was 197 ± 76.0 mmol (replete) and 67 ± 19.5 mmol (deplete), P = 0.03. Insulin sensitivity was 42.0 ± 11.3 µmol/kg·min (replete) and 37.0 ± 11.6 µmol/kg·min (deplete), P = 0.04 (a reduction of 12%). Blood pressure was 130 ± 21/78 ± 11 mmHg (replete) and 128 ± 12/73 ± 10 mmHg (deplete). Dietary sodium restriction may result in a decrease in peripheral insulin sensitivity in normotensive patients with NIDDM, possibly via an elevation in prevailing angiotensin II concentrations.

	Introduction

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RESISTANCE to insulin-mediated glucose uptake (insulin resistance) is an important pathophysiological feature of noninsulin-dependent diabetes mellitus (NIDDM) (1). Pharmacological and nonpharmacological interventions that influence insulin sensitivity may have an impact on glycemic control and, ultimately, the incidence of diabetic complications. Current dietary recommendations suggest dietary sodium restriction for both hypertensive and normotensive patients with diabetes (2, 3).

It has been reported that inhibitors of angiotensin-converting enzyme, possibly acting via withdrawal of angiotensin II (ANG II), may alleviate insulin resistance in diabetic (and nondiabetic) subjects (4, 5, 6). Activation of the renin-angiotensin system (RAS), which occurs during sodium restriction, might therefore be expected to result in decreased insulin sensitivity. In contrast to these observations, it has been demonstrated that acute infusion of a pressor dose of ANG II increases insulin sensitivity in healthy volunteers (7, 8, 9), and we have previously reported a similar effect with a subpressor dose of ANGII in patients with NIDDM (10).

Information on the metabolic effects of RAS activation for a longer duration than is possible during infusion studies is available from studies of dietary sodium restriction in healthy volunteers, but data are conflicting (11, 12, 13, 14). We have examined, for the first time, the effect of dietary sodium restriction on insulin sensitivity (peripheral and hepatic) in patients with NIDDM.

	Subjects and Methods

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Patients

Nine diet-controlled Caucasian patients with NIDDM (one female), age (mean ± SD) 57 ± 9.7 yr, body mass index 28.6 ± 3.9 kg/m², fasting plasma glucose 9.0 ± 2.2 mmol/L (range 5.7–12.4 mmol/L), hemoglobin A1_c (HbA1_c) 5.7 ± 0.8% (normal range 3.4–4.9%), total cholesterol 5.76 ± 1.25 mmol/L with median duration of diabetes 12 months (range 4–92) gave written informed consent to participate in this study, which was approved by the Ethics Committee of the West Glasgow Hospitals University NHS Trust. All patients underwent a 75-g oral glucose tolerance test at screening, and none had evidence of retinopathy (as determined by direct fundoscopy) or microalbuminuria. NIDDM was confirmed, according to WHO criteria (15). Mean blood pressure (BP) on screening was 148 ± 25/82 ± 7 mmHg; two were cigarette smokers. Patients were maintained throughout the study on an isocaloric diet consisting of 55% carbohydrate, 25% fat, and 20% protein. They were asked to refrain from tobacco or strenuous exercise, and none were receiving any proprietary or prescription medication.

Diets

Diets were transported by taxi to patients’ homes. The sodium replete (160 mmol/day) and sodium deplete (40 mmol/day) diets were allocated in a randomized double-blind placebo-controlled design for 4 days each (Fig. 1) (16). On day 1, each patient commenced a 40 mmol/day diet for 4 days before the first study day (day 5); on day 8, they began an identical 4-day period before the second study day (day 12). During these two periods of 40 mmol/day sodium diet, patients received slow sodium tablets (Ciba-Geigy, Horsham, UK) at 120 mmol/day or matching placebo. On the first day only of the sodium deplete regime, patients received a single dose of frusemide (40 mg); this was matched by an identical placebo on the first day of the sodium replete regime. The predetermined minimum criteria for adequate compliance were: 1) an absolute sodium excretion of less than 100 mmol/day on the sodium deplete diet; and 2) a differential sodium excretion of at least 80 mmol/day between the two periods.

