Decreased Plasma Glucose Levels Research Articles

Mucoadhesive and enzymatic inhibitory nanoparticles for transnasal insulin delivery.

To develop a novel nanocarrier with mucoadhesion and enzymatic inhibition for transnasal insulin delivery. METHODS & METHODS: The physicochemical characterization of the nanoparticles included size and morphology, as well as mucoadhesion and enzymatic inhibition. The in vitro release of insulin from the nanoparticles was evaluated in 3 mg/ml glucose medium. The cytocompatibility of the nanoparticles was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The interactions of the nanoparticles with Caco-2 cells and nasal epithelia, and the effect of the nanoparticles on transnasal insulin delivery were estimated. The nanoparticles were spherical in shape, with an average size of 100 nm, and presented strong enzymatic inhibitory activity and high mucin adsorption ability. The insulinloaded nanoparticles showed the rapid insulin release in 3 mg/ml glucose medium. The nanoparticles were noncytotoxic to Caco-2 cells. Furthermore, the insulin-loaded nanoparticles overcame mucosal barriers and significantly decreased plasma glucose levels.

Synthesis of 2-{2-[(α/β-naphthalen-1-ylsulfonyl)amino]-1,3-thiazol-4-yl} acetamides with 11β-hydroxysteroid dehydrogenase inhibition and in combo antidiabetic activities

Compounds 1–10 were designed using a bioisosteric approach and were prepared using a short synthetic route. The in vitro inhibitory activity of the compounds against 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) was evaluated. Compounds 5 (α-series) and 10 (β-series) had a moderate inhibitory enzyme activity (55.26% and 67.03% inhibition at 10 μM, respectively) and were as active as BVT.14225 (positive control). Both compounds have a piperidine ring in their structure, but the most active (10) was selected to establish its in vivo antidiabetic effect using a non insulin-dependent diabetes mellitus rat model. The antidiabetic activity of compound 10 was determined at 50 mg/kg single dose in an acute model, and also by short term sub-chronic administration for 5 days. The results indicated a significant decrease of plasma glucose levels, similar than BVT.14225. Additionally, a molecular docking of the most active compounds of each series into the ligand binding pocket of one subunit of human 11β-HSD1 was performed. In this model the oxygen atom of the sulfonamide make hydrogen bond interactions with the catalytic residues Ser170 and Ala172. We also observed important π–π interactions between the naphthyl group and Tyr177.

Glucose-stimulated Single Pancreatic Islets Sustain Increased Cytosolic ATP Levels during Initial Ca2+ Influx and Subsequent Ca2+ Oscillations

In pancreatic islets, insulin secretion occurs via synchronous elevation of Ca(2+) levels throughout the islets during high glucose conditions. This Ca(2+) elevation has two phases: a quick increase, observed after the glucose stimulus, followed by prolonged oscillations. In these processes, the elevation of intracellular ATP levels generated from glucose is assumed to inhibit ATP-sensitive K(+) channels, leading to the depolarization of membranes, which in turn induces Ca(2+) elevation in the islets. However, little is known about the dynamics of intracellular ATP levels and their correlation with Ca(2+) levels in the islets in response to changing glucose levels. In this study, a genetically encoded fluorescent biosensor for ATP and a fluorescent Ca(2+) dye were employed to simultaneously monitor the dynamics of intracellular ATP and Ca(2+) levels, respectively, inside single isolated islets. We observed rapid increases in cytosolic and mitochondrial ATP levels after stimulation with glucose, as well as with methyl pyruvate or leucine/glutamine. High ATP levels were sustained as long as high glucose levels persisted. Inhibition of ATP production suppressed the initial Ca(2+) increase, suggesting that enhanced energy metabolism triggers the initial phase of Ca(2+) influx. On the other hand, cytosolic ATP levels did not fluctuate significantly with the Ca(2+) level in the subsequent oscillation phases. Importantly, Ca(2+) oscillations stopped immediately before ATP levels decreased significantly. These results might explain how food or glucose intake evokes insulin secretion and how the resulting decrease in plasma glucose levels leads to cessation of secretion.

Lipoproteins and β-Cell Functions: From Basic to Clinical Data.

