Dose-dependent effect of galangin on fructose-mediated insulin resistance and oxidative events in rat kidney

Abstract

Galangin is an antioxidant flavonol present in high concentrations in the rhizome of Alpinia galanga. We investigated the effect of galangin on whole-body insulin resistance and kidney oxidative stress in a fructose-induced rat model of metabolic syndrome. Male albino Wistar rats were divided into 6 groups containing six animals each. Groups I and VI received a starch-based control diet, while groups II, III, IV and V were fed a high fructose diet (60 g/100 g). Groups III, IV and V additionally received galangin (50, 100 and 200 μg/kg body weight, respectively) while group VI received 200 μg galangin/kg body weight. At the end of 60 days, fructose-fed rats exhibited insulin resistance, increased levels of peroxidation end products and diminished antioxidant status. galangin, dose-dependently normalized blood glucose and insulin levels. The minimum effective dose was 100 μg galangin/kg body weight. At this dose, galangin also prevented the development of insulin resistance and the exaggerated the response to oral glucose challenge. The oxidant–antioxidant balance was maintained by galangin. Micro-albuminuria and tubular and glomerular changes observed in fructose-treated rats were significantly prevented by galangin (100 μg/kg body weight). These findings imply that galangin potentiates insulin sensitivity and antioxidant capacity and reduces renal damage in this dietary model of metabolic syndrome.     

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.     

Beneficial impact of L-carnitine in liver: a study in a rat model of syndrome X

The present study was designed to explore whether L-carnitine (CA) regulates insulin signaling and modulates the changes in liver in a well-characterized insulin resistant rat model. Adult male Wistar rats were divided into 4 groups. Groups I and IV animals received starch-based control diet, while groups II and III rats were fed a high fructose-diet (60 g/100 g). Groups III and IV animals additionally received CA (300 mg/kg/day i.p). After a period of 60 days hepatic tyrosine phosphorylation status was determined by assaying protein tyrosine phosphatase (PTP) and protein tyrosine kinase (PTK) activities. Oxidative damage was monitored by immunohistochemical localization of 4-hydroxynonenal (4-HNE), 3-nitrotyrosine (3-NT) and dinitrophenol (DNP)-protein adducts. In addition protein kinase C beta II (PKC beta II) expression, propidium iodide staining of isolated hepatocytes and histology of liver tissue were determined to examine liver integrity. Fructose-fed rats displayed reduced insulin action, increased expression of PKC beta II, altered histology, fragmentation of hepatocyte nuclear DNA, and accumulation of oxidatively modified proteins. Simultaneous treatment with CA alleviated the abnormalities associated with fructose feeding. In summary the data suggest that elevated oxidative damage and PKC expression could in part induce insulin resistance and CA has beneficial impact on liver during insulin resistance with modulatory effects at the post-receptor level.     

Galangin,a dietary flavonoid,improves antioxidant status and reduces hyperglycemia-mediated oxidative stress in streptozotocin-induced diabetic rats

Objective: To examine the effect of galangin on hyperglycemia-mediated oxidative stress in streptozotocin (STZ)-induced diabetic rats.

Methods: Diabetes was induced by intraperitoneal administration of low-dose STZ (40?mg/kg body weight (BW)) into male albino Wistar rats. Galangin (8?mg/kg BW) or glibenclamide (600?µg/kg BW) was given orally, once daily for 45 days to normal and STZ-induced diabetic rats.

Results: Diabetic rats showed significantly increased levels of plasma glucose, thiobarbituric acid reactive substances, lipid hydroperoxides, and conjugated dienes. The levels of insulin and non-enzymatic antioxidants (vitamin C, vitamin E, reduced glutathione) and the activity of enzymatic antioxidants (superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase (GST)) were decreased significantly in diabetic control rats. These altered plasma glucose, insulin, lipid peroxidation products, enzymatic and non-enzymatic antioxidants ions were reverted to near-normal level after the administration of galangin and glibenclamide.

Conclusion: The present study shows that galangin decreased oxidative stress and increased antioxidant status in diabetic rats, which may be due to its antidiabetic and antioxidant potential.     

