Acute treatment with candesartan cilexetil, an angiotensin II type 1 receptor blocker, improves insulin sensitivity in high-fructose-diet-fed rats.

We aimed to determine whether acute treatment with candesartan cilexetil (CV-11974), an angiotensin II type 1 receptor blocker (ARB) can improve insulin sensitivity in high-fructose-diet (HFD)-fed rats. In vivo glucose utilization was measured by applying the euglycemic clamp technique and the expression levels of insulin-signaling molecules in skeletal muscles were examined by western blotting. A bolus injection of CV-11974 improved the glucose infusion rate (GIR) of HFD-fed rats to the level of the control rats. Furthermore, restoration of impaired tyrosine phosphorylation of insulin receptor (IR) ß, Akt phosphorylation at Ser47³ and Thr³°8, and phosphorylation of the 160-kDa Akt substrate (AS160) in the skeletal muscles of HFD-fed rats were achieved by this treatment. These results suggest that acute administration of candesartan cilexetil can increase insulin sensitivity of HFD-fed rats, which is associated with improved insulin signaling in skeletal muscles.

Eicosapentaenoic acid enhances skeletal muscle hypertrophy without altering the protein anabolic signaling pathway.

This study aimed to examine the effect of eicosapentaenoic acid (EPA) on skeletal muscle hypertrophy induced by muscle overload and the associated intracellular signaling pathways. Male C57BL/6J mice were randomly assigned to oral treatment with either EPA or corn oil for 6 weeks. After 4 weeks of treatment, the gastrocnemius muscle of the right hindlimb was surgically removed to overload the plantaris and soleus muscles for 1 or 2 weeks. We examined the effect of EPA on the signaling pathway associated with protein synthesis using the soleus muscles. According to our analysis of the compensatory muscle growth, EPA administration enhanced hypertrophy of the soleus muscle but not hypertrophy of the plantaris muscle. Nevertheless, EPA administration did not enhance the expression or phosphorylation of Akt, mechanistic target of rapamycin (mTOR), or S6 kinase (S6K) in the soleus muscle. In conclusion, EPA enhances skeletal muscle hypertrophy, which can be independent of changes in the AKT-mTOR-S6K pathway.

Combined effects of short-term calorie restriction and exercise on insulin action in normal rats.

The present study examined the effect of combination of short-term calorie restriction (CR) and moderate exercise on insulin action in normal rats. Rats were divided randomly into 4 groups: ad libitum, sedentary (A-Sed); calorie restriction, sedentary (CR-Sed); ad libitum, exercise (A-Ex); and calorie restriction, exercise (CR-Ex). Rats in the exercise groups were run on a rodent treadmill. Rats in the CR groups were fed every alternate day. Oral glucose tolerance test (OGTT) showed improvements in both CR-Sed and A-Ex groups compared with the A-Sed group; no further improvement in glucose tolerance was observed in the CR-Ex group. In contrast, glucose infusion rates (GIRs) determined by the hyperinsulinemic-euglycemic clamp method indicated that the GIR of the CR and exercise combination was significantly better than that of the sole intervention of CR or exercise. There was no difference in the levels of fasting glucose, insulin, or high-molecular weight forms of adiponectin among the 4 groups. Protein expression of GLUT-4 in the skeletal muscle increased by exercise, but not by CR. Our findings indicate that the combination of exercise and CR may be effective in enhancing insulin sensitivity at the skeletal muscle in normal subjects.

Elution of residual monomers from dental composite materials.

AIM: This study was designed to determine the type and amount of the monomers leached from the different particle sizes of the composite materials. MATERIALS AND METHODS: Three different disk sizes (2, 4, 6 mm) prepared for each material group (Filtek Flow, Filtek A110, Filtek P60 and Filtek Supreme) were polymerised by LED and halogen light; the specimens were then placed in artificial saliva. The monomer release in 30 min and 24 hrs from the specimens was analyzed in HPLC calibrated for the monomer extracts before. RESULTS: TEGDMA release was detected in all material groups after 30 min and after 24 hrs. BisGMA and BisEMA were not determined in any groups and UDMA was detected only in Filtek Supreme. Significant differences in release of TEGDMA and UDMA were obtained between the different sizes of discs. Significantly high amount of TEGDMA and UDMA monomer release was obtained in LED than Halogen groups. Lower amount of monomer release was obtained in species of 30 min than 24 hrs. CONCLUSION: Data has revealed that the monomer release could be detected significantly high from the composite materials polymerized by a lower output curing light device; and higher elution of monomers was determined as the composite thickness has increased. Therefore, the clinical applications of composite materials and the type of curing units have very important effects on the success of restorations and in the decrease of potential side effects.

