Acute exercise decreases PTP-1B protein level and improves insulin signaling in the liver of old rats

It is now commonly accepted that chronic inflammation associated with obesity during aging induces insulin resistance in the liver. In the present study, we investigated whether the improvement in insulin sensitivity and insulin signaling, mediated by acute exercise, could be associated with modulation of protein-tyrosine phosphatase 1B (PTP-1B) in the liver of old rats. Aging rats were subjected to swimming for two 1.5-h long bouts, separated by a 45 min rest period. Sixteen hours after the exercise, the rats were sacrificed and proteins from the insulin signaling pathway were analyzed by immunoblotting. Our results show that the fat mass was increased in old rats. The reduction in glucose disappearance rate (Kitt) observed in aged rats was restored 16 h after exercise. Aging increased the content of PTP-1B and attenuated insulin signaling in the liver of rats, a phenomenon that was reversed by exercise. Aging rats also increased the IRβ/PTP-1B and IRS-1/PTP-1B association in the liver when compared with young rats. Conversely, in the liver of exercised old rats, IRβ/PTP-1B and IRS-1/PTP-1B association was markedly decreased. Moreover, in the hepatic tissue of old rats, the insulin signalling was decreased and PEPCK and G6Pase levels were increased when compared with young rats. Interestingly, 16 h after acute exercise, the PEPCK and G6Pase protein level were decreased in the old exercised group. These results provide new insights into the mechanisms by which exercise restores insulin signalling in liver during aging. © 2013 Moura et al; licensee BioMed Central Ltd.

Correlations between imatinib pharmacokinetics, pharmacodynamics, adherence, and clinical response in advanced metastatic gastrointestinal stromal tumor (GIST): An emerging role for drug blood level testing?

Imatinib is the standard of care for patients with advanced metastatic gastrointestinal stromal tumors (GIST), and is also approved for adjuvant treatment in patients at substantial risk of relapse. Studies have shown that maximizing benefit from imatinib depends on long-term administration at recommended doses. Pharmacokinetic (PK) and pharmacodynamic factors, adherence, and drug-drug interactions can affect exposure to imatinib and impact clinical outcomes. This article reviews the relevance of these factors to imatinib's clinical activity and response in the context of what has been demonstrated in chronic myelogenous leukemia (CML), and in light of new data correlating imatinib exposure to response in patients with GIST. Because of the wide inter-patient variability in drug exposure with imatinib in both CML and GIST, blood level testing (BLT) may play a role in investigating instances of suboptimal response, unusually severe toxicities, drug-drug interactions, and suspected non-adherence. Published clinical data in CML and in GIST were considered, including data from a PK substudy of the B2222 trial correlating imatinib blood levels with clinical responses in patients with GIST. Imatinib trough plasma levels <1100ng/mL were associated with lower rates of objective response and faster development of progressive disease in patients with GIST. These findings have been supported by other analyses correlating free imatinib (unbound) levels with response. These results suggest a future application for imatinib BLT in predicting and optimizing therapeutic response. Nevertheless, early estimates of threshold imatinib blood levels must be confirmed prospectively in future studies and elaborated for different patient subgroups.

Insulin secretion in monosodium glutamate (MSG) obese rats submitted to aerobic exercise training

The present study was designed to evaluate the effects of aerobic exercise training on glucose tolerance and insulin secretion of obese male Wistar rats (monosodium glutamate [MSG] administration, 4mg/g-body weight, each other day, from birth to the 14th day). Fourteen weeks after the drug administration, the rats were separated into two groups: MSG-S (sedentary) and MSG-T (T = swimming, 1 h/day, 5 days/week, with an overload of 5% body weight for 10 weeks). Rats of the same age and strain injected with saline were used as control (C) and subdivided into two groups: C-S and C-T. Insulin and glucose responses during an oral glucose tolerance test (GTT) were evaluated by the estimation of the total areas under serum insulin (AI) and glucose (AG) curves. Glucose-induced insulin secretion by isolated pancreatic islets was also evaluated. MSG-S rats showed higher AI than C-rats while MSG-T rats presented lower AI than MSG-S rats. No differences in AG were observed among the 4 groups. Pancreatic islets from MSG-rats showed higher insulin secretion in response to low (2.8) and moderate (8.3 mM) concentrations of glucose than those from their control counterparts and no differences were observed between MSG-S and MSG-T rats. These results provide evidences that the hyperinsulinemia at low or moderate glucose concentrations observed in MSG-obese rats is, at least in part, a consequence of direct hypersecretion of the B cells and that chronic aerobic exercise is able to partially counteract the hyperinsulinemic state of these animals without disrupting glucose homeostasis.

