Insulin Resistance Abstracts 8 - Salt or Sodium

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The effect of sodium supplementation on glucose tolerance and insulin concentrations in patients with hypertension and diabetes mellitus

            (Ames 2001) Download

Severe short-term sodium restriction or extreme sodium loading may alter glucose tolerance and insulin resistance in patients with hypertension, but it is unclear whether variations in sodium intake within the clinically observed range affect glucose tolerance. To examine this issue, 21 patients with primary hypertension with average sodium excretion of 116+/-55 mEq/day were randomized to consecutive 4-week periods of placebo therapy and sodium chloride supplementation 2 g four times a day in a single-blind crossover study design. A 75-g oral glucose tolerance test (GTT) with simultaneous insulin levels was performed at the end of each intervention period. For the group as a whole, urinary sodium excretion increased on sodium chloride to 267+/-118 mEq/day versus control (placebo) phase of 135+/-53 mEq/day, P < .001. Total glycemic response in the oral GTT (area under the glucose curve) was 8.0% lower during sodium supplementation, P < .001. Secondary analysis revealed that the effect of sodium was noteworthy in 1) type 2 diabetic subjects (n = 8), 2) sodium-sensitive subjects (n = 10), and 3) nondiabetic subjects receiving antihypertensive drug treatment (n = 6). The total insulinemic response to oral GTT was also lowered by sodium loading among diabetic subjects. Thus, an abundant sodium intake may improve glucose tolerance and insulin resistance, especially in diabetic, salt-sensitive, and or medicated essential hypertensive subjects.

Insulin, sodium-lithium countertransport, and microalbuminuria in hypertensive patients

            (Andronico, Ferrara et al. 1998) Download

Both microalbuminuria (>0.290 nmol/min [20 microg/min]) and high sodium-lithium countertransport (SLC) in diabetic or hypertensive humans are predictive of overt nephropathy and more aggressive cardiovascular complications, perhaps induced by insulin resistance. To analyze the relationships between microalbuminuria, SLC, microalbuminuria, and insulin in essential hypertension, we studied 90 hypertensive white patients, 25 of whom had microalbuminuria and 32 of whom were healthy. When urine sampling was completed for albuminuria determination, SLC was measured; all patients then underwent standard (75 g) oral glucose load to measure basal (0 minutes) and 2-hour glucose and insulin serum levels. Glucose-insulin ratio was used as insulin sensitivity index (ISI). In both hypertensive patients with normal microalbuminuria and those with pathological microalbuminuria, plasma insulin at 120 minutes was significantly higher than in control subjects. When the patients with pathological microalbuminuria were divided into thirds on the basis of their microalbuminuria, in the lower third, we found statistically significant less fasting insulin and higher basal ISI. SLC was higher in hypertensives than normotensives and, among hypertensives, higher in the subgroup with elevated microalbuminuria. In hypertensives, we found a weak but significant correlation between SLC and microalbuminuria, independent of insulin or ISI. The prevalence of high value of SLC (> or =0.383 mmol x L-1 x h-1) was significantly lower in hypertensives with normal rather than abnormal urinary albumin excretion. Our results indicate that in nondiabetic hypertensive whites, higher microalbuminuria is accompanied by signs of insulin resistance; moreover, a link exists between SLC and microalbuminuria, both predictive of aggressive complications of hypertension.

Insulin resistance is associated with high sodium-lithium countertransport in essential hypertension

