Abstract
Feeding a high-fructose diet induces hypertension and insulin-resistance in Sprague-Dawley rats.
To investigate whether insulin receptors contribute to abnormal glucose metabolism and whether their regulation is differentially regulated in different tissues, we evaluated the glycemic and insulinemic response to an oral glucose load, insulin receptor binding, and insulin receptor messengerRNA (mRNA) levels in tissues of rats that were fed either standard rat chow or a diet containing 66% fructose for 2 weeks.
Blood pressure and plasma triglycerides increased significantly in the fructose-fed rats, whereas body weight, fasting plasma glucose, and plasma insulin did not differ significantly from controls. Plasma glucose and insulin responses to oral glucose were significantly greater in fructose-fed than in control rats. Insulin receptor-binding characteristics were determined by an in situ autoradiographic technique associated with computerized microdensitometry. The insulin receptor number was significantly lower in both skeletal muscle and liver of fructose-fed rats as compared to controls, whereas no difference was observed in the kidney. No significant differences were found in binding affinity. Insulin receptor mRNA levels were determined by slot-blot hybridization with a cRNA probe encoding the 5′ end of the rat insulin receptor cDNA. Consistent with binding data, mRNA levels were significantly lower in skeletal muscle and liver of fructose-fed rats as compared to controls, but not in the kidney.
Decreased number of insulin receptors occurring at the level of gene expression is present in skeletal muscle and liver of fructose-fed rats and might contribute to insulin resistance in this model.
Clinical studies have demonstrated an association between hypertension, insulin resistance, and abnormal plasma lipid profile, findings that have been commonly referred to as syndrome X.1 Insulin resistance and hyperinsulinemia have been demonstrated also in genetic and nongenetic rat models of hypertension, such as the spontaneously hypertensive,2 Dahl salt-sensitive,3 Milan hypertensive,4 and fructose-fed rat,5 suggesting that similar mechanisms might be involved in these experimental models. In Sprague-Dawley rats, feeding a fructose-enriched diet induces an increase in blood pressure (BP) that is associated with hyperinsulinemia and hypertriglyceridemia. In these rats, restoration of normal insulin sensitivity by regular exercise6 and normalization of plasma insulin levels by somatostatin administration7 and other pharmacologic treatments that improve insulin sensitivity8,9,10 decrease BP, suggesting a pathogenetic role for insulin in hypertension.
Insulin resistance may occur through different mechanisms,11 including defects in insulin binding and signal transduction, or defects at the level of effector molecules such as glucose transporters and enzymes involved in carbohydrate metabolism. These molecular defects have been characterized in animal models of insulin resistance,11,12 including rat models of insulin resistance associated with hypertension.3,13,14 Initial studies have also addressed the molecular mechanism of insulin resistance in rats with fructose-induced hypertension, suggesting abnormalities in the action of insulin at a postreceptor level.15 The purpose of the present study was to characterize the insulin receptor at the level of tissue binding and messengerRNA (mRNA) in rats with fructose-induced hypertension. To evaluate possible tissue-specific abnormalities in insulin receptors we examined tissues that are directly involved in the metabolic actions of insulin such as skeletal muscle, liver, and tissues that are less directly related to carbohydrate metabolism but may contribute to the prohypertensive action of insulin such as the kidney.
Methods
Animal protocol
Experiments were performed in male Sprague-Dawley rats (Banting Kingman, Freemont, CA) weighing 150 to 180 g that were housed in climate-controlled conditions with a 12-h light/dark cycle and provided tap water ad libitum, as performed in previous studies.16 Rats were fed standard chow for 3 days and were subsequently divided in two groups: in one group, rats were maintained on standard chow and, in the other group, rats were fed a high-fructose diet (fructose 66%, fat 5%, casein 20%, cellulose 7%, vitamins 1%) for 14 days. Both diets contained a standard concentration of NaCl (0.3%) for rat chow. Body weight and BP were measured every other day.13 Systolic BP was measured in conscious, prewarmed (light lamp), restrained rats by the tail–cuff method with plethysmography and a physiograph recorder (Pulse Amplifier, ITTC Life Sciences, Woodland Hills, CA). For these measurements rats were trained adequately before the study. Rats were killed by decapitation after a 3-h fast; trunk blood was collected in EDTA for measurement of plasma glucose, insulin, and triglycerides, and skeletal muscle (always the same muscle groups from lower limbs), liver, and kidney were removed and snap frozen in liquid nitrogen for insulin receptor binding and total RNA isolation.
