Glucagon-like peptide-1 (GLP-1) (7-36) is a type of incretin hormone with unique antidiabetic potential. The introduction of orally active GLP-1 offers substantial benefits in the treatment of type 2 diabetes over conventional injection-based therapies. Because the intestinal absorption of GLP-1 is restricted by its natural characteristics, we developed a series of GLP-1 analogues via the site-specific conjugation of biotin-NHS and/or of biotin-poly(ethylene glycol)-NHS at Lys 26 and Lys 34 of GLP-1 (7-36), respectively, in order to improve oral delivery. The resultant GLP-1 analogues, Lys 26,34-DiBiotin-GLP-1 (DB-GLP-1) and Lys 26-Biotin-Lys 34-(Biotin-PEG)-GLP-1 (DBP-GLP-1), were prepared and studied in terms of their chemical, structural, and biological properties. DBP-GLP-1 demonstrated superior proteolytic stability against trypsin, intestinal fluid, and the major GLP-1 inactivation enzyme (dipeptidyl peptidase-IV (DPP-IV)) to native GLP-1 or DB-GLP-1 ( p < 0.001). The in vitro insulinotropic effects of DB-GLP-1 and DBP-GLP-1 showed potent biological activity in a dose-dependent manner, which resembled that of native GLP-1 in terms of stimulating insulin secretion in isolated rat islets of Langerhans. Intraperitoneal glucose tolerance tests (IPGTT) after the oral administration of GLP-1 analogues in diabetic db/db mice demonstrated that DB-GLP-1 and DBP-GLP-1 significantly reduced the AUC 0-180 min of glucose for 3 h by 14.9% and 24.5% compared to that of native GLP-1, respectively ( p < 0.01). In particular, DBP-GLP-1 concentration in plasma rapidly increased 30 min after oral administration in rats, presumably due to improved intestinal absorption. These findings revealed that site-specific biotinylated and biotin-PEGylated GLP-1 is absorbed by intestine and that it has biological activity in vivo. Therefore, we propose that this orally active bioconjugated GLP-1 might be considered as a potential oral antidiabetic agent for type 2 diabetes mellitus.
"To investigate intestinal absorption, the pharmacokinetic profiles of exendin-4 and its analogues were determined as follows   . Male Sprague-Dawley rats, cannulated in a jugular vein at one day before the experiment, were administered 10 μg of each agent per rat either i.v. "
[Show abstract][Hide abstract] ABSTRACT: An orally active glucagon-like peptide-1 (GLP-1) formulation would have great advantages over conventional injectable therapies for the treatment of diabetic patients. Because GLP-1 absorption in the intestine is restricted by its natural physiological characteristics, biotinylated exendin-4 analogues might useful as orally active GLP-1 receptor agonists. Three different biotinylated exendin-4 analogues, Lys(27)-Biotin-Exendin-4 (MB1-Ex-4), Lys(12)-Biotin-Exendin-4 (MB2-Ex-4), and Lys(12, 27)-Biotin-Exendin-4 (DB-Ex-4) were prepared, and their biological activities and enzymatic stabilities were studied in vitro. The hypoglycemic effects and pharmacokinetics of these analogues after oral administration were evaluated in db/db mice and Sprague-Dawley rats, respectively. These biotinylated exendin-4 analogues preserved GLP-1 receptor binding affinity and stimulated insulin secretion in RIN-m5F murine insulinoma cells and in isolated rat islets, respectively, and were as potent as exendin-4. In particular, DB-Ex-4 showed 9.0-fold better stability against rat intestinal fluid than exendin-4. When 0.1, 1, and 10 microg/mouse of DB-Ex-4 were orally administered, mean total hypoglycemic degrees (HGD) were increased by 36.8+/-1.2, 46.9+/-1.8, and 54.3+/-4.5%, respectively, whereas 1 microg/mouse of native exendin-4 showed an increase of 8.8+/-7.3%. This study demonstrates that biotinylated exendin-4 analogues are absorbed in the intestine and that they have biological efficacies of exendin-4. Furthermore, it indicates that biotinylated exendin-4 analogues could be used as potential oral antidiabetic agent for the treatment of type 2 diabetes.
[Show abstract][Hide abstract] ABSTRACT: This study was performed to prepare and characterize the biotinylated Salmon calcitonin (sCT) for oral delivery and evaluate the hypocalcemic effect of biotinylated-sCTs in rats. Biotinylated sCTs was characterized by using high performance liquid chromatography (HPLC) and MALDITOF-MS. The effect of biotinylation on permeability across Caco-2 cell monolayers was examined. Their hypocalcemic effect was determined in rats. Mono- and di-bio-sCTs were separated by reverse phase HPLC. The molecular weights of mono-bio-sCT and di-bio-sCT were determined to be 3,660.5 and 3,900.2 Da, respectively. The permeability of biotinylated-sCTs across Caco-2 cell monolayers was observed with a significant enhancement compared with sCT. Intrajejunal (ij) administration of mono-bio-sCT and di-bio-sCT resulted in sustained reduction in serum calcium levels, with a maximum reduction (% max(d)) of 21.6% and 30% after 4 h and 6 h of application, respectively. The biotin conjugation of sCT may be a promising strategy for increasing the oral bioavailability of sCT and achieving sustained calcium-lowering effects.
[Show abstract][Hide abstract] ABSTRACT: Sarcopenia - the progressive loss of muscle mass with advancing age is characterised by a deterioration of muscle quantity and quality leading to a gradual slowing of movement and a decline in strength and power. Sarcopenia is a highly significant public health problem. Frail elders often require assistance for accomplishing even basic tasks of independent living, and they are also at increased risk of serious injury from sudden falls and subsequent fractures. Since these age-related changes are largely attributed to the complex interaction of factors affecting neuromuscular transmission, muscle architecture, fibre composition, excitation-contraction coupling, and metabolism, the mechanisms responsible for these deleterious changes present numerous therapeutic targets for novel drug discovery. Objective: This review provides an update on some of the emerging drugs for sarcopenia that have been in development during 2005 - 2008. Methods: This is a review of the current status of emerging therapies and novel approaches for sarcopenia. Results: Considerable research and development in academic and research institutions and in large and small pharma is being directed to sarcopenia and related health issues; specifically the development and evaluation of novel therapeutic strategies to attenuate, prevent, or ultimately reverse age-related muscle wasting and weakness. Conclusions: Few, if any, drugs have been developed for sarcopenia specifically, but there are many existing and emerging drugs that have potential application for tackling age-related muscle wasting, particularly drugs for neurodegenerative diseases.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.