Modulation of insulin secretion by physical training during recovery from protein malnutrition in rats

Objective: The purpose of the present study was to examine insulin secretion in rats submitted to protein restriction and nutritional recovery associated or not to physical training. Methods: The experiment was designed in two sets of five weeks each. In the first set the rats were fed a nonnal-protein diet(17%-control group) or a low-protein diet (6%-malnourished group) for five weeks. After this, all animals were fed the 17% protein diet and separated into four groups: sedentary control(SC); trained eontrol(TC); sedentary recovered(SR) and trained recovered(TR). TC and TR rats performed swimming exercise. Results: The results indicated efficiency of the 6% protein diet in producing signs of malnutrition, as reduction in body weight gain and serum albumin levels, as well as liver fat. Serum insulin in the fed state and insulin secretion by isolated pancreatic islets in response to glucose were Keduced,but peripheral sensitivity to insulin was increased and glucose tolerance was not changed in the protein deficient rats, indicating adaptation to malnutrition. Diet protocol for nutritional recovery was efficient in repairing body weight gain, serum albumin and liver fat levels of the previously malnourished rats. Glucose induced insulin release by pancreatic islets remained low after nutritional recovery. Insulin secretion by the islets isolated from rats submitted to exercise training during nutritional recovery was improved when compared with the sedentary animals. Conclusion: This indicates that exercise training may be useful in the treatment of protein calorie malnutrition, concerning to glucose induced insulip secretion.

Exercise at anaerobic threshold intensity and insulin secretion by isolated pancreatic islets of rats

To evaluate the effect of acute exercise and exercise training at the anaerobic threshold (AT) intensity on aerobic conditioning and insulin secretion by pancreatic islets, adult male Wistar rats were submitted to the lactate minimum test (LMT) for AT determination. Half of the animals were submitted to swimming exercise training (trained), 1 h/day, 5 days/week during 8 weeks, with an overload equivalent to the AT. The other half was kept sedentary. At the end of the experimental period, the rats were submitted to an oral glucose tolerance test and to another LMT. Then, the animals were sacrificed at rest or immediately after 20 minutes of swimming exercise at the AT intensity for pancreatic islets isolation. At the end of the experiment mean workload (% bw) at AT was higher and blood lactate concentration (mmol/L) was lower in the trained than in the control group. Rats trained at the AT intensity showed no alteration in the areas under blood glucose and insulin during OGTT test. Islet insulin content of trained rats was higher than in the sedentary rats while islet glucose uptake did not differ among the groups. The static insulin secretion in response to the high glucose concentration (16.7 mM) of the sedentary group at rest was lower than the sedentary group submitted to the acute exercise and the inverse was observed in relation to the trained groups. physical training at the AT intensity improved the aerobic condition and altered insulin secretory pattern by pancreatic islets. © 2010 Landes Bioscience.