Glucose tolerance study
Glucose tolerance was measured in rats that were housed and fed as indicated. In brief, after an 8-h fast, glucose was administered (1.7 g/kg body weight) by gavage and blood samples were obtained from a tail vein at 0, 15, 30, and 60 min for measurement of plasma glucose and insulin concentration. The area under the curve was calculated by the trapezoidal rule.17
Insulin Receptor-Binding studies
The distribution and binding characteristics of insulin receptors in skeletal muscle, liver, and kidney were assessed by an in situ autoradiographic technique associated with computerized microdensitometry, as described previously.18,19 Briefly, adjacent tissue sections were liophylized, preincubated in KCl, and incubated for 120 min in a buffer containing 200 pmol/L 125I-Tyr-insulin (2200 Ci/mmol, DuPont-NEN, Dupont, Wilmington, DE) in the presence of increasing concentrations of unlabeled insulin (from 10 pmol/L to 1 mmol/L), then rinsed in ice-cold buffer, and dried. In the kidney, regional analysis of insulin binding was performed in renal cortex, and outer and inner renal medullas. Scatchard analysis of equilibrium binding data was done with the Ligand program of Munson and Rodbard and resulted in curvilinear profiles indicating either two classes of insulin receptors (high-affinity, low-capacity; and low-affinity, high-capacity) or a negative cooperative hormone-receptor interaction.18,19
Insulin receptor mRNA studies
Total RNA was isolated from frozen tissue as described previously.18 Insulin receptor mRNA levels were measured by slot-blot hybridization analysis using a 0.92-kb 32P-labeled antisense insulin receptor cRNA probe encoding the 5′ end of the rat insulin receptor cDNA, as previously described.18,20 To ensure equivalent loading conditions, duplicate blots were hybridized with a 32P-labeled oligonucleotide probe complementary to bases 4011 to 4036 of 28S ribosomal RNA.18
Plasma glucose, insulin,and triglycerides
Plasma glucose concentration in trunk blood was determined by the glucose oxidase method. Plasma triglycerides were assayed enzymatically by an automated method. Plasma insulin was measured by radioimmunoassay (Behring, Marburg, Germany).16
Statistical analysis
Data are expressed as mean ± SE. Comparisons between groups were done by Student t test. Variables with skewed distribution were normalized by log-transformation before comparison. Differences were considered as statistically significant when P was less than .05.
Results
Systolic BP (control, 151 ± 4 mm Hg; fructose-fed, 179 ± 10 mm Hg; P < .05) and plasma triglyceride (control, 0.87 ± 0.10 mmol/L; fructose-fed, 1.98 ± 0.32 mmol/L; P < .001) levels were significantly greater in the fructose-fed rats, whereas body weight (control, 241 ± 7 g; fructose-fed, 234 ± 2 g; P = NS) and fasting plasma glucose and insulin did not differ significantly between the groups (Table 1). Plasma glucose and plasma insulin responses to an oral glucose load, as evaluated by the area under the curve, were significantly greater in fructose-fed (glucose, 752 ± 36 mmol/L/min; insulin, 13,7790 ± 12,419 mmol/L/min) than control rats (glucose, 604 ± 24 mmol/L/min; insulin, 80,861 ± 7282 mmol/L/ min; both P < .01) with levels of both glucose and insulin that were significantly different at 15 and 30 min after load (Table 1).
Plasma glucose and plasma insulin levels after an oral glucose load (1.7 g/kg body weight) in control and fructose-fed rats
| Parameter | Time | Control Rats (n = 5) | Fructose-Fed Rats (n = 5) |
|---|---|---|---|
| Plasma glucose (mmol/L) | 0 min | 6.7 ± 0.3 | 6.8 ± 0.2 |
| 15 min | 13.6 ± 0.5 | 18.0 ± 0.4‡ | |
| 30 min | 9.9 ± 0.6 | 12.6 ± 0.5† | |
| 60 min | 8.5 ± 0.4 | 9.8 ± 0.4 | |
| Plasma insulin (mmol/L) | 0 min | 740 ± 106 | 963 ± 114 |
| 15 min | 2407 ± 208 | 3259 ± 199* | |
| 30 min | 1815 ± 158 | 2519 ± 142* | |
| 60 min | 1449 ± 147 | 1667 ± 131 |
| Parameter | Time | Control Rats (n = 5) | Fructose-Fed Rats (n = 5) |
|---|---|---|---|
| Plasma glucose (mmol/L) | 0 min | 6.7 ± 0.3 | 6.8 ± 0.2 |
| 15 min | 13.6 ± 0.5 | 18.0 ± 0.4‡ | |
| 30 min | 9.9 ± 0.6 | 12.6 ± 0.5† | |
| 60 min | 8.5 ± 0.4 | 9.8 ± 0.4 | |
| Plasma insulin (mmol/L) | 0 min | 740 ± 106 | 963 ± 114 |
| 15 min | 2407 ± 208 | 3259 ± 199* | |
| 30 min | 1815 ± 158 | 2519 ± 142* | |
| 60 min | 1449 ± 147 | 1667 ± 131 |
Values are means ± SE. Comparisons were done by Student t test.