Lipoproteins and β-Cell Functions: From Basic to Clinical Data.

Prolonged hypoglycemic effects obtained by two-layered dissolving microneedles containing insulin glargine

Two-layered dissolving microneedles (DMs) containing the long-acting insulin analog, insulin glargine (IG), were prepared and a pharmacodynamic study was performed to evaluate the prolonged hypoglycemic effects of IG DMs in rats. DMs were approximately 487 ± 16 sm (n = 8) in length and 293 ± 8 sm (n = 8) in diameter at their base. The length of the insulin-loaded space was approximately 225 ± 21 sm (n = 8). The level of IG in DMs was 3.96 ± 0.33 U (n = 8). In a one-month stability study, 98.2 ± 1.7 % (n = 8) of IG was recovered at 40 °C. A dissolution study revealed that 82.7 ± 10.3 % (n = 5) of IG was released within 2 min. The hypoglycemic effects of IG DMs were evaluated in rats in which subcutaneous injection preparations were used as the positive control. Decreased plasma glucose levels were maintained for 10 h. The total area above the plasma glucose level (AAG, % of the pre-dose level) vs. time curve as an index of the hypoglycemic effect was 147.5 ± 34.0 %-h (n = 5). AAG increased to 194.3 ± 20.6 %-h (n = 5) when the dose of IG was increased to 5.87 ± 0.85 U (n = 5). The relative pharmacological availabilities of IG from DMs were 79.1 ± 18.3 % (n = 5) and 85.3 ± 9.0 % (n = 5). A pharmacokinetic study showed that plasma IG levels were maintained between 100 and 200 sU/mL for 9 h. These results clearly demonstrated the usefulness of DM in obtaining long-term hypoglycemic effects in rats.

Continuous positive airway pressure therapy decreases plasma glucose levels after the glucose load even in non-diabetic patients with obstructive sleep apnea

Introduction Although much attention has been paid to a positive association between obstructive sleep apnea (OSA) and impaired glucose metabolism, no information is available on the effect of continuous positive airway pressure (CPAP) on plasma glucose levels in oral 75-g glucose tolerance tests (75-g OGTTs) in patients with OSA. Materials and methods A total of 47 non-diabetic patients who underwent full polysomnography for suspected OSA and who were newly diagnosed as having OSA with an apnea–hypopnea index (AHI) ⩾20 were prospectively enrolled in this study. The patients were divided into the following 2 groups: 29 patients in whom CPAP could be introduced (CPAP group) and 18 patients in whom CPAP could not be introduced (non-CPAP group). All patients underwent 75-g OGTTs at baseline and after 6months. Results There were no significant differences in age, body mass index, prevalence of men, hypertension, dyslipidemia or current smokers, medications and polysomnographic parameters between the 2 groups. In the CPAP group, AHI decreased significantly (51.8±15.7–5.6±5.5, p p =0.009), whereas the levels did not change significantly in the non-CPAP group (141.7±28.9–151.8±46.9mg/dl, p =0.33). The body mass index, fasting plasma glucose level and homeostasis model assessment for insulin resistance did not change in the both groups. Conclusion This study indicates that CPAP therapy can decrease the plasma glucose level after glucose load in non-diabetic patients with OSA, suggesting that CPAP therapy has a favorable effect on glucose metabolism even in non-diabetic patients with OSA.

Programming effects of high-carbohydrate feeding of larvae on adult glucose metabolism in zebrafish,Danio rerio

