Characterisation and antidiabetic utility of a novel hybrid peptide, exendin-4/gastrin/xenin-8-Gln.

Enteroendocrine derived hormones such as glucagon-like-peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), gastrin and xenin are known to exert complementary beneficial metabolic effects in diabetes. This study has assessed the biological activity and therapeutic utility of a novel GLP-1/gastrin/xenin hybrid peptide, namely exendin-4/gastrin/xenin-8-Gln hybrid, both alone and in combination with the stable GIP mimetic, (DAla2)GIP. Exendin-4/gastrin/xenin-8-Gln increased in vitro insulin secretion to a similar or superior extent, as the parent peptides. Insulinotropic effects were mainly linked to modulation of GLP-1 and neurotensin receptors. Exendin-4/gastrin/xenin-8-Gln also augmented the insulinotropic actions of (DAla2)GIP. Acute administration of exendin-4/gastrin/xenin-8-Gln in mice induced significant appetite suppressive, glucose lowering and insulin secretory effects, with a duration of biological action beyond 8 h. Twice daily administration of exendin-4, exendin-4/gastrin/xenin-8-Gln, either alone or in combination with (DAla2)GIP, reduced circulating glucose, increased plasma insulin as well as improving glucose tolerance, insulin sensitivity and metabolic response to GIP in high fat fed mice. Body weight, food intake, circulating glucagon and amylase activity were unaltered. All hybrid peptide treated high fat mice exhibited marked reductions in LDL-cholesterol and body fat mass. Energy expenditure and locomotor activity were increased in mice treated with exendin-4/gastrin/xenin-8-Gln in combination with (DAla2)GIP. Interestingly, exendin-4 and exendin-4/gastrin/xenin-8-Gln treatment, but not exendin-4/gastrin/xenin-8-Gln in combination with (DAla2)GIP, reduced pancreatic islet and beta-cell area when compared to high fat controls. These studies confirm that unimolecular multi-agonist peptide hormones exert beneficial metabolic effects in diabetes, highlighting their potential as novel treatment strategies.

Implication of the intestinal microbiome as a potential surrogate marker of immune responsiveness to experimental therapies in autoimmune diabetes.

Type 1 diabetes (T1D) is an autoimmune proinflammatory disease with no effective intervention. A major obstacle in developing new immunotherapies for T1D is the lack of means for monitoring immune responsiveness to experimental therapies. The LEW1.WR1 rat develops autoimmunity following infection with the parvovirus Kilham rat virus (KRV) via mechanisms linked with activation of proinflammatory pathways and alterations in the gut bacterial composition. We used this animal to test the hypothesis that intervention with agents that block innate immunity and diabetes is associated with a shift in the gut microbiota. We observed that infection with KRV results in the induction of proinflammatory gene activation in both the spleen and pancreatic lymph nodes. Furthermore, administering animals the histone deacetylase inhibitor ITF-2357 and IL-1 receptor antagonist (Anakinra) induced differential STAT-1 and the p40 unit of IL-12/IL-23 gene expression. Sequencing of bacterial 16S rRNA genes demonstrated that both ITF-2357 and Anakinra alter microbial diversity. ITF-2357 and Anakinra modulated the abundance of 23 and 8 bacterial taxa in KRV-infected animals, respectively, of which 5 overlapped between the two agents. Lastly, principal component analysis implied that ITF-2357 and Anakinra induce distinct gut microbiomes compared with those from untreated animals or rats provided KRV only. Together, the data suggest that ITF-2357 and Anakinra differentially influence the innate immune system and the intestinal microbiota and highlight the potential use of the gut microbiome as a surrogate means of assessing anti-inflammatory immune effects in type 1 diabetes.

Effects of Prednisolone, L-Asparaginase, Gemfibrozil, and Combinations of These Elements on Mice Lipid Profile, Liver, and Pancreas.

