Female Hormones Found To Protect Against Harmful Effects Of Fructose

Groundbreaking study in female mice links estrogen, lower blood pressure, and insulin resistance, despite a high fructose diet

(January 12, 2003) — Bethesda, MD ? High-fructose corn syrup replaced sucrose (table sugar) as a sweetener in most grocery products some 20 years ago. Today, about nine percent of the average dietary energy intake in the U.S. comes from fructose. However, a number of nutritionists are alarmed by the amount of the public’s consumption, as previous research has demonstrated that a fructose diet can lead to insulin resistance and hypertension, particularly in male laboratory animals.

Effects of Fructose In Female Rats?
Other study results have been uncertain as to whether elevated blood pressure found in female rats was related to impairments in insulin sensitivity, or if there were any differences between sexes in terms of insulin sensitivity. These findings raised an important question regarding the effects of fructose in female rats, and whether hyperinsulinemia and insulin resistance lead to hypertension as in male rats. Therefore, based on previous research, it has not been possible to discern what role sex plays in the relationship between hyperinsulinemia/insulin resistance and hypertension (if any).

Given the differences in the incidence and cause of cardiovascular disease in men and women, a team of Canadian researchers hypothesized that sex gender may affect the relationship between hyperinsulinemia/insulin resistance and hypertension. To investigate this hypothesis, they designed experiments to clarify the effect of a high-carbohydrate (fructose) diet in both male and female rats on the development of hyperinsulinemia, insulin resistance, and hypertension. They also examined the role of the sex hormones in the response to a fructose diet in females and examined vascular responses to insulin.

The Study
The authors of “Female Rats are Protected Against Fructose-Induced Changes in Metabolism and Blood Pressure,” are Denise Galipeau and John H. McNeill Division of Pharmacology and Toxicology, University of British Columbia, Vancouver, British Columbia, and Subodh Verma at the Division of Cardiac Surgery, The Toronto Hospital, Toronto, Ontario, Canada. Their findings are published in the December 2002 edition of the American Journal of Physiology-Heart and Circulatory Physiology. The Journal is one of 14 scientific journals published every month by the American Physiological Society (APS).

Methodology
Several experiments were conducted within this study.

Blood Pressure Study #1
Two experimental groups of Wistar rats were used in this study: eight female controls and eight female fructose treated. Pilot groups of male control (M) and fructose-treated (MT) rats were followed at the same time to observe hyperinsulinemia and hypertension but were not included in the statistical analyses. At the age of six weeks, treatment groups were started on a diet of 60 percent fructose for nine weeks, whereas control groups were maintained on normal laboratory rat chow. Systolic BP was measured before treatment and weekly throughout the study period via the tail-cuff method. Blood samples for determination of five hour fasted plasma insulin, glucose, and triglycerides were obtained at study weeks 0, 2, 5, and 7. An oral glucose tolerance test (OGTT) after an overnight fast was performed at study weeks 4 and 8. Glucose was administered orally, and blood samples were collected at the times of 0, 10, 20, 30, and 60 minutes. All blood samples were collected from the tail vein.

Blood Pressure Study #2
Four groups of female Wistar rats, 15 weeks of age, were used. Of this number, eight were in a control group, eight fructose-fed, eight ovariectomized, and eight ovariectomized and fructose-fed. The fructose fed groups began a 60 percent fructose diet that was started on the same day as the ovariectomy, whereas the control and ovariectomized groups received normal diet. Systolic blood pressure was measured weekly beginning at week 2. Blood samples were collected after a 5-hour fast during study weeks 0, 2, 4, and 6. At week 7, an OGTT was performed as described above. At termination, ovariectomy was confirmed by visual inspection, and blood was collected via cardiac puncture for measurement of plasma total estrogens.

Results
The findings demonstrated that female rats are protected against the metabolic defects and hypertension typically produced by fructose feeding in male rats. Hyperinsulinemia and insulin resistance are believed to be the primary defects that cause hypertension in the fructose-fed male rat model. (To the researchers’ knowledge, this is the first report measuring blood pressure and insulin sensitivity simultaneously in both sexes of fructose-fed rats.)
In both groups of intact female rats, the fructose diet failed to cause any increase in blood pressure, and neither glucose tolerance nor insulin sensitivity were affected. However, increases in plasma triglyceride concentrations were observed. In this experiment, the increase in plasma triglycerides required five weeks to develop in the female rats and was relatively mild compared with that seen in males. Whereas this is merely a qualitative comparison, it does suggest that there may be quantitative and duration-dependent differences between sexes in this response.
Discussion
The researchers suggest two possible explanations may be postulated for the sex differences described. First, there may be mechanisms present only in male rats necessary to facilitate the effects of fructose on metabolism, or, second, female rats may possess countermechanisms that protect against the adverse effects of fructose.

They suggest these mechanisms, if present, may be linked to sex hormones. They cite two earlier studies in sucrose-fed rats, an increase in blood pressure was observed in the study with juvenile rats as the experimental age group . A possible explanation for the discrepancy between past studies and these results could be the difference in hormonal status between juvenile and mature rats. If estrogen is indeed protective against the adverse effects of high carbohydrate feeding, blood pressure may increase in high carbohydrate-fed juvenile female rats because estrogen levels would likely not play a role until sexual maturity.

To determine whether female sex hormones were involved in preventing the effects of fructose on metabolism and blood pressure, the researchers examined the response to fructose in ovarectomized female rats. This experiment demonstrated that female rats, in the absence of normal levels of ovarian sex hormones, develop an increase in blood pressure as seen in male rats after being fed with fructose. Although it is well established that estrogen has many cardiovascular benefits, a lack of sex hormones alone in these animals did not cause a significant change in blood pressure. Their data indicated that the combination of fructose diet and estrogen/sex hormone deficiency are required to elevate blood pressure in female rats.

Conclusions
These experiments demonstrate that the effects of a fructose diet on metabolism and blood pressure are dependent on sex gender. Female rats are protected against fructose-induced hypertension, unlike their male counterparts, and the mechanisms responsible for this protection appear to be related to female sex hormones.

Furthermore, there appears to be a sex difference in the vascular actions of insulin, which may also be involved in the mechanisms responsible for the sex differences observed in this experiment. The results of these experiments represent a novel finding into the interrelationship among hyperinsulinemia, insulin resistance, and hypertension. The potential existence of sex differences in this intriguing association might help elucidate the mechanisms involved and are worthy of further investigation.

Source: December 2002 edition of the American Journal of Physiology-Heart and Circulatory Physiology.