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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

Fasting and glucose-stimulated human insulin levels and stimulation indices in control and lixisenatide-treated mice engrafted with human islets.Notes: Blood was collected at fasting and 15 minutes after ip glucose injection; plasma levels of (A) fasting human insulin and (B) glucose-stimulated human insulin are shown. (C) Stimulation indices (glucose-stimulated insulin/fasting insulin) from vehicle control and lixisenatide-treated mice are shown; n=4 or 5 per group, mean ± SEM.Abbreviations: ip, intraperitoneal; SEM, standard error of mean.
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f3-dmso-8-387: Fasting and glucose-stimulated human insulin levels and stimulation indices in control and lixisenatide-treated mice engrafted with human islets.Notes: Blood was collected at fasting and 15 minutes after ip glucose injection; plasma levels of (A) fasting human insulin and (B) glucose-stimulated human insulin are shown. (C) Stimulation indices (glucose-stimulated insulin/fasting insulin) from vehicle control and lixisenatide-treated mice are shown; n=4 or 5 per group, mean ± SEM.Abbreviations: ip, intraperitoneal; SEM, standard error of mean.

Mentions: At 2 weeks post-transplant, the fasting levels of human insulin showed no significant differences between control and any of the lixisenatide-treatment groups (Figure 3A). However, glucose-stimulated levels of human insulin were significantly increased with medium-dose lixisenatide treatment in Donors 1 and 4 transplant studies (Figure 3B). Of note, the stimulation index (ratio of stimulated to fasting human insulin) was significantly increased compared to controls in the medium-dose group for Donor 1, and both medium- and high-dose groups for Donors 3 and 4 transplants (Figure 3C). Mice in the Donor 2 and 5 transplant studies were excluded because the controls (as well as some of the treated mice) were hyperglycemic.


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)

Fasting and glucose-stimulated human insulin levels and stimulation indices in control and lixisenatide-treated mice engrafted with human islets.Notes: Blood was collected at fasting and 15 minutes after ip glucose injection; plasma levels of (A) fasting human insulin and (B) glucose-stimulated human insulin are shown. (C) Stimulation indices (glucose-stimulated insulin/fasting insulin) from vehicle control and lixisenatide-treated mice are shown; n=4 or 5 per group, mean ± SEM.Abbreviations: ip, intraperitoneal; SEM, standard error of mean.
© Copyright Policy
Related In: Results  -  Collection

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

f3-dmso-8-387: Fasting and glucose-stimulated human insulin levels and stimulation indices in control and lixisenatide-treated mice engrafted with human islets.Notes: Blood was collected at fasting and 15 minutes after ip glucose injection; plasma levels of (A) fasting human insulin and (B) glucose-stimulated human insulin are shown. (C) Stimulation indices (glucose-stimulated insulin/fasting insulin) from vehicle control and lixisenatide-treated mice are shown; n=4 or 5 per group, mean ± SEM.Abbreviations: ip, intraperitoneal; SEM, standard error of mean.
Mentions: At 2 weeks post-transplant, the fasting levels of human insulin showed no significant differences between control and any of the lixisenatide-treatment groups (Figure 3A). However, glucose-stimulated levels of human insulin were significantly increased with medium-dose lixisenatide treatment in Donors 1 and 4 transplant studies (Figure 3B). Of note, the stimulation index (ratio of stimulated to fasting human insulin) was significantly increased compared to controls in the medium-dose group for Donor 1, and both medium- and high-dose groups for Donors 3 and 4 transplants (Figure 3C). Mice in the Donor 2 and 5 transplant studies were excluded because the controls (as well as some of the treated mice) were hyperglycemic.

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