P < .02,
P < .01,
P < .001 v control.
Plasma glucose and plasma insulin levels after an oral glucose load (1.7 g/kg body weight) in control and fructose-fed rats
| Parameter | Time | Control Rats (n = 5) | Fructose-Fed Rats (n = 5) |
|---|---|---|---|
| Plasma glucose (mmol/L) | 0 min | 6.7 ± 0.3 | 6.8 ± 0.2 |
| 15 min | 13.6 ± 0.5 | 18.0 ± 0.4‡ | |
| 30 min | 9.9 ± 0.6 | 12.6 ± 0.5† | |
| 60 min | 8.5 ± 0.4 | 9.8 ± 0.4 | |
| Plasma insulin (mmol/L) | 0 min | 740 ± 106 | 963 ± 114 |
| 15 min | 2407 ± 208 | 3259 ± 199* | |
| 30 min | 1815 ± 158 | 2519 ± 142* | |
| 60 min | 1449 ± 147 | 1667 ± 131 |
| Parameter | Time | Control Rats (n = 5) | Fructose-Fed Rats (n = 5) |
|---|---|---|---|
| Plasma glucose (mmol/L) | 0 min | 6.7 ± 0.3 | 6.8 ± 0.2 |
| 15 min | 13.6 ± 0.5 | 18.0 ± 0.4‡ | |
| 30 min | 9.9 ± 0.6 | 12.6 ± 0.5† | |
| 60 min | 8.5 ± 0.4 | 9.8 ± 0.4 | |
| Plasma insulin (mmol/L) | 0 min | 740 ± 106 | 963 ± 114 |
| 15 min | 2407 ± 208 | 3259 ± 199* | |
| 30 min | 1815 ± 158 | 2519 ± 142* | |
| 60 min | 1449 ± 147 | 1667 ± 131 |
Values are means ± SE. Comparisons were done by Student t test.
P < .02,
P < .01,
P < .001 v control.
Binding of 125I -Tyr-insulin was homogeneously distributed in both skeletal muscle and liver and distribution was comparable in fructose-fed and control rats. Analysis of equilibrium binding data for a two-site receptor model showed a significantly decreased maximum-binding capacity (Bmax) of the high-affinity, low-capacity insulin receptor site in both skeletal muscle and liver of fructose-fed rats as compared to controls (Table 2, Fig. 1). No significant difference was found in the dissociation constant (Kd) of the high-affinity, low-capacity receptor site and in both the Kd and Bmax of the low-affinity, high-capacity receptor site. In the kidney, radiolabeled insulin binding was more abundant in the renal cortex than the medulla and the distribution was comparable in the two groups of rats. Analysis of binding data showed no differences in the Kd and Bmax of both insulin receptor sites between fructose-fed and control rats (Table 2, Fig. 1).
Effect of varying concentrations of unlabeled insulin on binding of 125I-insulin in skeletal muscle, liver, and kidney (cortex) obtained from control (solid circles) and fructose-fed (open circles) rats. Data were obtained by computerized microdensitometry and are means ± SE of 5 animals in each group. For each rat the area below the curve was calculated and the average of the groups compared with Student t test. Fructose diet decreased significantly insulin receptor binding in skeletal muscle and liver, but not in the kidney.