            (Doria, Fioretto et al. 1991) Download

The nature of the association between essential hypertension and insulin resistance remains unknown. We measured plasma glucose and insulin levels after an oral glucose tolerance test (OGTT), as well as insulin sensitivity (using a euglycemic hyperinsulinemic clamp), glucose turnover (Rd; using [6,6-2H2]- and [3-3H]glucose isotopic dilution), and forearm net balance of glucose (using arterial-venous difference) in 22 hypertensive patients with high (H2) red blood cell (RBC) sodium-lithium countertransport (Na(+)-Li+ CT; greater than 0.41 mmol.l RBC-1.h-1), 21 hypertensive patients with normal (H1) Na(+)-Li+ CT, and 22 normotensive controls (C). After OGTT, H2 patients had higher plasma glucose and insulin levels than H1 and C. During euglycemic hyperinsulinemia (approximately 100 microU/ml) Rd was lower in H2 [21.7 +/- 1.4 (SE) mumol.kg-1.min-1] than in H1 (44.3 +/- 2.9; P less than 0.01) and C (48.1 +/- 3.0; P less than 0.01), and an inverse correlation was found between rates of Na(+)-Li+ CT and Rd in H1 and H2 (rs = -0.76; P less than 0.01). Forearm glucose uptake was 40-50% lower in H2 compared with H1 and C (P less than 0.01). Lactate concentration increased more in C (from 511 +/- 24 to 1,207 +/- 69 microM) and in H1 (from 564 +/- 40 to 1,122 +/- 99) than in H2 (from 581 +/- 42 to 950 +/- 102, P less than 0.05 vs. both). Forearm blood flow increased more in C (31%, P less than 0.05) and H1 (22%, P less than 0.05) than in H2 (12%).(ABSTRACT TRUNCATED AT 250 WORDS)


Sodium-lithium countertransport is associated with insulin resistance and urinary albumin excretion in young African-Americans

            (Falkner, Canessa et al. 1997) Download

Increased activity of the sodium transporter, sodium-lithium countertransport (SLC), is reported in hypertensive white patients with evidence of cardiac and renal injury. The purpose of this study was to determine whether increased SLC activity detects risk for nephropathy or vascular disease in nondiabetic, young adult African-Americans. We examined 85 African-Americans aged 25 to 33 years with measurement of blood pressure, an oral glucose tolerance test to measure insulin response to glucose challenge, and an insulin clamp for insulin sensitivity (M). Fasting plasma lipids were measured, and the Vmax and Km for Na+ were assayed on red blood cells. Urinary albumin excretion (UAE) was measured on timed collections. There was a statistically significant correlation of the Vmax for SLC with M (r = -0.26, P = 0.02) and with UAE (r = 0.25, P = 0.02). The Km for Na+ to activate SLC was also elevated in the subgroup of subjects with elevated Vmax of SLC. There was no significant correlation of SLC with blood pressure in bivariate analysis. Step-wise multiple linear regression analysis of all variables on the Vmax SLC demonstrated that plasma triglyceride, UAE, body mass index, systolic blood pressure, M, and fasting insulin were step-wise selected into the linear regression model (F-ratio = 3.2, df = 77, R = 0.46, P < 0.009). In this young adult African-American population, elevated SLC activity is detected in association with metabolic and lipid alterations typical of insulin resistance. Elevated SLC activity is also associated with higher rates of UAE, suggesting possible evidence of early renal injury.

Insulin resistance and salt-sensitive hypertension in metabolic syndrome

            (Fujita 2007) Download

Metabolic syndrome, which is caused by obesity, is now a global pandemic. Metabolic syndrome is an aggregation of dyslipidaemia, hypertension and dia- betes. Moreover, metabolic syndrome is a highly predisposing condition for cardiovascular disease. Recent clinical studies have shown that metabolic syndrome also increases the risk for proteinuria and chronic kidney disease (CKD) [1]. For a definition of metabolic syndrome, indeed, visceral obesity is essential and more than two of the following compo- nents: blood pressure, glucose and lipid abnormalities. However, insulin resistance is a key factor to develop- ing these components of metabolic syndrome. Based on recent progress of research on adipocytes, visceral obesity plays a critical role in the development of insulin resistance. Indeed, angiotensionogen, one of adipokines such as TNF-a and NEFA, which are produced by visceral fat, might contribute to the devel- opment of insulin resistance in the muscle and adipose tissues [2]. In contrast, lack of insulin resistance in the kidney increases tubular sodium reabsorption by hyperinsulinaemia, leading to sodium retention in the body, and resultant salt-sensitive hypertension [3]. Therefore, there is an intimate relationship between insulin resistance and salt-sensitive hypertension in obese hypertensive patients with metabolic syndrome [4–7].

