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Lixisenatide accelerates restoration of normoglycemia and improves human beta-cell function and survival in diabetic immunodeficient NOD-scid IL-2rg() RIP-DTR mice engrafted with human islets.

Yang C, Loehn M, Jurczyk A, Przewozniak N, Leehy L, Herrera PL, Shultz LD, Greiner DL, Harlan DM, Bortell R - Diabetes Metab Syndr Obes (2015)

Bottom Line: Glucagon-like peptide-1 induces glucose-dependent insulin secretion and, in rodents, increases proliferation and survival of pancreatic beta cells.Grafts were analyzed for total beta- and alpha-cell number, percent proliferation, and levels of apoptosis.Because the proliferative capacity of human beta cells is limited, improved beta-cell survival coupled with enhanced beta-cell function following lixisenatide treatment may provide the greatest benefit for diabetic patients with reduced functional islet mass.

View Article: PubMed Central - PubMed

Affiliation: Program in Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA.

ABSTRACT

Objective: Glucagon-like peptide-1 induces glucose-dependent insulin secretion and, in rodents, increases proliferation and survival of pancreatic beta cells. To investigate the effects on human beta cells, we used immunodeficient mice transplanted with human islets. The goal was to determine whether lixisenatide, a glucagon-like peptide-1 receptor agonist, improves human islet function and survival in vivo.

Methods: Five independent transplant studies were conducted with human islets from five individual donors. Diabetic human islet-engrafted immunodeficient mice were treated with lixisenatide (50, 150, and 500 µg/kg) or vehicle. Islet function was determined by blood glucose, plasma human insulin/C-peptide, and glucose tolerance tests. Grafts were analyzed for total beta- and alpha-cell number, percent proliferation, and levels of apoptosis.

Results: Diabetic mice transplanted with marginal human islet mass and treated with lixisenatide were restored to euglycemia more rapidly than vehicle-treated mice. Glucose tolerance tests, human plasma insulin, and glucose-stimulation indices of lixisenatide-treated mice were significantly improved compared to vehicle-treated mice. The percentages of proliferating or apoptotic beta cells at graft recovery were not different between lixisenatide-treated and vehicle-treated mice. Nevertheless, in one experiment we found a significant twofold to threefold increase in human beta-cell numbers in lixisenatide-treated compared to vehicle-treated mice.

Conclusion: Diabetic human islet-engrafted immunodeficient mice treated with lixisenatide show improved restoration of normoglycemia, human plasma insulin, and glucose tolerance compared to vehicle-treated mice engrafted with the same donor islets. Because the proliferative capacity of human beta cells is limited, improved beta-cell survival coupled with enhanced beta-cell function following lixisenatide treatment may provide the greatest benefit for diabetic patients with reduced functional islet mass.

No MeSH data available.


Related in: MedlinePlus

Percent TUNEL-positive human beta cells in islet grafts recovered from control and lixisenatide-treated mice.Notes: Human islet grafts were immunostained for insulin and TUNEL, and the percent of TUNEL-positive beta cells was determined; n=3 or 4 per group for Donor 3 and 4 studies and n=2 for Donor 5 study, mean ± SEM.Abbreviations: SEM, standard error of mean; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling.
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f5-dmso-8-387: Percent TUNEL-positive human beta cells in islet grafts recovered from control and lixisenatide-treated mice.Notes: Human islet grafts were immunostained for insulin and TUNEL, and the percent of TUNEL-positive beta cells was determined; n=3 or 4 per group for Donor 3 and 4 studies and n=2 for Donor 5 study, mean ± SEM.Abbreviations: SEM, standard error of mean; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling.

Mentions: Treatment with GLP-1 receptor agonists has been reported to protect rodent pancreatic beta cells from apoptosis.1 To determine whether lixisenatide treatment modulates human beta-cell apoptosis, the islet grafts were recovered on days 29, 32, and 21 (for Donor 3, 4, and 5 studies, respectively) and examined by TUNEL staining (Figure 5). We found no significant differences in beta-cell apoptosis between the control and lixisenatide-treated groups at the time points examined (at the end of each islet transplant study). In addition, although there was a variability between donor islets, the average percent beta-cell apoptosis observed at the end of each study was very low (<1%).


