Protection From High-fat-diet-induced Impaired Glucose Tolerance In Female Sprague-Dawley Rats

Background and Objective:Diabetes is one of the most challenging health problems in the 21st century. The epidemiology study conducted by the International Diabetes Federation (IDF) showed that approximately 5.1% in the age group 20-79 have diabetes and 8.2% have impaired glucose tolerance (IGT) in 2003. More than 240 million people worldwide now have diabetes. This will grow to more than 380 million by 2025. Diabetes has long been appreciated to be a complex interlay of genetic and environmental factors. Insulin resistance (IR) and impaired pancreaticβ-cell function play very important role in the pathogenesis of type 2 diabetes (T2DM). And studies suggest that both of them have existed in the people with IFG and IGT, which have been recognized as a stage in the transition from normality to diabetes. But it is not clear whether there exists gender difference in the diabetes and IGT.It is well known that dietary fat has a significant effect on glucose metabolism. High fat diet, a common feature of modern nutrient intake, is able to induce IGT and T2DM in experimental animals. This impairement is associated with insulin resistance, a condition of reduced effect of insulin action, and decreased insulin secretion. Epidemiological data in humans suggest that subjects with higher intakes of fat, independent of fatty acid profile, are more prone to develop disturbance in glucose metabolism than subjects with lower intakes of fat. Interestingly, when reviewing the literature, it is not hard to perceive that very few studies exmained and charaterized the associated phenotype and consequences of high-fat diets in both males and females, the prevailing experiments have been conducted in men or male animals. However, gender-specific difference in rodent diabetes is not uncommon. For example, the cumulative incidence of diabetes in the NSY mouse is 98% in males and 31% in females at 48 weeks of age. Similarly, a greater degree of glucose intolerance has been observed in male transgenic mice of different genetic background in several studies. In Zucker diabetic fatty (ZDF) rats, only ZDF adult obese male rats are overtly diabetic and are used as the model of NIDDM. Other ZDF rats, including lean and female, are not overtly diabetic in their life span and should not be considered as NIDDM animals. In human studies, Modan et al reported that in nondiabetic first-degree relatives of NIDDM patients, adult males demonstrated greater glucose intolerance to oral glucose tolerance tests than adult females. Although whether type 2 diabetes in men and women is equally prevalent exists constant debate, the responses to high-fat feeding seems to be sexual dimorphic. While obesity is more prevalent in women than in men, the latter have higher predominance to suffer from metabolic disorders, including obesity, dyslipidemia, glucose intolerance, type 2 diabetes, and hypertension.The mechanism(s) responsible for these gender-difference remains largely unknown and merits further investigation.In this study, we examined the long-term influence of a high-fat diet on glucose metabolism in genetically normal Sprague-Dawley rats. As the diet was given for a period of 14 months it represents almost a life-long exposure of rats to the diet. Our result confirmed that dietary fat has a significant effect on glucose metabolism and higher intakes of fat results in impaired glucose tolerance (IGT). We have shown that this impairment displays remarkable gender-specific difference with female rats comparatively protected from IGT than their male counterparts in the response to high-fat feeding. We further demonstrated that this gender difference is most likely attributable to an alleviated peripheral insulin resistance as well as a preservedβcell function in female rats.Material and Methods:In this study, we examined the long-term influence of a high-fat diet on glucose metabolism in genetically normal Sprague-Dawley rats.1. Sprague-Dawley rats were fed a long-term up to 14 months of high-fat diet, the animal model of IGT and insulin resistance was established.2. Detection of body weight, plasma glucose and lipids were made by routine method. Lipid deposition in liver was observed using paraffin section and HE staining.3. The levels of IGT in intraperitoneal glucose tolerance test (IPGTT) of the rats were observed at 5th, 10th and 14th months subjected to high fat diet.4. Fasting plasma insulin (FINS) levels were measured, insulin resistance (HOMA-IR) was calculated according to the homeostasis model assessment and insulin secretion capacities were determined by the insulinogenic index at 14 month.5. The concentrations of malondialdehyde (MDA), glutathione (GSH) and catalase (CAT) in liver, muscle and pancreas were determined at 14th months to evaluate the oxidant and antioxidant capabilities in corresponding tissue.Results:1. The FPG levels slightly but significantly increased under HF-fed conditions at 1th , 2.5th , and 5th months (p<0.05), but remained similar with control groups after 5 months of feeding in both genders.2. The 2 hour plasma glucose(2h PG) levels were significantly elevated in male rats in 5~10 months on high-fat diet in IPGTT, and IGT (7.8mmol/L< 2h-PG <11.1mmol/L) developed in male of both chow- and HF-fed rats after 14 months of feeding. In sharp contrast, glucose disposal ablility, charaterized by 2h PG, still kept in normal range in IPGTT in age-matched female rats.3. Fast insulin levels in HF-fed male rats were significantly higher than that of age-matched female rats (p<0.05), and HOMA-IR was statistically different between high-fat fed groups as well at 14 months (p<0.05). In contrast, no significant differences were observed between two sexes under standard chow condition.4. The levels of free fatty acid (FFA) were higher in HF-fed male rats compared with female rats at 5th and 7.5th months. This difference is significant especially at 7.5th months.5. Insulin secretion in early phase was significantly higher in HF-fed female rats compared with male rats (p<0.05). In contrast, no significant difference in insulin secretion in early phase was detected under chow-diet condition.6. The levels of MDA significantly increased in liver and muscle tissues in HF-fed male rats compared with HF-fed female rats (p<0.05~0.01). The levels of CAT significantly decreased in liver and muscle tissue in HF-fed male rats compared with HF-fed female rats (p<0.05~0.01). The levels of MDA increased but did not reach statistical significance in pancreatic tissue in HF-fed male rats compared with HF-fed female rats. The levels of GSH and CAT decreased but did not reach statistical significance in pancreatic tissue in HF-fed male rats compared with HF-fed female rats.Conclusions:1. Disturbance in glucose metabolism deveolops earlier and more severe in male rats under high-fat condition compared with female rats.2. Protection from high-fat-diet-induced impaired glucose tolerance in female rats attributes to two hands, the one hand insulin resistance is significantly lower in high-fat fed female rats compared with male rats, the other hand the pancreaticβ-cell function is significantly better in high-fat fed female rats compared with male rats.3. Fat-induced insulin resistance is significantly lower in high-fat fed female rats compared with male rats, that attributes, at least partly, to the levels of FFA and oxidative stress in liver and muscle tissue.4. The pancreaticβ-cell function is significantly better in high-fat fed female rats compared with male rats, that attributes, at least partly, to ameliorated lipotoxicity of FFA and the lowered levels of oxidative stress in pancreatic tissue.