Insulin concentrations in cerebellum and body balance in diabetic male rats: Aerobic training effects

Brain insulin has had widespread metabolic, neurotrophic, and neuromodulatory functions and has been involved in the central regulation of food intake and body weight, learning and memory, neuronal development, and neuronal apoptosis. Purpose: The present study investigated the role of swimming training on cerebral metabolism on insulin concentrations in cerebellum and the body balance performance of diabetic rats. Methods: Forty Male Wistar rats were divided in four groups: sedentary control (SC), trained control (TC), sedentary diabetic (SD), and trained diabetic (TD). Diabetes was induced by alloxan (32 mg kg b.w.), single dose injection. The mean blood glucose of diabetic groups was 367 ± 40 mg/dl. Training program consisted in swimming 5 days/week, 1 h/day, 8 weeks, supporting a workload corresponding to 90% of maximal lactate steady state (MLSS). For the body balance testing rats were trained to traverse for 5 min daily for 5-7 days. All dependent variables were analyzed by one-way analysis of variance (ANOVA) and a significance level of p < 0.05 was used for all comparisons. Results: The body balance testing scores were different between groups. Insulin concentrations in cerebellum were not different between groups. Conclusion: It was concluded that in diabetic rats, aerobic training does not induce alterations on cerebellum insulin but induces important metabolic, hormonal and behavioral alterations which are associated with an improvement in glucose homeostasis, serum insulin concentrations and body balance. © 2013 Elsevier Inc.

BDNF Val66Met polymorphism influence on striatal blood-level-dependent response to monetary feedback depends on valence and agency

Animal work implicates the brain-derived neurotrophic factor (BDNF) in function of the ventral striatum (VS), a region known for its role in processing valenced feedback. Recent evidence in humans shows that BDNF Val66Met polymorphism modulates VS activity in anticipation of monetary feedback. However, it remains unclear whether the polymorphism impacts the processing of self-attributed feedback differently from feedback attributed to an external agent. In this study, we emphasize the importance of the feedback attribution because agency is central to computational accounts of the striatum and cognitive accounts of valence processing. We used functional magnetic resonance imaging and a task, in which financial gains/losses are either attributable to performance (self-attributed, SA) or chance (externally-attributed, EA) to ask whether BDNF Val66Met polymorphism predicts VS activity. We found that BDNF Val66Met polymorphism influenced how feedback valence and agency information were combined in the VS and in the right inferior frontal junction (IFJ). Specifically, Met carriers' VS response to valenced feedback depended on agency information, while Val/Val carriers' VS response did not. This context-specific modulation of valence effectively amplified VS responses to SA losses in Met carriers. The IFJ response to SA losses also differentiated Val/Val from Met carriers. These results may point to a reduced allocation of attention and altered motivational salience to SA losses in Val/Val compared to Met carriers. Implications for major depressive disorder are discussed.

Glucose homeostasis in pregnant rats submitted to dietary protein restriction

In the present work, we examined the effects of feeding a low protein diet during pregnancy on glucose-induced insulin secretion and glucose homeostasis in rats. Young (60 days), pregnant (P) or non-pregnant (NP) rats were fed during pregnancy or for 21 days (the NP) a normal (17%) or a low (6%) protein diet. Serum glucose and insulin levels and pancreas insulin content in the fed state; total area under serum glucose curve (AG) after a glucose load and serum glucose disappearance rate (Kitt) after insulin administration; as well as 86Rb outflow, 45Ca uptake and insulin secretion by isolated pancreatic islets in response to glucose were evaluated. Serum glucose was lower in 17%-P (12%) and 6%-P (27%) than in corresponding NP-rats. Serum insulin was higher in 17%- P (153%) and 6%-P (77%) compared to the corresponding NP-rats. Pancreatic insulin was higher in 6%-rats (55%) than in 17%-rats. No differences were found in AG among the groups whereas Kitt was lower in 6%-NP and higher in 6%-P than in the equivalent 17% rats. Increasing glucose concentration from 2.8 to 16.7 mmol/l, reduced 86Rb outflow from isolated islets from all groups. Increasing glucose concentration from 2.8 to 16.7 mmol/l elevated 45Ca uptake by 17%-NP (47%), 17%-P (40%) and 6%-P (214%) islets but not by 6%-NP ones. The increase in 45Ca uptake was followed by an increase in insulin release by the 17%-NP (2767%), 17%-P (2850%) and 6%-P (1200%) islets. In conclusion, 6%-P rats show impaired glucose induced insulin secretion related to reduced calcium uptake by pancreatic islets. However, the poor insulin secretion did not fully compensate the high peripheral sensitivity to the hormone, resulting in hypoglycemia.

