Lipoic acid prevents fructose-induced changes in liver carbohydrate metabolism: Role of oxidative stress

Background

Fructose administration rapidly induces oxidative stress that triggers compensatory hepatic metabolic changes. We evaluated the effect of an antioxidant, R/S-α-lipoic acid on fructose-induced oxidative stress and carbohydrate metabolism changes.

Methods

Wistar rats were fed a standard commercial diet, the same diet plus 10% fructose in drinking water, or injected with R/S-α-lipoic acid (35 mg/kg, i.p.) (control + L and fructose + L). Three weeks thereafter, blood samples were drawn to measure glucose, triglycerides, insulin, and the homeostasis model assessment-insulin resistance (HOMA-IR) and Matsuda indices. In the liver, we measured gene expression, protein content and activity of several enzymes, and metabolite concentration.

Results

Comparable body weight changes and calorie intake were recorded in all groups after the treatments. Fructose fed rats had hyperinsulinemia, hypertriglyceridemia, higher HOMA-IR and lower Matsuda indices compared to control animals. Fructose fed rats showed increased fructokinase gene expression, protein content and activity, glucokinase and glucose-6-phosphatase gene expression and activity, glycogen storage, glucose-6-phosphate dehydrogenase mRNA and enzyme activity, NAD(P)H oxidase subunits (gp91^phox and p22^phox) gene expression and protein concentration and phosphofructokinase-2 protein content than control rats. All these changes were prevented by R/S-α-lipoic acid co-administration.

Conclusions

Fructose induces hepatic metabolic changes that presumably begin with increased fructose phosphorylation by fructokinase, followed by adaptive changes that attempt to switch the substrate flow from mitochondrial metabolism to energy storage. These changes can be effectively prevented by R/S-α-lipoic acid co-administration.

General significance

Control of oxidative stress could be a useful strategy to prevent the transition from impaired glucose tolerance to type 2 diabetes.     

Effects of fructose and glucose on plasma leptin, insulin, and insulin resistance in lean and VMH-lesioned obese rats

To determine the influence of dietary fructose and glucose on circulating leptin levels in lean and obese rats, plasma leptin concentrations were measured in ventromedial hypothalamic (VMH)-lesioned obese and sham-operated lean rats fed either normal chow or fructose- or glucose-enriched diets (60% by calories) for 2 wk. Insulin resistance was evaluated by the steady-state plasma glucose method and intravenous glucose tolerance test. In lean rats, glucose-enriched diet significantly increased plasma leptin with enlarged parametrial fat pad, whereas neither leptin nor fat-pad weight was altered by fructose. Two weeks after the lesions, the rats fed normal chow had marked greater body weight gain, enlarged fat pads, and higher insulin and leptin compared with sham-operated rats. Despite a marked adiposity and hyperinsulinemia, insulin resistance was not increased in VMH-lesioned rats. Fructose brought about substantial insulin resistance and hyperinsulinemia in both lean and obese rats, whereas glucose led to rather enhanced insulin sensitivity. Leptin, body weight, and fat pad were not significantly altered by either fructose or glucose in the obese rats. These results suggest that dietary glucose stimulates leptin production by increasing adipose tissue or stimulating glucose metabolism in lean rats. Hyperleptinemia in VMH-lesioned rats is associated with both increased adiposity and hyperinsulinemia but not with insulin resistance. Dietary fructose does not alter leptin levels, although this sugar brings about hyperinsulinemia and insulin resistance, suggesting that hyperinsulinemia compensated for insulin resistance does not stimulate leptin production.     

Dietary fructose during the suckling period increases body weight and fatty acid uptake into skeletal muscle in adult rats

