Development of insulin sensitivity in rat skeletal muscle. Studies of glucose transporter and insulin receptor mRNA levels.

Expression of GLUT-4 and insulin receptor mRNAs was investigated in rat skeletal muscle by Northern hybridization. GLUT-4 mRNA was barely detectable in foetal muscle, was expressed at low levels by 1-8 days and at 2-3-fold higher levels during and after weaning (18-40 days). In contrast there was little change in insulin receptor mRNA levels prior to weaning and a reduction in mRNA abundance between 18 and 40 days. Weaning rats on to a diet rich in fat prevented the increase in GLUT-4 abundance seen between 15 and 29 days in animals weaned on a high-carbohydrate diet.     

N-3 polyunsaturated fatty acids prevent the defect of insulin receptor signaling in muscle

A high-fat diet containing polyunsaturated fatty acids (PUFA: n-3 or n-6) given for 4 wk to 5-wk-old male Wistar rats induced a clear hyperglycemia (10.4 +/- 0.001 mmol/l for n-6 rats and 10.1 +/- 0.001 for n-3 rats) and hyperinsulinemia (6.6 +/- 0.8 ng/ml for n-6 rats and 6.4 +/- 1.3 for n-3 rats), signs of insulin resistance. In liver, both diets (n-3 and n-6) significantly reduced insulin receptor (IR) number, IR and IR substrate (IRS)-1 tyrosine phosphorylation, and phosphatidylinositol (PI) 3'-kinase activity. In contrast, in leg muscle, IR density, as determined by Western blotting, was not affected, whereas IR and IRS-1 tyrosine phosphorylation in response to insulin treatment was restored in animals fed with n-3 PUFA to normal; in n-6 PUFA, the phosphorylation was depressed, as evidenced by Western blot analysis using specific antibodies. In addition, PI 3'-kinase activity and GLUT-4 content in muscle were maintained at normal levels in rats fed with n-3 PUFA compared with rats fed a normal diet. In rats fed with n-6 PUFA, both PI 3'-kinase activity and GLUT-4 content were reduced. Furthermore, in adipose tissue and using RT-PCR, we show that both n-3 and n-6 PUFA led to slight or strong reductions in p85 expression, respectively, whereas GLUT-4 and leptin expression was depressed in n-6 rats. The expression was not affected in n-3 rats compared with control rats. In conclusion, a high-fat diet enriched in n-3 fatty acids maintained IR, IRS-1 tyrosine phosphorylation, and PI 3'-kinase activity and total GLUT-44 content in muscle but not in liver. A high-fat diet (n-3) partially altered the expression of p85 but not that of GLUT-4 and leptin mRNAs in adipose tissue.     

Effect of β-Caryophyllene on insulin resistance in skeletal muscle of high fat diet and fructose-induced type-2 diabetic rats

High fat diet feeding results in hyperglycemia and insulin resistance, which is a major pathological feature of type-2 diabetes mellitus. The use of oral hypoglycaemic drugs is limited due to its deleterious side effects and there is a need to find more efficacious agents for diabetes management. Hence, it is of interest to show the mechanism of action of β-Caryophyllene on insulin signalling molecules in gastrocnemius muscle of high fat diet - induced type-2 diabetic rats. An oral effective dose of with β-Caryophyllene (200 mg/kg b.wt) was given for 30 days to high fat diet (comprising 2% cholesterol, 1% cholic acid, 30% coconut oil, 67% conventional rat feed) and fructose fed type-2 diabetic rats to find out whether β-Caryophyllene regulates IRS-1/Akt pathway of insulin signalling. The data shows that, β-Caryophyllene treatment significantly increased the mRNA and protein expression of insulin receptor (IR) in diabetic rats whereas there is no significant difference in mRNA expression of insulin receptor-substrate-1 (IRS-1) was observed among groups. The Akt mRNAand GLUT-4mRNA and protein level were also improved in gastrocnemius muscle of type-2 diabetic rats. Thus, we concluded that β-Caryophyllene could be used as potential phyto medicine for type-2 diabetes management.     

