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Treating diet-induced diabetes and obesity with human embryonic stem cell-derived pancreatic progenitor cells and antidiabetic drugs.

Bruin JE, Saber N, Braun N, Fox JK, Mojibian M, Asadi A, Drohan C, O'Dwyer S, Rosman-Balzer DS, Swiss VA, Rezania A, Kieffer TJ - Stem Cell Reports (2015)

Bottom Line: Human embryonic stem cell (hESC)-derived pancreatic progenitor cells effectively reverse hyperglycemia in rodent models of type 1 diabetes, but their capacity to treat type 2 diabetes has not been reported.All combination therapies rapidly improved body weight and co-treatment with either sitagliptin or metformin improved hyperglycemia after only 12 weeks.Therefore, a stem cell-based therapy may be effective for treating type 2 diabetes, particularly in combination with antidiabetic drugs.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular & Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.

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The Combination of Either Sitagliptin or Metformin with a Cell Transplant Resulted in Improved Glucose Tolerance within 12 Weeks(A–E) OGTTs were performed at 12 weeks post-transplantation in mice fed a 10% fat diet without drug (black/gray; all panels; Sham: n = 5 mice), 60% fat diet without drug (A and B, blue; Tx/Sham: n = 7 mice), 60% fat diet plus metformin (A and C, purple; Tx/Sham: n = 5 mice), 60% fat diet plus sitagliptin (A and D, orange; Tx: n = 7 mice, Sham: n = 8 mice), or 60% fat diet plus rosiglitazone (A and E, green; Tx: n = 7 mice, Sham: n = 6 mice). Blood glucose levels for sham mice from all treatment groups are shown together in (A). Sham mice (solid lines, closed symbols) and transplant recipients (Tx; dashed lines, open symbols) from each treatment group are shown together with LFD controls as a reference (B–E). The area under the curve (AUC) is shown in box-and-whisker plots to the right of each line graph, with separate data points representing individual mice. Data on line graphs are represented as mean ± SEM. (A) ∗p < 0.05 (one-way ANOVA versus LFD).(B–E) For glucose curves, two-way ANOVA was used to examine differences at each time point during the OGTT (∗p < 0.05, HFD Sham versus LFD; #p < 0.05, HFD Tx versus LFD). For the AUC, one-way ANOVA was used compare all groups (LFD versus HFD Sham, LFD versus HFD Tx, HFD Sham versus HFD Tx; ∗p < 0.05; ns, not significant).(F and G) Fasting mouse C-peptide levels at 4 weeks (F) or 16 weeks (G) post-transplantation. ∗p < 0.05, two-tailed t test (Tx versus Sham).(H) Human C-peptide levels were measured after an overnight fast and 60 min following an intraperitoneal glucose challenge. ∗p < 0.05, paired two-tailed t test (0 versus 60 min).
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fig7: The Combination of Either Sitagliptin or Metformin with a Cell Transplant Resulted in Improved Glucose Tolerance within 12 Weeks(A–E) OGTTs were performed at 12 weeks post-transplantation in mice fed a 10% fat diet without drug (black/gray; all panels; Sham: n = 5 mice), 60% fat diet without drug (A and B, blue; Tx/Sham: n = 7 mice), 60% fat diet plus metformin (A and C, purple; Tx/Sham: n = 5 mice), 60% fat diet plus sitagliptin (A and D, orange; Tx: n = 7 mice, Sham: n = 8 mice), or 60% fat diet plus rosiglitazone (A and E, green; Tx: n = 7 mice, Sham: n = 6 mice). Blood glucose levels for sham mice from all treatment groups are shown together in (A). Sham mice (solid lines, closed symbols) and transplant recipients (Tx; dashed lines, open symbols) from each treatment group are shown together with LFD controls as a reference (B–E). The area under the curve (AUC) is shown in box-and-whisker plots to the right of each line graph, with separate data points representing individual mice. Data on line graphs are represented as mean ± SEM. (A) ∗p < 0.05 (one-way ANOVA versus LFD).(B–E) For glucose curves, two-way ANOVA was used to examine differences at each time point during the OGTT (∗p < 0.05, HFD Sham versus LFD; #p < 0.05, HFD Tx versus LFD). For the AUC, one-way ANOVA was used compare all groups (LFD versus HFD Sham, LFD versus HFD Tx, HFD Sham versus HFD Tx; ∗p < 0.05; ns, not significant).(F and G) Fasting mouse C-peptide levels at 4 weeks (F) or 16 weeks (G) post-transplantation. ∗p < 0.05, two-tailed t test (Tx versus Sham).(H) Human C-peptide levels were measured after an overnight fast and 60 min following an intraperitoneal glucose challenge. ∗p < 0.05, paired two-tailed t test (0 versus 60 min).