View larger version (20K): [in this window] [in a new window]   Figure 1. Study design (see text).

Each patient attended two identical 5-h study days in our Clinical Investigation and Research Unit. After an overnight fast (water was permitted), patients attended at 0800 h and completed a 24-h urine collection on arrival. After 20-min supine rest, baseline BP and heart rate measurements were recorded (Dinamap, Critikon,). Venous cannulae were inserted into the left antecubital fossa for the administration of test substances and retrogradely into a heated right dorsal hand vein (55–60 C) for arterialization of blood samples (17).

Whole-body insulin sensitivity and endogenous glucose production (EGP) were assessed using a modification of the hyperinsulinemic glucose clamp method of De Fronzo et al. (18). A primed continuous infusion of high-performance liquid chromatography-purified [3-³H]glucose was given during a 2-h equilibration period (-120 to 0 min). A primed constant-rate infusion of soluble insulin (1.5 mU/kg/min) in a 10% (vol/vol) solution of the patient’s own blood in saline (0.9% NaCl) was administered from 0–150 min. Arterialized serum glucose concentration was measured at the bedside every 5 min. A variable rate infusion of exogenous 20% dextrose was given from 4–150 min using an IMED (IMED Gemini Volumetric, Abingdon, UK) intravenous infusion system to maintain serum glucose at the fasting level (i.e. the clamp was isoglycemic not euglycemic). A tracer quantity of [3-³H]glucose was added to the 20% dextrose solution to avoid underestimation of EGP (19). The total activity of ³H administered to each patient was 5.2 MBq.

At -120, -60, -30, -20, -10, 0, 60, 120, 130, 140, and 150 min, additional blood samples were withdrawn for measurement of glucose specific activity, serum insulin, C-peptide, electrolytes and triglycerides, and plasma renin activity (PRA) and aldosterone. Plasma ANG II was measured at -120, 0, and 150 min.

Laboratory methods

Glucose concentration was measured at the bedside using a Beckman II Glucose Analyser (Beckman, Fullerton, CA). Plasma for glucose specific activity was deproteinized, using Ba(OH)₂ and ZnSO₄, by the method of Somogyi (20); after centrifugation, the supernatant was passed sequentially through anion and cation exchange columns to remove charged molecules. ³H activity was detected in an automatic liquid scintillation counter. Aliquots of tracer infusate and labeled exogenous dextrose infusion were spiked into nonradioactive plasma and were processed in parallel with plasma samples to allow calculation of [3-³H]glucose infusion rates. Triglycerides were measured, using enzymatic techniques, on a Roche Lobas-Bio centrifugal analyzer (Roche Diagnostics, Welwyn, UK). All blood samples for hormone concentrations were collected in chilled tubes and separated for storage at -70 C until assay. Serum insulin and C-peptide, and plasma aldosterone and PRA were measured in batches by direct RIA (INCSTAR, Stillwater, MN; intraassay coefficients of variation (CVs) 7, 7, 5, and 5%, respectively). Plasma ANG II was assayed after high-performance liquid chromatography separation by direct RIA (intraassay CV 6%) (21).

Statistical analysis and calculations

Results are expressed as mean ± SD. All data were checked for normality using the Shapiro-Wilks test (Minitab statistical package, Minitab Inc, State College, PA). Insulin sensitivity (M-value) in µmol glucose/kg·min was calculated by applying DeFronzo’s space correction to the glucose infusion rate, under steady-state conditions, during the final 40 min of each clamp (18). The insulin sensitivity index was calculated (S_IP x 10⁴ dL/min·kg per mU/L) from the glucose infusion rate and ambient insulin and glucose concentrations during the same period (22). The equations of Steele (23), as modified by DeBodo et al. (24), were used to determine rates of glucose appearance and disappearance during the periods -30 to 0 min (fasting) and 120–150 min (hyperinsulinemia), assuming a pool fraction of 0.65 and an extracellular vol of 190 mL/kg. Infusion rates of [3-³H]glucose were calculated as the sum of the rate of tracer activity in the continuous infusion and the rate of tracer activity in the variable-rate 20% dextrose infusion. Rates of EGP were calculated by subtraction of the exogenous glucose infusion rates required to maintain isoglycemia from the isotopically-determined rates of glucose appearance. M-value, S_IP, and EGP were compared between the 2 study days (sodium replete and deplete) using paired t tests; 95% confidence intervals (CI) are quoted. Insulin, C-peptide, sodium, potassium, PRA, aldosterone, and ANGII were compared between study days, by ANOVA, using Bonferroni-corrected t tests to correct for multiple comparisons at individual time points.

