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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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Exposure to HFDs Does Not Affect the Function of hESC-Derived Pancreatic Endocrine Cells In VivoThe development of hESC-derived progenitor cells into pancreatic endocrine cells was assessed in mice fed a 10% fat (black), 45% or 60% fat (purple), or Western (green) diet. See Figure S2 for characterization of the progenitor cells pre-transplantation.(A) Human C-peptide levels were measured after an overnight fast and 40 min following an oral mixed-meal challenge (“fed”) at 8, 12, 16, and 20 weeks post-transplantation. ∗p < 0.05, paired t test (fast versus fed).(B and C) At 18 weeks post-transplantation, human C-peptide levels were measured during an i.p. glucose tolerance test (ipGTT). In (B) data are normalized to baseline levels, and in (C) raw levels (ng/ml) are presented for individual animals, with each diet group shown on a separate plot. ∗p < 0.05, one-way repeated-measures ANOVA (versus time 0).(D–F) At 24 weeks post-transplantation, an i.p. arginine tolerance test (ipArgTT) was performed. Plasma was collected after a 4-hr fast and 15 min following arginine administration to measure human insulin (D) and glucagon (E and F) levels. (E) shows glucagon levels at 0 and 15 minutes in transplant recipients, and (F) shows glucagon levels in sham-treated mice (Sham, striped bars) and transplant recipients (Tx, solid bars) at 15 minutes only. The red line indicates the lower limit of detection for the glucagon assay. (D and E) ∗p < 0.05, one-tailed paired t test (0 versus 15 min); (F) ∗p < 0.05, two-tailed t test (sham versus Tx). Data points from individual mice are shown as box-and-whisker plots.See also Table S2.
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fig2: Exposure to HFDs Does Not Affect the Function of hESC-Derived Pancreatic Endocrine Cells In VivoThe development of hESC-derived progenitor cells into pancreatic endocrine cells was assessed in mice fed a 10% fat (black), 45% or 60% fat (purple), or Western (green) diet. See Figure S2 for characterization of the progenitor cells pre-transplantation.(A) Human C-peptide levels were measured after an overnight fast and 40 min following an oral mixed-meal challenge (“fed”) at 8, 12, 16, and 20 weeks post-transplantation. ∗p < 0.05, paired t test (fast versus fed).(B and C) At 18 weeks post-transplantation, human C-peptide levels were measured during an i.p. glucose tolerance test (ipGTT). In (B) data are normalized to baseline levels, and in (C) raw levels (ng/ml) are presented for individual animals, with each diet group shown on a separate plot. ∗p < 0.05, one-way repeated-measures ANOVA (versus time 0).(D–F) At 24 weeks post-transplantation, an i.p. arginine tolerance test (ipArgTT) was performed. Plasma was collected after a 4-hr fast and 15 min following arginine administration to measure human insulin (D) and glucagon (E and F) levels. (E) shows glucagon levels at 0 and 15 minutes in transplant recipients, and (F) shows glucagon levels in sham-treated mice (Sham, striped bars) and transplant recipients (Tx, solid bars) at 15 minutes only. The red line indicates the lower limit of detection for the glucagon assay. (D and E) ∗p < 0.05, one-tailed paired t test (0 versus 15 min); (F) ∗p < 0.05, two-tailed t test (sham versus Tx). Data points from individual mice are shown as box-and-whisker plots.See also Table S2.

Mentions: Progenitor cells were encapsulated in Theracyte devices and transplanted subcutaneously into immunodeficient mice from each of the four diet regimens. We used immunodeficient mice because although macroencapsulation devices are predicted to protect human cells from allogeneic immune rejection (Tibell et al., 2001), they are unlikely to protect them from xenograft rejection (Brauker et al., 1996; Mckenzie et al., 2001). The immunoisolation devices allowed us to mimic studies in patients receiving macroencapsulated pancreatic progenitor cells (ClinicalTrials.gov, Identifier: NCT02239354). Following transplantation, hESC-derived cells from all diet groups secreted similar levels of human C-peptide under basal and fed conditions between 8 and 20 weeks (Figure 2A), and produced robust glucose-stimulated human C-peptide secretion at 18 weeks (Figures 2B and 2C). Similarly, human insulin secretion was induced by an arginine challenge in all diet groups at 24 weeks, although due to high variability, the Western-diet group did not reach statistical significance (Figure 2D). We observed a trend toward increased basal glucagon secretion in the HFD groups, but as four out of five mice in the LFD group had undetectable fasting glucagon levels, it was not possible to perform a statistical analysis (Figure 2E). Arginine-stimulated glucagon levels were similar between diet groups (Figures 2E and 2F), and we estimate that approximately half of the circulating glucagon may have originated from hESC-derived cells, as indicated by the difference between glucagon levels in sham-treated mice and transplant recipients (Tx; Figure 2F).