Oleoyl-estrone induces the massive loss of body weight in Zucker fa/fa rats fed a high-energy hyperlipidic diet

To test whether oleoyl-estrone plus a hyperlipidic diet affects body weight in Zucker fa/fa rats, 13-week-old male Zucker obese (fa/fa) rats initially weighing 440-470 g were used. They were fed for 15 days with a powdered hyperlipidic diet (16.97 MJ/kg metabolizable energy) in which 46.6% was lipid-derived and 16.1% was protein-derived energy and containing 1.23 +/- 0.39 μmol/kg of fatty-acyl esters of estrone. This diet was supplemented with added oleoyl-estrone to produce a diet with 33.3 μmol/kg of fatty-acyl estrone. Oral administration of oleoyl-estrone in a hyperlipidic diet (at a mean dose of 0.5 μmol. kg(-1).d(-1)) resulted in significant losses of fat, energy and, ultimately, weight. Treatment induced the maintenance of energy expenditure combined with lower food intake, creating an energy gap that was filled with internal fat stores while preserving body protein, in contrast with the marked growth of controls fed the hyperlipidic diet. Treatment of genetically obese rats with a hyperlipidic diet containing additional oleoyl-estrone resulted in the loss of fat reserves with scant modification of other metabolic parameters, except for lower plasma glucose and insulin levels. The results agree with the postulated role of oleoyl-estrone as a ponderostat signal.     

Beneficial effects of hydro-alcoholic extract of Caralluma fimbriata against high-fat diet-induced insulin resistance and oxidative stress in Wistar male rats

The main aim of this study was to investigate the beneficial effects of hydro-alcoholic extract of Caralluma fimbriata (CFE) on the effects of high-fat diet feeding on insulin resistance and oxidative stress in Wistar rats. High-fat diet (60 % of fat) and CFE (200 mg/kg body weight/day) were given concurrently to the rats for a period of 90 days. Feeding with high-fat diet resulted in the development of hyperglycemia, hyperinsulinemia, hyperleptinemia, and hypertriglyceridemia and impaired insulin sensitivity (P?<?0.05). Administration of CFE to high-fat diet-fed rats for 90 days resulted in a significant improvement in plasma glucose, insulin, leptin, and triglycerides. Regarding liver antioxidant status, high-fat fed rats showed higher levels of lipid peroxidation, protein oxidation and lower GSH levels and lower activities of enzymatic antioxidants, while CFE treatment prevented all these observed abnormalities. In conclusion, intake of CFE may be beneficial for the suppression of high-fat diet-induced insulin resistance and oxidative stress.     

Variations of glucose utilization in muscle and adipose tissue of sand rats (Psammomys obesus) during adaptation to laboratory holding

Sand rats, captured in Egypt and fed with a low caloric vegetable diet during adaptation, were investigated before and after 2.5 and 8 weeks diet treatment (30 and 40 kcal/100 g body weight daily). In hexobarbital anaesthesia the sand rats were loaded with 1 g glucose/kg body weight in a single dose intravenously. After a rapid increase the content of glucose in blood remained at a level of about 600 mg glucose/100 ml blood. The insulin immunoreactivity in blood did not change uniformly after application of glucose and remained in a physiologic range. In the islets of Langerhans a degranulation was found during diet treatment. The sensitivity of the epididymal adipose tissue towards insulin in vitro decreased to a nearly complete resistance in the course of diet treatment. A diminution of insulin sensitivity was also found in the m. soleus in vitro. The content of glucose-6-phosphate in the m. semimembranosus was found enhanced after the preparation of the animal. It was found progressively increased up to the five-fold at the end of diet treatment. In the corresponding muscle the glucose distribution volume was increased to about double the extracellular volume. An accumulation of free glucose within the muscle cell must be taken into account. In conclusion the treatment of sand rats with a diabetogenic diet results very quickly in a loss of insulin sensitivity of adipose tissue. The progressively increased stress-mediated accumulation of glucose-6-phosphate and free glucose refers to an inhibition of glucose utilization in the phosphorylation step of glucose in skeletal muscle.     

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.     

Anti-fertility effects of embelin in female Sprague-Dawley rats may be due to suppression of ovarian function

Effects of embelin on oestrous cycle, plasma levels of progesterone and oestradiol, and in vitro production of oestradiol and progesterone by mixed ovarian cells was studied. Forty adult (4 months old) regularly cycling female Sprague-Dawley rats were divided into four groups of 10 rats each. Groups I and II (controls) were given 1 ml/kg body weight of physiological saline or corn oil (vehicle). Groups III and IV received 10 mg/kg and 20 mg/kg body weight embelin in corn oil, respectively. Emberlin disrupted the oestrous cycles in Groups III and IV animals, and there was a significant depression in plasma oestradiol (p <0.05) and progesterone (p <0.02) at both 10 and 20 mg/kg body weights, respectively. Isolated mixed ovarian cells from embelin treated rats produced significantly less progesterone and estradiol than controls in vitro. It is concluded that embelin probably interferes with reproductive functions in female rats by suppressing ovarian production of sex steroid hormones.     