Mentions: Fasting blood glucose levels were not affected by any of the combination therapies throughout the study duration (Figure S7). At 12 weeks post-transplantation, mice in all HFD sham groups were glucose intolerant compared with LFD controls, regardless of the drug treatment used (Figure 7A). As expected based on our previous cohort, we found no effect of the cell therapy on glucose tolerance at 12 weeks post-transplantation in the HFD-fed mice without drug treatment (Figure 7B), and likewise, the combination with rosiglitazone was also ineffective at this time (Figure 7E). Interestingly, the cell therapy significantly improved glucose tolerance at 12 weeks post-transplantation when combined with either metformin (Figure 7C) or sitagliptin (Figure 7D) treatment. In fact, glycemic control during an oral glucose challenge was indistinguishable between the LFD controls and HFD-fed mice receiving sitagliptin with the cell therapy, with the exception of a marginally higher peak glucose level at 15 min post-gavage (Figure 7D). The improved glucose tolerance in cell transplant recipients from the metformin- and sitagliptin-treated groups was associated with significantly reduced fasting mouse C-peptide levels compared with their respective sham controls at 16 weeks post-transplantation (Figure 7G), an effect that was not yet evident at 4 weeks (Figure 7F). Interestingly, the improvements in glucose tolerance were not associated with differences in glucose-stimulated C-peptide secretion by hESC-derived grafts. All transplant recipients showed robust glucose-responsive human C-peptide secretion at 16 weeks, and there were no differences in human C-peptide levels between HFD-fed mice treated with different antidiabetic drugs (Figure 7H).


Treating diet-induced diabetes and obesity with human embryonic stem cell-derived pancreatic progenitor cells and antidiabetic drugs.

Bruin JE, Saber N, Braun N, Fox JK, Mojibian M, Asadi A, Drohan C, O'Dwyer S, Rosman-Balzer DS, Swiss VA, Rezania A, Kieffer TJ - Stem Cell Reports (2015)