Decreased mRNA expression of the PTH/PTHrP receptor and type II sodium-dependent phosphate transporter in the kidney of rats fed a high phosphorus diet accompanied with a decrease in serum calcium concentration

This study investigates the phosphorus (P) homeostasis in the process of an altered parathyroid hormone (PTH) action in the kidney of rats fed a high P diet. Four-week-old male Wistar strain rats were fed diets containing five different P levels (0.3, 0.6, 0.9, 1.2 and 1.5%) for 21 days. The serum PTH concentration and urinary excretion of P were elevated with increasing dietary P level. Compared to rats fed the 0.3% P diet, the serum calcium (Ca) concentration remained unchanged, while the serum 1,25(OH)(2)D(3) concentration and urinary excretion of cAMP were elevated with increasing dietary P level in rats fed the high P diets containing 0.6-0.9% P. On the other hand, a lower serum Ca concentration was observed in rats fed the high P diets containing 1.2% or greater P. The serum 1,25(OH)(2)D(3) concentration remained unchanged in rats fed the high P diets containing 1.2% or greater P, comparison with rats fed the 0.3% P diet. The urinary excretion of cAMP and PTH/PTH-related peptide (PTHrP) receptor and type II sodium-dependent phosphate transporter (NaPi-2) mRNA in the kidney were both decreased in rats fed the high P diets containing 1.2% or greater P. In conclusion, a high P diet with subsequent decrease in serum Ca concentration suppressed the PTH action in the kidney due to PTH/PTHrP receptor mRNA down-regulation. Furthermore, an increase in the urinary excretion of P might have been caused by decreased NaPi-2 mRNA expression without the effects of PTH and 1,25(OH)(2)D(3).     

Mechanisms underlying impaired GLUT-4 translocation in glycogen-supercompensated muscles of exercised rats

Exercise training induces an increase in GLUT-4 in muscle. We previously found that feeding rats a high-carbohydrate diet after exercise, with muscle glycogen supercompensation, results in a decrease in insulin responsiveness so severe that it masks the effect of a training-induced twofold increase in GLUT-4 on insulin-stimulated muscle glucose transport. One purpose of this study was to determine whether insulin signaling is impaired. Maximally insulin-stimulated phosphatidylinositol (PI) 3-kinase activity was not significantly reduced, whereas protein kinase B (PKB) phosphorylation was approximately 50% lower (P < 0.01) in muscles of chow-fed, than in those of fasted, exercise-trained rats. Our second purpose was to determine whether contraction-stimulated glucose transport is also impaired. The stimulation of glucose transport and the increase in cell surface GLUT-4 induced by contractions were both decreased by approximately 65% in glycogen-supercompensated muscles of trained rats. The contraction-stimulated increase in AMP kinase activity, which has been implicated in the activation of glucose transport by contractions, was approximately 80% lower in the muscles of the fed compared with the fasted rats 18 h after exercise. These results show that both the insulin- and contraction-stimulated pathways for muscle glucose transport activation are impaired in glycogen-supercompensated muscles and provide insight regarding possible mechanisms.     

Changes in rates of tissue protein synthesis in rats induced in vivo by consumption of kidney bean lectins

1. Plantaris and gastrocnemius muscles from rats fed a diet containing raw kidney beans lost proportionately more weight and protein than muscles from rats fed a protein free diet, resulting in a progressive reduction in the ratio muscle mass: body weight over a period of 6 days. Rates of muscle protein synthesis were also lower in rats fed raw beans.2. Destruction of the bean lectins by boiling abolished both these effects.3. Two hours after administration of a single dose of purified kidney bean lectin, rates of protein synthesis were unchanged in the muscle and liver but were increased in the gut mucosa.     

Effects of continuous low-carbohydrate diet after long-term exercise on GLUT-4 protein content in rat skeletal muscle.