Insulin-binding parameters in skeletal muscle, liver, and kidney of control and fructose-fed rats
| Parameter | Control Rats (n = 5) | Fructose-Fed Rats (n = 5) |
|---|---|---|
| Skeletal muscle | ||
| R1 | ||
| Kd × 10−10 mmol/L | 4.2 ± 1.2 | 4.1 ± 1.1 |
| Bmax, × 1010 receptors/mm3 | 10.0 ± 1.0 | 7.6 ± 0.7* |
| R2 | ||
| Kd × 10−7 mmol/L | 3.1 ± 1.2 | 3.4 ± 1.6 |
| Bmax × 1013 receptors/mm3 | 6.1 ± 1.9 | 6.0 ± 2.4 |
| Liver | ||
| R1 | ||
| Kd × 10−10 mmol/L | 4.4 ± 0.9 | 4.7 ± 1.2 |
| Bmax × 1010 receptors/mm3 | 9.3 ± 1.1 | 7.6 ± 0.9* |
| R2 | ||
| Kd × 10−7 mmol/L | 3.0 ± 1.5 | 2.9 ± 0.8 |
| Bmax × 1013 receptors/mm3 | 5.6 ± 1.5 | 5.3 ± 1.8 |
| Kidney | ||
| R1 | ||
| Kd × 10−10 mmol/L | 4.0 ± 1.1 | 4.3 ± 1.0 |
| Bmax × 1010 receptors/mm3 | 5.1 ± 0.8 | 5.2 ± 0.7 |
| R2 | ||
| Kd × 10−7 mmol/L | 2.9 ± 1.0 | 2.7 ± 1.3 |
| Bmax × 1013 receptors/mm3 | 4.9 ± 1.9 | 4.4 ± 1.6 |
| Parameter | Control Rats (n = 5) | Fructose-Fed Rats (n = 5) |
|---|---|---|
| Skeletal muscle | ||
| R1 | ||
| Kd × 10−10 mmol/L | 4.2 ± 1.2 | 4.1 ± 1.1 |
| Bmax, × 1010 receptors/mm3 | 10.0 ± 1.0 | 7.6 ± 0.7* |
| R2 | ||
| Kd × 10−7 mmol/L | 3.1 ± 1.2 | 3.4 ± 1.6 |
| Bmax × 1013 receptors/mm3 | 6.1 ± 1.9 | 6.0 ± 2.4 |
| Liver | ||
| R1 | ||
| Kd × 10−10 mmol/L | 4.4 ± 0.9 | 4.7 ± 1.2 |
| Bmax × 1010 receptors/mm3 | 9.3 ± 1.1 | 7.6 ± 0.9* |
| R2 | ||
| Kd × 10−7 mmol/L | 3.0 ± 1.5 | 2.9 ± 0.8 |
| Bmax × 1013 receptors/mm3 | 5.6 ± 1.5 | 5.3 ± 1.8 |
| Kidney | ||
| R1 | ||
| Kd × 10−10 mmol/L | 4.0 ± 1.1 | 4.3 ± 1.0 |
| Bmax × 1010 receptors/mm3 | 5.1 ± 0.8 | 5.2 ± 0.7 |
| R2 | ||
| Kd × 10−7 mmol/L | 2.9 ± 1.0 | 2.7 ± 1.3 |
| Bmax × 1013 receptors/mm3 | 4.9 ± 1.9 | 4.4 ± 1.6 |
Values are means ± SE.
R1 = high-affinity, low-capacity insulin binding site; R2 = low-affinity, high-capacity insulin binding site. Binding parameters (Kd, dissociation constant, Bmax, maximum binding capacity) were derived from Scatchard analysis of equilibrium binding data from competition experiments performed on adjacent tissue sections that, after incubation with radioligand, were placed in a gamma counter. Comparisons were done by Student t test.
P < .05 v. control.