Pancreatic β-cell defects in women at risk of type 2 diabetes

We evaluated insulin release and insulin sensitivity in women with basal and/or postprandial hyperglycemia but normal oral glucose tolerance test (OGTT) in previous pregnancy (GHG). These women were individually matched with females without previous hyperglycemia (NGT). Both groups consisted of normal glucose-tolerant women at the time of this study. They underwent OGTT (75g; n= 32 pairs) and hyperglycemic clamp experiments (10mmoll-1; n=27 pairs) with plasma glucose, insulin, and C-peptide measurements and calculation of insulinogenic index, first- and second-phase insulin release, and insulin sensitivity index (ISI). The GHG group showed higher glycosylated hemoglobin levels (6.2±0.6% versus 5.8±0.8%; P<0.05); lower insulinogenic index at 30min (134.03±62.69pmolmmol-1 versus 181.59±70.26pmolmmoll-1; P<0.05) and diminished C-peptide response in relation to glucose (4.05±0.36nmolmmol-1 versus 4.23±0.36nmolmmol-1; P<0.05) at OGTT. Both groups did not show difference in insulin secretion and ISI by hyperglycemic clamp technique. We concluded that in up to 12 years from index pregnancy, women with previous GHG, presenting normal glucose tolerance and well-matched with their controls, showed β-cell dysfunction without change in ISI. As women with previous GHG are at risk of type 2 diabetes, β-cell dysfunction may be its primary defect. © 2003 Elsevier B.V. All rights reserved.

Monosodium glutamate in standard and high-fiber diets: Metabolic syndrome and oxidative stress in rats

Objective: This study determined the effects of adding monosodium glutamate (MSG) to a standard diet and a fiber-enriched diet on glucose metabolism, lipid profile, and oxidative stress in rats. Methods: Male Wistar rats (65 ± 5 g, n = 8) were fed a standard diet (control), a standard diet supplemented with 100 g of MSG per kilogram of rat body weight, a diet rich in fiber, or a diet rich in fiber supplemented with 100 g of MSG per kilogram of body weight. After 45 d of treatment, sera were analyzed for concentrations of insulin, leptin, glucose, triacylglycerol, lipid hydroperoxide, and total antioxidant substances. A homeostasis model assessment index was estimated to characterize insulin resistance. Results: Voluntary food intake was higher and feed efficiency was lower in animals fed the standard diet supplemented with MSG than in those fed the control, fiber-enriched, or fiber- and MSG-enriched diet. The MSG group had metabolic dysfunction characterized by increased levels of glucose, triacylglycerol, insulin, leptin, and homeostasis model assessment index. The adverse effects of MSG were related to an imbalance between the oxidant and antioxidant systems. The MSG group had increased levels of lipid hydroperoxide and decreased levels of total antioxidant substances. Levels of triacylglycerol and lipid hydroperoxide were decreased in rats fed the fiber-enriched and fiber- and MSG-enriched diets, whereas levels of total antioxidant substances were increased in these animals. Conclusions: MSG added to a standard diet increased food intake. Overfeeding induced metabolic disorders associated with oxidative stress in the absence of obesity. The fiber-enriched diet prevented changes in glucose, insulin, leptin, and triacylglycerol levels that were seen in the MSG group. Because the deleterious effects of MSG, i.e., induced overfeeding, were not seen in the animals fed the fiber-enriched diets, it can be concluded that fiber supplementation is beneficial by discouraging overfeeding and improving oxidative stress that is induced by an MSG diet. © 2005 Elsevier Inc. All rights reserved.