Stimulation of AMPK and decreased glycogen levels in skeletal muscle have a deep involvement in enhanced insulin action and GLUT-4 protein content after exercise training. The present study examined the chronic effects of a continuous low-carbohydrate diet after long-term exercise on GLUT-4 protein content, glycogen content, AMPK, and insulin signaling in skeletal muscle. Rats were divided randomly into four groups: normal chow diet sedentary (N-Sed), low carbohydrate diet sedentary (L-Sed), normal chow diet exercise (N-Ex), and low carbohydrate diet exercise (L-Ex) groups. Rats in the exercise groups (N-Ex and L-Ex) were exercised by swimming for 6 hours/day in two 3-hour bouts separated by 45 minutes of rest. The 10-day exercise training resulted in a significant increase in the GLUT-4 protein content (p<0.01). Additionally, the GLUT-4 protein content in L-Ex rats was increased by 29% above that in N-Ex rats (p<0.01). Finally, the glycogen content in skeletal muscle of L-Ex rats was decreased compared with that of N-Ex rats. Taken together, we suggest that the maintenance of glycogen depletion after exercise by continuous low carbohydrate diet results in the increment of the GLUT-4 protein content in skeletal muscle.     

Role of insulin on exercise-induced GLUT-4 protein expression and glycogen supercompensation in rat skeletal muscle.

The purpose of this study was to investigate the role of insulin on skeletal muscle GLUT-4 protein expression and glycogen storage after postexercise carbohydrate supplementation. Male Sprague-Dawley rats were randomly assigned to one of six treatment groups: sedentary control (Con), Con with streptozocin (Stz/C), immediately postexercise (Ex0), Ex0 with Stz (Stz/Ex0), 5-h postexercise (Ex5), and Ex5 with Stz (Stz/Ex5). Rats were exercised by swimming (2 bouts of 3 h) and carbohydrate supplemented immediately after each exercise session by glucose intubation (1 ml of a 50% wt/vol). Stz was administered 72-h before exercise, which resulted in hyperglycemia and elimination of the insulin response to the carbohydrate supplement. GLUT-4 protein of Ex0 rats was 30% above Con in fast-twitch (FT) red and 21% above Con in FT white muscle. In Ex5, GLUT-4 protein was 52% above Con in FT red and 47% above Con in FT white muscle. Muscle glycogen in FT red and white muscle was also increased above Con in Ex5 rats. Neither GLUT-4 protein nor muscle glycogen was increased above Con in Stz/Ex0 or Stz/Ex5 rats. GLUT-4 mRNA in FT red muscle of Ex0 rats was 61% above Con but only 33% above Con in Ex5 rats. GLUT-4 mRNA in FT red muscle of Stz/C and Stz/Ex0 rats was similar but significantly elevated in Ex5/Stz rats. These results suggest that insulin is essential for the increase in GLUT-4 protein expression following postexercise carbohydrate supplementation.     

Exercise training increases glucose transporter protein GLUT-4 in skeletal muscle of obese Zucker (fa/fa) rats

The present study examined the level of GLUT-4 glucose transporter protein in gastrocnemius muscles of 36 week old genetically obese Zucker (fa/fa) rats and their lean (Fa/-) littermates, and in obese Zucker rats following 18 or 30 weeks of treadmill exercise training. Despite skeletal muscle insulin resistance, the level of GLUT-4 glucose transporter protein was similar in lean and obese Zucker rats. In contrast, exercise training increased GLUT-4 protein levels by 1.7 and 2.3 fold above sedentary obese rats. These findings suggest endurance training stimulates expression of skeletal muscle GLUT-4 protein which may be responsible for the previously observed increase in insulin sensitivity with training.     

Regulation of glucose transport in skeletal muscle.