Effects of 17β-estradiol and antioxidant administration on oxidative stress and insulin resistance in ovariectomized rats

The prevalence of insulin resistance syndrome increases during menopause with the overproduction of reactive oxygen species and impairment of the free radical scavenger function. Therefore, we investigated the effects of 17β-estradiol (E(2)) and vitamin E, as an antioxidant, on lipid peroxidation and antioxidant levels in the brain cortex and liver of ovariectomized rats as well as on insulin resistance in those rats. Forty female Sprague-Dawley rats, 3?months of age and weighing 231.5?± 9.4 g, were divided into 4 groups: sham, ovariectomized (OVX), OVX treated with E(2) (40 μg/kg subcutaneously), and OVX treated with E(2) and vitamin E (100?mg/kg intraperitoneally). The 4 groups received the appropriate treatment every day for 8?weeks. Levels of glutathione, glutathione peroxidase, superoxide dismutase , catalase, and malondialdehyde in the brain cortex and liver of ovariectomized rats were measured. Also, fasting plasma insulin, glucose, and homeostatis model assessment of insulin resistance (HOMA-IR) were determined. Malondialdehyde increased and antioxidants (glutathione, glutathione peroxidase, catalase, superoxide dismutase) decreased in the brain cortex and liver of OVX rats. Also, fasting glucose, insulin, and HOMA-IR increased in OVX rats. E(2) and E(2) plus vitamin E decreased malondialdehyde and increased antioxidants in the brain cortex and liver of OVX rats. Moreover, they decreased fasting glucose, insulin, and HOMA-IR in ovariectomized rats. This study demonstrates that E(2) and E(2) plus vitamin E supplementation to OVX rats may improve insulin resistance, strengthen the antioxidant system, and reduce lipid peroxidation.     

Protection against the diabetogenic effect of feeding tert-butylhydroquinone to rats prior to the administration of streptozotocin

We determined whether an oral administration of the synthetic antioxidant, tert-butylhydroquinone (TBHQ), or the naturally occurring lipoxygenase inhibitor, curcumin, to rats would provide protection against the diabetogenic effect of streptozotocin (STZ). Male Sprague-Dawley rats were fed on an AIN-76-based purified diet containing 0.0028% TBHQ or on the purified diet with a daily intragastric administration of curcumin (200 mg/kg of body weight) for one week while receiving intravenously administered STZ. The rats fed on the TBHQ-containing diet were resistant to diabetes development when compared with the rats fed on the TBHQ-free diet and had a higher body weight gain and lower serum glucose concentration. Glucose-stimulated insulin secretion from the pancreatic islet in the rats that had received TBHQ was higher than that in the control rats. The rats receiving curcumin showed no beneficial effect on these diabetic symptoms. These findings provide direct evidence for the suggestion that dietary supplementation of an antioxidant may exert a preventive effect on the diabetogenic action of free-radical producers.     

Reproductive activities of female albino rats treated with quassin, a bioactive triterpenoid from stem bark extract of Quassia amara

To evaluate the effect of quassin on female reproductive functions, 42 albino rats (35 females and 7 males) were used. The female albino rats were divided into seven groups of five rats each. Group I served as the control group and received distilled water while Groups II, III and IV rats were treatedorally with 0.1mg/kg, 1.0 mg/kg and 2.0 mg/kg body weight of quassin for 60 days respectively. Groups V, VI and VII rats were also treated orally with 0.1 mg/kg, 1.0mg/kg and 2.0 mg/kg body weight of quassin for 60 days but were left untreated for another 30 days, to serve as the recovery groups. At the end of each experimental period, blood samples were collected from each rat. Fertility study was done by cohabiting one untreated male with the five female rats in each group for 10 days. Quassin did not adversely affect the weight of the kidney, heart, liver and the body of the rats. However there was a significant decrease in the weight of the ovary and uterus in all the groups relative to the control. There was also a significant decrease in serum estrogen levels in quassin treated rats. The quassin treated rats had a significantly decreased mean litter number and weight. Histological studies show a disorganization and degeneration in the ovary while the uterus showed signs of vacuolation and disorganization. However, these effects were ameliorated after quassin was withdrawn from the rats. The results suggest that quassin has female anti-fertility properties, possibly acting via inhibition of estrogen secretion. Keyword: Quassin, Female rat, Reproduction, Estrogen.     