The aim of the present study was to determine the potential long-term metabolic effects of early nutritional programming on carbohydrate utilisation in adult zebrafish (Danio rerio). High-carbohydrate diets were fed to fish during four ontogenetic stages: from the first-feeding stage to the end of the yolk-sac larval stage; from the first-feeding stage to 2 d after yolk-sac exhaustion; after yolk-sac exhaustion for 3 or 5 d. The carbohydrate stimuli significantly increased the body weight of the first-feeding groups in the short term. The expression of genes was differentially regulated by the early dietary intervention. The high-carbohydrate diets resulted in decreased plasma glucose levels in the adult fish. The mRNA levels and enzyme activities of glucokinase, pyruvate kinase, α-amylase and sodium-dependent glucose co-transporter 1 were up-regulated in the first-feeding groups. There was no significant change in the mRNA levels of glucose-6-phosphatase (G6Pase) in any experimental group, and the activity of G6Pase enzyme in the FF-5 (first feeding to 2 d after yolk-sac exhaustion) group was significantly different from that of the other groups. The expression of phosphoenolpyruvate carboxykinase gene in all the groups was significantly decreased. In the examined early programming range, growth performance was not affected. Taken together, data reported herein indicate that the period ranging from the polyculture to the external feeding stage is an important window for potential modification of the long-term physiological functions. In conclusion, the present study demonstrates that it is possible to permanently modify carbohydrate digestion, transport and metabolism of adult zebrafish through early nutritional programming.

Effects of polysaccharide from pumpkin on biochemical indicator and pancreatic tissue of the diabetic rabbits

A water-soluble polysaccharide (PCE-CC) was obtained from pumpkin which belongs to the family Cucubitaceae by the water and ethanol extract, organic solvent fractional extraction and deproteinization. The present study was designed to investigate PCE-CC possible mechanism underlying the improvement of damaged pancreatic islets. Alloxan-induced diabetic rabbits were injected with PCE-CC for 21 days to assess effects on islet tissue morphology. After 21 days, the weights of the alloxan-induced diabetic and non-diabetic rabbits fed with diet contained PCE-CC were significantly increased as compared to the negative group. The data of blood glucose (BG), total cholesterol (TC), total triglyceride (TG) and glycosylated hemoglobin (HbA1c) indicated that PCE-CC had beneficial effects on the improvement in the control of blood glucose, serum lipid and glycosylated hemoglobin levels. Observing the pancreatic tissue of the diabetic rabbits revealed that PCE-CC could promote the regeneration of damaged pancreatic islets by stimulating β-cell proliferation, which was accompanied by a decrease in plasma glucose levels. PCE-CC was further separated and purified to obtain PCE-CCH by ion exchange and gel chromatography. PCE-CCH was a heteropolysaccharide and consisted of glucose, galactose, arabinose, rhamnose and little amount of hexuronic acid, with a molecular weight of 1.15×105Da.

Non–Islet Cell Tumor-Induced Hypoglycemia Associated with Macronodular Pulmonary Metastases from Poorly Differentiated Thyroid Carcinoma

Non-islet cell tumor-induced hypoglycemia (NICTH), a major cause of fasting hypoglycemia, is caused by the overproduction of incompletely processed, high molecular-weight insulin-like growth factor-II (IGF-II), termed "big" IGF-II. To the best of our knowledge, only two cases of thyroid carcinoma associated with NICTH have been documented. We report the case of a 72-year-old woman who was brought to the emergency department with impaired consciousness. The patient had a history of pulmonary metastases from poorly differentiated thyroid carcinoma (PDTC), spanning 12 years since initial treatment. Laboratory tests showed decreased plasma glucose levels even though immunoreactive insulin, IGF-I, and growth hormone (GH) were undetectable. Computed tomography (CT) scan revealed macronodular pulmonary metastases the estimated volume of which was 456 mL. Both the biochemical data and imaging results suggested NICTH. The results of Western blot analysis performed on a fractionated serum sample showed an increased expression of big IGF-II, an important indicator in the diagnosis of NICTH. Because the massive pulmonary metastases were considered inoperable, immunohistochemical analysis of stored formalin-fixed, paraffin-embedded tissues was performed. The analysis revealed that the tumor cells were positive for both IGF-II and thyroglobulin. A whole-body CT excluded extrapulmonary metastatic lesions. A retrospective review revealed a gradual decrease in glycohemoglobin levels accompanied by an increase in the estimated volume of pulmonary metastases. These findings suggested that NICTH had been caused by pulmonary metastases from PDTC. We describe here the third reported case of NICTH associated with thyroid carcinoma. This is also the first case reporting big IGF-II in the serum of a patient with thyroid carcinoma.