Low-salt diet increases insulin resistance in healthy subjects

            (Garg, Williams et al. 2011) Download

Low-salt (LS) diet activates the renin-angiotensin-aldosterone and sympathetic nervous systems, both of which can increase insulin resistance (IR). We investigated the hypothesis that LS diet is associated with an increase in IR in healthy subjects. Healthy individuals were studied after 7 days of LS diet (urine sodium <20 mmol/d) and 7 days of high-salt (HS) diet (urine sodium >150 mmol/d) in a random order. Insulin resistance was measured after each diet and compared statistically, unadjusted and adjusted for important covariates. One hundred fifty-two healthy men and women, aged 39.1 +/- 12.5 years (range, 18-65) and with body mass index of 25.3 +/- 4.0 kg/m(2), were included in this study. Mean (SD) homeostasis model assessment index was significantly higher on LS compared with HS diet (2.8 +/- 1.6 vs 2.4 +/- 1.7, P < .01). Serum aldosterone (21.0 +/- 14.3 vs 3.4 +/- 1.5 ng/dL, P < .001), 24-hour urine aldosterone (63.0 +/- 34.0 vs 9.5 +/- 6.5 mug/d, P < .001), and 24-hour urine norepinephrine excretion (78.0 +/- 36.7 vs 67.9 +/- 39.8 mug/d, P < .05) were higher on LS diet compared with HS diet. Low-salt diet was significantly associated with higher homeostasis model assessment index independent of age, sex, blood pressure, body mass index, serum sodium and potassium, serum angiotensin II, plasma renin activity, serum and urine aldosterone, and urine epinephrine and norepinephrine. Low-salt diet is associated with an increase in IR. The impact of our findings on the pathogenesis of diabetes and cardiovascular disease needs further investigation.

Sodium/lithium countertransport, insulin resistance, insulin peptides and microalbuminuria in clinically healthy 58-year-old men

            (Herlitz, Bokemark et al. 2001) Download

The activity of the erythrocyte transport system, sodium/lithium countertransport (SLC), has been linked to the metabolic syndrome characterized by insulin resistance and compensatory hyperinsulinaemia. We measured SLC and insulin sensitivity with the euglycaemic hyperinsulinaemic clamp method in a patient sample (n = 93) randomly selected from a large clinically healthy group of 58-year-old men (n = 818). The lipid profile, blood pressure, body mass index (BMI) and insulin were also analysed. There was a significant difference (P < 0.001) in SLC between subjects with the metabolic syndrome (n = 19) and subjects without any components of this syndrome (n = 20). There was a highly significant correlation between SLC and BMI, waist/hip ratio, total body fat mass, serum triglycerides, plasma insulin, proinsulin split products and C-peptide in a univariate analysis. There was also a significant correlation between SLC and insulin sensitivity measured as insulin-mediated glucose uptake (P < 0.01). In multiple regression analysis, only two of the variables showing univariate significance were independently correlated to SLC, i.e. serum triglycerides (P < 0.001) and BMI (P < 0.01). The subjects with a SLC value in the highest tertile had a 6-fold higher prevalence of insulin resistance (low-insulin-mediated glucose uptake) as compared with those with a SLC value in the lowest tertile. We conclude that, in clinically healthy 58-year-old men from the general population, erythrocyte SLC is closely linked to metabolic syndrome, in particular to obesity, triglycerides and insulin resistance.

Significant improvement of insulin resistance of GK rats by treatment with sodium selenate

            (Iizuka, Ueda et al. 2011) Download

We studied the effect of sodium selenate on insulin resistance of Goto-Kakizaki (GK) rats. Rats were kept on standard laboratory chow with and without i.p. injections of sodium selenate (0.173 mg/kg body weight) for 14 days, and then subjected to the glucose clamp. The glucose clamp studies confirmed an improvement in insulin-stimulated glucose disposal in GK rats treated with sodium selenate, with respect to both insulin sensitivity and responsiveness. This amelioration of insulin resistance may be partly due to a direct effect of the sodium selenate on peripheral tissues. 2-Deoxyglucose uptake in sodium selenate-treated adipocytes was increased and the insulin findings suggest that sodium selenate increases not only insulin sensitivity but also insulin responsiveness. Sodium selenate also accelerated glucose incorporation into adipocytes of rats, suggesting that the action of sodium selenate is peripheral. Interestingly, sodium selenate at a high concentration (about 1 mmol/L) was more effective than insulin in enhancing glucose uptake. The present study suggested that sodium selenate treatment led to substantial improvement in peripheral insulin resistance.

