Limits...
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 improved glycemic control in spontaneous type 2 diabetes db/db mice. (a) Nonfasting blood glucose levels normalized by setting blood glucose levels in the control group to 100%. The mini figure shows the nonfasting blood glucose levels at 1 hour and 5 hours after E2HSA and exendin-4 administration on the first day. (b) Changes in fasting blood glucose levels relative to levels before E2HSA treatment. ((c) and (d)) Blood glucose curves and AUC of OGTT on the 2nd week. ((e) and (f)) Blood glucose curves and AUC of OGTT on the 5th week. (g) HbA1c levels on the 37th day. (h) Insulin/glucose ratios at 10 minutes following glucose challenge on the 5th week. 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


getmorefigures.php?uid=PMC4553314&req=5

fig4: Chronic treatment with E2HSA improved glycemic control in spontaneous type 2 diabetes db/db mice. (a) Nonfasting blood glucose levels normalized by setting blood glucose levels in the control group to 100%. The mini figure shows the nonfasting blood glucose levels at 1 hour and 5 hours after E2HSA and exendin-4 administration on the first day. (b) Changes in fasting blood glucose levels relative to levels before E2HSA treatment. ((c) and (d)) Blood glucose curves and AUC of OGTT on the 2nd week. ((e) and (f)) Blood glucose curves and AUC of OGTT on the 5th week. (g) HbA1c levels on the 37th day. (h) Insulin/glucose ratios at 10 minutes following glucose challenge on the 5th week. 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: During 43 days of treatment, 1 mg/kg, 3 mg/kg, and 9 mg/kg doses of E2HSA all significantly decreased nonfasting and fasting blood glucose levels in a dose-dependent manner, and such effects were maintained throughout the entire treatment (Figures 4(a)-4(b)). Exendin-4 showed a comparable reduction in nonfasting and fasting blood glucose levels for the first two or three weeks, but then its efficacy became variable and the glycemic control in that group was worse than E2HSA-treated groups in the following weeks. OGTTs were performed on the 1st, 2nd, 3rd, and 5th weeks of E2HSA administration (the data from 1st and 3rd week are not shown). The results of the 2nd and 5th weeks are shown in Figures 4(c)–4(f). Glucose tolerance in E2HSA-treated db/db mice was significantly improved at all weeks tested. By the 2nd week, blood glucose levels following glucose challenge decreased significantly; the AUC in three doses of E2HSA-treated groups dropped 31.5%, 35.2%, and 40.1%, compared to the control group (Figures 4(c)-4(d)). By the 5th week, glucose levels after glucose challenge were still greatly reduced by all doses of E2HSA, with 23.8%, 31.0%, and 30.1% reduction in AUC, respectively (Figures 4(e)-4(f)). Ratios of insulin to glucose at 10 minutes after oral glucose loading were also increased significantly in groups treated with 3 mg/kg and 9 mg/kg E2HSA (Figure 4(h)), suggesting improved β-cell function. Exendin-4 significantly reduced the AUC (e.g., 16.0% and 13.0% at 2nd and 5th weeks, resp.) as well as suppressed blood glucose levels following glucose challenge, as shown in Figures 4(c)–4(f). Glycated hemoglobin, HbA1c, was tested at the end of E2HSA treatment. Compared to db/m mice, db/db mice in the control group displayed elevated HbA1c levels. On the 37th day of treatment, 3 mg/kg and 9 mg/kg E2HSA both reduced HbA1c levels significantly, indicating efficient glycemic control over the entire course of treatment (Figure 4(g)). On the other hand, exendin-4 was unable to show a significant HbA1c lowering effect at the same time (Figure 4(g)).


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 improved glycemic control in spontaneous type 2 diabetes db/db mice. (a) Nonfasting blood glucose levels normalized by setting blood glucose levels in the control group to 100%. The mini figure shows the nonfasting blood glucose levels at 1 hour and 5 hours after E2HSA and exendin-4 administration on the first day. (b) Changes in fasting blood glucose levels relative to levels before E2HSA treatment. ((c) and (d)) Blood glucose curves and AUC of OGTT on the 2nd week. ((e) and (f)) Blood glucose curves and AUC of OGTT on the 5th week. (g) HbA1c levels on the 37th day. (h) Insulin/glucose ratios at 10 minutes following glucose challenge on the 5th week. 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

fig4: Chronic treatment with E2HSA improved glycemic control in spontaneous type 2 diabetes db/db mice. (a) Nonfasting blood glucose levels normalized by setting blood glucose levels in the control group to 100%. The mini figure shows the nonfasting blood glucose levels at 1 hour and 5 hours after E2HSA and exendin-4 administration on the first day. (b) Changes in fasting blood glucose levels relative to levels before E2HSA treatment. ((c) and (d)) Blood glucose curves and AUC of OGTT on the 2nd week. ((e) and (f)) Blood glucose curves and AUC of OGTT on the 5th week. (g) HbA1c levels on the 37th day. (h) Insulin/glucose ratios at 10 minutes following glucose challenge on the 5th week. 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: During 43 days of treatment, 1 mg/kg, 3 mg/kg, and 9 mg/kg doses of E2HSA all significantly decreased nonfasting and fasting blood glucose levels in a dose-dependent manner, and such effects were maintained throughout the entire treatment (Figures 4(a)-4(b)). Exendin-4 showed a comparable reduction in nonfasting and fasting blood glucose levels for the first two or three weeks, but then its efficacy became variable and the glycemic control in that group was worse than E2HSA-treated groups in the following weeks. OGTTs were performed on the 1st, 2nd, 3rd, and 5th weeks of E2HSA administration (the data from 1st and 3rd week are not shown). The results of the 2nd and 5th weeks are shown in Figures 4(c)–4(f). Glucose tolerance in E2HSA-treated db/db mice was significantly improved at all weeks tested. By the 2nd week, blood glucose levels following glucose challenge decreased significantly; the AUC in three doses of E2HSA-treated groups dropped 31.5%, 35.2%, and 40.1%, compared to the control group (Figures 4(c)-4(d)). By the 5th week, glucose levels after glucose challenge were still greatly reduced by all doses of E2HSA, with 23.8%, 31.0%, and 30.1% reduction in AUC, respectively (Figures 4(e)-4(f)). Ratios of insulin to glucose at 10 minutes after oral glucose loading were also increased significantly in groups treated with 3 mg/kg and 9 mg/kg E2HSA (Figure 4(h)), suggesting improved β-cell function. Exendin-4 significantly reduced the AUC (e.g., 16.0% and 13.0% at 2nd and 5th weeks, resp.) as well as suppressed blood glucose levels following glucose challenge, as shown in Figures 4(c)–4(f). Glycated hemoglobin, HbA1c, was tested at the end of E2HSA treatment. Compared to db/m mice, db/db mice in the control group displayed elevated HbA1c levels. On the 37th day of treatment, 3 mg/kg and 9 mg/kg E2HSA both reduced HbA1c levels significantly, indicating efficient glycemic control over the entire course of treatment (Figure 4(g)). On the other hand, exendin-4 was unable to show a significant HbA1c lowering effect at the same time (Figure 4(g)).

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