Objective: The suckling period is one potentially “critical” period during which nutritional intake may permanently “program” metabolism to promote increased adult body weight and insulin resistance in later life. This study determined whether fructose introduced during the suckling period altered body weight and induced changes in fatty acid transport leading to insulin resistance in adulthood in rats. Methods and Procedures: Pups were randomly assigned to one of four diets: suckle controls (SCs), rat milk substitute formula (Rat Milk Substitute), fructose‐containing formula (Fructose), or galactose‐containing formula (Galactose). Starting at weaning, all pups received the same diet; at 8 weeks of age, half of the SC rats began ingesting a diet containing 65% kcal fructose (SC‐Fructose). This continued until animals were 12 weeks old and the study ended. Results: At weeks 8, 10, and 11, the Fructose group weighed more than SC and SC‐Fructose groups (P < 0.05). At weeks 8 and 10 of age, the Fructose group had significantly higher insulin concentrations vs. rats in the SC‐Fructose group. ³H‐Palmitate transport into vesicles from hind limb skeletal muscle was higher in Fructose vs. SC rats (P < 0.05). CD36 expression was increased in the sarcolemma but not in whole tissue homogenates from skeletal muscle from Fructose rats (P < 0.05) suggesting a redistribution of this protein associated with fatty acid uptake across the plasma membrane. This change in subcellular localization of CD36 is associated with insulin resistance in muscle. Discussion: Consuming fructose during suckling may result in lifelong changes in body weight, insulin secretion, and fatty acid transport involving CD36 in muscle and ultimately promote insulin resistance.     

Cinnamon improves insulin sensitivity and alters the body composition in an animal model of the metabolic syndrome

Polyphenols from cinnamon (CN) have been described recently as insulin sensitizers and antioxidants but their effects on the glucose/insulin system in vivo have not been totally investigated. The aim of this study was to determine the effects of CN on insulin resistance and body composition, using an animal model of the metabolic syndrome, the high fat/high fructose (HF/HF) fed rat. Four groups of 22 male Wistar rats were fed for 12 weeks with:

(i)

(HF/HF) diet to induce insulin resistance,

(ii)

HF/HF diet containing 20 g cinnamon/kg of diet (HF/HF + CN),

(iii)

Control diet (C) and

(iv)

Control diet containing 20 g cinnamon/kg of diet (C + CN).

Data from hyperinsulinemic euglycemic clamps showed a significant decrease of the glucose infusion rates in rats fed the HF/HF diet. Addition of cinnamon to the HF/HF diet increased the glucose infusion rates to those of the control rats. The HF/HF diet induced a reduction in pancreas weight which was prevented in HF/HF + CN group (p < 0.01). Mesenteric white fat accumulation was observed in HF/HF rats vs. control rats (p < 0.01). This deleterious effect was alleviated when cinnamon was added to the diet. In summary, these results suggest that in animals fed a high fat/high fructose diet to induce insulin resistance, CN alters body composition in association with improved insulin sensitivity.     

Progressive Induction of Type 2 Diabetes: Effects of a Reality–Like Fructose Enriched Diet in Young Wistar Rats

Purpose

The aim of this study was to characterize short and medium-lasting effects of fructose supplementation on young Wistar rats. The diet was similar to actual human consumption.

Methods

Three week old male rats were randomly divided into 2 groups: control (C; n = 16), fructose fed (FF; n = 16) with a fructose enriched drink for 6 or 12 weeks. Bodyweight, fasting glycemia and systolic blood pressure were monitored. Glucose tolerance was evaluated using an oral glucose tolerance test. Insulinemia was measured concomitantly and enable us to calculate insulin resistance markers (HOMA-IR, Insulin Sensitivity Index for glycemia: ISI-gly). Blood chemistry analyses were performed.

Results

After six weeks of fructose supplementation, rats were not overweight but presented increased fasting glycemia, reduced glucose tolerance, and lower insulin sensitivity compared to control group. Systolic blood pressure and heart weight were also increased without any change in renal function (theoretical creatinine clearance). After twelve weeks of fructose supplementation, FF rats had increased bodyweight and presented insulin resistance (higher HOMA-IR, lower ISI-gly). Rats also presented higher heart volume and lower ASAT/ALAT ratio (presumed liver lesion). Surprisingly, the Total Cholesterol/Triglycerides ratio was increased only after six weeks of fructose supplementation, predicting a higher LDL presence and thus a higher risk of developing cardiovascular disease. This risk was no longer present after twelve weeks of a fructose enriched diet.

Conclusion

On young Wistar rats, six weeks of fructose supplementation is sufficient to induce signs of metabolic syndrome. After twelve weeks of fructose enriched diet, rats are insulin resistant. This model enabled us to study longitudinally the early development of type 2 diabetes.     