Insulin-binding parameters in skeletal muscle, liver, and kidney of control and fructose-fed rats
| Parameter | Control Rats (n = 5) | Fructose-Fed Rats (n = 5) |
|---|---|---|
| Skeletal muscle | ||
| R1 | ||
| Kd × 10−10 mmol/L | 4.2 ± 1.2 | 4.1 ± 1.1 |
| Bmax, × 1010 receptors/mm3 | 10.0 ± 1.0 | 7.6 ± 0.7* |
| R2 | ||
| Kd × 10−7 mmol/L | 3.1 ± 1.2 | 3.4 ± 1.6 |
| Bmax × 1013 receptors/mm3 | 6.1 ± 1.9 | 6.0 ± 2.4 |
| Liver | ||
| R1 | ||
| Kd × 10−10 mmol/L | 4.4 ± 0.9 | 4.7 ± 1.2 |
| Bmax × 1010 receptors/mm3 | 9.3 ± 1.1 | 7.6 ± 0.9* |
| R2 | ||
| Kd × 10−7 mmol/L | 3.0 ± 1.5 | 2.9 ± 0.8 |
| Bmax × 1013 receptors/mm3 | 5.6 ± 1.5 | 5.3 ± 1.8 |
| Kidney | ||
| R1 | ||
| Kd × 10−10 mmol/L | 4.0 ± 1.1 | 4.3 ± 1.0 |
| Bmax × 1010 receptors/mm3 | 5.1 ± 0.8 | 5.2 ± 0.7 |
| R2 | ||
| Kd × 10−7 mmol/L | 2.9 ± 1.0 | 2.7 ± 1.3 |
| Bmax × 1013 receptors/mm3 | 4.9 ± 1.9 | 4.4 ± 1.6 |
| Parameter | Control Rats (n = 5) | Fructose-Fed Rats (n = 5) |
|---|---|---|
| Skeletal muscle | ||
| R1 | ||
| Kd × 10−10 mmol/L | 4.2 ± 1.2 | 4.1 ± 1.1 |
| Bmax, × 1010 receptors/mm3 | 10.0 ± 1.0 | 7.6 ± 0.7* |
| R2 | ||
| Kd × 10−7 mmol/L | 3.1 ± 1.2 | 3.4 ± 1.6 |
| Bmax × 1013 receptors/mm3 | 6.1 ± 1.9 | 6.0 ± 2.4 |
| Liver | ||
| R1 | ||
| Kd × 10−10 mmol/L | 4.4 ± 0.9 | 4.7 ± 1.2 |
| Bmax × 1010 receptors/mm3 | 9.3 ± 1.1 | 7.6 ± 0.9* |
| R2 | ||
| Kd × 10−7 mmol/L | 3.0 ± 1.5 | 2.9 ± 0.8 |
| Bmax × 1013 receptors/mm3 | 5.6 ± 1.5 | 5.3 ± 1.8 |
| Kidney | ||
| R1 | ||
| Kd × 10−10 mmol/L | 4.0 ± 1.1 | 4.3 ± 1.0 |
| Bmax × 1010 receptors/mm3 | 5.1 ± 0.8 | 5.2 ± 0.7 |
| R2 | ||
| Kd × 10−7 mmol/L | 2.9 ± 1.0 | 2.7 ± 1.3 |
| Bmax × 1013 receptors/mm3 | 4.9 ± 1.9 | 4.4 ± 1.6 |
Values are means ± SE.
R1 = high-affinity, low-capacity insulin binding site; R2 = low-affinity, high-capacity insulin binding site. Binding parameters (Kd, dissociation constant, Bmax, maximum binding capacity) were derived from Scatchard analysis of equilibrium binding data from competition experiments performed on adjacent tissue sections that, after incubation with radioligand, were placed in a gamma counter. Comparisons were done by Student t test.
P < .05 v. control.
Slot-blot analysis of muscular and hepatic insulin receptor mRNA showed significantly lower levels in rats fed a fructose-enriched diet as compared to controls, whereas no difference was found in renal tissue (Fig. 2).
Bar graph of blood pressure and insulin receptor (IR) mRNA in skeletal muscle, liver, and kidney of control (hatched bars) and fructose-fed (shaded bars) rats. Systolic blood pressure was measured in conscious, prewarmed (light lamp), restrained rats by the tail–cuff method with plethysmography and a physiograph recorder. The mRNA data were obtained from slot-blot analysis performed using a 0.92-kb 32P-labeled antisense insulin receptor cRNA probe. Optical density was determined by computerized densitometry and normalized for 28S ribosomal RNA. Data are the means ± SE of 5 animals in each group. Muscular and hepatic insulin receptor mRNA levels were significantly lower in fructose-fed than control rats, whereas no difference was observed in the kidney.
Discussion
The results of this study demonstrate that fructose-fed rats have a decreased insulin receptor density in tissues, such as skeletal muscle and liver, which are primarily involved in the effects of insulin on carbohydrate metabolism. In these tissues, decreased receptor number is associated with decreased insulin receptor mRNA, thereby providing a possible molecular explanation for the decreased sensitivity to insulin present in these rats. In comparison to the skeletal muscle and liver, no significant differences in either insulin binding or insulin receptor mRNA levels were observed in the kidney, suggesting tissue-specific regulation of the receptor in this model.
