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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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Cell Transplant Recipients on HFDs Show Improved Glucose Homeostasis Compared with Sham-Treated Mice(A and B) HbA1C levels were measured at 12 (A) and 24 (B) weeks post-transplantation in sham mice (solid bars) and transplant recipients (Tx, striped bars).(C) At 20 weeks post-transplantation, blood glucose levels were measured after an overnight fast and 40 min following an oral meal challenge (“Fed”).(D and E) ipGTTs were performed at 18 (D) and 24 (E) weeks post-transplantation in sham mice (solid lines with closed symbols; solid bars) and transplant recipients (Tx, dashed lines with open symbols; striped bars) on 10% fat (gray; 18 weeks: Tx/Sham, n = 4 mice; 24 weeks: Tx, n = 5 and Sham, n = 4 mice), 45% or 60% fat (purple; 18 weeks: Tx, n = 12 and Sham, n = 7 mice; 24 weeks: Tx, n = 13 and Sham, n = 6 mice), or Western (green; 18 weeks: Tx, n = 5 and Sham, n = 4 mice; 24 weeks: Tx, n = 6 and Sham, n = 3 mice) diets. The area under the curve is shown to the right for each ipGTT.(F) An ITT was performed at 22 weeks post-transplantation in sham and transplant recipients from each diet group (10% Tx, n = 5 mice; 10% Sham, n = 4 mice; 45%–60% Tx, n = 12 mice; 45%–60% Sham, n = 6 mice; West Tx, n = 6 mice; West Sham, n = 4 mice). The area above the curve (right panel) was calculated using the fasting glucose level (100%) for each animal as the baseline. For clarity, all glucose curves (GTTs and ITTs) from sham and transplanted mice are shown separately for each diet group. See Figure S4 for glucose curves combined on the same plots. Data are represented as mean ± SEM (line graphs) or as box-and-whisker plots showing individual mice as separate data points. For all box-and-whisker plots: ∗p < 0.05, one-way ANOVA versus 10% sham; #p < 0.05, two-tailed t test (Tx versus sham). For all line graphs: ∗p < 0.05, two-way ANOVA, Tx versus sham. See Figure S3 for long-term body weight and blood glucose tracking, and Figure S5 for the effect of cell transplants on endogenous pancreas, liver, fat, and circulating leptin levels.See also Table S2.
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fig5: Cell Transplant Recipients on HFDs Show Improved Glucose Homeostasis Compared with Sham-Treated Mice(A and B) HbA1C levels were measured at 12 (A) and 24 (B) weeks post-transplantation in sham mice (solid bars) and transplant recipients (Tx, striped bars).(C) At 20 weeks post-transplantation, blood glucose levels were measured after an overnight fast and 40 min following an oral meal challenge (“Fed”).(D and E) ipGTTs were performed at 18 (D) and 24 (E) weeks post-transplantation in sham mice (solid lines with closed symbols; solid bars) and transplant recipients (Tx, dashed lines with open symbols; striped bars) on 10% fat (gray; 18 weeks: Tx/Sham, n = 4 mice; 24 weeks: Tx, n = 5 and Sham, n = 4 mice), 45% or 60% fat (purple; 18 weeks: Tx, n = 12 and Sham, n = 7 mice; 24 weeks: Tx, n = 13 and Sham, n = 6 mice), or Western (green; 18 weeks: Tx, n = 5 and Sham, n = 4 mice; 24 weeks: Tx, n = 6 and Sham, n = 3 mice) diets. The area under the curve is shown to the right for each ipGTT.(F) An ITT was performed at 22 weeks post-transplantation in sham and transplant recipients from each diet group (10% Tx, n = 5 mice; 10% Sham, n = 4 mice; 45%–60% Tx, n = 12 mice; 45%–60% Sham, n = 6 mice; West Tx, n = 6 mice; West Sham, n = 4 mice). The area above the curve (right panel) was calculated using the fasting glucose level (100%) for each animal as the baseline. For clarity, all glucose curves (GTTs and ITTs) from sham and transplanted mice are shown separately for each diet group. See Figure S4 for glucose curves combined on the same plots. Data are represented as mean ± SEM (line graphs) or as box-and-whisker plots showing individual mice as separate data points. For all box-and-whisker plots: ∗p < 0.05, one-way ANOVA versus 10% sham; #p < 0.05, two-tailed t test (Tx versus sham). For all line graphs: ∗p < 0.05, two-way ANOVA, Tx versus sham. See Figure S3 for long-term body weight and blood glucose tracking, and Figure S5 for the effect of cell transplants on endogenous pancreas, liver, fat, and circulating leptin levels.See also Table S2.