The entry of glucose into muscle cells is achieved primarily via a carrier-mediated system consisting of protein transport molecules. GLUT-1 transporter isoform is normally found in the sarcolemmal (SL) membrane and is thought to be involved in glucose transport under basal conditions. With insulin stimulation, glucose transport is accelerated by translocating GLUT-4 transporters from an intracellular pool out to the T-tubule and SL membranes. Activation of transporters to increase the turnover number may also be involved, but the evidence is far from conclusive. When insulin binds to its receptor, it autophosphorylates tyrosine and serine residues on the beta-subunit of the receptor. The tyrosine residues are thought to activate tyrosine kinases, which in turn phosphorylate/activate as yet unknown second messengers. Insulin receptor antibodies, however, have been reported to increase glucose transport without increasing kinase activity. Insulin resistance in skeletal muscle is a major characteristic of obesity and diabetes mellitus, especially NIDDM. A decrease in the number of insulin receptors and the ability of insulin to activate receptor tyrosine kinase has been documented in muscle from NIDDM patients. Most studies report no change in the intracellular pool of GLUT-4 transporters available for translocation to the SL. Both the quality and quantity of food consumed can regulate insulin sensitivity. A high-fat, refined sugar diet, similar to the typical U.S. diet, causes insulin resistance when compared with a low-fat, complex-carbohydrate diet. On the other hand, exercise increases insulin sensitivity. After an acute bout of exercise, glucose transport in muscle increases to the same level as with maximum insulin stimulation. Although the number of GLUT-4 transporters in the sarcolemma increases with exercise, neither insulin or its receptor is involved. After an initial acute phase, which may involve calcium as the activator, a secondary phase of increased insulin sensitivity can last for up to a day after exercise. The mechanism responsible for the increased insulin sensitivity with exercise is unknown. Regular exercise training also increases insulin sensitivity, which can be documented several days after the final bout of exercise, and again the mechanism is unknown. An increase in the muscle content of GLUT-4 transporters with training has recently been reported. Even though significant progress has been made in the past few years in understanding glucose transport in skeletal muscle, the mechanisms involved in regulating transport are far from being understood.     

Glucose uptake and glucose transporter proteins in skeletal muscle from undernourished rats

Undernutrition in rats impairs secretion of insulin but maintains glucose normotolerance, because muscle tissue presents an increased insulin-induced glucose uptake. We studied glucose transporters in gastrocnemius muscles from food-restricted and control anesthetized rats under basal and euglycemic hyperinsulinemic conditions. Muscle membranes were prepared by subcellular fractionation in sucrose gradients. Insulin-induced glucose uptake, estimated by a 2-deoxyglucose technique, was increased 4- and 12-fold in control and food-restricted rats, respectively. Muscle insulin receptor was increased, but phosphotyrosine-associated phosphatidylinositol 3-kinase activity stimulated by insulin was lower in undernourished rats, whereas insulin receptor substrate-1 content remained unaltered. The main glucose transporter in the muscle, GLUT-4, was severely reduced albeit more efficiently translocated in response to insulin in food-deprived rats. GLUT-1, GLUT-3, and GLUT-5, minor isoforms in skeletal muscle, were found increased in food-deprived rats. The rise in these minor glucose carriers, as well as the improvement in GLUT-4 recruitment, is probably insufficient to account for the insulin-induced increase in the uptake of glucose in undernourished rats, thereby suggesting possible changes in other steps required for glucose metabolism.     

Effect of carbohydrate supplementation on postexercise GLUT-4 protein expression in skeletal muscle.

The effect of carbohydrate supplementation on skeletal muscle glucose transporter GLUT-4 protein expression was studied in fast-twitch red and white gastrocnemius muscle of Sprague-Dawley rats before and after glycogen depletion by swimming. Exercise significantly reduced fast-twitch red muscle glycogen by 50%. During a 16-h exercise recovery period, muscle glycogen returned to control levels (25.0 +/- 1.4 micromol/g) in exercise-fasted rats (24.2 +/- 0. 3 micro). However, when carbohydrate supplementation was provided during and immediately postexercise by intubation, muscle glycogen increased 77% above control (44.4 +/- 2.1 micromol/g). Exercise-fasting resulted in an 80% increase in fast-twitch red muscle GLUT-4 mRNA but only a 43% increase in GLUT-4 protein concentration. Conversely, exercise plus carbohydrate supplementation elevated fast-twitch red muscle GLUT-4 protein concentration by 88% above control, whereas GLUT-4 mRNA was increased by only 40%. Neither a 16-h fast nor carbohydrate supplementation had an effect on fast-twitch red muscle GLUT-4 protein concentration or on GLUT-4 mRNA in sedentary rats, although carbohydrate supplementation increased muscle glycogen concentration by 40% (35.0 +/- 0.9 micromol/g). GLUT-4 protein in fast-twitch white muscle followed a pattern similar to fast-twitch red muscle. These results indicate that carbohydrate supplementation, provided with exercise, will enhance GLUT-4 protein expression by increasing translational efficiency. Conversely, postexercise fasting appears to upregulate GLUT-4 mRNA, possibly to amplify GLUT-4 protein expression on an increase in glucose availability. These regulatory mechanisms may help control muscle glucose uptake in accordance with glucose availability and protect against postexercise hypoglycemia.     