Salt, aldosterone, and insulin resistance: impact on the cardiovascular system

            (Lastra, Dhuper et al. 2010) Download

Hypertension and type 2 diabetes mellitus (T2DM) are powerful risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD), both of which are leading causes of morbidity and mortality worldwide. Research into the pathophysiology of CVD and CKD risk factors has identified salt sensitivity and insulin resistance as key elements underlying the relationship between hypertension and T2DM. Excess dietary salt and caloric intake, as commonly found in westernized diets, is linked not only to increased blood pressure, but also to defective insulin sensitivity and impaired glucose homeostasis. In this setting, activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS), as well as increased signaling through the mineralocorticoid receptor (MR), result in increased production of reactive oxygen species and oxidative stress, which in turn contribute to insulin resistance and impaired vascular function. In addition, insulin resistance is not limited to classic insulin-sensitive tissues such as skeletal muscle, but it also affects the cardiovascular system, where it participates in the development of CVD and CKD. Current clinical knowledge points towards an impact of salt restriction, RAAS blockade, and MR antagonism on cardiovascular and renal protection, but also on improved insulin sensitivity and glucose homeostasis.

Insulin resistance due to chronic salt restriction is corrected by alpha and beta blockade and by L-arginine

            (Ruivo, Leandro et al. 2006) Download

Dietary salt restriction is associated with evidence of low insulin sensitivity. The current study was undertaken to investigate whether sympathetic nervous system and l-arginine-nitric oxide pathway activities are linked to insulin resistance in rats under chronic low salt intake. Male Wistar rats were fed a low (LSD) or normal (NSD) salt diet from weaning to adulthood. A euglycemic hyperinsulinemic clamp was performed in 4 sub-groups on each diet: (1) sympathetic nervous system blockade (propranolol and prazosin), (2) vehicle, (3) L-arginine, and (4) D-arginine. Blood pressure, heart rate and metabolic measurements were done before and 45 min after drug infusion and at the end of the clamp. At baseline conditions, body weight, hematocrit, blood glucose, plasma insulin, cholesterol, and triacylglycerols were higher in LSD than in NSD rats. Systolic blood pressure was lower and heart rate was higher in rats on LSD than on NSD. Glucose uptake was lower on LSD compared to NSD. Sympathetic nervous system blockade and L-arginine did, and vehicle and D-arginine did not improve glucose uptake in LSD rats. On NSD there was no effect of any of the infused drugs. A positive correlation between plasma nitrate and nitrite at the end of clamp and glucose uptake was observed in L-arginine--but not in D-arginine-infused LSD rats. These results provide evidence that the sympathetic nervous system and the L-arginine-nitric oxide pathway are involved in the glucose uptake impairment induced by chronic dietary salt restriction.


Insulin resistance and salt sensitivity. A renal hemodynamic abnormality?

            (Weir 1996) Download

Salt has been a staple of the human diet for millennia and has long been known to be a critical factor in blood pressure regulation. The threshold and precise relationship between dietary salt and blood pressure has not been established. Moreover, there is significant variability in blood pressure responses to changes in dietary salt between patients. This variation approximates a Gaussian distribution, is highly reproducible in individual patients, and is persistent over time. Recent clinical studies have demonstrated that blood pressure, salt sensitivity and insulin resistance frequently coexist. It is likely that neurohormonal systems, particularly the sympathetic nervous system and the renin-angiotensin system, play a critical role in explaining the interrelationship of salt sensitivity, insulin resistance, and an impaired pressure-natriuresis response.

