A second clinical study investigated the pharmacokinetics, pharmacodynamics and safety of weekly exenatide ER subcutaneous injections (0 mg or 2 mg) versus placebo in patients with type 2 diabetes over a period of 15 weeks

Furthermore, population-based analyses of these studies were performed to further define the exposure-response relationships associated with exenatide ER.RESULTS: Exenatide exposure increased with dose (2 mg, 5 mg, 7 mg or 10 mg) and exhibited a multiple-peak profile over approximately 10 weeks. Multiple-dosing pharmacokinetics were predicted from superpositioning of single-dose data; weekly administration of exenatide ER 0 mg and 2 mg for 15 weeks confirmed the predictions. Weekly dosing resulted in steady-state plasma exenatide concentrations after 6-7 weeks. Fasting plasma glucose levels were reduced similarly with both doses after 15 weeks (-42 ± 15 mg/dL with the 0 mg dose and -39 ± 9 mg/dL with the 2 mg dose; both p < 001 vs placebo), and the integrated exposure-response analysis demonstrated that the drug concentration producing 50% of the maximum effect (EC(50)) on fasting plasma glucose was 56 pg/mL (a concentration achieved with both the 0 mg and 2 mg doses of exenatide ER). The 2 mg dose reduced bodyweight (-3 ± 1 kg; p < 05 vs placebo) and postprandial glucose excursions.

Glycosylated haemoglobin (HbA(1c)) levels were reduced with the 0 mg dose (-1 ± 0%; baseline 8%) and with the 2 mg dose (-1 ± 0%; baseline 8%) [both p < 001 vs placebo]. Adverse events were generally transient and mild to CONCLUSION: These studies demonstrated that (i) a single subcutaneous dose of exenatide ER resulted in dose-related increases in plasma exenatide concentrations; (ii) single-dose exposure successfully predicted the weekly-dosing exposure, with 0 mg and 2 mg weekly subcutaneous doses of exenatide ER eliciting therapeutic concentrations of exenatide; and (iii) weekly dosing with either 0 or 2 mg of exenatide ER improved fasting plasma glucose control, whereas only the 2 mg dose was associated with improved postprandial glucose control and weight loss. [Clinicaltrials.gov Identifier: NCT00103935].Isoprenoid Derivatives of Lysophosphatidylcholines Enhance Insulin and GLP-1 Secretion through Lipid-Binding GPCRs.and Food Sciences, Lodz University of Technology, Stefanowskiego 4/10, 90-924 Sciences, Norwida 25, 50-375 Wrocław, Poland.Insulin plays a significant role in carbohydrate homeostasis as the blood glucose lowering hormone.

Glucose-induced insulin secretion (GSIS) is augmented by glucagon-like peptide (GLP-1), a gastrointestinal peptide released in response to ingesting nutriments. The secretion of insulin and GLP-1 is mediated by the binding of nutrients to G protein-coupled receptors (GPCRs) expressed by pancreatic β-cells and enteroendocrine cells, respectively. Therefore, insulin secretagogues and incretin mimetics currently serve as antidiabetic treatments. This study demonstrates the potency of synthetic isoprenoid derivatives of lysophosphatidylcholines (LPCs) to stimulate GSIS and GLP-1 release. Murine insulinoma cell line (MIN6) and enteroendocrinal L cells (GLUTag) were incubated with LPCs bearing geranic acid (1-GA-LPC), citronellic acid (1-CA-LPC), 3,7-dimethyl-3-vinyloct-6-enoic acid (GERA-LPC), and (E)-3,7,11-trimethyl- 3-vinyldodeca-6,10-dienoic acid (1-FARA-LPC). Respective free terpene acids were also tested for comparison. Besides their insulin- and GLP-1-secreting capabilities, we also investigated the cytotoxicity of tested compounds, the ability to intracellular calcium ion mobilization, and targeted GPCRs involved in maintaining lipid and carbohydrate homeostasis.

We observed the high cytotoxicity of 1-GERA-LPC and 1-FARA-LPC in contrast 1-CA-LPC and 1-GA-LPC. Moreover, 1-CA-LPC and 1-GA-LPC demonstrated the stimulatory effect on GSIS and 1-CA-LPC augmented GLP-1 secretion. Insulin and GLP-1 release appeared to be GPR40-, GPR55-, GPR119- and GPR120-dependent.Conflict of interest statement: The authors declare no conflicts of interest.Non-Covalent Albumin Ligands in FDA-Approved Therapeutic Peptides and Proteins.An increasing number of drugs that consist of a therapeutic peptide or protein linked to an albumin-binding structure are being approved. In this perspective, the pharmacokinetic data of currently marketed drugs of this type will be presented.

semaglutide  with fatty acids or fatty α,ω-dicarboxylic acids has been used successfully to prepare long-acting analogs of insulin, GLP-1, and other peptides but not of larger proteins. With a tetrazole-sulfonylamide fatty acid bioisostere, it has now been possible to prepare a long-acting analog of human growth hormone (191 amino acids), which is suitable for once-weekly In vivo dynamic distribution of 131I-glucagon-like peptide-1 (7-36) amide in the The in vivo distribution of glucagon-like peptide-1 (7-36) amide (GLP-1) was studied in a rat model using radiolabeled GLP-1 (131I-GLP-1) depicted by a gamma-camera. The dynamic scan showed a rapid clearance from the blood circulation after an intravenous (i.v.) injection of 131I-GLP-1. After  semaglutide , the major part of the radioactivity was accumulated in the kidneys, whereas about 9% (of the blood value) was found in the brain.