PL10 Hydrogen sulfide, glucose, and methylglyoxal formation

Hydrogen sulfide, an important gasotransmitter, has been implicated in the pathogenesis of diabetes. Increased methylglyoxal (MG) level is linked to the development of type 2 diabetes and hypertension. As a member of the reactive carbonyl species, MG is formed mainly through the nonenzymatic conversion of triosephosphates, such as dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate (GA3P). The triosephosphate pool, in turn, is regulated by cellular levels of glucose and fructose. The present study investigated whether MG level was altered in mice with cystathionine r-lyase knockout (CSE-KO) and its underlying mechanisms. We measured plasma and renal MG levels in both CSE-KO and wild type (WT) mice at different age groups (6–22 weeks). We also evaluated the role of fructose-1,6-bisphosphatase (FBPase) and related signaling pathway in the regulation of MG formation. We observed a significant decrease in plasma glucose levels along with a significant increase in plasma MG levels in all three age groups (6–8, 14–16, and 20–22 week-old) of the CSE-KO mice. Renal MG, DHAP and GA3P were increased, whereas renal FBPase activity and its mRNA levels were decreased in CSE-KO mice. Decreased FBPase activity was accompanied by lower levels of its product, fructose-6-phosphate, and higher levels of its substrate, fructose-1,6-bisphosphate, in renal extracts from CSE-KO mice. These data indicate an important role of hydrogen sulfide in the regulation of glucose metabolism and MG generation.

Discovery, synthesis and in combo studies of a tetrazole analogue of clofibric acid as a potent hypoglycemic agent

A tetrazole isosteric analogue of clofibric acid (1) was prepared using a short synthetic route and was characterized by elemental analysis, NMR (1H, 13C) spectroscopy, and single-crystal X-ray diffraction. The in vitro inhibitory activity of 1 against 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) was evaluated, showing a moderate inhibitory enzyme activity (51.17% of inhibition at 10μM), being more active than clofibrate and clofibric acid. The antidiabetic activity of compound 1 was determined at 50mg/Kg single dose using a non insulin dependent diabetes mellitus rat model. The results indicated a significant decrease of plasma glucose levels, during the 7h post-administration. Additionally, we performed a molecular docking of 1 into the ligand binding pocket of one subunit of human 11β-HSD1. In this model, compound 1 binds into the catalytic site of 11β-HSD1 in two different orientations. Both of them, show important short contacts with the catalytic residues Ser 170, Tyr 183, Asp 259 and also with the nicotinamide ring of NADP+.

Discovery of Thiazolidine‐2,4‐Dione/Biphenylcarbonitrile Hybrid as Dual PPAR α/γ Modulator with Antidiabetic Effect: In vitro, In Silico and In Vivo Approaches

A small series of thiazolidine-2,4-dione and barbituric acid derivatives 1-4 was prepared using a short synthetic route, and all compounds were characterized by elemental analysis, mass spectrometry, and NMR ((1)H, (13)C) spectroscopy. Their in vitro relative expression of peroxisome proliferator-activated receptor α and peroxisome proliferator-activated receptor γ was evaluated. Compound 1 showed an increase in the mRNA expression of both peroxisome proliferator-activated receptor isoforms, as well as the GLUT-4 levels. The antidiabetic activity of compound 1 was determined at 50 mg/kg single dose using a non-insulin-dependent diabetes mellitus rat model. The results indicated a significant decrease in plasma glucose levels. Additionally, we performed a molecular docking of compound 1 into the ligand binding pocket of peroxisome proliferator-activated receptor α and peroxisome proliferator-activated receptor γ. In these binding models, compound 1 may bind into the active site of both isoforms showing important short contacts with the peroxisome proliferator-activated receptor γ residues: Tyr 473, His 449, Ser 289, His 323; and peroxisome proliferator-activated receptor α residues: Tyr 464, His 440, Ser 280 and Tyr 314.

