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Effects of E2HSA, a Long-Acting Glucagon Like Peptide-1 Receptor Agonist, on Glycemic Control and Beta Cell Function in Spontaneous Diabetic db/db Mice.

Hou S, Li C, Huan Y, Liu S, Liu Q, Sun S, Jiang Q, Jia C, Shen Z - J Diabetes Res (2015)

Bottom Line: Chronic E2HSA treatment in db/db mice significantly improved glucose tolerance, reduced elevated nonfasting and fasting plasma glucose levels, and also decreased HbA1c levels.Furthermore, immunofluorescence analysis showed that E2HSA increased β-cell area, improved islet morphology, and reduced β-cell apoptosis.In conclusion, with prolonged glucose lowering effects and promoting β-cell function and survival, the fusion protein, E2HSA, is a promising new therapeutic for once weekly treatment of type 2 diabetes.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

ABSTRACT
Glucagon like peptide-1 (GLP-1) receptor agonists such as exendin-4 have been widely used but their short half-life limits their therapeutic value. The recombinant protein, E2HSA, is a novel, long-acting GLP-1 receptor agonist generated by the fusion of exendin-4 with human serum albumin. In mouse pancreatic NIT-1 cells, E2HSA activated GLP-1 receptor with similar efficacy as exendin-4. After single-dose administration in ICR mice, E2HSA showed prolonged glucose lowering effects which lasted up to four days and extended inhibition on gastric emptying for at least 72 hours. Chronic E2HSA treatment in db/db mice significantly improved glucose tolerance, reduced elevated nonfasting and fasting plasma glucose levels, and also decreased HbA1c levels. E2HSA also increased insulin secretion and decreased body weight and appetite. Furthermore, immunofluorescence analysis showed that E2HSA increased β-cell area, improved islet morphology, and reduced β-cell apoptosis. In accordance with the promotion of β-cell function and survival, E2HSA upregulated genes such as Irs2, Pdx-1, Nkx6.1, and MafA and downregulated the expression levels of FoxO1 and proapoptotic Bcl-2 family proteins. In conclusion, with prolonged glucose lowering effects and promoting β-cell function and survival, the fusion protein, E2HSA, is a promising new therapeutic for once weekly treatment of type 2 diabetes.

No MeSH data available.


Related in: MedlinePlus

E2HSA exhibits GLP-1 receptor activating efficacy in NIT-1 cells. NIT-1 cells transiently transfected with Peak12 RIP-CRE 6x Luciferase reporter gene plasmid were treated with indicated concentrations of E2HSA and exendin-4 for 24 hours. Luciferase expression in cell lysates was measured by chemiluminescence. Data obtained were used to calculate the activation fold at different concentrations. Values are expressed as means ± S.E.M and are representative of data from two independent experiments, each performed in quadruplicate.
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fig1: E2HSA exhibits GLP-1 receptor activating efficacy in NIT-1 cells. NIT-1 cells transiently transfected with Peak12 RIP-CRE 6x Luciferase reporter gene plasmid were treated with indicated concentrations of E2HSA and exendin-4 for 24 hours. Luciferase expression in cell lysates was measured by chemiluminescence. Data obtained were used to calculate the activation fold at different concentrations. Values are expressed as means ± S.E.M and are representative of data from two independent experiments, each performed in quadruplicate.

Mentions: E2HSA produced a dose-dependent activation of the GLP-1 receptor in NIT-1 cells with concentrations ranging from 0.1 nM to 1000 nM. Compared to exendin-4, E2SHA showed a similar max GLP-1R activation fold (3.3-fold) but different EC50 (28.2 nM for E2HSA versus 0.215 nM for exendin-4) (Figure 1). The results showed that the recombinant fusion protein of exendin-4 and human serum albumin (HSA) possessed the same efficacy as exendin-4 to recognize and activate GLP-1 receptor but with lower potency perhaps due to steric hindrance of the HSA.