	Results

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The infusions and diets were well tolerated. Nine patients gave informed consent, but one patient was withdrawn owing to failure of compliance. There were no significant differences on the sodium replete and deplete diets in systolic BP, diastolic BP, or weight (Table 1).

On the sodium deplete diet, 24-h urinary sodium excretion and serum sodium concentrations were significantly lower (Table 1; also see Fig. 3); and the corresponding PRA, ANGII, and plasma aldosterone levels were significantly higher, both at baseline and throughout the clamp studies (Fig. 2). There were no significant differences in baseline or insulin-mediated reductions in serum potassium or triglycerides between the 2 study days (Fig. 3).

View larger version (14K): [in this window] [in a new window]   Figure 3. Mean ± SD profiles of sodium, potassium, and triglycerides, 2 h before and during clamp. , sodium replete; , sodium deplete; *, P < 0.05 (sodium replete vs. sodium replete).

View larger version (16K): [in this window] [in a new window]   Figure 2. Mean ± SD profiles of PRA, ANGII, and aldosterone, 2 h before and during clamp. , sodium replete; , sodium deplete; *, P < 0.05; **, P < 0.01; ***, P < 0.001 (sodium replete vs. deplete).

There were no significant differences in fasting serum insulin or glucose levels (Table 1). Similarly, there were no significant differences in steady-state serum insulin concentrations (Fig. 4).

View larger version (17K): [in this window] [in a new window]   Figure 4. Mean ± SD profiles of insulin and C-peptide, 2 h before and during clamp. , sodium replete; , sodium deplete.

The CVs of serum glucose at steady state were 3.1% (sodium replete) and 2.4% (sodium deplete). Insulin sensitivity (M-value) decreased from 42.0 ± 11.3 on the sodium replete diet to 37.0 ± 11.6 µmol/kg·min on the sodium deplete diet, P = 0.04, 95% CI: -10.1 and -0.23 (a reduction of 12%) (Fig. 5). Insulin sensitivity index (S_IP) fell from 5.8 ± 2.69 dL/min·kg per mU/L to 4.6 ± 2.04 x 10⁴ dL/min·kg per mU/L, P = 0.02, 95% CI: -2.14 and -0.29. Fasting EGP was similar on the two diets (9.1 ± 4.69 vs. 8.2 ± 5.02 µmol/kg·min, P = 0.74, 95% CI: -6.76 and 5.04), but there was a trend towards blunting of insulin-mediated EGP suppression on the sodium deplete diet that failed to reach statistical significance (-3.5 ± 5.24 vs. -0.93 ± 6.33 µmol/kg·min, P = 0.09, 95% CI: -5.78 and 0.57) (Fig. 6).

View larger version (16K): [in this window] [in a new window]   Figure 5. M-value (µmol glucose/kg·min) on sodium replete and sodium deplete diets. *, P < 0.05.

View larger version (16K): [in this window] [in a new window]   Figure 6. EGP (µmol glucose/kg·min) fasting and at steady-state hyperinsulinemia on sodium replete and sodium deplete diets.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

To the best of our knowledge, the effect of dietary sodium restriction on insulin sensitivity in patients with NIDDM has not previously been reported. In healthy volunteers, Sharma et al. detected no change in insulin sensitivity, as measured by the insulin suppression test, when subjects were maintained on 240 mmol/day vs. 20 mmol/day dietary sodium for 7 days (11). Similar findings have been reported using the euglycemic clamp technique and less severe sodium restriction (200 mmol/day vs. 80 mmol/day) (14). Donovan et al. reported increased insulin sensitivity, measured by the clamp technique, when subjects were maintained on very low (10 mmol/day), compared with very high (200 mmol/day), sodium diets for 5 days (12). In contrast, in a further study using the same technique, insulin sensitivity was decreased after 3 days on a low-sodium diet (20 mmol/24 h) (13). With one exception (14), these studies were open in design and used either very high or very low sodium diets, compliance with which is only achievable in a clinical research setting.

