Helen Ho

Fructose-induced insulin resistance and hypertension in rats.

To determine if hypertension could be produced in normal rats by feeding them a fructose-enriched diet, Sprague-Dawley rats were fed either normal chow or a diet containing 66% fructose as a percentage of total calories for approximately 2 weeks. At the end of this period systolic blood pressure had increased from 124 +/- 2 to 145 +/- 2 (SEM) mm Hg in the fructose-fed rats, whereas no change occurred in the control group. In addition, hyperinsulinemia and hypertriglyceridemia were associated with hypertension in fructose-fed rats. The addition of clonidine to the drinking water inhibited fructose-induced hypertension, but not the increase in plasma insulin or triglyceride concentration seen in fructose-fed rats. Thus, the metabolic changes associated with fructose-induced hypertension are unlikely to be secondary to an increase in sympathetic activity. Whether or not this is also true of the hypertension remains to be clarified.

Effect of Age and Diet on Insulin Secretion and Insulin Action in the Rat

The effects of aging on various aspects of insulin secretion and action were studied in male Sprague-Dawley rats, maintained from 1½ to 12 mo of age on conventional rat chow, sucrose-rich, or calorie-restricted diets. In chow-fed rats, islet volume increased as the animals grew from 1½ to 12 mo of age, but glucose-stimulated insulin secretion (per volume islet) declined over the same interval. In addition, in vivo insulin-stimulated glucose utilization fell in these rats. However, the plasma insulin response to an oral glucose challenge was sufficient to prevent frank decompensation of glucose tolerance (presumably due to an increase in total pancreatic endocrine cell mass). All these changes, with the exception of the decline in glucose-stimulated insulin secretion per volume islet, were accentuated by feeding sucrose. Thus, 12-mo-old sucrose-fed rats had larger islets and higher plasma insulin levels in response to an oral glucose challenge, and the rats were more insulin-resistant than chow-fed rats. However, glucose-stimulated insulin release per volume islet was similar in 12-mo-old chow-fed and sucrose-fed rats. In contrast, calorie restriction led to an amelioration in all but one of the age-related changes, i.e., islets from calorie-restricted rats were comparable in size to those of 2-mo-old rats, the animals had lower plasma insulin levels in response to an oral glucose load, and they were less insulin resistant than the other two groups of 12-mo-old rats. On the other hand, glucose-stimulated insulin secretion per volume islet was similar to that of the other 12-mo-old rats. These results suggest that aging leads to marked changes in both insulin secretion and insulin action. The decline in glucose-stimulated insulin secretion per unit endocrine pancreas appears to be an inevitable consequence of the aging process. In contrast, the age-related changes in islet size, insulin response to a glucose load, and in vivo insulin-stimulated glucose uptake are extremely responsive to variations in amount and kind of calories.

Somatostatin inhibition of fructose-induced hypertension.

The role of insulin resistance and byperinsulinemia in the etiology of fructose-induced hypertension was studied in male Sprague-Dawley rats. Rats consumed a fructose-enriched diet (containing 66% of total calories as fructose) for 11 days and were infused continuously during the last 7 days with either a somatostatin analogue or vehicle. At the end of this period, rats receiving the somatostatin analogue had a lower plasma insulin concentration (52±4 vs. 70±6 μunits/ml, p < 0.01) and a lower blood pressure (133±2 vs. 150±2 mm Hg) than did the rats infused with the control solution. In addition, the increase in plasma triglyceride concentration in response to the fructose-enriched diet was significantly attenuated (p<0.001) in the rats infused with somatostatin. These data provide further support that the increase in blood pressure that occurs when normal rats are fed a high fructose diet is dependent on the ability of this intervention to cause insulin resistance and hyperinsulinemia.

Attenuation of fructose-induced hypertension in rats by exercise training.

This study was initiated to see if the insulin resistance, hyperinsulinemia, and hypertension that follow feeding nonnotensive Sprague-Dawley rats a fructose-rich diet could be prevented by letting rats run spontaneously in exercise wheel cages. Blood pressure in sedentary rats increased from (mean ± SEM) 125 ± 2 to 148 ± 3 mm Hg in response to 2 weeks of a high fructose diet, and this increment was significantly (p < 0.001) attenuated in exercising rats (from 121 ± 1 to 131 ± 2 mm Hg). In addition, mean (±SEM) plasma insulin concentration was lower in fructose-fed rats allowed to run spontaneously (44 ± 2 vs 62 ± 5 μU/ml; p < 0.01). Finally, resistance to insulin-stimulated glucose uptake was assessed by determining the steady state plasma glucose response to a continuous glucose and exogenous Insulin infusion during a period in which endogenous insulin secretion was suppressed. The results of these studies indicated that the mean (± SEM) steady state plasma glucose concentration was significantly lower in the exercise-trained rats (127 ± 5 vs 168 ± 6 mg/dl; p < 0.001), despite tbe fact that the steady state plasma insulin levels were also lower in rats allowed to run spontaneously (75 ± 4 vs 90 ± 5 μU/ml; p < 0.05). Thus, the ability of exercise-trained rats to stimulate glucose disposal was enhanced as compared with that of sedentary rats fed the same fructose-rich diet. These data demonstrate that the insulin resistance, hyperinsulinemia, and hypertension produced hi nonnotensive rats by feeding them a high fructose diet can be attenuated if rats are allowed to run spontaneously. These results provide further support for the hypothesis that insulin resistance and hyperinsulinemia play a role in the pathogenesis of fructose-induced hypertension.