Salt sensitivity is associated with insulin resistance, sympathetic overactivity, and decreased suppression of circulating renin activity in lean patients with essential hypertension

            (Yatabe, Yatabe et al. 2010) Download

BACKGROUND: The mechanisms by which a derangement of glucose metabolism causes high blood pressure are not fully understood. OBJECTIVES: This study aimed to clarify the relation between salt sensitivity of blood pressure and insulin resistance, which are important subcharacteristics of hypertension and impaired glucose metabolism, respectively. Effects on the renin-angiotensin and sympathetic nervous systems were also studied. DESIGN: The state of glucose metabolism was assessed by a hyperinsulinemic euglycemic glucose clamp technique and a 75-g oral-glucose-tolerance test in 24 essential hypertensive patients who were lean and without diabetes or chronic kidney disease. The subjects were classified as salt-sensitive or salt-resistant on the basis of the difference (Delta mean blood pressure >/=5%) between 24-h ambulatory blood pressure monitoring results on the seventh day of low-salt (34 mmol/d) and high-salt (252 mmol/d) diets. Urine and blood samples were collected for analyses. RESULTS: There was a robust inverse relation between the glucose infusion rate (GIR) and the salt sensitivity index. The GIR correlated directly with the change in urinary sodium excretion and was inversely related to the change in hematocrit when the salt diet was changed from low to high, which is indicative of salt and fluid retention in salt-sensitive subjects. The GIR also showed an inverse correlation compared with the changes in urinary norepinephrine excretion, plasma renin activity, and plasma aldosterone concentration. CONCLUSIONS: Salt sensitivity of blood pressure is strongly associated with insulin resistance in lean, essential hypertensive patients. Hyperinsulinemia, sympathetic overactivation, and reduced suppression of the renin-angiotensin system may play a role in this relation.

References

Ames, R. P. (2001). "The effect of sodium supplementation on glucose tolerance and insulin concentrations in patients with hypertension and diabetes mellitus." Am J Hypertens 14(7 Pt 1): 653-9.

Andronico, G., L. Ferrara, et al. (1998). "Insulin, sodium-lithium countertransport, and microalbuminuria in hypertensive patients." Hypertension 31(1): 110-3.

Doria, A., P. Fioretto, et al. (1991). "Insulin resistance is associated with high sodium-lithium countertransport in essential hypertension." Am J Physiol 261(6 Pt 1): E684-91.

Falkner, B., M. Canessa, et al. (1997). "Sodium-lithium countertransport is associated with insulin resistance and urinary albumin excretion in young African-Americans." Am J Kidney Dis 29(1): 45-53.

Fujita, T. (2007). "Insulin resistance and salt-sensitive hypertension in metabolic syndrome." Nephrol Dial Transplant 22(11): 3102-7.

Garg, R., G. H. Williams, et al. (2011). "Low-salt diet increases insulin resistance in healthy subjects." Metabolism 60(7): 965-8.

Herlitz, H., L. Bokemark, et al. (2001). "Sodium/lithium countertransport, insulin resistance, insulin peptides and microalbuminuria in clinically healthy 58-year-old men." Clin Sci (Lond) 100(4): 443-9.

Iizuka, Y., Y. Ueda, et al. (2011). "Significant improvement of insulin resistance of GK rats by treatment with sodium selenate." Biol Trace Elem Res 138(1-3): 265-71.

Lastra, G., S. Dhuper, et al. (2010). "Salt, aldosterone, and insulin resistance: impact on the cardiovascular system." Nat Rev Cardiol 7(10): 577-84.

Ruivo, G. F., S. M. Leandro, et al. (2006). "Insulin resistance due to chronic salt restriction is corrected by alpha and beta blockade and by L-arginine." Physiol Behav 88(4-5): 364-70.

Weir, M. R. (1996). "Insulin resistance and salt sensitivity. A renal hemodynamic abnormality?" Am J Hypertens 9(12 Pt 2): 193S-199S.

Yatabe, M. S., J. Yatabe, et al. (2010). "Salt sensitivity is associated with insulin resistance, sympathetic overactivity, and decreased suppression of circulating renin activity in lean patients with essential hypertension." Am J Clin Nutr.