The aim of this study is to determine the effects of L-asparaginase (L-ASP), corticosteroids (CSs), and antilipidemics, separately and in combination, on the lipid profiles and the liver and pancreas histology in mice. This study included 8 groups of 7 mice each. Before any drug administration, serum samples were taken from all of the mice. Then, normal saline was applied to the control group, and a medication or combination of medications was applied to the other groups. Levels of triglycerides, cholesterol (COL), and high-density lipoprotein (HDL) and low-density lipoprotein (LDL) were determined, and the livers and pancreases were evaluated histologically at the end of the study. Triglycerides increased significantly in the CS-only and the L-ASP-only groups, COL increased significantly in the CS-only group, and HDL increased significantly in the CS-only and the antilipidemic-only groups. LDL was significantly lower in the CS-only and the L-ASP-only groups. CSs and L-ASP were significantly effective in liver necrosis, L-ASP was significantly effective in liver balloon degeneration, and CS were significantly effective in pancreas vacuolization. Triglyceride measurement is recommended before/during CS and/or L-ASP treatment. Starting with an antilipidemic agent can be considered to avoid possible complications in patients with significantly high rates. Indicators of a possible liver or pancreas injury should also be considered.

Effect of an aqueous extract of Cucurbita ficifolia Bouché on the glutathione redox cycle in mice with STZ-induced diabetes.

ETHNOPHARMACOLOGICAL IMPORTANCE: Cucurbita ficifolia is used in Mexican traditional medicine as an anti-diabetic and anti-inflammatory agent and its actions can be mediated by antioxidant mechanisms. Disturbance in the homeostasis of glutathione has been implicated in the etiology and progression of diabetes mellitus and its complications. MATERIAL AND METHODS: It was evaluated, the effect of an aqueous extract of Cucurbita ficifolia on glycemia, plasma lipid peroxidation; as well as levels of reduced (GSH) and oxidized (GSSG) glutathione and activities of enzymes involved in glutathione redox cycle: glutathione peroxidase (GPx) and glutathione reductase (GR) in liver, pancreas, kidney and heart homogenates of streptozotocin-induced diabetic mice. RESULTS: Increased blood glucose and lipid peroxidation, together with decreased of GSH concentration, GSH/GSSG ratio and its redox potential (E(h)), and enhanced activity of GPx and GR in liver, pancreas and kidney were the salient features observed in diabetic mice. Administration of the aqueous extract of Cucurbita ficifolia to diabetic mice for 30 days, used at a dose of 200 mg/kg, resulted in a significant reduction in glycemia, polydipsia, hyperphagia and plasma lipid peroxidation. Moreover, GSH was increased in liver, pancreas and kidney, and GSSG was reduced in liver, pancreas and heart, therefore GSH/GSSG ratio and its E(h) were restored. Also, the activities involved in the glutathione cycle were decreased, reaching similar values to controls. CONCLUSIONS: An aqueous extract of Cucurbita ficifolia with hypoglycemic action, improve GSH redox state, increasing glutathione pool, GSH, GSH/GSSG ratio and its E(h), mechanism that can explain, at least in part, its antioxidant properties, supporting its use as an alternative treatment for the control of diabetes mellitus, and prevent the induction of complications by oxidative stress.

Some clinical evidence of the hypothesis of an indirect antiviral effect of propranolol through immunoactivation.

The hypothesis of an indirect antiviral effect on the immune system of propranolol has been confirmed on a small scale by treating viral infections with herpes simplex I, shingles and influenza virus infections diagnosed clinically; in one case influenza virus infection was confirmed with a specific influenza test. Herpes simplex infections were treated successfully with propranolol in 2 days, influenza infections in 2 to 3 days, chronic shingles lesions in a month. Other interesting effects of propranolol have been observed, for example on the skin, the liver, the pancreas and on the nervous system.

Antidiabetogenic constituents from the Thai traditional medicine Cotylelobium melanoxylon.

The methanolic extracts from the wood and bark of Cotylelobium melanoxylon were found to inhibit plasma glucose elevation after sucrose loading in rats and triglyceride elevation after olive oil loading in mice. A new stilbene dimer, melanoxylin A, together with the known stilbene dimers [(+)-ampelopsin F, (+)-isoampelopsin F, and (+)-epsilon-viniferin] and a trimer (vaticanol G) and a lignan [(+)-lyoniresinol] were isolated from the wood extract, and a new stilbene trimer, melanoxylin B, together with the known stilbene dimers [(+)-epsilon-viniferin and cis-(+)-epsilon-viniferin] and trimers (vaticanols A, E, and G) were isolated from the bark extract of C. melanoxylon. The principal constituents, vaticanols A, E, and/or G, inhibited plasma glucose and triglyceride elevation after sucrose loading in rats and olive oil loading in mice, respectively. In addition, vaticanols A, E, and/or G inhibited the enzyme activities of rat intestinal alpha-glucosidase, porcine pancreatic lipase, and rat lens aldose reductase.

