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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 normalized islet morphology, increased β-cell area, and inhibited β-cell apoptosis in spontaneous type 2 diabetes db/db mice. (a) Immunofluorescence double staining with anti-insulin and anti-glucagon antibodies on pancreatic sections. (b) TUNEL assay on β-cells costained with anti-insulin antibodies. Representative images are shown. (c) Total β-cell area as percentage of total islet areas (n = 5). (d) Percentage of TUNEL positive β-cells in insulin positive cells (n = 3 per group). Data are expressed as mean ± S.E.M. ∗P < 0.05 and ∗∗P < 0.01 versus Con.
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fig7: Chronic treatment with E2HSA normalized islet morphology, increased β-cell area, and inhibited β-cell apoptosis in spontaneous type 2 diabetes db/db mice. (a) Immunofluorescence double staining with anti-insulin and anti-glucagon antibodies on pancreatic sections. (b) TUNEL assay on β-cells costained with anti-insulin antibodies. Representative images are shown. (c) Total β-cell area as percentage of total islet areas (n = 5). (d) Percentage of TUNEL positive β-cells in insulin positive cells (n = 3 per group). Data are expressed as mean ± S.E.M. ∗P < 0.05 and ∗∗P < 0.01 versus Con.

Mentions: Long-term treatment with E2HSA in db/db mice improved glucose tolerance and stimulated first-phase insulin secretion, suggesting an enhancement in β-cell function. To determine whether E2HSA had any effect on islet morphology and β-cell area, we double-stained islets with anti-insulin and anti-glucagon antibodies. As previously reported, islet morphology was impaired in db/db mice. Compared to db/m mice, β-cell area in db/db mice was less and the normal distribution of α-cells and β-cells was also perturbed. Intriguingly, E2HSA treatment significantly increased β-cell area and restored normal distribution of α-cells and β-cells, with α-cells on the outside and β-cells on the inside (Figures 7(a) and 7(c)). TUNEL assay revealed that chronic E2HSA treatment reduced the ratio of TUNEL positive nuclei to insulin positive β-cells, suggesting that β-cell apoptosis was also reduced (Figures 7(b) and 7(d)).


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 normalized islet morphology, increased β-cell area, and inhibited β-cell apoptosis in spontaneous type 2 diabetes db/db mice. (a) Immunofluorescence double staining with anti-insulin and anti-glucagon antibodies on pancreatic sections. (b) TUNEL assay on β-cells costained with anti-insulin antibodies. Representative images are shown. (c) Total β-cell area as percentage of total islet areas (n = 5). (d) Percentage of TUNEL positive β-cells in insulin positive cells (n = 3 per group). Data are expressed as mean ± S.E.M. ∗P < 0.05 and ∗∗P < 0.01 versus Con.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4553314&req=5

fig7: Chronic treatment with E2HSA normalized islet morphology, increased β-cell area, and inhibited β-cell apoptosis in spontaneous type 2 diabetes db/db mice. (a) Immunofluorescence double staining with anti-insulin and anti-glucagon antibodies on pancreatic sections. (b) TUNEL assay on β-cells costained with anti-insulin antibodies. Representative images are shown. (c) Total β-cell area as percentage of total islet areas (n = 5). (d) Percentage of TUNEL positive β-cells in insulin positive cells (n = 3 per group). Data are expressed as mean ± S.E.M. ∗P < 0.05 and ∗∗P < 0.01 versus Con.
Mentions: Long-term treatment with E2HSA in db/db mice improved glucose tolerance and stimulated first-phase insulin secretion, suggesting an enhancement in β-cell function. To determine whether E2HSA had any effect on islet morphology and β-cell area, we double-stained islets with anti-insulin and anti-glucagon antibodies. As previously reported, islet morphology was impaired in db/db mice. Compared to db/m mice, β-cell area in db/db mice was less and the normal distribution of α-cells and β-cells was also perturbed. Intriguingly, E2HSA treatment significantly increased β-cell area and restored normal distribution of α-cells and β-cells, with α-cells on the outside and β-cells on the inside (Figures 7(a) and 7(c)). TUNEL assay revealed that chronic E2HSA treatment reduced the ratio of TUNEL positive nuclei to insulin positive β-cells, suggesting that β-cell apoptosis was also reduced (Figures 7(b) and 7(d)).

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