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)

Exposure to HFDs Does Not Affect the Function of hESC-Derived Pancreatic Endocrine Cells In VivoThe development of hESC-derived progenitor cells into pancreatic endocrine cells was assessed in mice fed a 10% fat (black), 45% or 60% fat (purple), or Western (green) diet. See Figure S2 for characterization of the progenitor cells pre-transplantation.(A) Human C-peptide levels were measured after an overnight fast and 40 min following an oral mixed-meal challenge (“fed”) at 8, 12, 16, and 20 weeks post-transplantation. ∗p < 0.05, paired t test (fast versus fed).(B and C) At 18 weeks post-transplantation, human C-peptide levels were measured during an i.p. glucose tolerance test (ipGTT). In (B) data are normalized to baseline levels, and in (C) raw levels (ng/ml) are presented for individual animals, with each diet group shown on a separate plot. ∗p < 0.05, one-way repeated-measures ANOVA (versus time 0).(D–F) At 24 weeks post-transplantation, an i.p. arginine tolerance test (ipArgTT) was performed. Plasma was collected after a 4-hr fast and 15 min following arginine administration to measure human insulin (D) and glucagon (E and F) levels. (E) shows glucagon levels at 0 and 15 minutes in transplant recipients, and (F) shows glucagon levels in sham-treated mice (Sham, striped bars) and transplant recipients (Tx, solid bars) at 15 minutes only. The red line indicates the lower limit of detection for the glucagon assay. (D and E) ∗p < 0.05, one-tailed paired t test (0 versus 15 min); (F) ∗p < 0.05, two-tailed t test (sham versus Tx). Data points from individual mice are shown as box-and-whisker plots.See also Table S2.
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fig2: Exposure to HFDs Does Not Affect the Function of hESC-Derived Pancreatic Endocrine Cells In VivoThe development of hESC-derived progenitor cells into pancreatic endocrine cells was assessed in mice fed a 10% fat (black), 45% or 60% fat (purple), or Western (green) diet. See Figure S2 for characterization of the progenitor cells pre-transplantation.(A) Human C-peptide levels were measured after an overnight fast and 40 min following an oral mixed-meal challenge (“fed”) at 8, 12, 16, and 20 weeks post-transplantation. ∗p < 0.05, paired t test (fast versus fed).(B and C) At 18 weeks post-transplantation, human C-peptide levels were measured during an i.p. glucose tolerance test (ipGTT). In (B) data are normalized to baseline levels, and in (C) raw levels (ng/ml) are presented for individual animals, with each diet group shown on a separate plot. ∗p < 0.05, one-way repeated-measures ANOVA (versus time 0).(D–F) At 24 weeks post-transplantation, an i.p. arginine tolerance test (ipArgTT) was performed. Plasma was collected after a 4-hr fast and 15 min following arginine administration to measure human insulin (D) and glucagon (E and F) levels. (E) shows glucagon levels at 0 and 15 minutes in transplant recipients, and (F) shows glucagon levels in sham-treated mice (Sham, striped bars) and transplant recipients (Tx, solid bars) at 15 minutes only. The red line indicates the lower limit of detection for the glucagon assay. (D and E) ∗p < 0.05, one-tailed paired t test (0 versus 15 min); (F) ∗p < 0.05, two-tailed t test (sham versus Tx). Data points from individual mice are shown as box-and-whisker plots.See also Table S2.
Mentions: Progenitor cells were encapsulated in Theracyte devices and transplanted subcutaneously into immunodeficient mice from each of the four diet regimens. We used immunodeficient mice because although macroencapsulation devices are predicted to protect human cells from allogeneic immune rejection (Tibell et al., 2001), they are unlikely to protect them from xenograft rejection (Brauker et al., 1996; Mckenzie et al., 2001). The immunoisolation devices allowed us to mimic studies in patients receiving macroencapsulated pancreatic progenitor cells (ClinicalTrials.gov, Identifier: NCT02239354). Following transplantation, hESC-derived cells from all diet groups secreted similar levels of human C-peptide under basal and fed conditions between 8 and 20 weeks (Figure 2A), and produced robust glucose-stimulated human C-peptide secretion at 18 weeks (Figures 2B and 2C). Similarly, human insulin secretion was induced by an arginine challenge in all diet groups at 24 weeks, although due to high variability, the Western-diet group did not reach statistical significance (Figure 2D). We observed a trend toward increased basal glucagon secretion in the HFD groups, but as four out of five mice in the LFD group had undetectable fasting glucagon levels, it was not possible to perform a statistical analysis (Figure 2E). Arginine-stimulated glucagon levels were similar between diet groups (Figures 2E and 2F), and we estimate that approximately half of the circulating glucagon may have originated from hESC-derived cells, as indicated by the difference between glucagon levels in sham-treated mice and transplant recipients (Tx; Figure 2F).

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