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A novel long-acting glucose-dependent insulinotropic peptide analogue: enhanced efficacy in normal and diabetic rodents.

Tatarkiewicz K, Hargrove DM, Jodka CM, Gedulin BR, Smith PA, Hoyt JA, Lwin A, Collins L, Mamedova L, Levy OE, D'Souza L, Janssen S, Srivastava V, Ghosh SS, Parkes DG - Diabetes Obes Metab (2013)

Bottom Line: AC163794 was synthesized by solid-phase peptide synthesis.AC163794 exhibited nanomolar functional GIP receptor potency in vitro similar to GIP and [d-Ala(2) ]GIP(1-42).AC163794 was metabolically more stable in vitro and displayed longer duration of insulinotropic action in vivo versus GIP and [d-Ala(2) ]GIP(1-42).

View Article: PubMed Central - PubMed

Affiliation: Amylin Pharmaceuticals, LLC, San Diego, CA, USA.

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Related in: MedlinePlus

Plasma glucose (A) and insulin (B) excursions during an oral glucose tolerance test (OGTT) performed in high-fat-fed streptozotocin (HF-STZ) diabetic mice after 4-week continuous treatment with 100 nmol/kg/day AC163794. Insets represent calculated AUC for glucose (A) and insulin (B) excursion curves. *p < 0.05 versus HF-STZ vehicle-treated control (n = 6–8).
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fig07: Plasma glucose (A) and insulin (B) excursions during an oral glucose tolerance test (OGTT) performed in high-fat-fed streptozotocin (HF-STZ) diabetic mice after 4-week continuous treatment with 100 nmol/kg/day AC163794. Insets represent calculated AUC for glucose (A) and insulin (B) excursion curves. *p < 0.05 versus HF-STZ vehicle-treated control (n = 6–8).

Mentions: In a glucose tolerance test performed at the end of the study in HF-STZ mice, fasting plasma glucose in AC163794-treated group was similar to concentrations in non-diabetic mice and significantly lower than in diabetic controls (p < 0.05) (Table 2). Glucose excursions had a trend to be reduced when compared with diabetic controls and AUC0-2h to be elevated relative to non-diabetic controls (figure 7A). FIns concentrations were significantly higher in AC163794-treated group than in diabetic counterparts (p < 0.05, Table 2). Glucose-stimulated insulin concentrations and AUC0–2h were not significantly different between AC163794- and vehicle-treated diabetic groups and significantly reduced versus non-diabetic controls (p < 0.05, figure 7B). Calculated values for HOMA-R and HOMA-B along with measured terminal percentage of body fat, hepatic lipid content, plasma adipokines (Il-6, Resistin, PAI-1), cholesterol and triglycerides are presented in Table 2. AC163794 improved insulin sensitivity and β-cell function, and had no effect on body fat content and fat metabolism-related endpoints.


A novel long-acting glucose-dependent insulinotropic peptide analogue: enhanced efficacy in normal and diabetic rodents.

Tatarkiewicz K, Hargrove DM, Jodka CM, Gedulin BR, Smith PA, Hoyt JA, Lwin A, Collins L, Mamedova L, Levy OE, D'Souza L, Janssen S, Srivastava V, Ghosh SS, Parkes DG - Diabetes Obes Metab (2013)

Plasma glucose (A) and insulin (B) excursions during an oral glucose tolerance test (OGTT) performed in high-fat-fed streptozotocin (HF-STZ) diabetic mice after 4-week continuous treatment with 100 nmol/kg/day AC163794. Insets represent calculated AUC for glucose (A) and insulin (B) excursion curves. *p < 0.05 versus HF-STZ vehicle-treated control (n = 6–8).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4237114&req=5

fig07: Plasma glucose (A) and insulin (B) excursions during an oral glucose tolerance test (OGTT) performed in high-fat-fed streptozotocin (HF-STZ) diabetic mice after 4-week continuous treatment with 100 nmol/kg/day AC163794. Insets represent calculated AUC for glucose (A) and insulin (B) excursion curves. *p < 0.05 versus HF-STZ vehicle-treated control (n = 6–8).
Mentions: In a glucose tolerance test performed at the end of the study in HF-STZ mice, fasting plasma glucose in AC163794-treated group was similar to concentrations in non-diabetic mice and significantly lower than in diabetic controls (p < 0.05) (Table 2). Glucose excursions had a trend to be reduced when compared with diabetic controls and AUC0-2h to be elevated relative to non-diabetic controls (figure 7A). FIns concentrations were significantly higher in AC163794-treated group than in diabetic counterparts (p < 0.05, Table 2). Glucose-stimulated insulin concentrations and AUC0–2h were not significantly different between AC163794- and vehicle-treated diabetic groups and significantly reduced versus non-diabetic controls (p < 0.05, figure 7B). Calculated values for HOMA-R and HOMA-B along with measured terminal percentage of body fat, hepatic lipid content, plasma adipokines (Il-6, Resistin, PAI-1), cholesterol and triglycerides are presented in Table 2. AC163794 improved insulin sensitivity and β-cell function, and had no effect on body fat content and fat metabolism-related endpoints.

Bottom Line: AC163794 was synthesized by solid-phase peptide synthesis.AC163794 exhibited nanomolar functional GIP receptor potency in vitro similar to GIP and [d-Ala(2) ]GIP(1-42).AC163794 was metabolically more stable in vitro and displayed longer duration of insulinotropic action in vivo versus GIP and [d-Ala(2) ]GIP(1-42).

View Article: PubMed Central - PubMed

Affiliation: Amylin Pharmaceuticals, LLC, San Diego, CA, USA.

Show MeSH
Related in: MedlinePlus