Treating diet-induced diabetes and obesity with human embryonic stem cell-derived pancreatic progenitor cells and antidiabetic drugs.
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.
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
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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).
Affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular & Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.