Pancreatic insulin secretion in rats fed a soy protein high fat diet depends on the interaction between the amino acid pattern and isoflavones

Obesity is frequently associated with the consumption of high carbohydrate/fat diets leading to hyperinsulinemia. We have demonstrated that soy protein (SP) reduces hyperinsulinemia, but it is unclear by which mechanism. Thus, the purpose of the present work was to establish whether SP stimulates insulin secretion to a lower extent and/or reduces insulin resistance, and to understand its molecular mechanism of action in pancreatic islets of rats with diet-induced obesity. Long-term consumption of SP in a high fat (HF) diet significantly decreased serum glucose, free fatty acids, leptin, and the insulin:glucagon ratio compared with animals fed a casein HF diet. Hyperglycemic clamps indicated that SP stimulated insulin secretion to a lower extent despite HF consumption. Furthermore, there was lower pancreatic islet area and insulin, SREBP-1, PPARgamma, and GLUT-2 mRNA abundance in comparison with rats fed the casein HF diet. Euglycemic-hyperinsulinemic clamps showed that the SP diet prevented insulin resistance despite consumption of a HF diet. Incubation of pancreatic islets with isoflavones reduced insulin secretion and expression of PPARgamma. Addition of amino acids resembling the plasma concentration of rats fed casein stimulated insulin secretion; a response that was reduced by the presence of isoflavones, whereas the amino acid pattern resembling the plasma concentration of rats fed SP barely stimulated insulin release. Infusion of isoflavones during the hyperglycemic clamps did not stimulate insulin secretion. Therefore, isoflavones as well as the amino acid pattern seen after SP consumption stimulated insulin secretion to a lower extent, decreasing PPARgamma, GLUT-2, and SREBP-1 expression, and ameliorating hyperinsulinemia observed during obesity.     

Differential regulation of the GLUT-1 and GLUT-4 glucose transport systems by glucose and insulin in L6 muscle cells in culture

The regulation by glucose and insulin of the muscle-specific facilitative glucose transport system GLUT-4 was investigated in L6 muscle cells in culture. Hexose transport activity, mRNA expression, and the subcellular localization of the GLUT-4 protein were analyzed. As observed previously (Walker, P. S., Ramlal, T., Sarabia, V., Koivisto, U.-M., Bilan, P. J., Pessin, J. E., and Klip, A. (1990) J. Biol. Chem. 265, 1516-1523), 24 h of glucose starvation and 24 h of insulin treatment each increase glucose transport activity severalfold. Here we report a differential regulation of the GLUT-4 and GLUT-1 transport systems under these conditions. (a) The level of GLUT-4 mRNA was not affected by glucose starvation and was diminished by prolonged (24 h) administration of insulin; in contrast, the level of GLUT-1 mRNA was elevated under both conditions. (b) Glucose starvation and prolonged insulin administration increased the amount of both GLUT-4 and GLUT-1 proteins in the plasma membrane. (c) In intracellular membranes, glucose starvation elevated, and prolonged insulin administration reduced, the GLUT-4 protein content. In contrast, the GLUT-1 protein content in these membranes decreased with glucose starvation and increased with insulin treatment. Glucose transport was rapidly curbed upon refeeding glucose to glucose-starved cells, with half-maximal reversal after 30 min and maximal reversal after 4 h. This was followed by a marked decrease in the levels of GLUT-1 mRNA without major changes in GLUT-4 mRNA. Neither 2-deoxy-D-glucose nor 3-O-methyl-D-glucose could substitute for D-glucose in these effects. It is proposed that glucose and insulin differentially regulate the two glucose transport systems in L6 muscle cells and that the rapid down-regulation of hexose transport activity by glucose is regulated by post-translational mechanisms.     