Fructose Diet-Induced Skin Collagen Abnormalities Are Prevented by Lipoic Acid

Nonenzymatic glycation of proteins, leading to chemical modification and cross-linking are of importance in the pathology of diabetic complications.We studied the effect of α-lipoic acid (LA) on the content and characteristics of the protein collagen from skin of high-fructose fed rats. The rats were divided into 4 groups of 6 each. Two groups of rats were fed with a high fructose diet (60 g/100 g diet) and administered either LA (35 mg/kg b.w., i.p) (FRU+LA) or 0.2 ml vehicle (saline) (FRU) for 45 days. The other 2 groups were fed with control diet containing starch (60 g/100 g diet) and administered either saline (CON) or lipoic acid (CON+LA). The rats were maintained for 45 days and then sacrificed. Plasma glucose, insulin, fructosamine, protein glycation, and blood glycated hemoglobin (HbA₁C) were measured. Collagen was isolated from skin and the physicochemical properties of collagen were studied. Fructose administration caused accumulation of collagen in skin. Extensive cross-linking was evidenced by enhanced glycation and AGE-linked fluorescence. Increased peroxidation and changes in physicochemical properties such as shrinkage temperature, aldehyde content, solubililty pattern, susceptibility to denaturing agents were observed in fructose-fed rats. SDS gel pattern of collagen from these rats showed elevated β component of type I collagen. These changes were alleviated by the simultaneous administration of LA. Administration of LA to fructose-fed rats had a positive influence on both quantitative and qualitative properties of collagen. The results suggest a mechanism for the ability of LA to delay diabetic complications.     

Relationship between renal and cardiovascular changes in a murine model of glucose intolerance

Nutrition is an important variable which may affect the risk for renal disease. We previously showed that a high fructose diet in mice produced hypertension and sympathetic activation [8]. The purpose of this study was to determine if a fructose diet altered renal function. A high fructose diet for 12 weeks impaired glucose tolerance, but caused no change in body weight, blood glucose or plasma insulin. Impairment in renal function was documented by the almost two fold increase in urinary protein excretion (Control: 6.6+/-0.6 vs. Fructose: 15.0+/-0.7 mmol protein/mmol creatinine; p<0.05) which was also accompanied by increases in urinary volume. The diet produced little change in renal histology, kidney weight or kidney weight/body weight ratio. Urinary excretion of angiotensin II/creatinine (Control: 78.9+/-16.6 vs. Fructose: 80.5+/-14.2 pg/mmol) and renal angiotensin converting enzyme activity (Control: 9.2+/-1.6 vs. Fructose: 7.6+/-1.0 ACE units) were not different between groups. There was a positive correlation between mean arterial pressure (r=0.7, p=0.01), blood pressure variability (BPV) (r=0.7, p=0.02), low frequency BPV component (r=0.677, p=0.03) and urinary protein excretion. Results show that consumption of a high fructose diet in mice had deleterious effects on renal function, which were correlated with cardiovascular changes.     

Fructose transport and metabolism in adipose tissue of Zucker rats: Diminished GLUT5 activity during obesity and insulin resistance

Fructose is a major dietary sugar, which is elevated in the serum of diabetic humans, and is associated with metabolic syndromes important in the pathogenesis of diabetic complications. The facilitative fructose transporter, GLUT5, is expressed in insulin-sensitive tissues (skeletal muscle and adipocytes) of humans and rodents, where it mediates the uptake of substantial quantities of dietary fructose, but little is known about its regulation. We found that GLUT5 abundance and activity were compromised severely during obesity and insulin resistance in Zucker rat adipocytes. Adipocytes from young obese (fa/fa), highly insulin-responsive Zucker rats contained considerably more plasma membrane GLUT5 than those from their lean counterparts (1.8-fold per microgram membrane protein), and consequently exhibited higher fructose transport (fivefold) and metabolism (threefold) rates. Lactate production was the preferred route for fructose metabolism in these cells. As the rats aged and become more obese and insulin-resistant, adipocyte GLUT5 surface density (12-fold) and fructose transport (10-fold) and utilisation rates (threefold) fell markedly. The GLUT5 loss was more dramatic in adipocytes from obese animals, which developed a more marked insulin resistance than lean counterparts. The decline of GLUT5 levels in adipocytes from older, obese animals was not a generalised effect, and was not observed in kidney, nor was this expression pattern shared by the 1 subunit of the Na⁺/K⁺ ATPase. Our findings suggest that plasma membrane GLUT5 levels and thus fructose utilisation rates in adipocytes are dependent upon cellular insulin sensitivity, inferring a possible role for GLUT5 in the elevated circulating fructose observed during diabetes, and associated pathological complications. (Mol Cell Biochem 261: 23–33, 2004)     

Effects of hypophysectomy and acute growth hormone treatment upon glucose metabolism in adipose tissues and isolated adipocytes of rats.

