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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

Effects of E2HSA on islet hormone secretion and plasma lipid levels in spontaneous type 2 diabetes db/db mice. (a) Fasting plasma insulin levels at the 2nd week. (b) Plasma insulin levels at 2 minutes and 5 minutes after intravenous glucose challenge in IVGTT. (c) Fasting plasma glucagon levels at the end of the experiment. ((d)–(f)) Fasting plasma triglyceride levels from the 5th week (d), fasting total plasma cholesterol levels from the 1st week (e), and fasting plasma FFA levels from the 2nd week (f) were represented here. Nor., db/m mice administered normal saline. 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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fig5: Effects of E2HSA on islet hormone secretion and plasma lipid levels in spontaneous type 2 diabetes db/db mice. (a) Fasting plasma insulin levels at the 2nd week. (b) Plasma insulin levels at 2 minutes and 5 minutes after intravenous glucose challenge in IVGTT. (c) Fasting plasma glucagon levels at the end of the experiment. ((d)–(f)) Fasting plasma triglyceride levels from the 5th week (d), fasting total plasma cholesterol levels from the 1st week (e), and fasting plasma FFA levels from the 2nd week (f) were represented here. Nor., db/m mice administered normal saline. 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: Chronic E2HSA treatment dose-dependently increased fasting plasma insulin levels in db/db mice (Figure 5(a)), while fasting plasma glucagon levels in E2HSA-treated groups showed an overall trend towards reduction (decreased by 28.0%, 23.7%, and 24.1% for 1 mg/kg, 3 mg/kg, and 9 mg/kg E2HSA, resp.) but with no dose-dependency (Figure 5(c)). Exendin-4-treated db/db mice displayed enhanced insulin secretion, while their plasma glucagon levels were comparable to the control group. To determine whether E2HSA treatment could increase phase I insulin secretion, we measured the acute insulin-secretory response to glucose by utilizing a simplified IVGTT. Blood samples taken at 2 minutes, 5 minutes, and 8 minutes after glucose challenge were analyzed. Insulin levels at 2 minutes were higher than those at 5 minutes and 8 minutes (insulin levels at 8 minutes were the lowest and not shown). Both 3 mg/kg and 9 mg/kg doses of E2HSA produced a significant increase in plasma insulin levels at 2 minutes (Figure 5(b)). Since first-phase insulin secretion occurs within the first 10 minutes after glucose infusion, we could conclude that chronic E2HSA and exendin-4 treatment significantly increased first-phase insulin secretion. During the treatment, E2HSA also significantly reduced fasting plasma triglyceride levels on the 1st week (not shown), 3rd week (not shown), and 5th week (Figure 5(d)) in db/db mice. Total plasma cholesterol and FFA levels were decreased in the first two weeks (Figures 5(e)-5(f)), but the effects were not sustained in the following weeks (data not shown).


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)

Effects of E2HSA on islet hormone secretion and plasma lipid levels in spontaneous type 2 diabetes db/db mice. (a) Fasting plasma insulin levels at the 2nd week. (b) Plasma insulin levels at 2 minutes and 5 minutes after intravenous glucose challenge in IVGTT. (c) Fasting plasma glucagon levels at the end of the experiment. ((d)–(f)) Fasting plasma triglyceride levels from the 5th week (d), fasting total plasma cholesterol levels from the 1st week (e), and fasting plasma FFA levels from the 2nd week (f) were represented here. Nor., db/m mice administered normal saline. 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

fig5: Effects of E2HSA on islet hormone secretion and plasma lipid levels in spontaneous type 2 diabetes db/db mice. (a) Fasting plasma insulin levels at the 2nd week. (b) Plasma insulin levels at 2 minutes and 5 minutes after intravenous glucose challenge in IVGTT. (c) Fasting plasma glucagon levels at the end of the experiment. ((d)–(f)) Fasting plasma triglyceride levels from the 5th week (d), fasting total plasma cholesterol levels from the 1st week (e), and fasting plasma FFA levels from the 2nd week (f) were represented here. Nor., db/m mice administered normal saline. 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: Chronic E2HSA treatment dose-dependently increased fasting plasma insulin levels in db/db mice (Figure 5(a)), while fasting plasma glucagon levels in E2HSA-treated groups showed an overall trend towards reduction (decreased by 28.0%, 23.7%, and 24.1% for 1 mg/kg, 3 mg/kg, and 9 mg/kg E2HSA, resp.) but with no dose-dependency (Figure 5(c)). Exendin-4-treated db/db mice displayed enhanced insulin secretion, while their plasma glucagon levels were comparable to the control group. To determine whether E2HSA treatment could increase phase I insulin secretion, we measured the acute insulin-secretory response to glucose by utilizing a simplified IVGTT. Blood samples taken at 2 minutes, 5 minutes, and 8 minutes after glucose challenge were analyzed. Insulin levels at 2 minutes were higher than those at 5 minutes and 8 minutes (insulin levels at 8 minutes were the lowest and not shown). Both 3 mg/kg and 9 mg/kg doses of E2HSA produced a significant increase in plasma insulin levels at 2 minutes (Figure 5(b)). Since first-phase insulin secretion occurs within the first 10 minutes after glucose infusion, we could conclude that chronic E2HSA and exendin-4 treatment significantly increased first-phase insulin secretion. During the treatment, E2HSA also significantly reduced fasting plasma triglyceride levels on the 1st week (not shown), 3rd week (not shown), and 5th week (Figure 5(d)) in db/db mice. Total plasma cholesterol and FFA levels were decreased in the first two weeks (Figures 5(e)-5(f)), but the effects were not sustained in the following weeks (data not shown).

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