Dehydroepiandrosterone prevents age-associated alterations, increasing insulin sensitivity

The age decline in DHEA levels has been associated with the appearance of age-related disorders such as obesity and insulin resistance. The aim of this study was to analyse the effect of chronic administration (13 weeks) of DHEA (5 g/kg diet) to old female rats fed on a high-fat diet on body weight and adiposity, and concretely on the expression of the adipokines related to obesity and insulin resistance, such as leptin, adiponectin and resistin. DHEA treatment induced a decrease in body weight, adipose tissue mass and serum insulin, adiponectin and leptin levels. Adiponectin mRNA expression in visceral fat depots decreased with aging, but this reduction was attenuated by DHEA treatment. DHEA treatment also stimulated resistin gene expression in the ovaric and renal adipose depots, which is associated with an increase in its circulating levels. In conclusion, DHEA treatment decreases body weight and adiposity in old female rats fed a high-fat diet, leading to an improvement of the HOMA index for insulin sensitivity, with decreasing circulating insulin levels, and preventing the age-associated decline of visceral-adipose adiponectin expression.     

Effect of age and dietary restriction on protein synthesis by isolated kidney cells

The influence of age and food restriction on kidney protein synthesis was studied in Fischer F344 rats. The rate of total protein synthesis by suspensions of kidney cells declined 60% between 4 and 31 months of age. The rate of protein synthesis by kidney cells isolated from 19-month old rats fed a restricted diet (60% of diet consumed by rats fed ad libitum) was 45% higher than the rate of protein synthesis by kidney cells isolated from 19-month old rats fed ad libitum. The excretion of protein in the urine was measured to assess the effect of the age related decline in protein synthesis on kidney function. A dramatic increase in proteinuria was observed with increasing age, and rats fed the restricted diet excreted significantly less protein in the urine than rats fed ad libitum.     

Effects of a new hypoglycemic agent A-4166 on glucose metabolism in rat adipocytes and muscle tissues

The effects of the oral administration of a non-sulfonylurea hypoglycemic agent, the phenylalanine derivative A-4166, on serum insulin and glucose levels and glucose metabolism in isolated rat adipocytes and slices of muscle tissues were studied. An increase in serum insulin and a decrease in glucose levels were observed 30 minutes after A-4166 administration to rats fed basal or high fat diet. No changes in basal glucose transport in isolated fat cells were observed after the administration of A-4166. The effect of in vitro added insulin was, however, stronger in rats fed basal diet and treated with A-4166. An elevation of the membrane glucose transporter GLUT 4 was observed in rats treated with A-4166. An increase of basal lipogenesis, measured by incorporation of radiocarbon labeled glucose into lipids, was noted in adipocytes from rats fed high fat diet. The addition of insulin was followed by stimulation of lipogenesis in rats fed basal diet, however, this hormone had no effect in rats fed high fat diet. The administration of A-4166 did not affect the basal or insulin stimulated lipogenesis. Basal glucose oxidation in the diaphragm was not influenced by high fat diet or by A-4166 treatment. In the soleus muscle, basal glucose oxidation was decreased in rats fed high fat diet, and treatment with A-4166 increased the glucose oxidation up to values observed in the control basal diet fed rats. These results indicate that the administration of A-4166 can affect glucose metabolism in muscle tissue and the sensitivity of adipocytes to insulin.     