It is not possible to be certain of the mechanism for the consistent decrease in insulin sensitivity observed in the present study, but RAS activation is a strong candidate because ANGII has both gluconeogenic and glycogenolytic properties (25, 26). However, we cannot exclude involvement of the sympathetic nervous system, because it is known that subpressor doses of adrenaline reduce insulin sensitivity in healthy subjects (27). Indeed, ANGII is known to potentiate sympathetic neurotransmission in sodium-restricted subjects (28). Additionally, the observed decrease in serum sodium and the expected decrease in plasma volume during sodium restriction may have provided conflicting stimuli to the posterior pituitary: receptors for vasopressin are present in the liver and may modify hepatic glucose turnover, but there have been no published studies directly assessing the effect of the peptide on peripheral insulin sensitivity.

Ascribing the decrease in insulin sensitivity to increased levels of ANGII during sodium restriction may seem to conflict with previous reports, by ourselves and others, of hemodynamically-mediated insulin-sensitizing effects of acute infusions of ANGII (7, 8, 9, 10). It should be noted that ANG II has complex metabolic effects (29), including cross-talk with key components of the insulin signaling pathway, such as protein kinase C activation (30) and inhibition of insulin-stimulated PI 3-kinase activity (31). In the present study, high plasma ANGII concentrations were sustained over a period of days rather than hours, and it is known that down-regulation of vascular angiotensin receptors occurs at high endogenous levels of ANGII (32). If the mechanism was ANGII-related, it is more likely to have been metabolic rather than hemodynamic, given that plasma concentrations were elevated only moderately and that BP did not change.

It is interesting to speculate regarding the possible metabolic effects of more prolonged steady-state sodium restriction in our patients, particularly in view of the reported attenuation, after 7 days, of the decrease in insulin sensitivity reported after 3 days in the study by Fliser et al. (13). However, our patients (many of whom were in full-time employment) would have been reluctant to comply with a more prolonged period of sodium restriction or with serial 24-h urine collections to confirm steady-state sodium balance. If the observed effect was a transient nonbalance phenomenon, one might have expected a difference in effect size, depending on the order of treatment; this was not evident from inspection of the data.

Aldosterone release in response to ANGII is enhanced during hyperinsulinemia (33) and sodium restriction (34), but the decrease in insulin sensitivity we observed in the present study cannot readily be attributed to aldosterone because measured concentrations were comparable with those observed during acute ANGII infusion in our previous study, in which an increase in insulin sensitivity was observed (10). The observed effect was unlikely to be an artifact of plasma volume contraction caused by sodium restriction because expression of the results using the insulin sensitivity index (which adjusts for variations in steady-state clamp insulin concentrations) resulted in a larger and more statistically significant effect (21%).

Regardless of the underlying mechanism for the decrease in insulin sensitivity during moderate dietary sodium restriction in these patients, it may (if confirmed) have clinical, as well as metabolic, relevance. Current dietary recommendations for diabetes (in both Europe and the United States) are for normotensive patients to restrict sodium intake to 50–100 mmol/day (3–6 g) and for patients with coexisting hypertension to restrict intake to 40–50 mmol/day (2.4–3 g) (2, 3). We conclude that moderate dietary sodium restriction may not be an entirely harmless intervention in patients with NIDDM.

	Acknowledgments

 
We are grateful to Dr. Ian Morton for performing the ANGII assays.

	Footnotes

 
¹ This work was supported by the British Diabetic Association.

Received March 20, 1997.

Revised December 31, 1997.

Accepted February 6, 1998.

	References

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Petrie, J. R. Articles by MC Connell, J. Search for Related Content PubMed PubMed Citation Articles by Petrie, J. R. Articles by MC Connell, J.