The Combination of Either Sitagliptin or Metformin with a Cell Transplant Resulted in Improved Glucose Tolerance within 12 Weeks(A–E) OGTTs were performed at 12 weeks post-transplantation in mice fed a 10% fat diet without drug (black/gray; all panels; Sham: n = 5 mice), 60% fat diet without drug (A and B, blue; Tx/Sham: n = 7 mice), 60% fat diet plus metformin (A and C, purple; Tx/Sham: n = 5 mice), 60% fat diet plus sitagliptin (A and D, orange; Tx: n = 7 mice, Sham: n = 8 mice), or 60% fat diet plus rosiglitazone (A and E, green; Tx: n = 7 mice, Sham: n = 6 mice). Blood glucose levels for sham mice from all treatment groups are shown together in (A). Sham mice (solid lines, closed symbols) and transplant recipients (Tx; dashed lines, open symbols) from each treatment group are shown together with LFD controls as a reference (B–E). The area under the curve (AUC) is shown in box-and-whisker plots to the right of each line graph, with separate data points representing individual mice. Data on line graphs are represented as mean ± SEM. (A) ∗p < 0.05 (one-way ANOVA versus LFD).(B–E) For glucose curves, two-way ANOVA was used to examine differences at each time point during the OGTT (∗p < 0.05, HFD Sham versus LFD; #p < 0.05, HFD Tx versus LFD). For the AUC, one-way ANOVA was used compare all groups (LFD versus HFD Sham, LFD versus HFD Tx, HFD Sham versus HFD Tx; ∗p < 0.05; ns, not significant).(F and G) Fasting mouse C-peptide levels at 4 weeks (F) or 16 weeks (G) post-transplantation. ∗p < 0.05, two-tailed t test (Tx versus Sham).(H) Human C-peptide levels were measured after an overnight fast and 60 min following an intraperitoneal glucose challenge. ∗p < 0.05, paired two-tailed t test (0 versus 60 min).
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fig7: The Combination of Either Sitagliptin or Metformin with a Cell Transplant Resulted in Improved Glucose Tolerance within 12 Weeks(A–E) OGTTs were performed at 12 weeks post-transplantation in mice fed a 10% fat diet without drug (black/gray; all panels; Sham: n = 5 mice), 60% fat diet without drug (A and B, blue; Tx/Sham: n = 7 mice), 60% fat diet plus metformin (A and C, purple; Tx/Sham: n = 5 mice), 60% fat diet plus sitagliptin (A and D, orange; Tx: n = 7 mice, Sham: n = 8 mice), or 60% fat diet plus rosiglitazone (A and E, green; Tx: n = 7 mice, Sham: n = 6 mice). Blood glucose levels for sham mice from all treatment groups are shown together in (A). Sham mice (solid lines, closed symbols) and transplant recipients (Tx; dashed lines, open symbols) from each treatment group are shown together with LFD controls as a reference (B–E). The area under the curve (AUC) is shown in box-and-whisker plots to the right of each line graph, with separate data points representing individual mice. Data on line graphs are represented as mean ± SEM. (A) ∗p < 0.05 (one-way ANOVA versus LFD).(B–E) For glucose curves, two-way ANOVA was used to examine differences at each time point during the OGTT (∗p < 0.05, HFD Sham versus LFD; #p < 0.05, HFD Tx versus LFD). For the AUC, one-way ANOVA was used compare all groups (LFD versus HFD Sham, LFD versus HFD Tx, HFD Sham versus HFD Tx; ∗p < 0.05; ns, not significant).(F and G) Fasting mouse C-peptide levels at 4 weeks (F) or 16 weeks (G) post-transplantation. ∗p < 0.05, two-tailed t test (Tx versus Sham).(H) Human C-peptide levels were measured after an overnight fast and 60 min following an intraperitoneal glucose challenge. ∗p < 0.05, paired two-tailed t test (0 versus 60 min).
Mentions: Fasting blood glucose levels were not affected by any of the combination therapies throughout the study duration (Figure S7). At 12 weeks post-transplantation, mice in all HFD sham groups were glucose intolerant compared with LFD controls, regardless of the drug treatment used (Figure 7A). As expected based on our previous cohort, we found no effect of the cell therapy on glucose tolerance at 12 weeks post-transplantation in the HFD-fed mice without drug treatment (Figure 7B), and likewise, the combination with rosiglitazone was also ineffective at this time (Figure 7E). Interestingly, the cell therapy significantly improved glucose tolerance at 12 weeks post-transplantation when combined with either metformin (Figure 7C) or sitagliptin (Figure 7D) treatment. In fact, glycemic control during an oral glucose challenge was indistinguishable between the LFD controls and HFD-fed mice receiving sitagliptin with the cell therapy, with the exception of a marginally higher peak glucose level at 15 min post-gavage (Figure 7D). The improved glucose tolerance in cell transplant recipients from the metformin- and sitagliptin-treated groups was associated with significantly reduced fasting mouse C-peptide levels compared with their respective sham controls at 16 weeks post-transplantation (Figure 7G), an effect that was not yet evident at 4 weeks (Figure 7F). Interestingly, the improvements in glucose tolerance were not associated with differences in glucose-stimulated C-peptide secretion by hESC-derived grafts. All transplant recipients showed robust glucose-responsive human C-peptide secretion at 16 weeks, and there were no differences in human C-peptide levels between HFD-fed mice treated with different antidiabetic drugs (Figure 7H).

Bottom Line: Human embryonic stem cell (hESC)-derived pancreatic progenitor cells effectively reverse hyperglycemia in rodent models of type 1 diabetes, but their capacity to treat type 2 diabetes has not been reported.All combination therapies rapidly improved body weight and co-treatment with either sitagliptin or metformin improved hyperglycemia after only 12 weeks.Therefore, a stem cell-based therapy may be effective for treating type 2 diabetes, particularly in combination with antidiabetic drugs.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular & Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.

Show MeSH
Related in: MedlinePlus