The Effects of Chromium Complex and Level on Glucose Metabolism and Memory Acquisition in Rats Fed High-Fat Diet

Conditions in which glucose metabolism is impaired due to insulin resistance are associated with memory impairment. It was hypothesized that supplemental chromium (Cr) may alleviate insulin resistance in type 2 diabetes and consequently improve memory acquisition, depending upon its source and level. In a complete randomized design experiment, male Wistar rats (n=60; weighing 200-220 g) were fed either normal (8%, normal diet (ND)) or high-fat (40%, high-fat diet (HFD)) diet and supplemented with Cr as either chromium-glycinate (CrGly) or chromium-acetate (CrAc) at doses of 0, 40, or 80 μg/kg body weight (BW) via drinking water from 8 to 20 weeks of age. Feeding HFD induced type 2 diabetes, as reflected by greater glucose/insulin ratio (2.98 vs. 2.74) comparing to feeding ND. Moreover, HFD rats had greater BW (314 vs. 279 g) and less serum (53 vs. 68 μg/L) and brain (14 vs. 24 ng/g) Cr concentrations than ND rats. High-fat diet caused a 32% reduction in expressions of glucose transporters 1 and 3 (GLUTs) in brain tissue and a 27% reduction in mean percentage time spent in the target quadrant and a 38% increase in spatial memory acquisition phase (SMAP) compared with ND. Compared with supplemental Cr as CrAc, CrGly was more effective to ameliorate response variables (i.e., restoration of tissue Cr concentration, enhancement of cerebral GLUTs expressions, and reduction of the glucose/insulin ratio and SMAP) in a dose-response manner, especially in rats fed HFD. Supplemental Cr as CrGly may have therapeutic potential to enhance insulin action and alleviate memory acquisition in a dose-dependent manner, through restoring tissue Cr reserve and enhancing cerebral GLUTs expressions.     

Garlic and vitamin E provides antioxidant defence in tissues of female rats treated with nicotine

Nicotine is known to induce oxidative stress in rat tissues and the antioxidant properties of garlic have been reported. This study was designed to determine if the peroxidative damage caused by nicotine administration can be effectively prevented with garlic juice, and vitamin E, a known antioxidant.Four groups of six rats each were divided into: Group I: (control) received 0.2ml of 0.9% normal saline, group II (received nicotine 0.6mg/kg b.w subcutaneously), group III (received nicotine 0.6mg/kg b.w + garlic juice 100mg/kg b.w orally), and group IV (received nicotine 0.6mg/kg b.w + Vitamin E 100mg/kg b.w orally). All animals were treated for 21 days. The pituitary gland, ovary, uterus, heart, liver and kidney of the animals were harvested, weighed and homogenized. Malondialdehyde (MDA), superoxide dismutase (SOD) and reduced glutathione (GSH) were then measured.Concentration of MDA was significantly increased in tissues of nicotine treated rats when compared with the control. In group III and IV, MDA levels were significantly reduced when compared with nicotine group. The activities of SOD and GSH significantly decreased in group II (nicotine only) rat tissues, while it was significantly increased in group III and IV rat tissues. The study showed that garlic juice extract (100mg/kg b.w) and vitamin E (100mg/kg b.w) administration prevented oxidative damage in rat tissues treated with nicotine. The study also showed that vitamin E has a more potent antioxidant activity than garlic juice in preventing nicotine induced oxidative damage in rat. Keywords: Nicotine, Vitamin E, Garlic, antioxidant.     