Twenty-Four Months' Resistance and Endurance Training Improves Muscle Size and Physical Functions but Not Muscle Quality in Older Adults Requiring Long-Term Care.

OBJECTIVES: To assess the effects of 24 months training on muscle quality, size, strength, and gait abilities in older adults who need long-term care. DESIGN: Non-randomized controlled trial Setting: Kawai Rehabilitation Center and Kajinoki Medical Clinic. PARTICIPANTS: Ten older participants who needed long-term care (age, 76.7 ± 5.6 years) were participated as training group (Tr-group) and 10 older men and women who did not require long-term care (age, 72.9 ± 6.6 years) comprised the control group (Cont-group). INTERVENTION: Tr-group performed resistive and endurance exercises once or twice a week for 24 months. MEASUREMENTS: Using ultrasound images, echo intensity (EI) and muscle thickness were measured in the rectus femoris and biceps femoris as an index of muscle quality and size. Physical performance was measured before and after the training; performance parameters included knee extension peak torque, 5-m normal and maximal walk test, sit-to-stand and timed up and go test. RESULTS: After the training, there was no change in EI, while BF thickness was increased (pre; 1.82 ± 0.29 cm, 24 months; 2.14 ± 0.23 cm, p < 0.05) in Tr-group. Walk-related performances were improved after the training in Tr-group (i.e. 5-m walk test and timed up and go test). The percent change of knee extension peak torque explained the percent change of EI in the rectus femoris (regression coefficient = 1.24, R = 0.91, adjusted R2 = 0.82, p < 0.001). CONCLUSIONS: Twenty-four months' training induced muscle hypertrophy and improved physical functions. Increased muscle quality in the rectus femoris could be a key to improved knee extension peak torque, with the potential to eventually reduce the need for long-term care in older individuals.

Effect of prior chronic aerobic exercise on overload-induced skeletal muscle hypertrophy in mice.

This study aimed to examine how regular aerobic training can affect the muscle hypertrophy induced by overloading. Male C57BL/6J mice were randomly divided into three groups: rest group, low-intensity aerobic exercise group, and high-intensity aerobic exercise group. Mice in the exercise groups were assigned to run at a speed of 10 m/min (low-intensity) or 25 m/min (high-intensity) for 30 min/day, five days/week, for four weeks. Then, the right hind leg gastrocnemius muscles were surgically removed to overload the plantaris and soleus muscles, while the left hind leg was subjected to a sham-operation. Both the plantaris and soleus muscles grew larger in the overloaded legs than those in the sham-operated legs. Muscle growth increased in the plantaris muscles in the low-intensity exercise group compared to that in the rest or high-intensity exercise groups at one and two weeks after overloading. This enhancement was not observed in the soleus muscles. Consistently, we observed changes in the expression of proteins involved in anabolic intracellular signaling, including Akt, mechanistic target of rapamycin (mTOR), and p70S6K, in the plantaris muscles. Our data showed for the first time that chronic low-intensity aerobic exercise precipitates overload-induced muscle growth.

Luseogliflozin, A Sodium Glucose Co-transporter 2 Inhibitor, Alleviates Hepatic Impairment in Japanese Patients with Type 2 Diabetes.

