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Boc5, a non-peptidic glucagon-like Peptide-1 receptor agonist, invokes sustained glycemic control and weight loss in diabetic mice.

Su H, He M, Li H, Liu Q, Wang J, Wang Y, Gao W, Zhou L, Liao J, Young AA, Wang MW - PLoS ONE (2008)

Bottom Line: Our 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.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 beta-cells), stimulation of insulin secretion (which was glucose-dependent), and elevation in insulin sensitivity.Our findings suggest that Boc5 is the only non-peptidic molecule reported thus far to simultaneously activate this spectrum of antidiabetic effects.

View Article: PubMed Central - PubMed

Affiliation: The National Center for Drug Screening, Shanghai, China.

ABSTRACT

Background: Our 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 findings: C57BL/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 beta-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/significance: Our findings suggest that Boc5 is the only non-peptidic molecule reported thus far to simultaneously activate this spectrum of antidiabetic effects.

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Related in: MedlinePlus

Antiobesity effects of Boc5.(A) Time course of Boc5 effect on changes in body weight. (B) Fat mass and fat percent of body weight. (C) Plasma leptin levels following 4-week daily i.p. treatment with Boc5 in db/db mice.
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pone-0002892-g002: Antiobesity effects of Boc5.(A) Time course of Boc5 effect on changes in body weight. (B) Fat mass and fat percent of body weight. (C) Plasma leptin levels following 4-week daily i.p. treatment with Boc5 in db/db mice.

Mentions: Daily Boc5 administration to db/db mice led to a dose-dependent reduction in body weight, relative to the weight gain observed in vehicle treated controls. The ∼7.5 g relative weight loss (3 mg/day dose group) amounted to ∼16% of the initial 46 g body weight of the db/db mice (Fig. 2A). Effects on body composition were examined in further experiments on both db/db and wildtype C57BL/6J mice treated i.p. for 4 weeks with vehicle, 1 mg, or 3 mg Boc5 daily. Diabetic db/db mice were ∼2.2-fold heavier than wildtype mice, and had ∼19-fold more dissectible fat which contributed to an 8-fold elevation of fat as a percent of body weight. The fat depots sampled in these experiments comprised 22% of total body weight in db/db mice. This was ∼42% of the value (52±2%) reported for total fat extracted from db/db mice by chloroform-methanol [25]. The 2.2 g lost from the 4 fat depots after 3 mg/day Boc5 treatment in the current study may therefore signify a greater amount of total fat loss (e.g. 5.3 g if proportionate, representing 71% of the 7.5 g body weight change, relative to controls). While Boc5 invoked weight loss in db/db mice, it did not in wildtype mice (P = 0.0014 and P = 0.724, respectively, ANOVA). Similarly, while Boc5 reduced body fat in db/db mice, it did not in wildtype mice (P = 0.0067 and P = 0.311, respectively, ANOVA). Although fat as a percent of total body mass trended downward with increasing Boc5 dose in db/db mice (P = 0.074, ANOVA), there was no similar trend in wildtype mice (Fig. 2B).


Boc5, a non-peptidic glucagon-like Peptide-1 receptor agonist, invokes sustained glycemic control and weight loss in diabetic mice.

Su H, He M, Li H, Liu Q, Wang J, Wang Y, Gao W, Zhou L, Liao J, Young AA, Wang MW - PLoS ONE (2008)

Antiobesity effects of Boc5.(A) Time course of Boc5 effect on changes in body weight. (B) Fat mass and fat percent of body weight. (C) Plasma leptin levels following 4-week daily i.p. treatment with Boc5 in db/db mice.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2483413&req=5

pone-0002892-g002: Antiobesity effects of Boc5.(A) Time course of Boc5 effect on changes in body weight. (B) Fat mass and fat percent of body weight. (C) Plasma leptin levels following 4-week daily i.p. treatment with Boc5 in db/db mice.
Mentions: Daily Boc5 administration to db/db mice led to a dose-dependent reduction in body weight, relative to the weight gain observed in vehicle treated controls. The ∼7.5 g relative weight loss (3 mg/day dose group) amounted to ∼16% of the initial 46 g body weight of the db/db mice (Fig. 2A). Effects on body composition were examined in further experiments on both db/db and wildtype C57BL/6J mice treated i.p. for 4 weeks with vehicle, 1 mg, or 3 mg Boc5 daily. Diabetic db/db mice were ∼2.2-fold heavier than wildtype mice, and had ∼19-fold more dissectible fat which contributed to an 8-fold elevation of fat as a percent of body weight. The fat depots sampled in these experiments comprised 22% of total body weight in db/db mice. This was ∼42% of the value (52±2%) reported for total fat extracted from db/db mice by chloroform-methanol [25]. The 2.2 g lost from the 4 fat depots after 3 mg/day Boc5 treatment in the current study may therefore signify a greater amount of total fat loss (e.g. 5.3 g if proportionate, representing 71% of the 7.5 g body weight change, relative to controls). While Boc5 invoked weight loss in db/db mice, it did not in wildtype mice (P = 0.0014 and P = 0.724, respectively, ANOVA). Similarly, while Boc5 reduced body fat in db/db mice, it did not in wildtype mice (P = 0.0067 and P = 0.311, respectively, ANOVA). Although fat as a percent of total body mass trended downward with increasing Boc5 dose in db/db mice (P = 0.074, ANOVA), there was no similar trend in wildtype mice (Fig. 2B).

Bottom Line: Our 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.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 beta-cells), stimulation of insulin secretion (which was glucose-dependent), and elevation in insulin sensitivity.Our findings suggest that Boc5 is the only non-peptidic molecule reported thus far to simultaneously activate this spectrum of antidiabetic effects.

View Article: PubMed Central - PubMed

Affiliation: The National Center for Drug Screening, Shanghai, China.

ABSTRACT

Background: Our 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 findings: C57BL/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 beta-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/significance: Our findings suggest that Boc5 is the only non-peptidic molecule reported thus far to simultaneously activate this spectrum of antidiabetic effects.

Show MeSH
Related in: MedlinePlus