Glucose oxidation and incorporation into lipid were measured in epididymal adipose tissues and isolated adipose cells of normal and hypophysectomized rats in an effort to determine whether the acute hypoglycemic effect of a systemic growth hormone (GH) injection was related to alterations in the glucose metabolism of adipose tissue. The rats were fed rat chow or a high sucrose diet and received 100 mug GH intraperitoneally 30 minutes or three and one-half hours before sacrifice. Hypophysectomized rats showed a lower plasma glucose as compared with normal rats on both diets. Thirty minutes after a GH injection there was a further decrease of the plasma glucose which, however, was not present in those rats receiving GH three and one-half hours before sacrifice. Adipose tissues from hypophysectomized rats fed the high sucrose diet showed a blunted insulin sensitivity as compared with normal rats on a similar diet. The insulin sensitivity of these tissues was further decreased 30 minutes after a GH injection. Basal glucose metabolism of isolated adipocytes from hypophysectomized rats, as compared with normal rats, was depressed if they were fed rat chow, was at normal levels if they were fed the high sucrose diet and was increased if they were fed the sucrose diet and received triiodothyronine and cortisone supplements. No manipulations of diet or hormonal treatments made the isolated adipocyte from hypophysectomized rats sensitive to insulin either 30 minutes or three and one-half hours after a GH injection. Since basal glucose utilization is not enhanced by GH injection and both the blunted insulin sensitivity of adipose tissue and the absent insulin sensitivity of adipopocytes would be expected to produce hyperglycemia rather than hypoglycemia, it is concluded that immediate systemic effects of a GH injection on carbohydrate metabolism are not related to changes in glucose metabolism of the peripheral adipose tissues.     

Effects of fructose and/or fat in the diet on developing the type 2 diabetic-like syndrome in CD-1 mice

The aim of the present study was to examine the interactions of fructose and fat on glucose regulation and lipid metabolism in CD-1 mice. Mice were assigned in five groups. The control group was provided with tap water and a gavage of vehicle; four experimental groups were treated with 150 g/l fructose solution (FS1), fat emulsion (FE), 150 g/l fructose solution and fat emulsion (FS1+FE), or 70 g/l fructose solution and fat emulsion (FS2+FE) for 12 weeks. At the end of the 8th week, both oral glucose tolerance test and insulin tolerance test were conducted. Lipid profiles in serum, liver, and red gastrocnemius muscle, and serum insulin and glucose concentrations were assessed. The FS1+FE group showed combined glucose intolerance (CGI) and decrease of insulin sensitivity. The low-density lipoprotein cholesterol (LDL-C) concentrations were elevated in all experimental groups (p<0.05). The combined diet groups showed statistically significant (p<0.01) increase in total cholesterol (TC) level in comparison with the control FE (p<0.05), or FS1 (p<0.05) group. Triglyceride levels in liver and red gastrocnemius muscle were significantly increased in FE and combined groups. In conclusion, combination of FE and 150 g/l fructose solution for 8 weeks led to CGI. Fructose enhanced the adverse effect of FE on glucose regulation with increasing percentage in the diet. Furthermore, there was a synergistic effect of fructose and fat on elevating the serum TC level.     

