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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 insulin secretion and insulin sensitivity.(A) Effect of prior administration of Boc5 on insulinogenic index, the slope of the relationship between plasma insulin and blood glucose concentrations in quasi-steady-state, during the decay phase of an intraperitoneal (i.p.) glucose challenge in fasted C57BL/6J (C57) mice. (B) Dose response for effects of Boc5 and exendin-4 on insulinogenic index in C57 mice during an i.p. glucose challenge. (C) Effect of prior administration of exendin-4 and Boc5 on insulinogenic index in fasted db/db mice. Gray band depicts the slope range of different Boc5 doses (0.3, 1, 3 and 6 mg). (D) Dose response for effects of Boc5 and exendin-4 on insulinogenic index in db/db mice during an i.p. glucose challenge. (E) Dose response for effect of 4-week prior administration of Boc5 on fasting insulin concentrations in db/db (open circles) and non-diabetic C57 mice (closed circles). (F) Dose response for effect of Boc5 on HOMAir, an index of insulin resistance derived from fasting insulin and glucose concentrations. (G) Dose response for effect of 4-week prior Boc5 administration on QUICKI, an alternate index of insulin sensitivity derived from fasting insulin and glucose concentrations. (H) Effect of 4-week administration of Boc5 (3 mg/day) on Kitt, a measure of insulin-mediated glucose clearance, in C57 and db/db mice.
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pone-0002892-g004: Effects of Boc5 on insulin secretion and insulin sensitivity.(A) Effect of prior administration of Boc5 on insulinogenic index, the slope of the relationship between plasma insulin and blood glucose concentrations in quasi-steady-state, during the decay phase of an intraperitoneal (i.p.) glucose challenge in fasted C57BL/6J (C57) mice. (B) Dose response for effects of Boc5 and exendin-4 on insulinogenic index in C57 mice during an i.p. glucose challenge. (C) Effect of prior administration of exendin-4 and Boc5 on insulinogenic index in fasted db/db mice. Gray band depicts the slope range of different Boc5 doses (0.3, 1, 3 and 6 mg). (D) Dose response for effects of Boc5 and exendin-4 on insulinogenic index in db/db mice during an i.p. glucose challenge. (E) Dose response for effect of 4-week prior administration of Boc5 on fasting insulin concentrations in db/db (open circles) and non-diabetic C57 mice (closed circles). (F) Dose response for effect of Boc5 on HOMAir, an index of insulin resistance derived from fasting insulin and glucose concentrations. (G) Dose response for effect of 4-week prior Boc5 administration on QUICKI, an alternate index of insulin sensitivity derived from fasting insulin and glucose concentrations. (H) Effect of 4-week administration of Boc5 (3 mg/day) on Kitt, a measure of insulin-mediated glucose clearance, in C57 and db/db mice.

Mentions: Insulin secretory stimulation can be quantified in mice using an insulinogenic index [31], which describes the relationship between insulin secretory response and a secretory stimulus, such as glucose delivered intravenously or intraperitoneally. The slope of the relationship between quasi-steady-state insulin and glucose concentrations (or changes in concentration) quantifies the amplification of secretion typical of incretin action. In the present study, the insulinogenic index derived from an i.p. glucose challenge in the presence of vehicle, was increased 3.2-fold by both Boc5 and exendin-4 (P<0.002, ANOVA; Figs. 4A and 4B). Boc5 was 2700-fold less potent (on a mass basis) than exendin-4 injected i.p. in the same assay (ED50 0.97 mg and 0.36 µg, respectively; Fig. 4B), comparable to the potency ratio observed with INS-1E cells in vitro.


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 insulin secretion and insulin sensitivity.(A) Effect of prior administration of Boc5 on insulinogenic index, the slope of the relationship between plasma insulin and blood glucose concentrations in quasi-steady-state, during the decay phase of an intraperitoneal (i.p.) glucose challenge in fasted C57BL/6J (C57) mice. (B) Dose response for effects of Boc5 and exendin-4 on insulinogenic index in C57 mice during an i.p. glucose challenge. (C) Effect of prior administration of exendin-4 and Boc5 on insulinogenic index in fasted db/db mice. Gray band depicts the slope range of different Boc5 doses (0.3, 1, 3 and 6 mg). (D) Dose response for effects of Boc5 and exendin-4 on insulinogenic index in db/db mice during an i.p. glucose challenge. (E) Dose response for effect of 4-week prior administration of Boc5 on fasting insulin concentrations in db/db (open circles) and non-diabetic C57 mice (closed circles). (F) Dose response for effect of Boc5 on HOMAir, an index of insulin resistance derived from fasting insulin and glucose concentrations. (G) Dose response for effect of 4-week prior Boc5 administration on QUICKI, an alternate index of insulin sensitivity derived from fasting insulin and glucose concentrations. (H) Effect of 4-week administration of Boc5 (3 mg/day) on Kitt, a measure of insulin-mediated glucose clearance, in C57 and db/db mice.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2483413&req=5

pone-0002892-g004: Effects of Boc5 on insulin secretion and insulin sensitivity.(A) Effect of prior administration of Boc5 on insulinogenic index, the slope of the relationship between plasma insulin and blood glucose concentrations in quasi-steady-state, during the decay phase of an intraperitoneal (i.p.) glucose challenge in fasted C57BL/6J (C57) mice. (B) Dose response for effects of Boc5 and exendin-4 on insulinogenic index in C57 mice during an i.p. glucose challenge. (C) Effect of prior administration of exendin-4 and Boc5 on insulinogenic index in fasted db/db mice. Gray band depicts the slope range of different Boc5 doses (0.3, 1, 3 and 6 mg). (D) Dose response for effects of Boc5 and exendin-4 on insulinogenic index in db/db mice during an i.p. glucose challenge. (E) Dose response for effect of 4-week prior administration of Boc5 on fasting insulin concentrations in db/db (open circles) and non-diabetic C57 mice (closed circles). (F) Dose response for effect of Boc5 on HOMAir, an index of insulin resistance derived from fasting insulin and glucose concentrations. (G) Dose response for effect of 4-week prior Boc5 administration on QUICKI, an alternate index of insulin sensitivity derived from fasting insulin and glucose concentrations. (H) Effect of 4-week administration of Boc5 (3 mg/day) on Kitt, a measure of insulin-mediated glucose clearance, in C57 and db/db mice.
Mentions: Insulin secretory stimulation can be quantified in mice using an insulinogenic index [31], which describes the relationship between insulin secretory response and a secretory stimulus, such as glucose delivered intravenously or intraperitoneally. The slope of the relationship between quasi-steady-state insulin and glucose concentrations (or changes in concentration) quantifies the amplification of secretion typical of incretin action. In the present study, the insulinogenic index derived from an i.p. glucose challenge in the presence of vehicle, was increased 3.2-fold by both Boc5 and exendin-4 (P<0.002, ANOVA; Figs. 4A and 4B). Boc5 was 2700-fold less potent (on a mass basis) than exendin-4 injected i.p. in the same assay (ED50 0.97 mg and 0.36 µg, respectively; Fig. 4B), comparable to the potency ratio observed with INS-1E cells in vitro.

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