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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

Chronic treatment with E2HSA decreased average body weight, inhibited average food, and water intake in spontaneous type 2 diabetes db/db mice. (a) Delta body weight change per mouse per week. (b) Average food intake per mouse per week. (c) Average water consumption per mouse per week. Con., db/db mice administered normal saline. Data are expressed as mean ± S.E.M (n = 10-11). ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus Con.
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fig6: Chronic treatment with E2HSA decreased average body weight, inhibited average food, and water intake in spontaneous type 2 diabetes db/db mice. (a) Delta body weight change per mouse per week. (b) Average food intake per mouse per week. (c) Average water consumption per mouse per week. Con., db/db mice administered normal saline. Data are expressed as mean ± S.E.M (n = 10-11). ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus Con.

Mentions: During the chronic treatment of db/db mice, we monitored changes in body weight and food and water intake every day. As shown in Figure 6(a), E2HSA significantly decreased body weight in the first two weeks, although this effect diminished gradually. Body weight in the exendin-4-treated group showed only a very modest declining trend at the end of treatment. Food intake in all E2HSA-treated mice was significantly reduced in the first week. Interestingly, 9 mg/kg E2HSA maintained this effect until the 5th week, while the other two doses gradually lost efficacy (Figure 6(b)). On the other hand, Figure 6(c) showed that there was extensive water consumption in vehicle treated db/db mice compared to db/m mice, suggesting that diabetes-induced polydipsia might exist in these mice. E2HSA significantly reduced water consumption in a dose-dependent manner throughout the treatment (Figure 6(c)).


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)

Chronic treatment with E2HSA decreased average body weight, inhibited average food, and water intake in spontaneous type 2 diabetes db/db mice. (a) Delta body weight change per mouse per week. (b) Average food intake per mouse per week. (c) Average water consumption per mouse per week. Con., db/db mice administered normal saline. Data are expressed as mean ± S.E.M (n = 10-11). ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus Con.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig6: Chronic treatment with E2HSA decreased average body weight, inhibited average food, and water intake in spontaneous type 2 diabetes db/db mice. (a) Delta body weight change per mouse per week. (b) Average food intake per mouse per week. (c) Average water consumption per mouse per week. Con., db/db mice administered normal saline. Data are expressed as mean ± S.E.M (n = 10-11). ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus Con.
Mentions: During the chronic treatment of db/db mice, we monitored changes in body weight and food and water intake every day. As shown in Figure 6(a), E2HSA significantly decreased body weight in the first two weeks, although this effect diminished gradually. Body weight in the exendin-4-treated group showed only a very modest declining trend at the end of treatment. Food intake in all E2HSA-treated mice was significantly reduced in the first week. Interestingly, 9 mg/kg E2HSA maintained this effect until the 5th week, while the other two doses gradually lost efficacy (Figure 6(b)). On the other hand, Figure 6(c) showed that there was extensive water consumption in vehicle treated db/db mice compared to db/m mice, suggesting that diabetes-induced polydipsia might exist in these mice. E2HSA significantly reduced water consumption in a dose-dependent manner throughout the treatment (Figure 6(c)).

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