Mentions: Long-term tracking revealed that mice in all HFD groups continued to be overweight (Figure S3A) and hyperglycemic under fasting conditions (Figure S3E) compared with LFD controls throughout the duration of the study. Transplantation of hESC-derived cells did not affect either BW (Figures S3B–S3D) or fasting blood glucose levels (Figures S3F–S3H) compared with sham surgery. However, we did observe significant improvements in long-term glycemic control, as measured by HbA1C, following transplantation (Figures 5A and 5B). HbA1C levels were elevated at 12 and 24 weeks in all HFD sham mice compared with LFD sham controls, and were significantly reduced by transplantation in the 45%–60% fat group at both ages (Figures 5A and 5B). Transplant recipients on 45%–60% fat diets also displayed a significantly lower glucose excursion following a mixed-meal stimulus compared with sham mice at 20 weeks (Figure 5C), and all HFD transplant recipients had significantly improved glucose tolerance at 24 weeks post-transplantation (Figures 5E and S4B). These improvements were not yet evident at 18 weeks (Figures 5D and S4A). Glucose tolerance in the 45%–60% fat group was not completely ameliorated at 24 weeks, but the area under the curve for transplant recipients in the Western group was indistinguishable from that obtained for controls (Figures 5E and S4B). Interestingly, we also observed a modest but statistically significant improvement in insulin sensitivity at 22 weeks in transplanted HFD-fed mice compared with shams (Figures 5F, S4C, and S4D), which may have contributed to the improved glucose tolerance in HFD transplant recipients (Figure 5E).


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)

Cell Transplant Recipients on HFDs Show Improved Glucose Homeostasis Compared with Sham-Treated Mice(A and B) HbA1C levels were measured at 12 (A) and 24 (B) weeks post-transplantation in sham mice (solid bars) and transplant recipients (Tx, striped bars).(C) At 20 weeks post-transplantation, blood glucose levels were measured after an overnight fast and 40 min following an oral meal challenge (“Fed”).(D and E) ipGTTs were performed at 18 (D) and 24 (E) weeks post-transplantation in sham mice (solid lines with closed symbols; solid bars) and transplant recipients (Tx, dashed lines with open symbols; striped bars) on 10% fat (gray; 18 weeks: Tx/Sham, n = 4 mice; 24 weeks: Tx, n = 5 and Sham, n = 4 mice), 45% or 60% fat (purple; 18 weeks: Tx, n = 12 and Sham, n = 7 mice; 24 weeks: Tx, n = 13 and Sham, n = 6 mice), or Western (green; 18 weeks: Tx, n = 5 and Sham, n = 4 mice; 24 weeks: Tx, n = 6 and Sham, n = 3 mice) diets. The area under the curve is shown to the right for each ipGTT.(F) An ITT was performed at 22 weeks post-transplantation in sham and transplant recipients from each diet group (10% Tx, n = 5 mice; 10% Sham, n = 4 mice; 45%–60% Tx, n = 12 mice; 45%–60% Sham, n = 6 mice; West Tx, n = 6 mice; West Sham, n = 4 mice). The area above the curve (right panel) was calculated using the fasting glucose level (100%) for each animal as the baseline. For clarity, all glucose curves (GTTs and ITTs) from sham and transplanted mice are shown separately for each diet group. See Figure S4 for glucose curves combined on the same plots. Data are represented as mean ± SEM (line graphs) or as box-and-whisker plots showing individual mice as separate data points. For all box-and-whisker plots: ∗p < 0.05, one-way ANOVA versus 10% sham; #p < 0.05, two-tailed t test (Tx versus sham). For all line graphs: ∗p < 0.05, two-way ANOVA, Tx versus sham. See Figure S3 for long-term body weight and blood glucose tracking, and Figure S5 for the effect of cell transplants on endogenous pancreas, liver, fat, and circulating leptin levels.See also Table S2.