S 23521 Decreases Food Intake and Body Weight Gain in Diet‐Induced Obese Rats

Objective: To investigate the effect of S 23521, a new glucagon‐like peptide‐1‐(7‐36) amide analogue, on food intake and body weight gain in obese rats, as well as on gene expression of several proteins involved in energy homeostasis. Research Methods and Procedures: Lean and diet‐induced obese rats were treated with either S 23521 or vehicle. S 23521 was given either intraperitoneally (10 or 100 μg/kg) or subcutaneously (100 μg/kg) for 14 and 20 days, respectively. Because the low‐dose treatment did not affect food intake and body weight, the subcutaneous treatment at high dose was selected to test the effect on selected end‐points. Results: Treated obese rats significantly decreased their cumulative energy intake in relation to vehicle‐treated counterparts (3401 ± 65 vs. 3898 ± 72 kcal/kg per 20 days; p < 0.05). Moreover, their body weight gain was reduced by 110%, adiposity was reduced by 20%, and plasma triglyceride levels were reduced by 38%. The treatment also improved glucose tolerance and insulin sensitivity of obese rats. Regarding gene expression, no changes in uncoupling protein‐1, uncoupling protein‐3, leptin, resistin, and peroxisome proliferator‐activated receptor (PPAR)‐γ were observed. Discussion: S 23521 is an effective glucagon‐like peptide‐1‐(7‐36) amide analogue, which induced a decrease in energy intake, body weight, and adiposity in a rat model of diet‐induced obesity. In addition, the treatment also improved glucose tolerance and insulin sensitivity of obese rats. These results strongly support S 23521 as a putative molecule for the treatment of obesity.     

Curcumin prevents liver fat accumulation and serum fetuin-A increase in rats fed a high-fat diet

Fetuin-A is synthesized in the liver and is secreted into the bloodstream. Clinical studies suggest involvement of fetuin-A in metabolic disorders such as visceral obesity, insulin resistance, diabetes, and fatty liver. Curcumin is extracted from the rhizome Curcuma longa and has been shown to possess potent antioxidant, anticarcinogenic, anti-inflammatory, and hypoglycemic properties. In this study, we investigated the effect of curcumin treatment on serum fetuin-A levels as well as hepatic lipids and prooxidant–antioxidant status in rats fed a high-fat diet (HFD). Male Sprague–Dawley rats were divided into six groups. Group 1 was fed control diet (10 % of total calories from fat). Groups 2 and 3 were given curcumin (100 and 400 mg/kg bw/day, respectively ) by gavage for 8 weeks and were fed control diet. Group 4 was fed with HFD (60 % of total calories from fat). Groups 5 and 6 received HFD together with the two doses of curcumin, respectively. Curcumin treatment appeared to be effective in reducing liver triglycerides and serum fetuin-A levels. These findings suggest that the reduction of fetuin-A may contribute to the beneficial effects of curcumin in the pathogenesis of obesity.     

Lipoic acid attenuates hypertension and improves insulin sensitivity,kallikrein activity and nitrite levels in high fructose-fed rats

Chronic feeding of fructose to normal rats causes impaired glucose tolerance, loss of tissue sensitivity to insulin, hyperinsulinemia and hypertension. -Lipoic acid (LA), a co-enzyme known for its potent antioxidant effects, stimulates insulin-mediated glucose uptake in clinical and experimental diabetes. The purpose of this study was to examine whether LA can mitigate fructose-induced insulin resistance and associated abnormalities. Male Wistar rats of body weights 150–170 g were divided into 4 groups containing 12 rats each. Control rats received a control diet containing starch and water ad libitum. Fructose rats received a fructose-enriched diet (>60% of total calories). Fructose + LA rats received a fructose diet and LA (35 mg/kg b.w.) intraperitoneally. Control + LA rats received a normal diet and LA (35 mg/kg b.w.) intraperitoneally. After the treatment period of 20 days, blood pressure (BP) was measured. Oral glucose-tolerance test, insulin-sensitivity index, urea and creatinine clearance tests, and plasma and urinary sodium and potassium levels were analysed. Kallikrein activity and nitrite content were assayed. Additionally, the activities of RBC-membrane Na⁺/K⁺ ATPase and Ca²⁺ ATPase enzymes were assayed. Fructose rats showed increased BP, decreased glucose tolerance, decreased insulin sensitivity and altered sodium and potassium levels and renal clearance. LA supplementation mitigated these alterations. The increase in BP was attenuated and the levels of biochemical parameters were brought close to normal. The BP-lowering effect of LA in fructose rats may be related to improvement in insulin sensitivity.Communicated by L.C.-H. Wang.     