Papel da eritropoetina recombinante humana sobre o metabolismo dos carboidratos, paratormônio, cálcio iônico, zinco, prolactina e níveis pressóricos em renais crônicos tratados com hemodiálise

Objective: To evaluate the influence of recombinant human erythropoietin (Epho) on carbohydrate metabolism, parathyroid hormone, calcium ionic, zinc, prolactin and blood pressure (BP) in chronic renal failure treated by hemodialysis. Methods: Ten patients in hemodialysis were followed during 24 weeks in two phases: 12 weeks pre-Epho (BP was measured pre and post hemodialysis sessions) and 12 weeks post-Epho (BP was measured as above and also the blood levels of glucose, insulin, parathyroid hormone, calcium ionic, prolactin, and zinc). Results: Patients were 39.8±8.5 y, 50% males. Hematocrit and hemoglobin presented a significant increase four weeks after Epho (22.3±2.3 to 28.1±2.6% and 7.4±0.8 to 9.4±0.9 g/dL, p<0.05). BP (mmHg) and weight pre-Epho: 158±99 and 59±13 (before hemodialysis), 147±96 and 55±13 (after hemo) and post-Epho: 161±100 and 59±13 (before hemo) 155±101 and 56±12 (after hemo) were all not statistically different in any moment. There are also no difference pre and post-Epho in fast glucose (91.8±6.5 and 90.8±6.1 mg/dL, p>0.05), parathyroid hormone (341.4±249.3 and 515.7±310 pg/ mL), calcium ionic (3,66±0.63 and 3.76±0.45 mmol/L), prolactin (males: 327±144.1 and 298.1 ±145.2 μg/mL; females: 666.2±426.6 and 659±395.3 μg/mL) and zinc (median of 0.73 and 0.71 μg\L). Basal insulin was lower after Epho (median of 9.1 to 3.8 μg/mL, p<0.05). Conclusion: These data suggest that recombinant human erythropoietin was effective to improve the anemia and the carbohydrate metabolism in patients with chronic renal failure treated by hemodialysis. © Copyright Moreira Jr. Editors. Todos os direitos reservados.

Daytime variations in glucose tolerance in people with impaired glucose tolerance

To determine whether glucose tolerance varies throughout the day in people with impaired glucose tolerance (IGT). We studied 15 healthy IGT, and 18 matched normal glucose tolerant (NGT) individuals. Blood samples were taken every 30-120 min during a 24 h period in which all individuals had three mixed meals and nocturnal sleep. We measured glucose, free fatty acids, specific insulin, intact proinsulin, cortisol and growth hormone. Variable responses were considered as concentrations and areas under the curves. Comparison between the groups was by Student's t-test, Mann-Whitney, and analysis of variance. Higher total glucose response, inappropriate normal total insulin response, and unproportionally increased proinsulin total response were observed in the IGT group. Lower glucose tolerance occurred in IGT after dinner, as in the NGT, and after breakfast associated with increased insulin response after breakfast, and similar proinsulin response after all three meals. IGT had higher glucose response than NGT after breakfast and lunch, similar insulin responses, and increased proinsulin-insulin ratio after all three meals. Data from this study demonstrate that IGT individuals present lower glucose tolerance in the evening, as those with NGT, and in the morning, as reported in patients with type 2 diabetes. © 2006 Elsevier B.V. All rights reserved.

Leucine-rich diet alters the eukaryotic translation initiation factors expression in skeletal muscle of tumour-bearing rats

Background: Cancer-cachexia induces a variety of metabolic disorders on protein turnorver, decreasing protein synthesis and increasing protein degradation. Controversly, insulin, other hormones, and branched-chain amino acids, especially leucine, stimulate protein synthesis and modulate the activity of translation initiation factors involved in protein synthesis. Since the tumour effects are more pronounced when associated with pregnancy, ehancing muscle-wasting proteolysis, in this study, the influence of a leucine-rich diet on the protein synthesis caused by cancer were investigated. Methods: Pregnant rats with or without Walker 256 tumour were distributed into six groups. During 20 days of experiment, three groups were fed with a control diet: C - pregnant control, W - tumour-bearing, and P - pair-fed, which received the same amount of food as ingested by the W group; three other groups of pregnant rats were fed a leucine-rich diet: L - pregnant leucine, WL - tumour-bearing, and PL - pair-fed, which received the same amount of food as ingested by the WL group. Results: The gastrocnemius muscle of WL rats showed increased incorporation of leucine in protein compared to W rats; the leucine-rich diet also prevented the decrease in plasma insulin normally seen in W. The expression of translation initiation factors increased when tumour-bearing rats fed leucine-rich diet, with increase of ∼35% for eIF2α and eIF5, ∼17% for eIF4E and 20% for eIF4G; the expression of protein kinase S6K1 and protein kinase C was also highly enhanced. Conclusion: The results suggest that a leucine-rich diet increased the protein synthesis in skeletal muscle in tumour-bearing rats possibly through the activation of eIF factors and/or the S6kinase pathway. © 2007 Ventrucci et al; licensee BioMed Central Ltd.