Lixisenatide accelerates restoration of normoglycemia and improves human beta-cell function and survival in diabetic immunodeficient NOD-scid IL-2rg() RIP-DTR mice engrafted with human islets.

Yang C, Loehn M, Jurczyk A, Przewozniak N, Leehy L, Herrera PL, Shultz LD, Greiner DL, Harlan DM, Bortell R - Diabetes Metab Syndr Obes (2015)

Percent TUNEL-positive human beta cells in islet grafts recovered from control and lixisenatide-treated mice.Notes: Human islet grafts were immunostained for insulin and TUNEL, and the percent of TUNEL-positive beta cells was determined; n=3 or 4 per group for Donor 3 and 4 studies and n=2 for Donor 5 study, mean ± SEM.Abbreviations: SEM, standard error of mean; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4548726&req=5

f5-dmso-8-387: Percent TUNEL-positive human beta cells in islet grafts recovered from control and lixisenatide-treated mice.Notes: Human islet grafts were immunostained for insulin and TUNEL, and the percent of TUNEL-positive beta cells was determined; n=3 or 4 per group for Donor 3 and 4 studies and n=2 for Donor 5 study, mean ± SEM.Abbreviations: SEM, standard error of mean; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling.
Mentions: Treatment with GLP-1 receptor agonists has been reported to protect rodent pancreatic beta cells from apoptosis.1 To determine whether lixisenatide treatment modulates human beta-cell apoptosis, the islet grafts were recovered on days 29, 32, and 21 (for Donor 3, 4, and 5 studies, respectively) and examined by TUNEL staining (Figure 5). We found no significant differences in beta-cell apoptosis between the control and lixisenatide-treated groups at the time points examined (at the end of each islet transplant study). In addition, although there was a variability between donor islets, the average percent beta-cell apoptosis observed at the end of each study was very low (<1%).

Bottom Line: Glucagon-like peptide-1 induces glucose-dependent insulin secretion and, in rodents, increases proliferation and survival of pancreatic beta cells.Grafts were analyzed for total beta- and alpha-cell number, percent proliferation, and levels of apoptosis.Because the proliferative capacity of human beta cells is limited, improved beta-cell survival coupled with enhanced beta-cell function following lixisenatide treatment may provide the greatest benefit for diabetic patients with reduced functional islet mass.

View Article: PubMed Central - PubMed

Affiliation: Program in Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA.

ABSTRACT

Objective: Glucagon-like peptide-1 induces glucose-dependent insulin secretion and, in rodents, increases proliferation and survival of pancreatic beta cells. To investigate the effects on human beta cells, we used immunodeficient mice transplanted with human islets. The goal was to determine whether lixisenatide, a glucagon-like peptide-1 receptor agonist, improves human islet function and survival in vivo.

Methods: Five independent transplant studies were conducted with human islets from five individual donors. Diabetic human islet-engrafted immunodeficient mice were treated with lixisenatide (50, 150, and 500 µg/kg) or vehicle. Islet function was determined by blood glucose, plasma human insulin/C-peptide, and glucose tolerance tests. Grafts were analyzed for total beta- and alpha-cell number, percent proliferation, and levels of apoptosis.

Results: Diabetic mice transplanted with marginal human islet mass and treated with lixisenatide were restored to euglycemia more rapidly than vehicle-treated mice. Glucose tolerance tests, human plasma insulin, and glucose-stimulation indices of lixisenatide-treated mice were significantly improved compared to vehicle-treated mice. The percentages of proliferating or apoptotic beta cells at graft recovery were not different between lixisenatide-treated and vehicle-treated mice. Nevertheless, in one experiment we found a significant twofold to threefold increase in human beta-cell numbers in lixisenatide-treated compared to vehicle-treated mice.

Conclusion: Diabetic human islet-engrafted immunodeficient mice treated with lixisenatide show improved restoration of normoglycemia, human plasma insulin, and glucose tolerance compared to vehicle-treated mice engrafted with the same donor islets. Because the proliferative capacity of human beta cells is limited, improved beta-cell survival coupled with enhanced beta-cell function following lixisenatide treatment may provide the greatest benefit for diabetic patients with reduced functional islet mass.

No MeSH data available.


Related in: MedlinePlus