Synthesis and Evaluation of 1,ω‐Bis(1,2,3,5‐thiatriazol‐5‐yl)alkanes as In Vitro and In Vivo α‐Amylase and Lipase Inhibitors

Thionyl chloride reacts with 1,ω-bis-(1-tosylamidrazone)alkanes 1 to give a series of 1,ω-bis-(4-alkyl-2-tosyl-1,2,3,5-thiatriazol-5-yl)alkanes 2. All the newly synthesized compounds were characterized by IR, 1H NMR, 13C NMR, elemental analysis, and ESI-MS spectral data. All the new compounds were screened for their inhibitory effect on key enzymes related to diabetes and obesity, such as α-amylase and lipase. In vitro and in vivo studies revealed that these thiatriazole derivatives exert an inhibitory action against these key enzymes. Moreover the administration of these compounds to surviving diabetic rats induced a significant decrease in plasma glucose level. Additively 2d significantly protected the liver-kidney functions and modulated lipid metabolism, which were evidenced by the decrease in aspartate transaminase (AST), alanine transaminase (ALT), and gamma-glutamyl transpeptidase (GGT) activities and creatinine, urea albumin, LDL-cholesterol and triglycerides levels as well as an increase in the HDL-cholesterol level in surviving diabetic rats. Overall, the findings of the current study indicate that 2d exhibits attractive properties and can, therefore, be considered for future application in the development of anti-diabetic and hypolipidemic drugs.

Long‐term high density lipoprotein infusion ameliorates metabolic phenotypes of diabetic db/db mice

Lower quantity and quality of high density lipoprotein (HDL) are important characteristics of type 2 diabetes mellitus. Acute HDL infusion results in a greater fall of plasma glucose in diabetes patients. Here, we aim to investigate the influence of long-term HDL infusion on metabolic phenotypes of diabetic db/db mice. High density lipoprotein was introduced to db/db mice twice a week for 4 weeks. The phenotypes of the mice were monitored by analyzing metabolic parameters. Glycogen analysis was performed with amyloglucosidase. The corresponding signaling molecules were detected by western blot. Long-term introduction of HDL decreased plasma glucose levels of db/db mice. Glycogen deposition was enhanced in gastrocnemius muscle, paralleling the elevated glycogen synthase kinase-3 phosphorylation. Meanwhile, increased Akt-Ser473 and adenosine monophosphate-activated protein kinase phosphorylations were detected in the muscle. Moreover, HDL reduced blood glucose and free fatty acids and improved pancreatic islet structure and function with increased C-peptide. Furthermore, decreased interleukin-6, C-reactive protein, monocyte chemoattractant protein-1, resistin, and malondialdehyde, as well as enhanced leptin levels were detected in HDL-treated mice. Results of the present study suggest that long-term HDL infusion has positive therapeutic effects on the metabolic disturbances of db/db diabetic mice.

What Characteristics at Baseline Are Associated with the Glucose-lowering Effect of Colestimide in Patients with Type 2 Diabetes and Hypercholesterolemia According to Response to Treatment?

Colestimide, an anion exchange resin, reportedly improves glycemic control in patients with type 2 diabetes. However, no studies of the glucose-lowering effect of colestimide have identified responders and nonresponders. In the present study, we compared glycemic control, lipids, and body-mass index (BMI) among patients with type 2 diabetes receiving colestimide (n=59) until 24 weeks after the start of treatment. Subjects were classified as responders to treatment (n=40), who showed a 15% or greater decrease in glycated hemoglobin (HbA1c) or a 20% or greater decrease in plasma glucose level or both after 24 weeks of colestimide treatment as compared with baseline; nonresponders showed HbA1c>11.5% or fasting plasma glucose (FPG)>250 mg/dL during the course of the study and <15% decrease in HbA1c levels or <20% decrease in FPG levels or both after 24 weeks of colestimide treatment as compared with baseline. In responders, FPG decreased significantly from 196 ± 91 mg/dL to 125 ± 47 mg/dL after 24 weeks (P<0.001), and HbA1c decreased from 9.1% ± 2.0% to 7.0% ± 0.9% (P<0.001). In nonresponders, HbA1c decreased significantly from 7.7% ± 2.9% to 7.6% ± 1.2% (P<0.05). Multiple logistic regression analysis revealed that baseline HbA1c and the presence of cholelithiasis were significant determinants of the response to colestimide treatment when corrected for sex, age, triglyceride levels, and BMI at baseline and the presence of fatty liver. In conclusion, baseline HbA1c and the presence of cholelithiasis have strong and independent influences on the glucose-lowering effect of colestimide.

