Abstract
BackgroundOur recent discovery of the substituted cyclobutane Boc5, one of the first non-peptidic agonists at glucagon-like peptide-1 receptors, offers the potential of combining oral availability with full agonism capable of eliciting antidiabetic and antiobesity effects. The present study was aimed at determining the in vivo pharmacologic properties of Boc5 in both normal and diabetic mice following chronic administration, with emphasis on glycemic control and weight loss.Methodology/Principal FindingsC57BL/6J and db/db mice were treated daily with Boc5 for 4 weeks and a range of pharmacologic parameters, including hemoglobin A1c, intraperitoneal glucose tolerance, insulin tolerance, fasting insulin and leptin levels, food intake, body weight and fat mass, were assessed before and after the treatment. Effects on food intake, gastric emptying, and insulinogenic index were also investigated in animals acutely administered with Boc5. Boc5 (3 mg) was able to induce a durable restoration of glycemic control (normalization of both hemoglobin A1c and intraperitoneal glucose tolerance) in db/db mice, following 4 weeks of daily administration. As with peptidic glucagon-like peptide-1 receptor agonists, its glycemic benefit and weight (fat) loss were associated with dose-dependent effects that included reduction in food intake, slowing of gastric emptying (both of which reduce nutrient-drive at β-cells), stimulation of insulin secretion (which was glucose-dependent), and elevation in insulin sensitivity. There was little effect on normal mice treated in the same manner.Conclusions/SignificanceOur findings suggest that Boc5 is the only non-peptidic molecule reported thus far to simultaneously activate this spectrum of antidiabetic effects.
Highlights
Metabolic syndrome [1], known as ‘‘insulin resistance syndrome’’ and ‘‘syndrome-X’’, embraces a clustering of cardiovascular risks that result largely from hypernutrition [2]
Measures of glycemic control Boc5 administered for 4 weeks did not lower hemoglobin A1c (HbA1c) in non-diabetic C57BL/6J mice
The present study examined the in vivo pharmacology of the substituted cyclobutane Boc5, the first non-peptidic GLP-1 receptor (GLP-1R) agonist to show effects in whole animals
Summary
Metabolic syndrome [1], known as ‘‘insulin resistance syndrome’’ and ‘‘syndrome-X’’, embraces a clustering of cardiovascular risks that result largely from hypernutrition [2]. Peptidic glucagon-like peptide-1 (GLP-1) receptor agonists, exemplified by the first incretin mimetic, exenatide, can ameliorate several of these elements, including adiposity [5], dysglycemia, dyslipidemia, insulin resistance and hypertension [6]. They offer the potential to diminish the cardiovascular sequelae of epidemic type 2 diabetes mellitus and obesity, claiming, respectively, 9.3% [7] and 24% of the U.S population [7,8]. The present study was aimed at determining the in vivo pharmacologic properties of Boc in both normal and diabetic mice following chronic administration, with emphasis on glycemic control and weight loss
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have