The secretagogue effect of the poison from Centruroides limpidus limpidus on the pancreas of mice and the antagonistic action of the Bouvardia ternifolia extract.

In Mexican traditional medicine the plant species Bouvardia ternifolia is used as remedy to treat patients who have been stung by scorpions. In the preceding study, the methanol extract from the roots of this plant was capable of reducing the poisonous effect of Centruroides limpidus limpidus on mice. The poisoning from scorpion C. limpidus limpidus includes manifestations associated with the pancreatitis. This study evaluated the effect produced by the hexane and methanol extract from the root of B. ternifolia upon the acutely inflamed pancreas induced by the venom of C. limpidus limpidus on rats, and the release of amylase in the isolated pancreas of mice. The intravenous administration of venom induced the extravasation of labelled albumin, in a dose dependant manner. The pre-administration of both extracts of Bouvardia ternifolia reduced significantly (p < 0.05) the extravasation by 60%. Upon measuring the secretagogue effect of the venom in the isolated pancreas of mice, the EC50 of the venom was 3.76 x 10(-3) mg ml(-1), whilst in the presence of the methanol and hexane extracts, this EC50 was 9.13 x 10(-3) mg ml(-1) and 0.01629 mg ml(-1). In conclusion, the C. limpidus limpidus venom possesses a secretagogue effect of amylase on the pancreas of mice and produces an inflamed pancreas which is effectively antagonised by the hexane and methanol extracts from the roots of B. ternifolia.

CCK-B receptor antagonist YF476 inhibits pancreatic enzyme secretion at a duodenal level in pigs.

BACKGROUND: To evaluate the mechanisms by which cholecystokinin (CCK) regulates the exocrine pancreas, the role and location of CCK receptors in the pig were investigated using the CCK-B receptor antagonist YF476 and different administration routes of CCK. METHODS: In 11 anaesthetized pigs, catheters were surgically implanted in the pancreatic duct for juice collection, and in the gastric arteries and jugular vein, so that infusions of CCK-33 could be directed to the duodenal/gastric, duodenal/pancreatic or general circulations, respectively. Experiments were performed under control conditions, and after pretreatment by gavage feeding with YF476, using either a single, low dose of 0.3 micromol kg, which would block the CCK-B receptors, or a 1000 times higher dose (300 micromol kg), which would also block the CCK-A receptors. RESULTS: The increase in the pancreatic output of protein and the enzymes trypsin and amylase observed after the infusion of CCK-33 at 13 pmol kg to the duodenum/stomach or duodenum/pancreas was inhibited by pretreatment with YF476 at both dosages. In contrast, the increase in protein and enzyme output after the infusion of a supraphysiological dose of CCK-33 (130 pmol kg) to the general circulation was not affected by pretreatment with low dosage YF476, whereas high dosage YF476 completely inhibited the stimulated secretion. CONCLUSIONS: These data indicate that CCK-33 given locally to the duodenum in doses raising CCK to physiological plasma levels stimulates the pancreatic enzyme secretion via duodenal CCK-B receptors. Supra-physiological doses of CCK-33 to the general circulation appeared to affect the pancreatic enzyme secretion via CCK-A receptors located elsewhere than in the pancreatic and duodenal tissue.

Inhibitory effects of human and porcine alpha-amylase on CCK-8-stimulated lipase secretion of isolated rat pancreatic acini.

Previously we have demonstrated inhibitory effects of the plant lectin wheat germ agglutinin (WGA) on (125)I-CCK-8 binding to pancreatic AR42J cells as well as on CCK-8-stimulated Ca(2+) release and alpha-amylase secretion of rat pancreatic acini or acinar cells. Therefore, it is entirely conceivable that alpha-amylase having several lectin-like carbohydrate recognition domains can modulate the CCK-8 stimulated lipase secretion. Human alpha-amylase, purified from pancreatic juice by affinity chromatography to homogeneity, and commercial porcine pancreatic alpha-amylase inhibit CCK-8-stimulated lipase secretion of rat pancreatic acini in a concentration-dependent manner. Acarbose, a specific inhibitor of alpha-amylase, was without effect on CCK-8-induced cellular lipase secretion. The data presented here provide evidence for a regulatory function of alpha-amylase in CCK-8-stimulated pancreatic secretion.