Luseogliflozin, a selective inhibitor of sodium glucose co-transporter 2 (SGLT2), was previously shown to improve the blood glucose and hemoglobin A1c (HbA1c) levels of patients with type 2 diabetes in a clinical setting. Although patients with type 2 diabetes often have hepatic impairment, few reports have been published concerning the influence of luseogliflozin on HbA1c and hepatic function in patients with type 2 diabetes accompanied by hepatic impairment. The present study was undertaken to evaluate the influence of luseogliflozin on HbA1c and hepatic function in patients with type 2 diabetes divided into 2 groups according to hepatic function parameters (a normal group and an elevated group). In this study, luseogliflozin significantly improved both HbA1c and body weight to similar extents in both the normal group and the elevated group, accompanied by marked reductions in the aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyl transpeptidase (γ-GTP) levels. These results suggested that luseogliflozin can be safely used in patients with type 2 diabetes who also exhibit hepatic impairment. The results additionally suggest the possibility that luseogliflozin might be capable of alleviating hepatic impairment in patients with type 2 diabetes.

The Beneficial Effects of the DPP-4 Inhibitor Alogliptin on Hemoglobin A1c and Serum Lipids in Japanese Patients with Type 2 Diabetes.

It has been reported that dipeptidyl peptidase-4 (DPP-4) inhibitors improve hemoglobin A1c (HbA1c) levels in diabetic patients and may also improve the serum lipids. However, few studies have examined relationship between the effects of the DPP-4 inhibitor and the pretreatment HbA1c levels in diabetic patients. Furthermore, it has been reported that prolonged treatment with DPP-4 inhibitors may make glycemic control difficult in some patients. In the present study, we investigated (1) the effect of the DPP-4 inhibitor alogliptin on HbA1c, blood glucose (BG), and serum lipid in Japanese patients with type 2 diabetes, (2) the relationship between the HbA1c levels at baseline and the effects of alogliptin, and (3) the effects of switching of the DPP-4 inhibitor to alogliptin after 12 months' administration of sitagliptin on glycemic control and serum lipids. After 6-months' treatment with alogliptin, we found reductions of HbA1c, BG, and serum total cholesterol, and LDL cholesterol levels. Pretreatment level of HbA1c was well correlated with the degree of reduction of both HbA1c and BG levels after the treatment. Also, alogliptin kept levels of HbA1c and BG reduced by sitagliptin for 12 months, and relapsing of these levels and serum lipids were not observed. This study revealed that alogliptin improved HbA1c, BG, and serum lipid profiles in type 2 diabetic patients, and the effect of alogliptin on HbA1c and BG levels was correlated with HbA1c level at pretreatment. Furthermore, long-term treatment with alogliptin did not cause relapsing of glycemic control and serum lipids.

Experimental atherosclerosis-like lesions induced by hyperinsulinism in Wistar rats.

To elucidate the possible role of hyperinsulinism in the etiology of diabetic macroangiopathy, we studied the long-term effects of insulin injection on the arterial wall of the rat both biochemically and histologically. Fifty male Wistar rats were divided into two groups. One group was subjected to daily injection of insulin-zinc suspension (20 U/kg), and the other group was treated with saline. After 1 yr, all the animals were killed, and the lipid contents in the intimal media of their aortas were determined. Parts of the ascending aortic tissues were further examined by use of either light or electron microscopy. The triglyceride content of the insulin-treated rat aortas was significantly (P less than .05) increased compared with that of the saline-treated rat aortas. As determined by light microscopy, the intimas of the aortas from the insulin-treated rats were significantly (P less than .001) thickened, and the subendothelial tissues consisted of eosinophilic fiber bundles, amorphous ground substances, and irregularly arranged cells. These cells were identified by electron microscopy as having smooth muscle cell origin. All these findings suggest that atherosclerosis-like lesions could be induced by long-term insulin injection in the aortas of the rat and that hyperinsulinism plays a certain role in the development of diabetic macroangiopathy.

Ca/P mol ratio of cries-affected dentin structures.

