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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

Long-acting effects of E2HSA on nonfasting blood glucose levels (a), gastric emptying (b), and food intake per mouse (c) in normal ICR mice injected with a single dose subcutaneously. Food intake was measured per cage and expressed as food intake per mouse within the indicated time period. Nor., normal ICR mice administered saline. Data are expressed as mean ± S.E.M (n = 10). ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus Nor.
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fig3: Long-acting effects of E2HSA on nonfasting blood glucose levels (a), gastric emptying (b), and food intake per mouse (c) in normal ICR mice injected with a single dose subcutaneously. Food intake was measured per cage and expressed as food intake per mouse within the indicated time period. Nor., normal ICR mice administered saline. Data are expressed as mean ± S.E.M (n = 10). ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus Nor.

Mentions: In normal ICR mice, a single administration of E2HSA dose-dependently reduced glucose levels and area under curves (AUC) after oral glucose challenge at 20 minutes and 4 hours after administration on the first day. On the other hand, exendin-4 (Ex-4) ceased to suppress elevated glucose levels at 4 hours after administration (Figures 2(a)–2(d)). Furthermore, from the second day to the fifth day, E2HSA still significantly suppressed the elevated blood glucose levels at 30 minutes after oral glucose challenge. Eventually, the effect of E2HSA on blood glucose levels diminished on the last two days (Figure 2(e)). Thus, the glucose lowering effect of E2HSA could last at least 4 days and in a dose-dependent manner. We also observed such changes in nonfasting blood glucose levels after a single administration of E2HSA (Figure 3(a)). As expected, E2HSA displayed an extended, dose-dependent blood glucose lowering effect that lasted to the 4th day, though the effect of 1 mg/kg E2HSA was not significant on the 3rd and 4th days. Notably, exendin-4 lost its effect on the second day.


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)

Long-acting effects of E2HSA on nonfasting blood glucose levels (a), gastric emptying (b), and food intake per mouse (c) in normal ICR mice injected with a single dose subcutaneously. Food intake was measured per cage and expressed as food intake per mouse within the indicated time period. Nor., normal ICR mice administered saline. Data are expressed as mean ± S.E.M (n = 10). ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus Nor.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Long-acting effects of E2HSA on nonfasting blood glucose levels (a), gastric emptying (b), and food intake per mouse (c) in normal ICR mice injected with a single dose subcutaneously. Food intake was measured per cage and expressed as food intake per mouse within the indicated time period. Nor., normal ICR mice administered saline. Data are expressed as mean ± S.E.M (n = 10). ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus Nor.
Mentions: In normal ICR mice, a single administration of E2HSA dose-dependently reduced glucose levels and area under curves (AUC) after oral glucose challenge at 20 minutes and 4 hours after administration on the first day. On the other hand, exendin-4 (Ex-4) ceased to suppress elevated glucose levels at 4 hours after administration (Figures 2(a)–2(d)). Furthermore, from the second day to the fifth day, E2HSA still significantly suppressed the elevated blood glucose levels at 30 minutes after oral glucose challenge. Eventually, the effect of E2HSA on blood glucose levels diminished on the last two days (Figure 2(e)). Thus, the glucose lowering effect of E2HSA could last at least 4 days and in a dose-dependent manner. We also observed such changes in nonfasting blood glucose levels after a single administration of E2HSA (Figure 3(a)). As expected, E2HSA displayed an extended, dose-dependent blood glucose lowering effect that lasted to the 4th day, though the effect of 1 mg/kg E2HSA was not significant on the 3rd and 4th days. Notably, exendin-4 lost its effect on the second day.

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