Grape seed proanthocyanidin extracts alleviate oxidative stress and ER stress in skeletal muscle of low‐dose streptozotocin‐ and high‐carbohydrate/high‐fat diet‐induced diabetic rats

Although ER stress in pancreas, liver, and adipose tissue was reported to be a novel event linked to the pathogenesis of type 2 diabetes mellitus, there is much less information on this event in skeletal muscle. Some studies indicated that treatment with antioxidants had beneficial effects on ER stress and diabetes. This study focuses on the effects of a strong antioxidant, grape seed proanthocyanidin extracts (GSPE), on skeletal muscle in diabetic rats induced with low dose streptozotocin- and a high-carbohydrate/high-fat diet. After 16 wk of GSPE treatment, diabetic rats showed decreased plasma glucose levels and insulin resistance. The efficacious effect of GSPE was manifested by the amelioration of muscular damage and dysfunction, as observed by histological examination and periodic acid Schiff staining. Concurrently, calcium overload and the abnormal activities of antioxidant enzymes and ATPases in diabetic muscles were partially reversed by GSPE treatment. GSPE also increased the activity of protein kinase B (a mediator of insulin's metabolic action) and partially alleviated severe ER stress. These findings suggest that GSPE may have auxiliary therapeutic potential for type 2 diabetes mellitus by decreasing oxidative stress and ER stress in skeletal muscle.

A new recombinant pituitary adenylate cyclase-activating peptide-derived peptide efficiently promotes glucose uptake and glucose-dependent insulin secretion

The recombinant peptide, DBAYL, a promising therapeutic peptide for type 2 diabetes, is a new, potent, and highly selective agonist for VPAC2 generated through site-directed mutagenesis based on sequence alignments of pituitary adenylate cyclase-activating peptide (PACAP), vasoactive intestinal peptide (VIP), and related analogs. The recombinant DBAYL was used to evaluate its effect and mechanism in blood glucose metabolism and utilization. As much as 28.9 mg recombinant DBAYL peptide with purity over 98% can be obtained from 1 l of Luria-Bertani medium culture by the method established in this study and the prepared DBAYL with four mutations (N10Q, V18L, N29Q, and M added to the N-terminal) were much more stable than BAY55-9837. The half-life of recombinant DBAYL was about 25 folds compared with that of BAY55-9837 in vitro. The bioactivity assay of DBAYL showed that it displaced [(125)I]PACAP38 and [(125)I]VIP from VPAC2 with a half-maximal inhibitory concentration of 48.4 ± 6.9 and 47.1 ± 4.9 nM, respectively, which were significantly lower than that of BAY55-9837, one established VPAC2 agonists. DBAYL enhances the cAMP accumulation in CHO cells expressing human VPAC2 with a half-maximal stimulatory concentration (EC(50)) of 0.68 nM, whereas the receptor potency of DBAYL at human VPAC1 (EC(50) of 737 nM) was only 1/1083 of that at human VPAC2, and DBAYL had no activity toward human PAC1 receptor. Western blot analysis of the key proteins of insulin receptor signaling pathway: insulin receptor substrate 1 (IRS-1) and glucose transporter 4 (GLUT4) indicated that the DBAYL could significantly induce the insulin-stimulated IRS-1 and GLUT4 expression more efficiently than BAY55-9837 and VIP in adipocytes. Compared with BAY55-9837 and PACAP38, the recombinant peptide DBAYL can more efficiently promote insulin release and decrease plasma glucose level in Institute of Cancer Research (ICR) mice. These results suggested that DBAYL could efficiently improve glucose uptake and glucose-dependent insulin secretion by VPAC2-mediated effect.