Slc2a5 (Glut5) Is Essential for the Absorption of Fructose in the Intestine and Generation of Fructose-induced Hypertension

The identity of the transporter responsible for fructose absorption in the intestine in vivo and its potential role in fructose-induced hypertension remain speculative. Here we demonstrate that Glut5 (Slc2a5) deletion reduced fructose absorption by ∼75% in the jejunum and decreased the concentration of serum fructose by ∼90% relative to wild-type mice on increased dietary fructose. When fed a control (60% starch) diet, Glut5^-/- mice had normal blood pressure and displayed normal weight gain. However, whereas Glut5^+/+ mice showed enhanced salt absorption in their jejuna in response to luminal fructose and developed systemic hypertension when fed a high fructose (60% fructose) diet for 14 weeks, Glut5^-/- mice did not display fructose-stimulated salt absorption in their jejuna, and they experienced a significant impairment of nutrient absorption in their intestine with accompanying hypotension as early as 3–5 days after the start of a high fructose diet. Examination of the intestinal tract of Glut5^-/- mice fed a high fructose diet revealed massive dilatation of the caecum and colon, consistent with severe malabsorption, along with a unique adaptive up-regulation of ion transporters. In contrast to the malabsorption of fructose, Glut5^-/- mice did not exhibit an absorption defect when fed a high glucose (60% glucose) diet. We conclude that Glut5 is essential for the absorption of fructose in the intestine and plays a fundamental role in the generation of fructose-induced hypertension. Deletion of Glut5 results in a serious nutrient-absorptive defect and volume depletion only when the animals are fed a high fructose diet and is associated with compensatory adaptive up-regulation of ion-absorbing transporters in the colon.Fructose is a monosaccharide and is one of the three most important blood sugars along with glucose and galactose (1–3). It plays an essential role in vital metabolic functions in the body, including glycolysis and gluconeogenesis (4–6). Fructose is predominantly metabolized in the liver. A high flux of fructose to the liver perturbs glucose metabolism and leads to a significantly enhanced rate of triglyceride synthesis. In addition, fructose can be metabolized in the liver to uric acid, a potent antioxidant (7, 8).The classic model of sugar absorption indicates that sodium glucose cotransporter 1 (Sglt1)³ and Glut5 absorb glucose and fructose, respectively, from intestinal lumen to cytosol, and Glut2 transports both glucose and fructose from the cytosol to the blood (9–19). Glut2 has high affinity for glucose and a moderate affinity for fructose, whereas Glut5 predominantly transports fructose with very low affinity for glucose (9–19; reviews in Refs. 14, 17–19). The expression of Glut5 or Glut2 in the small intestine increases in rats or mice fed a diet high in fructose or perfused with increased fructose concentration (11–14, 18, 19).Glut2 is predominantly found on the basolateral membrane and in the cytoplasm of enterocytes at basal state but is thought to be recruited to the apical membrane in the presence of increased glucose or fructose in the intestinal lumen (11, 19). Given the fact that both Glut5 and Glut2 can transport fructose in vitro and given the ability of Glut2 to traffic to the apical membrane, the contribution of Glut5 to the absorption of fructose in vivo and systemic fructose homeostasis remains speculative.The marked increase in dietary fructose consumption in the form of high fructose corn syrup, a common sweetener used in the food industry, table sugar, and fruits correlates with the increased incidence of metabolic syndrome, which is reaching an epidemic proportion in developed countries and is a major contributor to premature morbidity and mortality in our society (20–22). Increased dietary fructose intake recapitulates many aspects of metabolic syndrome, including dyslipidemia, insulin resistance, and hypertension in rat and mouse (23–26). Recent studies demonstrate that fructose-induced hypertension is initiated by increased absorption of salt and fructose in the intestine (27); however, the one or more molecules (Glut2, Glut5, Glut7, or Sglt1) that are responsible for the absorption of fructose in the intestine remain speculative. Further, although Glut7, Glut5, and Glut2 can transport fructose in vitro, the role of Glut5 in in vivo fructose absorption remains unknown. To ascertain the role of Glut5 in fructose absorption in the intestine in vivo and fructose-induced hypertension, mice lacking the Glut5 gene (Glut5^-/-) were placed on either high fructose or normal diet and compared with their wild-type littermates (Glut5^+/+).     