Low-dose streptozotocin-induced diabetes in the spontaneously hypertensive rat☆

Streptozotocin (STZ, 35 mg/kg body weight) was injected into spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, and plasma glucose and triglyceride concentrations measured 10 days later. Neither mean (+/- SEM) plasma glucose (130 +/- 3 v 136 +/- 3 mg/dL) nor triglyceride (93 +/- 6 v 108 +/- 7 mg/dL) concentrations increased in WKY rats. In contrast, both plasma glucose (141 +/- 3 v 262 +/- 36) and triglyceride (121 +/- 8 v 196 +/- 7 mg/dL) concentrations increased significantly (P less than .01) following administration of STZ in SHR. Furthermore, when SHR previously injected with STZ were fed a diet enriched in fructose, they had a further increase (P less than .01) in both plasma glucose (343 +/- 38 mg/dL) and triglyceride (774 +/- 57 mg/dL) concentrations. Plasma triglyceride concentration also increased significantly (P less than .05) when STZ-injected WKY rats ingested the fructose-enriched diet, but plasma glucose levels still remained within the normal range (152 +/- 5 mg/dL). These results indicate that SHR were more sensitive to the effects of a decrease in pancreatic beta-cell function (STZ) and an increase in insulin resistance (fructose feeding) than WKY rats.

Salt-Sensitive and Carbohydrate-Sensitive Rodent Hypertension: Evidence of Strain Differences

It is well-established that diets enriched either with salt or simple sugars are associated with variable increases in blood pressure, but the interrelationship between carbohydrate- and salt-sensitive hypertension has received comparatively little attention. The effects of varying salt intake on blood pressure responses to a fructose-enriched diet were examined in a variety of common laboratory rat strains. Sprague-Dawley, Fischer 344, and Wistar rats were placed on diets enriched in fructose, salt, or a combination of both for 12 days. Measurements of blood pressure (tail-cuff) and fasting plasma insulin concentrations were recorded before and after dietary intervention. In response to the fructose-enriched diet (normal salt), all strains developed a significant increase in plasma insulin (1-2 fold, p < 0.05). However, only Sprague-Dawley rats showed an increase in blood pressure in response to the fructose-enriched diet (21 mmHg, p < 0.05). A high salt diet increased blood pressure only in Fischer 344 rats (10 mmHg, p < 0.05), but the combination of high fructose and high salt increased blood pressure significantly in both Fischer 344 and Wistar rats (mean of 19 mmHg, p < 0.05). In conclusion, the ability of a fructose-enriched diet to increase blood pressure varies as a function of strain, and can be modulated by changes in salt intake.

Evidence of an age-related decline in mitochondrial glycerophosphate dehydrogenase activity of isolated rat islets☆

The activities of three enzymes--two mitochondrial and one microsomal--were measured in isolated islets of Langerhans from 2-month-old and 12-month-old rats. Mitochondrial glycerophosphate dehydrogenase activity (expressed as nanomoles of iodonitrotetrazolium reduced per minute per milligram of protein), decreased (P less than 0.01) from a mean (+/- SEM) of 73.2 +/- 11.2 (2-month-old) to 34.7 +/- 5.9 (12-month-old). In contrast, activities of neither mitochondrial monoamine oxidase nor microsomal NADH cytochrome-c reductase changed with age. These results demonstrate that the activity of the glycerophosphate shuttle decreases as rats grow older, and it raises the possibility that the consequent difficulty in regenerating cytosolic NAD+ may play a role in the insulin secretory defect associated with aging.

Effects of Low Sodium Diet and Unilateral Nephrectomy on the Development of Carbohydrate-Induced Hypertension

Since there appear to be important interactions between mechanisms of salt-sensitive and carbohydrate-sensitive hypertension, the goal of this study was to evaluate the effects of greatly reducing dietary salt intake and removal of one kidney (to increase salt sensitivity) on the hemodynamic and metabolic responses to carbohydrate-enriched diets in three different rat strains. All three strains of laboratory rat developed significant increases in fasting plasma insulin (1-2 fold, p < 0.03) and triglyceride (2-3 fold, p < 0.01) concentrations in response to fructose (or sucrose) enriched diets, irrespective of salt content. Blood pressure increased significantly in response to carbohydrate feeding in both Sprague-Dawley (S-D) and Dahl salt-sensitive rats, but not in Fischer 344 rats, and decreasing salt intake had no effect on the development of carbohydrate-induced hypertension: e.g., delta BP in S-D rats was +20 mmHg after the fructose-0.5% NaCl diet as compared with +19 mmHg after fructose-0.02% NaCl, and delta BP in Dahl salt-sensitive rats was +22 mmHg after fructose-0.02% NaCl. Finally, nephrectomy neither accentuated the degree of hypertension in fructose-fed S-D rats, nor increased blood pressure in fructose-fed Fischer 344 rats. These results emphasize the strain specific characteristics of carbohydrate-induced hypertension in rats, and indicate that the hemodynamic responses of different rat strains to dietary carbohydrate are not modified by either decreasing salt intake or removing one kidney.