Cycloart-23-ene-3β, 25-diol stimulates GLP-1 (7–36) amide secretion in streptozotocin–nicotinamide induced diabetic Sprague Dawley rats: A mechanistic approach

In previous study, we have reported cycloart-23-ene-3β, 25-diol is an active antidiabetic constituent isolated from stem bark of Pongamia pinnata (Linn.) Pierre. The objective of the present investigation was to evaluate cycloart-23-ene-3β, 25-diol stimulates glucagon like peptide-1 (GLP-1) (7–36) amide secretion in streptozotocin–nicotinamide induced diabetic Sprague Dawley rats. Molecular docking studies were performed to elucidate the molecular basis for GLP-1 receptor agonistic activity. Type 2 diabetes was induced in overnight fasted Sprague Dawley rats pre-treated with nicotinamide (100mg/kg, i.p.) followed by administration of streptozotocin (55mg/kg, i.p.) 20min after. The rats were divided into following groups; I- non-diabetic, II- diabetic control, III- sitagliptin (5mg/kg, p.o.), IV- cycloart-23-ene-3β, 25-diol (1mg/kg, p.o.). The cycloart-23-ene-3β, 25-diol and sitagliptin treatment was 8 week. Plasma glucose was estimated every week (week 0 to week 8). Body weight, food and water intake were recorded daily. Glycosylated haemoglobin, lipid profile, plasma and colonic active (GLP-1) (7–36) amide, mRNA expression of proglucagnon GLP-1, plasma and pancreatic insulin, histology of pancreata as well as biomarkers of oxidative stress (superoxidase dismutase, reduced glutathione, malondialdehyde, glutathione peroxidase, glutathione S transferase) were measured after 8th week treatment. In acute study, active GLP-1 (7–36) amide release, plasma glucose and insulin were measured during oral glucose tolerance test. The docking data clearly indicated cycloart-23-ene-3β, 25-diol bind to the GLP-1 receptor. It decreased plasma glucose level, increased plasma and pancreatic insulin level as well as increased plasma and colonic active GLP-1 (7–36) amide secretion in streptozotocin–nicotinamide induced diabetic Sprague Dawley rats.

Potentiating exercise training with resveratrol

Potentiating exercise training with resveratrol

FK1706, a novel non-immunosuppressive immunophilin ligand, modifies gene expression in the dorsal root ganglia during painful diabetic neuropathy

Objectives: FK1706, a non-immunosuppressive immunophilin ligand, potentiated nerve growth factor-induced neurite outgrowth, putatively mediated via FKBP-52 and the Ras/Raf/MAPK signaling pathway. It also improved mechanical allodynia accompanied by the recovery of intraepidermal nerve fiber density in a painful diabetic neuropathy in rats. The aim of this study was to demonstrate the gene expression profiling in dorsal root ganglion in streptozotocin-induced diabetic rats related to pain and anti-allodynia effects of FK1706 administration to elucidate the putative mechanisms of its neurotrophic activity in vivo. Here, we analyzed gene expression of the dorsal root ganglia using microarray together with behavioral measurement of mechanical allodynia in diabetic rats to try to capture the global fingerprint of changes in gene expression associated with FK1706 administration.Methods: The withdrawal threshold of streptozotocin-induced diabetic rats was measured by an electronic von Frey system. The gene expression of the ganglia from L4 to L6 obtained from streptozotocin-treated rats with or without chronic administration of FK1706 was analyzed using an Affymetrix GeneChip to extract interesting genes in the development of mechanical allodynia in diabetes and anti-allodynia effect of FK1706.Results: Daily oral administration of FK1706 improved mechanical allodynia without decreasing plasma glucose levels. From gene expression analysis, the expression of thioredoxin interacting protein gene was sustained to increased change, whereas those of collagen I alpha1, II alpha1 and IX alpha1 genes were decreased from 2 to 4 weeks after streptozotocin injection. While no changes occurred after 1 week of commencing of FK1706 administration (2 weeks after streptozotocin injection), changes in expression more than 1·5-fold were observed for genes such as Ckm, Actn3, Atp2a1, Bglap, Acta1, Myl1, Tnnc2, and Mylpf at 2 weeks of FK1706 administration (3 weeks after streptozotocin injection). The genes RGD1564519, Hbb, LOC689064, Arpc4 and S100a9 were upregulated in comparison with streptozotocin-injected control group at 3 weeks of FK1706 administration; on the other hand, those of Actn3, Atp2a1 were downregulated by FK1706.Discussion: FK1706 ameliorates mechanical allodynia with accompanying increases in gene expressions possibly related to neurite outgrowth, development, differentiation, and nociceptive sensitivity.