Effect of galangin supplementation on oxidative damage and inflammatory changes in fructose-fed rat liver

The study examined the effects of galangin (GA) on oxidative stress, inflammatory cytokine levels and nuclear factor-kappa B (NF-κB) activation in fructose-fed rat liver. Adult male albino Wistar rats were divided into 4 groups. Groups 1 and 4 received the control diet containing starch as the source of carbohydrate while groups 2 and 3 were fed a diet containing fructose. Groups 3 and 4 additionally received GA (100 μg/kg, p.o) from the 15th day. At the end of 60 days, the levels of plasma glucose, insulin and triglycerides, insulin sensitivity indices and oxidative stress markers in the liver were determined. Cytokines of interest were assayed by ELISA and RT-PCR and NF-κB p65 nuclear translocation by Western blot and RT-PCR. Compared to control diet-fed animals, fructose-fed animals developed hyperglycemia, hyperinsulinemia, hypertriglyceridemia and insulin resistance (IR) (all p < 0.01). GA prevented the rise in plasma glucose, insulin and triglycerides and improved insulin sensitivity. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels in plasma and the mRNA and protein levels of TNF-α and transforming growth factor-β1(TGF-β₁) in liver were significantly higher in fructose-fed rats than control rats. However, treatment with GA downregulated the expression of these cytokines. Translocation of NF-κB into the nucleus was also increased in fructose diet-fed animals, which was prevented by GA. These results suggest that GA prevents oxidative damage and has a downregulatory effect on the inflammatory pathway in liver of fructose-fed rats.     

Salt-induced hypertension in WKY rats: Prevention by α-lipoic acid supplementation

There is strong evidence that points to excess dietary salt as a major factor contributing to the development of hypertension. Salt sensitivity is associated with glucose intolerance and insulin resistance in both animal models and humans. In insulin resistance, impaired glucose metabolism leads to elevated endogenous aldehydes which bind to vascular calcium channels, increasing cytosolic [Ca²⁺]_i and blood pressure. In an insulin resistant animal model of hypertension, spontaneously hypertensive rats (SHRs), dietary supplementation with lipoic acid lowers tissue aldehydes and plasma insulin levels and normalizes blood pressure. The objective of this study is to examine the effects of a high salt diet on tissue aldehydes, cytosolic [Ca²⁺]_i and blood pressure in WKY rats and to investigate whether dietary supplementation with lipoic acid can prevent a salt induced increase in blood pressure. Starting at 7 weeks of age, WKY rats were divided into three groups of six animals each and treated for 10 weeks with diets as follows: WKY-normal salt (0.7% NaCl); WKY-high salt (8% NaCl); WKY-high salt + lipoic acid (8% NaCl diet + lipoic acid 500 mg/Kg feed). At completion, animals in the high salt group had elevated systolic blood pressure, platelet [Ca²⁺]_i, and tissue aldehyde conjugates compared with the normal salt group and showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidneys. Dietary -lipoic acid supplementation in high salt-treated WKY rats normalized systolic blood pressure and cytosolic [Ca²⁺]_i and aldehydes in liver and aorta. Kidney aldehydes and renal vascular changes were attenuated, but not normalized.     

Dietary fructose vs glucose lowers copper solubility in the digesta in the small intestine of rats

The hypothesis was tested that dietary fructose vs glucose lowers copper solubility in the digesta in the small intestine of rats, which in turn causes a decreased copper absorption. Male rats were fed adequate-copper (5 mg Cu/kg) diets containing either fructose or glucose (709.4 g monosaccharide/kg) for a period of 5 wk. Fructose vs glucose significantly lowered copper concentrations in plasma and the liver, but did not alter hepatic copper mass. Fructose feeding resulted in a significantly lesser intestinal solubility of copper as based on either a smaller soluble fraction of copper in the liquid phase of small intestinal contents or a lower copper concentration in the liquid phase. The latter fructose effect can be explained by the observed fructose-induced increase in volume of liquid phase of intestinal digesta. After administration of a restricted amount of diet extrinsically labeled with⁶⁴Cu, rats fed fructose also had significantly lower soluble⁶⁴Cu fraction in the digesta of the small intestine. Although this study shows that fructose lowered intestinal copper solubility, only a slight reduction of apparent copper absorption was observed. It is suggested that the fructose-induced lowering of copper status in part counteracted the fructose effect on copper absorption at the level of the intestinal lumen.     

Protective effects of Withania somnifera root on inflammatory markers and insulin resistance in fructose-fed rats

Background:

We investigated the effects of Withania somnifera root (WS) on insulin resistance, tumor necrosis factor α (TNF-α), and interleukin-6 (IL-6) in fructose-fed rats.