BACKGROUND: A new approach called "minimum intervention" has been introduced for restoration of carious lesions to preserve tooth structure. This approach suggests that perhaps caries need not always be removed completely from deeper portions of the cavity. It is, therefore, important to characterize caries-affected dentin structures, because of the potential changes in bonding quality when using different dentinal substrates. MATERIALS AND METHOD: Ninety teeth (30 teeth each group) were studied. The first group (CF) consisted of 30 caries-free teeth. The second group (CC) consisted of 30 teeth, for which caries-free dentin teeth was chemically demineralized. The third group (ND) consisted of 30 extracted human molars with coronal carious lesions. After all tooth samples were water-polished with grit #600 SiC paper, they were tested by surface contact angle measurements and the electron-probe microanalyzer to measure Ca/P mol ratio. RESULTS: Contact angles were CF = 60.07 degrees ; CC = 30.8 degrees; ND = 26.11 degrees , p<0.05. Ca/P mol ratios were as follows; CF = 1.549 (+/-0.0435); CC = 1.324 (+/-0.2305); ND = 1.568 (+/-0.0523), p<0.05. Weibull analyses for Ca/P mol ratio indicated shape parameter (m) of CF was 13.3; it was 12.8 for ND and 11.8 for CC. Above the delta point (=1.65 in Ca/P ratio), for both groups m = 3.4. CONCLUSION: Caries-affected dentin surfaces (naturally-developed and chemically created) were statistically more chemically active than caries-free dentin surface. Ca/P mol ratio of chemically created caries was less than other two groups.

Effects of coupling methods on galvanic corrosion behavior of commercially pure titanium with dental precious alloys.

BACKGROUND: When a dissimilar couple is exposed to corrosive environment, it will normally exhibit a galvanic corrosion. The galvanic corrosion might be influenced by various factors, including type and concentration of electrolyte, surface area ratio between anode and cathode, type of coupling material, and coupling manner. PURPOSE: The purpose of this study was to investigate and compare the galvanic corrosion behavior of commercially pure titanium when coupled with type IV Au alloy, Au-Ag-Pt alloy, and Ag-Au-Pd alloy by different coupling methods. MATERIALS AND METHODS: Couples were prepared by a laser welding or a mechanical adhering method. Electrochemical corrosion studies were conducted in a Ringer's solution at a scanning rate of 0.1 mV/sec in a range from -250 mV to +250 mV with respect to E(OCP). Corrosion parameters (E(OCP), I(CORR), E(CORR)) were obtained. RESULTS: It was found that (i) there was a significant difference between LWC and AJC for three couples (p<0.05), (ii) the crevice line caused all three couples more corrosive than weld joint line, (iii) for both joint, it was found that type (IV) Au alloy exhibited discoloration to some extent. CONCLUSIONS: It is concluded that among the three couples with two different coupling methods, Ti/Ag-Au-Pd couple exhibited best corrosion resistance in a room temperature Ringer's solution.

DPP-4 Inhibitor Teneligliptin Improves Insulin Resistance and Serum Lipid Profile in Japanese Patients with Type 2 Diabetes.

Dipeptidyl peptidase-4 (DPP-4) inhibitors have been reported to improve the glycemic control and blood hemoglobin A1c (HbA1c) concentrations. However, there are few reports as yet suggesting that DPP-4 inhibitors may also improve insulin resistance and the serum lipid profile in the clinical setting. This study was aimed at investigating the effect of 14-week treatment with teneligliptin (20 mg/day) on the homeostasis model assessment ratio (HOMA-R), an indicator of insulin resistance, and serum lipid profile in 9 patients with type 2 diabetes. The treatment produced a significant decrease of the blood glucose and HbA1c concentration (blood glucose: p=0.008; HbA1c: p=0.038), and also improved HOMA-R (p=0.039). Furthermore, the patients showed elevation of the serum HDL-cholesterol level (p=0.032), and a tendency towards reduction of the serum triglyceride level. The results indicate that teneligliptin acts not only to improve the blood glucose control, but also to improve the insulin resistance and serum lipid profile in Japanese type 2 diabetes patients.

The effect of nitric oxide synthase inhibitor on improved insulin action by pioglitazone in high-fructose-fed rats.

