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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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Diet-Induced Obesity Was Reversed Following Progenitor Cell Transplantation Combined with an Antidiabetic Drug(A–F) Fasting body weight was assessed in mice fed a 10% fat diet without drug (black/gray; all panels; n = 8 mice), 60% fat diet without drug (A and B, blue; n = 7–8 mice per group), 60% fat diet plus metformin (A and C, purple; n = 7–8 mice per group), 60% fat diet plus sitagliptin (A and D, orange; n = 8 mice per group), or 60% fat diet plus rosiglitazone (A and E, green; n = 8 mice per group). Body weight tracking for sham mice from all treatment groups is shown in (A). Sham mice (solid lines, closed symbols) and transplant recipients (Tx; dashed lines, open symbols) from each treatment group are shown together with the LFD control as a reference (B–E). The change in body weight from day −2 to day 12 is shown in box-and-whisker plots to the right of each line graph, with each data point representing an individual mouse. Data on line graphs are represented as mean ± SEM. (F) Body weight pre-transplant (day −2) and post-transplantation (day 75).(G and H) Epididymal fat pad weight relative to body weight (G) and plasma mouse leptin levels (H) were assessed at 20 weeks post-transplantation.(A–E) ∗p < 0.05, one-way ANOVA for comparisons of all groups (LFD versus HFD Sham, LFD versus HFD Tx, HFD Sham versus HFD Tx); (F–H) #p < 0.05, one-way ANOVA for comparison of each group to LFD control; ∗p < 0.05, two-tailed t test, Tx versus Sham. See Figure S6 for the phenotype of mice on HFDs in cohort 2 (pre-transplant) and Figure S7 for long-term blood glucose tracking following administration of drugs with or without cell transplants.
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fig6: Diet-Induced Obesity Was Reversed Following Progenitor Cell Transplantation Combined with an Antidiabetic Drug(A–F) Fasting body weight was assessed in mice fed a 10% fat diet without drug (black/gray; all panels; n = 8 mice), 60% fat diet without drug (A and B, blue; n = 7–8 mice per group), 60% fat diet plus metformin (A and C, purple; n = 7–8 mice per group), 60% fat diet plus sitagliptin (A and D, orange; n = 8 mice per group), or 60% fat diet plus rosiglitazone (A and E, green; n = 8 mice per group). Body weight tracking for sham mice from all treatment groups is shown in (A). Sham mice (solid lines, closed symbols) and transplant recipients (Tx; dashed lines, open symbols) from each treatment group are shown together with the LFD control as a reference (B–E). The change in body weight from day −2 to day 12 is shown in box-and-whisker plots to the right of each line graph, with each data point representing an individual mouse. Data on line graphs are represented as mean ± SEM. (F) Body weight pre-transplant (day −2) and post-transplantation (day 75).(G and H) Epididymal fat pad weight relative to body weight (G) and plasma mouse leptin levels (H) were assessed at 20 weeks post-transplantation.(A–E) ∗p < 0.05, one-way ANOVA for comparisons of all groups (LFD versus HFD Sham, LFD versus HFD Tx, HFD Sham versus HFD Tx); (F–H) #p < 0.05, one-way ANOVA for comparison of each group to LFD control; ∗p < 0.05, two-tailed t test, Tx versus Sham. See Figure S6 for the phenotype of mice on HFDs in cohort 2 (pre-transplant) and Figure S7 for long-term blood glucose tracking following administration of drugs with or without cell transplants.

Mentions: At the time of transplantation (1 week after drug administration), all HFD-fed mice were significantly heavier than LFD controls (Figure 6F). Interestingly, weight loss was observed within the first 2 weeks following transplantation in HFD-fed mice on antidiabetic drugs (Figures 6C–6E). In contrast, no change in BW was observed during this time in either HFD transplant recipients without drug treatment (Figure 6B) or sham mice on any drug (Figures 6A–6E). All transplant recipients that received antidiabetic drugs had significantly lower BW on day 75 (Figure 6F) and reduced epididymal fat pad weight (relative to BW; Figure 6G) compared with sham mice, such that neither parameter was different from LFD-fed sham controls. As in our previous cohort (Figures S3 and S5E), there was no effect of transplantation on BW (Figures 6B and 6F) or circulating leptin levels (Figure 6H) in HFD-fed mice without drug treatment, although we did observe a reduction in relative epididymal fat pad weight in this cohort (Figure 6G). Interestingly, the combination of a cell transplant with either metformin or sitagliptin resulted in significantly reduced circulating leptin levels in the transplant recipients compared with their respective sham controls (Figure 6G). The cell therapy had no effect on restoring leptin levels in the rosiglitazone group (Figure 6G).