Methods:

Forty-eight Wistar-Albino male rats were randomly divided into four groups (n=12); Group I as control, Group II as sham-treated with WS by 62.5mg/g per diet, Group III fructose-fed rats received 10%W/V fructose, and Group IV fructose- and WS-fed rats. After eight weeks blood samples were collected to measure glucose, insulin, IL-6, and TNF-α levels in sera.

Results:

Blood glucose, insulin, homeostasis model assessment for insulin resistance (HOMA-R), IL-6, and TNF-α levels were all significantly greater in the fructose-fed rats than in the controls. Treatment with WS significantly (P < 0.05) inhibited the fructose-induced increases in glucose, insulin, HOMA-R, IL-6, and TNF-α.

Conclusion:

Our data suggest that WS normalizes hyperglycemia in fructose-fed rats by reducing inflammatory markers and improving insulin sensitivity.Key Words: Withania somnifera, Insulin resistance, IL-6, TNF- α     

Effects of Dietary D-Psicose on Diurnal Variation in Plasma Glucose and Insulin Concentrations of Rats

The effects of supplemental D-psicose in the diet on diurnal variation in plasma glucose and insulin concentrations were investigated in rats. Forty-eight male Wistar rats were divided into four groups. Each group except for the control group was fed a diet of 5% D-fructose, D-psicose, or psico-rare sugar (3:1 mixture of D-fructose and D-psicose) for 8 weeks. Plasma glucose levels were lower and plasma insulin levels were higher at all times of day in the psicose and psico-rare sugar groups than in the control and fructose groups. Weight gain was significantly lower in the psicose group than in the control and fructose groups. Liver glycogen content, both before and after meals was higher in the psicose group than in the control and fructose groups. These results suggest that supplemental D-psicose can lower plasma glucose levels and reduce body fat accumulation. Hence, D-psicose might be useful in preventing postprandial hyperglycemia in diabetic patients.     

The influence of lipoic acid on adriamycin induced nephrotoxicity in rats

Adriamycin, which is widely used in the treatment of various neoplastic conditions, exerts toxic effects in several organs. Adriamycin nephrotoxicity has been recently documented in a variety of animal species. The present study was designed to investigate the effect of lipoic acid on the nephrotoxic potential of adriamycin. The study was carried out with adult male albino rats of Wistar strain. Test animals were divided into four groups of six rats each as follows: Group I (control) received only normal saline throughout the course of the experiment. Group II (ADR) received intravenous injections of adriamycin through the tail vein (1 mg kg^–1 body wt day^–1) once a week for a period of 12 weeks. Group III (LA) received lipoic acid (35 mg kg^–1 body wt day^–1) intraperitoneally once a week for a period of 12 weeks. Group IV (ADR + LA) received a single injection of lipoic acid intraperitoneally 24 h prior to the administration of adriamycin through the tail vein once a week for a period of 12 weeks. Intravenous injections of adriamycin resulted in decreased activities of the glycolytic enzymes; hexokinase, phosphoglucoisomerase, aldolase and lactate dehydrogenase in the rat renal tissue. The gluconeogenic enzymes; glucose-6-phosphatase and fructose-1,6-diphosphatase, showed a decline in their activities on adriamycin administration. The transmembrane enzymes namely the Na⁺,K⁺-ATPase, Ca²⁺-ATPase, Mg²⁺-ATPase and the brush-border enzyme alkaline phosphatase also showed a decrease in their activities. This decrease in the activities of ATPases and alkaline phosphatase suggests basolateral and brush-border membrane damage. Decreased activities of the TCA cycle enzymes isocitrate dehydrogenase, succinate dehydrogenase and malate dehydrogenase, suggest a loss in mitochondrial function and integrity. Nephrotoxicity was evident from the increased excretions of N-acetyl--D-glucosaminidase and -glutamyl transferase in the urine of adriamycin administered rats. These biochemical disturbances were effectively counteracted on pretreatment with lipoic acid, which brought about an increase in the activities of glycolytic enzymes, ATPases and the TCA cycle enzymes. On the other hand, the gluconeogenic enzymes showed a further decrease in their activities on lipoic acid pretreatment. LA pretreatment also restored the activities of the urinary enzymes to normal. These observations shed light on the nephroprotective action of lipoic acid rendered against experimental aminoglycoside toxicity.