The present study was performed to investigate whether nitric oxide synthase (NOS) inhibition influences the increased whole-body insulin action by pioglitazone in high-fructose-fed rats. Male Wistar rats aged 6 weeks were randomly divided into 3 groups and each group was fed one of the following diets for 3 weeks: standard chow diet (control group), high-fructose diet (fructose-fed group), and high-fructose diet plus pioglitazone (pioglitazone-treated group). The control and pioglitazone-treated groups were further divided into 2 subgroups respectively, and some rats of each subgroup were infused the NOS inhibitor, N(G)-monomethyl-l-arginine (L-NMMA), during the euglycemic clamp studies. In vivo insulin action was determined by the 2-step (3 and 30 mU/kg body weight [BW]/min low- and high-dose, respectively) hyperinsulinemic euglycemic clamp procedure in the awake condition. Glucose infusion rate (GIR) was considered as the index of insulin action. Endothelium-type NOS (eNOS) and inducible NOS (iNOS) in skeletal muscle were also measured. At the low-dose clamp, high-fructose feeding produced a marked decrease in GIR compared with the control group. Pioglitazone-treated animals showed a significant increase in GIR, reaching a similar level as the control group. However, the improved GIR was decreased to the level of the fructose-fed group by L-NMMA infusion. The GIR of the control group was not affected by L-NMMA infusion. The same tendency as the low-dose clamp was found at the high-dose clamp. In skeletal muscle, eNOS and iNOS protein content were not affected by high-fructose feeding and/or pioglitazone treatment. These results suggest that NOS inhibition can decrease the improved insulin resistance by pioglitazone in high-fructose-fed rats. Therefore, although NOS protein content is not changed by high-fructose feeding and/or pioglitazone treatment, it could be concluded that nitric oxide (NO) plays an important role in the improvement of insulin action by pioglitazone.

Insulin activation of pyruvate dehydrogenase complex is enhanced by exercise training.

We studied the effects of exercise training on the activity of the pyruvate dehydrogenase (PDH) complex in rat gastrocnemius muscle (experiment 1) and the response of the complex to glucose and insulin infusion (euglycemic clamp) in trained and sedentary rats (experiment 2). In experiment 1, half of the rats were randomly allocated as sedentary animals and the other half were trained by voluntary running exercise for 8 weeks. The total activity of the PDH complex was not affected by exercise training, and the activity state (proportion of the active form) of the PDH complex was decreased from 15.0%+/-2.4% to 7.5%+/-1.1% by exercise training. The activity of 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase ([3-HADH] an enzyme in beta-oxidation) was significantly higher in trained versus sedentary rats. In experiment 2, sedentary and trained rats were starved for 24 hours before performing the euglycemic clamp. Glucose and insulin infusion was performed by a euglycemic clamp (insulin infusion rate, 6 mU/kg/min) for 90 minutes. The PDH complex was inactivated to less than 1% in both sedentary and trained rats after 24 hours of starvation. The glucose infusion rate (GIR) during the euglycemic clamp was higher in trained versus sedentary rats. The euglycemic clamp resulted in activation of the PDH complex in both sedentary and trained rats, but the response of the PDH complex to the euglycemic clamp was significantly higher in trained rats (5.8%+/-0.5%) than in sedentary rats (2.9%+/-0.5%). These results suggest that exercise training promotes fatty acid oxidation in association with suppression of glucose oxidation in skeletal muscle under resting conditions, but increases the rate of carbohydrate oxidation when glucose flux into muscle cells is stimulated by insulin.

Exercise training prevents maturation-induced decreases in insulin receptor substrate-1 and phosphatidylinositol 3-kinase in rat skeletal muscle.

We have previously reported that exercise training prevents a maturation-induced decrease in insulin sensitivity and suggested that an improvement of insulin sensitivity by exercise training was attributable, in part, to an increase in insulin-sensitive GLUT-4 on the skeletal muscle plasma membrane. In this study, we examined the effects of maturation and exercise training on the gene expression and protein content of the components of post-insulin receptor signal transduction in rat skeletal muscle. Rats aged 3 weeks were sedentary or trained by voluntary running through 4 or 27 weeks of age, and then the rats in both the sedentary and trained groups were killed and the gastrocnemius muscle was immediately removed for analysis of mRNA and protein content. The concentration of mRNA and protein for insulin receptor substrate-1 (IRS-1) in sedentary rats significantly decreased with maturation (49% and 63%, respectively, at age 27 weeks v age 4 weeks), but in trained rats they did not decrease with maturation. Although the level of phosphatidylinositol 3-kinase (PI 3-kinase) mRNA in sedentary rats was not altered with maturation, PI 3-kinase protein in sedentary rats significantly decreased with maturation (73% at 27 weeks v 4 weeks). However, PI 3-kinase protein in trained rats did not decrease with maturation. These results suggest that the prevention of maturation-induced decreases in the protein content of IRS-1 and PI 3-kinase is involved in the mechanisms responsible for the improvement of insulin sensitivity by exercise training, and exercise training may affect transcriptional regulation of the IRS-1 gene and posttranscriptional regulation of PI 3-kinase expression.