Effects of E2HSA, a Long-Acting Glucagon Like Peptide-1 Receptor Agonist, on Glycemic Control and Beta Cell Function in Spontaneous Diabetic db/db Mice.

Hou S, Li C, Huan Y, Liu S, Liu Q, Sun S, Jiang Q, Jia C, Shen Z - J Diabetes Res (2015)

E2HSA exhibits GLP-1 receptor activating efficacy in NIT-1 cells. NIT-1 cells transiently transfected with Peak12 RIP-CRE 6x Luciferase reporter gene plasmid were treated with indicated concentrations of E2HSA and exendin-4 for 24 hours. Luciferase expression in cell lysates was measured by chemiluminescence. Data obtained were used to calculate the activation fold at different concentrations. Values are expressed as means ± S.E.M and are representative of data from two independent experiments, each performed in quadruplicate.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4553314&req=5

fig1: E2HSA exhibits GLP-1 receptor activating efficacy in NIT-1 cells. NIT-1 cells transiently transfected with Peak12 RIP-CRE 6x Luciferase reporter gene plasmid were treated with indicated concentrations of E2HSA and exendin-4 for 24 hours. Luciferase expression in cell lysates was measured by chemiluminescence. Data obtained were used to calculate the activation fold at different concentrations. Values are expressed as means ± S.E.M and are representative of data from two independent experiments, each performed in quadruplicate.
Mentions: E2HSA produced a dose-dependent activation of the GLP-1 receptor in NIT-1 cells with concentrations ranging from 0.1 nM to 1000 nM. Compared to exendin-4, E2SHA showed a similar max GLP-1R activation fold (3.3-fold) but different EC50 (28.2 nM for E2HSA versus 0.215 nM for exendin-4) (Figure 1). The results showed that the recombinant fusion protein of exendin-4 and human serum albumin (HSA) possessed the same efficacy as exendin-4 to recognize and activate GLP-1 receptor but with lower potency perhaps due to steric hindrance of the HSA.

Bottom Line: Chronic E2HSA treatment in db/db mice significantly improved glucose tolerance, reduced elevated nonfasting and fasting plasma glucose levels, and also decreased HbA1c levels.Furthermore, immunofluorescence analysis showed that E2HSA increased β-cell area, improved islet morphology, and reduced β-cell apoptosis.In conclusion, with prolonged glucose lowering effects and promoting β-cell function and survival, the fusion protein, E2HSA, is a promising new therapeutic for once weekly treatment of type 2 diabetes.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

ABSTRACT
Glucagon like peptide-1 (GLP-1) receptor agonists such as exendin-4 have been widely used but their short half-life limits their therapeutic value. The recombinant protein, E2HSA, is a novel, long-acting GLP-1 receptor agonist generated by the fusion of exendin-4 with human serum albumin. In mouse pancreatic NIT-1 cells, E2HSA activated GLP-1 receptor with similar efficacy as exendin-4. After single-dose administration in ICR mice, E2HSA showed prolonged glucose lowering effects which lasted up to four days and extended inhibition on gastric emptying for at least 72 hours. Chronic E2HSA treatment in db/db mice significantly improved glucose tolerance, reduced elevated nonfasting and fasting plasma glucose levels, and also decreased HbA1c levels. E2HSA also increased insulin secretion and decreased body weight and appetite. Furthermore, immunofluorescence analysis showed that E2HSA increased β-cell area, improved islet morphology, and reduced β-cell apoptosis. In accordance with the promotion of β-cell function and survival, E2HSA upregulated genes such as Irs2, Pdx-1, Nkx6.1, and MafA and downregulated the expression levels of FoxO1 and proapoptotic Bcl-2 family proteins. In conclusion, with prolonged glucose lowering effects and promoting β-cell function and survival, the fusion protein, E2HSA, is a promising new therapeutic for once weekly treatment of type 2 diabetes.

No MeSH data available.


Related in: MedlinePlus