Excess aldosterone-induced changes in insulin signaling molecules and glucose oxidation in gastrocnemius muscle of adult male rat

Emerging evidences demonstrate that excess aldosterone and insulin interact at target tissues. It has been shown that increased levels of aldosterone contribute to the development of insulin resistance and thus act as a risk factor for the development of type-2 diabetes mellitus. However, the molecular mechanisms involved in this scenario are yet to be identified. This study was designed to assess the dose-dependent effects of aldosterone on insulin signal transduction and glucose oxidation in the skeletal muscle (gastrocnemius) of adult male rat. Healthy adult male albino rats of Wistar strain (Rattus norvegicus) weighing 180?C200?g were used in this study. Rats were divided into four groups. Group I: control (treated with 1?% ethanol only), group II: aldosterone treated (10???g /kg body weight, twice daily for 15?days), group III: aldosterone treated (20???g /kg body weight, twice daily for 15?days), and group IV: aldosterone treated (40???g/kg body weight, twice daily for 15?days). Excess aldosterone caused glucose intolerance in a dose-dependent manner. Serum insulin and aldosterone were significantly increased, whereas serum testosterone was decreased. Aldosterone treatment impaired the rate of glucose uptake, oxidation, and insulin signal transduction in the gastrocnemius muscle through defective expression of IR, IRS-1, Akt, AS160, and GLUT4 genes. Phosphorylation of IRS-1, ??-arrestin-2, and Akt was also reduced in a dose-dependent manner. Excess aldosterone results in glucose intolerance as a result of impaired insulin signal transduction leading to decreased glucose uptake and oxidation in skeletal muscle. In addition to this, it is inferred that excess aldosterone may act as one of the causative factors for the onset of insulin resistance and thus increased incidence of type-2 diabetes.     

Protein-restriction diet during the suckling phase programs rat metabolism against obesity and insulin resistance exacerbation induced by a high-fat diet in adulthood

Protein restriction during the suckling phase can malprogram rat offspring to a lean phenotype associated with metabolic dysfunctions later in life. We tested whether protein-caloric restriction during lactation can exacerbate the effect of a high-fat (HF) diet at adulthood. To test this hypothesis, we fed lactating Wistar dams with a low-protein (LP; 4% protein) diet during the first 2 weeks of lactation or a normal-protein (NP; 23% protein) diet throughout lactation. Rat offspring from NP and LP mothers received a normal-protein diet until 60 days old. At this time, a batch of animals from both groups was fed an HF (35% fat) diet, while another received an NF (7% fat) diet. Maternal protein-caloric restriction provoked lower body weight and fat pad stores, hypoinsulinemia, glucose intolerance, higher insulin sensitivity, reduced insulin secretion and altered autonomic nervous system (ANS) function in adult rat offspring. At 90 days old, NP rats fed an HF diet in adulthood displayed obesity, impaired glucose homeostasis and altered insulin secretion and ANS activity. Interestingly, the LP/HF group also presented fat pad and body weight gain, altered glucose homeostasis, hyperleptinemia and impaired insulin secretion but at a smaller magnitude than the NP-HF group. In addition, LP/HF rats displayed elevated insulin sensitivity. We concluded that protein-caloric restriction during the first 14 days of life programs the rat metabolism against obesity and insulin resistance exacerbation induced by an obesogenic HF diet.     

Acute peripheral but not central administration of olanzapine induces hyperglycemia associated with hepatic and extra-hepatic insulin resistance

Atypical antipsychotic drugs such as Olanzapine induce weight gain and metabolic changes associated with the development of type 2 diabetes. The mechanisms underlying the metabolic side-effects of these centrally acting drugs are still unknown to a large extent. We compared the effects of peripheral (intragastric; 3 mg/kg/h) versus central (intracerebroventricular; 30 μg/kg/h) administration of Olanzapine on glucose metabolism using the stable isotope dilution technique (Experiment 1) in combination with low and high hyperinsulinemic-euglycemic clamps (Experiments 2 and 3), in order to evaluate hepatic and extra-hepatic insulin sensitivity, in adult male Wistar rats. Blood glucose, plasma corticosterone and insulin levels were measured alongside endogenous glucose production and glucose disappearance. Livers were harvested to determine glycogen content. Under basal conditions peripheral administration of Olanzapine induced pronounced hyperglycemia without a significant increase in hepatic glucose production (Experiment 1). The clamp experiments revealed a clear insulin resistance both at hepatic (Experiment 2) and extra-hepatic levels (Experiment 3). The induction of insulin resistance in Experiments 2 and 3 was supported by decreased hepatic glycogen stores in Olanzapine-treated rats. Central administration of Olanzapine, however, did not result in any significant changes in blood glucose, plasma insulin or corticosterone concentrations nor in glucose production. In conclusion, acute intragastric administration of Olanzapine leads to hyperglycemia and insulin resistance in male rats. The metabolic side-effects of Olanzapine appear to be mediated primarily via a peripheral mechanism, and not to have a central origin.