Insulin-nonspecific reduction in skeletal muscle glucose transport in high-fat-fed rats.

High-fat feeding diminishes insulin-stimulated glucose transport in skeletal muscle. However, conflicting results are reported regarding whether phosphatidylinositol (PI)-3 kinase-independent glucose transport is also impaired in insulin-resistant high-fat-fed rodents. The aim of the present study was to study whether non-insulin-dependent mechanisms for stimulation of glucose transport are defective in skeletal muscle from high-fat-fed rats. Rats were fed normal chow diet or high-fat diet for 4 weeks and isolated epitrochlearis muscles were used for measuring glucose transport. Insulin-stimulated glucose transport was significantly lower in rats fed the high-fat diet compared with chow-fed rats (P < .05). Hypoxia-stimulated glucose transport was also reduced in high-fat-fed rats (P < .05). Nevertheless, hypoxia-stimulated adenosine monophosphate-activated protein kinase (AMPK) phosphorylation (Thr172) level was not affected by high-fat feeding. Glucose transport by sodium nitroprusside stimulation was reduced in high-fat-fed rats (P < .05). Protein content of glucose transporter (GLUT)-4 and AMPK-alpha, and glycogen content were comparable between both groups. Our findings provide evidence that high-fat feeding can affect not only insulin but also non-insulin-stimulated glucose transport. A putative defect in common steps in glucose transport may play a role to account for impaired insulin-stimulated glucose transport in rats fed a high-fat diet.

Long-term mild jogging increases insulin action despite no influence on body mass index or VO2 max.

Physical training has been shown to improve glucose tolerance and insulin sensitivity. In the present study, insulin action was determined using the euglycemic clamp technique in six untrained nonobese subjects before, during, and after long-term mild regular jogging. After 1 yr of jogging, steady-state plasma insulin levels (I) decreased significantly, and the metabolic clearance rate of insulin was increased by 87%, although insulin infusion rate during the clamp was constant for each individual. The amount of glucose infused (glucose metabolism, M) tended to increase from 6.16 +/- 0.94 to 8.15 +/- 1.94 mg.kg-1.min-1 after regular jogging for 1 yr, although that was not statistically significant. However, M/I increases significantly from 0.060 +/- 0.012 to 0.184 +/- 0.056 (P less than 0.05) after 1 yr. The concentrations of plasma free fatty acids during the hyperinsulinemic clamp decreased more significantly after 1 yr of jogging (P less than 0.05). The concentrations of plasma glycerol decreased gradually before and after long-term regular jogging, showing only a 50-60% reduction in 120 min. Therefore, long-term mild regular jogging, which did not influence either body mass index or maximal O2 uptake, appears to improve insulin action in both carbohydrate and lipid metabolism and to increase the metabolic clearance rate of insulin.

Exercise training prevents maturation-induced decrease in insulin sensitivity.