An involvement of insulin in the pathophysiology of arterial hypertension has been postulated after the observation that insulin resistance is present in patients with essential hypertension as well as experimental hypertensive models. Chronic feeding with sucrose-enriched21 or fructose-enriched5 diets induces an increase in BP that is associated with insulin resistance and compensatory hyperinsulinemia. Despite some controversy, mainly related to the possibility to reproduce hypertension22 and fasting hyperinsulinemia,16 the fructose hypertensive model has been used widely to study the pathophysiology of the association between insulin resistance and hypertension.
Insulin resistance may occur for different reasons,11 including defects in insulin binding caused by decreased receptor number or affinity, defects in signal transduction involving receptor autophosphorylation and tyrosine kinase activity, or postreceptor defects at the level of substrates of phosphorylation or effector molecules such as glucose transporters (ie, GLUT-4) and enzymes involved in glucose metabolism. These molecular defects have been widely characterized in humans with type 2 diabetes mellitus,23,24 as well as experimental models of insulin resistance.11,12 Mechanisms of insulin resistance have been studied also in some experimental models of hypertension. In the spontaneously hypertensive rat, a decrease in insulin receptor density,13 insulin-stimulated receptor autophosphorylation,14 phosphorylation of the insulin receptor substrate-1 (IRS-1),14 and GLUT-4 mRNA levels,25 has been observed in comparison to normotensive controls. In Dahl rats, insulin receptor number and mRNA levels are comparable in muscle and kidney of salt-sensitive and salt-resistant animals,3 whereas no studies have been performed, to our knowledge, on the early steps of insulin action.
Few studies have addressed the molecular mechanism of insulin resistance in fructose-fed rats: initial studies26 suggested a diminished ability of insulin to suppress hepatic glucose output and no significant changes in insulin receptor binding and tyrosine kinase function were found in the liver.27 We have evaluated insulin receptor binding and mRNA levels and have found that both insulin receptor number and mRNA levels are significantly decreased in skeletal muscle and liver of fructose-fed rats as compared to controls, although no difference in receptor affinity is present. These findings indicate downregulation at the level of insulin receptor gene expression and suggest a possible molecular mechanism for insulin resistance that could reasonably explain the greater response of plasma glucose and insulin to an oral glucose load. We speculate that high fructose might regulate insulin receptors through an increase in plasma insulin levels followed by “homologous” insulin receptor downregulation11; alternatively, metabolic intermediates generated inside the cells might activate intracellular mechanisms affecting insulin receptor gene expression.
It is important to notice that several studies have indicated that the predominant mechanism in human diseases characterized by insulin resistance is located at a postreceptor level.23 This has been demonstrated both in patients with type 2 diabetes24 and obesity,28 although obese patients present also with reduced insulin receptor number in some tissues.28 Indirect evidence of the role of postreceptor defects in insulin resistant states is provided by the correction of the defect after administration of drugs, such as thiazolidinediones, that affect by a complex interaction with peroxisome proliferator-activated receptors, the intracellular steps of insulin action.29 This evidence may appear to be in contrast with our present findings and consequently limit the applicability of the fructose model to human disease. However, demonstration of abnormalities in insulin receptor number should not preclude the possibility of abnormal intracellular transduction mechanisms. In fact, Bezerra et al15 have demonstrated abnormalities in the action of insulin at a postreceptor level in muscle and liver of fructose-fed rats, including decreased phosphorylation of IRS-1 and decreased association of IRS-1 with phosphatidylinositol 3-kinase and phosphotyrosine phosphatase.
In our study, no significant difference in insulin receptor number and mRNA levels was found in the kidneys of fructose-fed and control rats. Similarly, Feraille et al30 found comparable density of insulin receptors in all nephron segments of kidneys obtained from fructose hypertensive and normotensive rats. These findings are not surprising because it is known that resistance to the action of insulin may differ among tissues. For instance, it has been shown that spontaneously hypertensive rats have a decreased sensitivity to insulin while they maintain the same antinatriuretic response to this hormone as their normotensive controls.13,31 The present study confirms the possibility of a tissue-specific regulation of insulin receptors and suggests a possible molecular mechanism to explain the different functional response to insulin in muscle, liver, and kidney.
In conclusion, this study indicates a possible cellular mechanism for the reduced sensitivity to insulin present in rats with fructose-induced hypertension. Further studies will be required to assess the contribution of insulin receptor abnormalities to the development of the hypertensive response to chronic fructose feeding in rats.