Up-regulation of phosphatidylinositol 3-kinase and glucose transporter 4 in muscle of rats subjected to maternal undernutrition

Early postnatal nutrition has been associated with the long-term effects on glucose homeostasis in adulthood. To elucidate the molecular mechanisms by which undernutrition during early life leads to changes in insulin sensitivity, we investigated the insulin signaling in skeletal muscle of rats during development. Offspring of dams fed with either protein-free or normal diets during the first 10 days of lactation were studied from lactation period until adulthood. Early maternal undernutrition impaired secretion of insulin but maintained normal blood glucose levels until adulthood. Insulin receptor (IR) activation after insulin stimulation was decreased during the period of protein restriction. In addition, glucose uptake, insulin receptor substrate 1 (IRS-1) phosphorylation and glucose transporter 4 (GLUT-4) translocation in muscle were reduced in response to insulin during suckling. In contrast, non- or insulin-stimulated glucose uptake and GLUT-4 translocation were found significantly increased in muscle of adult offspring. Finally, basal association of phosphatidylinositol 3-kinase (PI3-kinase) with IRS-1 was increased and was highly stimulated by insulin in muscle from adult rats. Our findings suggest that early postnatal undernutrition increases insulin sensitivity in adulthood, which appears to be directly related to changes in critical steps required for glucose metabolism.     

Insulin secretion and GLUT-2 expression in undernourished neonate rats

In previous studies, we verified increased insulin sensitivity in adult male offspring of lactating rats readjusting to lack of insulin secretion reduction brought about by protein restriction during lactation. The present study aims to evaluate the effects of maternal protein undernutrition during lactation on glucose-induced insulin secretion and GLUT-2 expression in beta-cells of neonate male and female rats. Lactating Wistar rats were given a protein-free diet during the first 10 days and a normal diet (22% of protein) until weaning. The neonates were separated at birth by sex and diet and studied at 4, 8 and 21 days of lactation. Glucose-induced insulin secretion by pancreatic islets was analyzed by radioimmunoassay and GLUT-2 expression in beta-cells by Western blot. Glucose-induced insulin secretion of the undernourished groups was higher than in the control groups except among females. When comparing the male and female groups and the control and undernourished groups, female neonates showed significantly greater insulin secretion than the male group. Also it was noted that undernutrition induced greater GLUT-2 expression. For instance, comparing the undernourished male and female neonates there was an increase in female GLUT-2 expression on day 4. On the other hand, in undernourished male neonates a GLUT-2 expression increased later in lactation. In conclusion, during a short term, maternal undernutrition induces an increase of the glucose-induced insulin secretion only in male neonates and is associated with an increase in GLUT-2 expression in the beta-cell.     

Myricetin, a naturally occurring flavonol, ameliorates insulin resistance induced by a high-fructose diet in rats

The present study was conducted to explore the effects of myricetin on insulin resistance in rats fed for 6 weeks with a diet containing 60% fructose. Repeated intravenous (i.v.) injection of myricetin (1 mg/kg per injection, 3 times daily) for 14 days was found to significantly decrease the high glucose and triglyceride levels in plasma of fructose chow-fed rats. Also, the higher degree of insulin resistance in fructose chow-fed rats as measured by homeostasis model assessment of basal insulin resistance was significantly decreased by myricetin treatment. Myricetin increased the whole-body insulin sensitivity in fructose chow-fed rats, as evidenced by the marked elevation of composite whole-body insulin sensitivity index during the oral glucose tolerance test. Myricetin was found to reverse the defect in expression of insulin receptor substrate-1 (IRS-1) and the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase) in soleus muscle of fructose chow-fed rats under the basal state, despite the protein expression of insulin receptor (IR). Increased basal phosphorylation of IR and IRS-1 as well as Akt was observed in parallel. The reduced level of insulin action on phosphorylation of IR, IRS-1 and Akt in soleus muscle of fructose chow-fed rats was reversed by myricetin treatment. Furthermore, myricetin treatment improved the defective insulin action on the translocation of glucose transporter subtype 4 (GLUT 4) in insulin-resistant soleus muscle. These findings indicate that myricetin improves insulin sensitivity through the enhancement of insulin action on IRS-1-associated PI 3-kinase and GLUT 4 activity in soleus muscles of animals exhibiting insulin resistance.