Limits...
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

Photomicrographs of human islet grafts from control and lixisenatide-treated mice.Notes: Human islets from a single donor (Donor 5) engrafted in three vehicle control mice (top panel) and representative islet grafts from low-, medium-, and high-dose lixisenatide-treated mice (bottom panel, 1 of 3 islet graphs from each lixisenatide treatment group is shown) are shown; red, green, and blue indicate insulin, glucagon, and DAPI staining, respectively.Abbreviation: DAPI, 4′,6-diamidino-2-phenylindole.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4548726&req=5

f8-dmso-8-387: Photomicrographs of human islet grafts from control and lixisenatide-treated mice.Notes: Human islets from a single donor (Donor 5) engrafted in three vehicle control mice (top panel) and representative islet grafts from low-, medium-, and high-dose lixisenatide-treated mice (bottom panel, 1 of 3 islet graphs from each lixisenatide treatment group is shown) are shown; red, green, and blue indicate insulin, glucagon, and DAPI staining, respectively.Abbreviation: DAPI, 4′,6-diamidino-2-phenylindole.

Mentions: In the Donor 5 transplant study, medium- and high-dose lixisenatide-treated mice displayed significantly greater beta-cell numbers within the graft compared to control mice. In this study, an average of ~2,000 beta cells was detected in the islet grafts of control mice compared to an average of ~12,500 and ~4,500 beta cells in the control groups of Donor 3 and 4 studies, respectively. Interestingly, Donor 5 control mice remained hyperglycemic throughout the study, whereas normoglycemia was restored in control group mice in the Donor 3 and 4 studies. The beta (and alpha)-cell counts in the low-dose lixisenatide-treated group from the Donor 5 study were approximately twofold higher than the control group, even though the blood glucose of these mice remained elevated (~400 mg/dL, Figure 1A). The blood glucose values in the medium- and high-dose groups were significantly lower than the control group, and these mice had approximately threefold higher numbers of beta (and alpha) cells. In support of this, the islet grafts from three vehicle control mice appear noticeably smaller than from lixisenatide-treated mice (Figure 8), consistent with the significantly lower beta- and alpha-cell counts in the control group.


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)

Photomicrographs of human islet grafts from control and lixisenatide-treated mice.Notes: Human islets from a single donor (Donor 5) engrafted in three vehicle control mice (top panel) and representative islet grafts from low-, medium-, and high-dose lixisenatide-treated mice (bottom panel, 1 of 3 islet graphs from each lixisenatide treatment group is shown) are shown; red, green, and blue indicate insulin, glucagon, and DAPI staining, respectively.Abbreviation: DAPI, 4′,6-diamidino-2-phenylindole.
© Copyright Policy
Related In: Results  -  Collection

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

f8-dmso-8-387: Photomicrographs of human islet grafts from control and lixisenatide-treated mice.Notes: Human islets from a single donor (Donor 5) engrafted in three vehicle control mice (top panel) and representative islet grafts from low-, medium-, and high-dose lixisenatide-treated mice (bottom panel, 1 of 3 islet graphs from each lixisenatide treatment group is shown) are shown; red, green, and blue indicate insulin, glucagon, and DAPI staining, respectively.Abbreviation: DAPI, 4′,6-diamidino-2-phenylindole.
Mentions: In the Donor 5 transplant study, medium- and high-dose lixisenatide-treated mice displayed significantly greater beta-cell numbers within the graft compared to control mice. In this study, an average of ~2,000 beta cells was detected in the islet grafts of control mice compared to an average of ~12,500 and ~4,500 beta cells in the control groups of Donor 3 and 4 studies, respectively. Interestingly, Donor 5 control mice remained hyperglycemic throughout the study, whereas normoglycemia was restored in control group mice in the Donor 3 and 4 studies. The beta (and alpha)-cell counts in the low-dose lixisenatide-treated group from the Donor 5 study were approximately twofold higher than the control group, even though the blood glucose of these mice remained elevated (~400 mg/dL, Figure 1A). The blood glucose values in the medium- and high-dose groups were significantly lower than the control group, and these mice had approximately threefold higher numbers of beta (and alpha) cells. In support of this, the islet grafts from three vehicle control mice appear noticeably smaller than from lixisenatide-treated mice (Figure 8), consistent with the significantly lower beta- and alpha-cell counts in the control group.

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