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fig5: Cell Transplant Recipients on HFDs Show Improved Glucose Homeostasis Compared with Sham-Treated Mice(A and B) HbA1C levels were measured at 12 (A) and 24 (B) weeks post-transplantation in sham mice (solid bars) and transplant recipients (Tx, striped bars).(C) At 20 weeks post-transplantation, blood glucose levels were measured after an overnight fast and 40 min following an oral meal challenge (“Fed”).(D and E) ipGTTs were performed at 18 (D) and 24 (E) weeks post-transplantation in sham mice (solid lines with closed symbols; solid bars) and transplant recipients (Tx, dashed lines with open symbols; striped bars) on 10% fat (gray; 18 weeks: Tx/Sham, n = 4 mice; 24 weeks: Tx, n = 5 and Sham, n = 4 mice), 45% or 60% fat (purple; 18 weeks: Tx, n = 12 and Sham, n = 7 mice; 24 weeks: Tx, n = 13 and Sham, n = 6 mice), or Western (green; 18 weeks: Tx, n = 5 and Sham, n = 4 mice; 24 weeks: Tx, n = 6 and Sham, n = 3 mice) diets. The area under the curve is shown to the right for each ipGTT.(F) An ITT was performed at 22 weeks post-transplantation in sham and transplant recipients from each diet group (10% Tx, n = 5 mice; 10% Sham, n = 4 mice; 45%–60% Tx, n = 12 mice; 45%–60% Sham, n = 6 mice; West Tx, n = 6 mice; West Sham, n = 4 mice). The area above the curve (right panel) was calculated using the fasting glucose level (100%) for each animal as the baseline. For clarity, all glucose curves (GTTs and ITTs) from sham and transplanted mice are shown separately for each diet group. See Figure S4 for glucose curves combined on the same plots. Data are represented as mean ± SEM (line graphs) or as box-and-whisker plots showing individual mice as separate data points. For all box-and-whisker plots: ∗p < 0.05, one-way ANOVA versus 10% sham; #p < 0.05, two-tailed t test (Tx versus sham). For all line graphs: ∗p < 0.05, two-way ANOVA, Tx versus sham. See Figure S3 for long-term body weight and blood glucose tracking, and Figure S5 for the effect of cell transplants on endogenous pancreas, liver, fat, and circulating leptin levels.See also Table S2.
Mentions: Long-term tracking revealed that mice in all HFD groups continued to be overweight (Figure S3A) and hyperglycemic under fasting conditions (Figure S3E) compared with LFD controls throughout the duration of the study. Transplantation of hESC-derived cells did not affect either BW (Figures S3B–S3D) or fasting blood glucose levels (Figures S3F–S3H) compared with sham surgery. However, we did observe significant improvements in long-term glycemic control, as measured by HbA1C, following transplantation (Figures 5A and 5B). HbA1C levels were elevated at 12 and 24 weeks in all HFD sham mice compared with LFD sham controls, and were significantly reduced by transplantation in the 45%–60% fat group at both ages (Figures 5A and 5B). Transplant recipients on 45%–60% fat diets also displayed a significantly lower glucose excursion following a mixed-meal stimulus compared with sham mice at 20 weeks (Figure 5C), and all HFD transplant recipients had significantly improved glucose tolerance at 24 weeks post-transplantation (Figures 5E and S4B). These improvements were not yet evident at 18 weeks (Figures 5D and S4A). Glucose tolerance in the 45%–60% fat group was not completely ameliorated at 24 weeks, but the area under the curve for transplant recipients in the Western group was indistinguishable from that obtained for controls (Figures 5E and S4B). Interestingly, we also observed a modest but statistically significant improvement in insulin sensitivity at 22 weeks in transplanted HFD-fed mice compared with shams (Figures 5F, S4C, and S4D), which may have contributed to the improved glucose tolerance in HFD transplant recipients (Figure 5E).

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