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)

Diet-Induced Obesity Was Reversed Following Progenitor Cell Transplantation Combined with an Antidiabetic Drug(A–F) Fasting body weight was assessed in mice fed a 10% fat diet without drug (black/gray; all panels; n = 8 mice), 60% fat diet without drug (A and B, blue; n = 7–8 mice per group), 60% fat diet plus metformin (A and C, purple; n = 7–8 mice per group), 60% fat diet plus sitagliptin (A and D, orange; n = 8 mice per group), or 60% fat diet plus rosiglitazone (A and E, green; n = 8 mice per group). Body weight tracking for sham mice from all treatment groups is shown in (A). Sham mice (solid lines, closed symbols) and transplant recipients (Tx; dashed lines, open symbols) from each treatment group are shown together with the LFD control as a reference (B–E). The change in body weight from day −2 to day 12 is shown in box-and-whisker plots to the right of each line graph, with each data point representing an individual mouse. Data on line graphs are represented as mean ± SEM. (F) Body weight pre-transplant (day −2) and post-transplantation (day 75).(G and H) Epididymal fat pad weight relative to body weight (G) and plasma mouse leptin levels (H) were assessed at 20 weeks post-transplantation.(A–E) ∗p < 0.05, one-way ANOVA for comparisons of all groups (LFD versus HFD Sham, LFD versus HFD Tx, HFD Sham versus HFD Tx); (F–H) #p < 0.05, one-way ANOVA for comparison of each group to LFD control; ∗p < 0.05, two-tailed t test, Tx versus Sham. See Figure S6 for the phenotype of mice on HFDs in cohort 2 (pre-transplant) and Figure S7 for long-term blood glucose tracking following administration of drugs with or without cell transplants.
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fig6: Diet-Induced Obesity Was Reversed Following Progenitor Cell Transplantation Combined with an Antidiabetic Drug(A–F) Fasting body weight was assessed in mice fed a 10% fat diet without drug (black/gray; all panels; n = 8 mice), 60% fat diet without drug (A and B, blue; n = 7–8 mice per group), 60% fat diet plus metformin (A and C, purple; n = 7–8 mice per group), 60% fat diet plus sitagliptin (A and D, orange; n = 8 mice per group), or 60% fat diet plus rosiglitazone (A and E, green; n = 8 mice per group). Body weight tracking for sham mice from all treatment groups is shown in (A). Sham mice (solid lines, closed symbols) and transplant recipients (Tx; dashed lines, open symbols) from each treatment group are shown together with the LFD control as a reference (B–E). The change in body weight from day −2 to day 12 is shown in box-and-whisker plots to the right of each line graph, with each data point representing an individual mouse. Data on line graphs are represented as mean ± SEM. (F) Body weight pre-transplant (day −2) and post-transplantation (day 75).(G and H) Epididymal fat pad weight relative to body weight (G) and plasma mouse leptin levels (H) were assessed at 20 weeks post-transplantation.(A–E) ∗p < 0.05, one-way ANOVA for comparisons of all groups (LFD versus HFD Sham, LFD versus HFD Tx, HFD Sham versus HFD Tx); (F–H) #p < 0.05, one-way ANOVA for comparison of each group to LFD control; ∗p < 0.05, two-tailed t test, Tx versus Sham. See Figure S6 for the phenotype of mice on HFDs in cohort 2 (pre-transplant) and Figure S7 for long-term blood glucose tracking following administration of drugs with or without cell transplants.
Mentions: At the time of transplantation (1 week after drug administration), all HFD-fed mice were significantly heavier than LFD controls (Figure 6F). Interestingly, weight loss was observed within the first 2 weeks following transplantation in HFD-fed mice on antidiabetic drugs (Figures 6C–6E). In contrast, no change in BW was observed during this time in either HFD transplant recipients without drug treatment (Figure 6B) or sham mice on any drug (Figures 6A–6E). All transplant recipients that received antidiabetic drugs had significantly lower BW on day 75 (Figure 6F) and reduced epididymal fat pad weight (relative to BW; Figure 6G) compared with sham mice, such that neither parameter was different from LFD-fed sham controls. As in our previous cohort (Figures S3 and S5E), there was no effect of transplantation on BW (Figures 6B and 6F) or circulating leptin levels (Figure 6H) in HFD-fed mice without drug treatment, although we did observe a reduction in relative epididymal fat pad weight in this cohort (Figure 6G). Interestingly, the combination of a cell transplant with either metformin or sitagliptin resulted in significantly reduced circulating leptin levels in the transplant recipients compared with their respective sham controls (Figure 6G). The cell therapy had no effect on restoring leptin levels in the rosiglitazone group (Figure 6G).

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