We examined the effects of exercise training initiated before maturation or after maturation on insulin sensitivity and glucose transporter GLUT-4 content in membrane fractions of skeletal muscle. Female Wistar rats (4 wk of age) were divided into sedentary and exercise-trained groups. At 12 wk of age, a subset of the trained animals (Tr) was killed along with a subset of sedentary controls (Sed). One-half of the remaining sedentary animals remained sedentary (Sed-Sed) while the other half began exercise training (Sed-Tr). The remaining rats in the original trained group continued to train (Tr-Tr). Euglycemic clamp (insulin infusion rate at 6 mU.kg body wt-1. min-1) was performed at 4, 12, and 27 wk. After euglycemic clamp in all animals except the 4-wk-old, hindlimb (gastrocnemius and part of quadriceps) muscles were removed for preparation of membrane fractions. In sedentary rats, glucose infusion rate (GIR) during euglycemic clamp was decreased from 15.9 mg.kg-1.min-1 at 4 wk of age to 9.8 mg.kg-1.min-1 at 12 wk of age and 9.1 mg.kg-1.min-1 at 27 wk of age. In exercise-trained rats, the GIR was not significantly decreased by maturation (at 12 wk) and further aging (at 27 wk). Initiation of exercise after maturation restored the GIR at 27 wk of age to the same levels as these for the corresponding exercise-trained rats. GLUT-4 content in plasma and intracellular membrane fractions of hindlimb muscle obtained just after euglycemic clamp showed the same trend as the results of GIR. These results suggest that exercise training prevented the maturation-induced decrease in insulin sensitivity. Improvement of insulin sensitivity caused by exercise training was attributed, at least in part, to the increase in insulin-sensitive GLUT-4 on the plasma membrane in skeletal muscle.

Effects of daily physical activity on insulin action in the elderly.

The effects of daily physical activity on peripheral insulin action were investigated in aged individuals. Glucose infusion rates (GIR) during the euglycemic insulin clamp procedure in aged bedridden, aged controls, and aged athletes were compared with those in young controls and young athletes at insulin infusion rates of 40 and 400 mU.m-2.min-1 to estimate insulin action at physiological and maximal insulin concentrations, respectively. At both insulin infusion rates, GIR was significantly higher in aged athletes and significantly lower in aged bedridden subjects than in aged controls. Although there was no statistical difference in GIR at 400 mU.m-2 x min-1 between young athletes and young controls, GIR at 40 mU.m-2 x min-1 was higher in young athletes than in young controls. Comparison of the aged and young groups showed that although GIR at 400 mU.m-2 x min-1 was significantly lower in aged controls than in young controls, there was no significant difference between the aged athletes and the young athletes. We conclude that insulin responsiveness (insulin action at the postreceptor binding site) may decrease with the aging process and may be further affected by physical inactivity. Although physical training may improve insulin responsiveness in aged individuals up to levels similar to those in young athletes, physical training in young individuals may improve only insulin sensitivity.

In vitro pharmacological profile of nonpeptide CRF1 receptor antagonists, CRA1000 and CRA1001.

We investigated pharmacological properties of CRA1000 (2-(N-(2-methylthio-4-isopropylphenyl)-N-ethylamino-4-(4-(3-fluoro phenyl)-1,2,3,6-tetrahydropyridin-1-yl)-6-methylpyrimidine) and CRA1001 (2-( N-(2-bromo-4-isopropylphenyl)-N-ethylamino-4-(4-(3-fluorophenyl)-1 ,2,3,6-tetrahydropyridin-1-yl)-6-methylpyrimidine), novel and selective antagonists for the corticotropin-releasing factor1 (CRF1) receptor. Both CRA1000 and CRA1001 inhibited [125I]ovine CRF binding to membranes of COS-7 cells expressing the rat CRF1 receptor with IC50 values of 30 and 38 nM, respectively, without affecting [125I]sauvagine binding to membranes of COS-7 cells expressing the rat CRF2alpha receptor. CRF elicited intracellular cyclic AMP (cAMP) accumulation in AtT-20 cells which express the CRF1 receptor but not the CRF2 receptor, and COS-7 cells expressing CRF1 or CRF2alpha receptors. The CRF-induced cAMP accumulation was inhibited by both CRA1000 and CRA1001, concentration-dependently, in AtT-20 cells and COS-7 cells expressing the CRF1 receptor, while these compounds did not attenuate the CRF response in COS-7 cells expressing the CRF2alpha receptor. CRF increased adrenocorticotropin (ACTH) secretion from AtT-20 cells, and CRA1000 and CRA1001 inhibited CRF-induced ACTH secretion, concentration-dependently, as did other CRF1 receptor antagonists. These results show that both CRA1000 and CRA1001 are potent and selective CRF1 receptor antagonists.