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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

Effects of Boc5 on nutrient appearance, Ra.(A) Time course of acute effect on food intake in fasted db/db mice with different i.p. doses of Boc5. (B) Dose response for effect on food intake at different times after i.p. administration of Boc5. (C) Time course for chronic effect of Boc5 administered for 4 weeks in db/db mice on cumulative food intake. (D) Effect of Boc5 on conditioned taste aversion (CTA) in C57BL/6J mice. (E) Effect of Boc5 (3 mg i.p.) on gastric emptying of 3-[3H]glucose at different times after Boc5 administration in C57BL/6J mice (C57). (F) Dose response for effect of i.p. Boc5 on gastric emptying measured 6 h after Boc5 administration in both C57 and db/db mice. Band is the effect of fully inhibiting (1 µg) dose of exendin-4 in the same protocol (mean±SD).
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pone-0002892-g003: Effects of Boc5 on nutrient appearance, Ra.(A) Time course of acute effect on food intake in fasted db/db mice with different i.p. doses of Boc5. (B) Dose response for effect on food intake at different times after i.p. administration of Boc5. (C) Time course for chronic effect of Boc5 administered for 4 weeks in db/db mice on cumulative food intake. (D) Effect of Boc5 on conditioned taste aversion (CTA) in C57BL/6J mice. (E) Effect of Boc5 (3 mg i.p.) on gastric emptying of 3-[3H]glucose at different times after Boc5 administration in C57BL/6J mice (C57). (F) Dose response for effect of i.p. Boc5 on gastric emptying measured 6 h after Boc5 administration in both C57 and db/db mice. Band is the effect of fully inhibiting (1 µg) dose of exendin-4 in the same protocol (mean±SD).

Mentions: Boc5 dose-dependently inhibited food intake by up to 50% at 6 h after acute administration in db/db mice (P<0.002, ANOVA; ED50 0.91 mg; Figs. 3A and 3B). A similar anorectic effect of Boc5 has been observed in wildtype mice [24]. The absence of Boc5 effect on insulin sensitivity in wildtype mice, reported below, suggests that its anorexic and insulin-sensitizing effects may be dissociable. A similar dose-dependent effect of Boc5 to inhibit food intake in db/db mice by up to 42% endured throughout 4 weeks of daily administration, as reflected by cumulative intake (Fig. 3C).


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)

Effects of Boc5 on nutrient appearance, Ra.(A) Time course of acute effect on food intake in fasted db/db mice with different i.p. doses of Boc5. (B) Dose response for effect on food intake at different times after i.p. administration of Boc5. (C) Time course for chronic effect of Boc5 administered for 4 weeks in db/db mice on cumulative food intake. (D) Effect of Boc5 on conditioned taste aversion (CTA) in C57BL/6J mice. (E) Effect of Boc5 (3 mg i.p.) on gastric emptying of 3-[3H]glucose at different times after Boc5 administration in C57BL/6J mice (C57). (F) Dose response for effect of i.p. Boc5 on gastric emptying measured 6 h after Boc5 administration in both C57 and db/db mice. Band is the effect of fully inhibiting (1 µg) dose of exendin-4 in the same protocol (mean±SD).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0002892-g003: Effects of Boc5 on nutrient appearance, Ra.(A) Time course of acute effect on food intake in fasted db/db mice with different i.p. doses of Boc5. (B) Dose response for effect on food intake at different times after i.p. administration of Boc5. (C) Time course for chronic effect of Boc5 administered for 4 weeks in db/db mice on cumulative food intake. (D) Effect of Boc5 on conditioned taste aversion (CTA) in C57BL/6J mice. (E) Effect of Boc5 (3 mg i.p.) on gastric emptying of 3-[3H]glucose at different times after Boc5 administration in C57BL/6J mice (C57). (F) Dose response for effect of i.p. Boc5 on gastric emptying measured 6 h after Boc5 administration in both C57 and db/db mice. Band is the effect of fully inhibiting (1 µg) dose of exendin-4 in the same protocol (mean±SD).
Mentions: Boc5 dose-dependently inhibited food intake by up to 50% at 6 h after acute administration in db/db mice (P<0.002, ANOVA; ED50 0.91 mg; Figs. 3A and 3B). A similar anorectic effect of Boc5 has been observed in wildtype mice [24]. The absence of Boc5 effect on insulin sensitivity in wildtype mice, reported below, suggests that its anorexic and insulin-sensitizing effects may be dissociable. A similar dose-dependent effect of Boc5 to inhibit food intake in db/db mice by up to 42% endured throughout 4 weeks of daily administration, as reflected by cumulative intake (Fig. 3C).

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