Induction of the 72 kDa heat shock protein by glucose ingestion in black pregnant women

Obese Black women are at increased risk for development of gestational diabetes mellitus and have worse perinatal outcomes than do obese women of other ethnicities. Since hsp72 has been associated with the regulation of obesity-induced insulin resistance, we evaluated associations between glucose ingestion, hsp72 release and insulin production in Black pregnant women. Specifically, the effect of a 50-g glucose challenge test (GCT) on heat shock protein and insulin levels in the circulation 1 h later was evaluated. Hsp27 and hsp60 levels remained unchanged. In contrast, serum levels of hsp72 markedly increased after glucose ingestion (p = 0.0054). Further analysis revealed that this increase was limited to women who were not obese (body mass index <30). Insulin levels pre-GCT were positively correlated with body mass index (p = 0.0189). Median insulin concentrations also increased post GCT in non-obese women but remained almost unchanged in obese women. Post-GCT serum hsp72 concentrations were inversely correlated with post GCT insulin concentrations (p = 0.0111). These observations suggest that glucose intake during gestation in Black women rapidly leads to an elevation in circulating hsp72 only in non-obese Black women. The release of hsp72 may regulate the extent of insulin production in response to a glucose challenge and, thereby, protect the mother and/or fetus from development of hyperglycemia, hyperinsulinemia, and/or immune system alterations. © 2013 Cell Stress Society International.

Glucose homoeostasis in rats exposed to acute intermittent hypoxia

Aim: Chronic exposure to intermittent hypoxia commonly induces the activation of sympathetic tonus and the disruption of glucose homoeostasis. However, the effects of exposure to acute intermittent hypoxia (AIH) on glucose homoeostasis are not yet fully elucidated. Herein, we evaluated parameters related to glucose metabolism in rats exposed to AIH. Methods: Male adult rats were submitted to 10 episodes of hypoxia (6% O2, for 45 s) interspersed with 5-min intervals of normoxia (21%), while the control (CTL) group was kept in normoxia. Results: Acute intermittent hypoxia rats presented higher fasting glycaemia, normal insulinaemia, increased lactataemia and similar serum lipid levels, compared to controls (n = 10, P < 0.05). Additionally, AIH rats exhibited increased glucose tolerance (GT) (n = 10, P < 0.05) and augmented insulin sensitivity (IS) (n = 10, P < 0.05). The p-Akt/Akt protein ratio was increased in the muscle, but not in the liver and adipose tissue of AIH rats (n = 6, P < 0.05). The elevated glycaemia in AIH rats was associated with a reduction in the hepatic glycogen content (n = 10, P < 0.05). Moreover, the AIH-induced increase in blood glucose concentration, as well as reduced hepatic glycogen content, was prevented by prior systemic administration of the β-adrenergic antagonist (P < 0.05). The effects of AIH on glycaemia and Akt phosphorylation were transient and not observed after 60 min. Conclusions: We suggest that AIH induces an increase in blood glucose concentration as a result of hepatic glycogenolysis recruitment through sympathetic activation. The augmentation of GT and IS might be attributed, at least in part, to increased β-adrenergic sympathetic stimulation and Akt protein activation in skeletal muscles, leading to a higher glucose availability and utilization. © 2013 Scandinavian Physiological Society.