Glucose responsive insulin production from human embryonic germ (EG) cell derivatives.
Type 1 diabetes mellitus subjects millions to a daily burden of disease management, life threatening hypoglycemia and long-term complications such as retinopathy, nephropathy, heart disease, and stroke. Cell transplantation therapies providing a glucose-regulated supply of insulin have been implemented clinically, but are limited by safety, efficacy and supply considerations. Stem cells promise a plentiful and flexible source of cells for transplantation therapies. Here, we show that cells derived from human embryonic germ (EG) cells express markers of definitive endoderm, pancreatic and beta-cell development, glucose sensing, and production of mature insulin. These cells integrate functions necessary for glucose responsive regulation of preproinsulin mRNA and expression of insulin C-peptide in vitro. Following transplantation into mice, cells become insulin and C-peptide immunoreactive and produce plasma C-peptide in response to glucose. These findings suggest that EG cell derivatives may eventually serve as a source of insulin producing cells for the treatment of diabetes.
Clark
Gregory O
GO
Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Yochem
Robert L
RL
Axelman
Joyce
J
Sheets
Timothy P
TP
Kaczorowski
David J
DJ
Shamblott
Michael J
MJ
D000818:Animals; D002096:C-Peptide / Q000378:metabolism; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D005854:Germ Cells / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000096:biosynthesis*; D051379:Mice; D010179:Pancreas / Q000196:embryology; D039904:Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism*; D011384:Proinsulin / Q000096:biosynthesis; D011498:Protein Precursors / Q000096:biosynthesis; D033581:Stem Cell Transplantation; D014157:Transcription Factors / Q000096:biosynthesis; D014183:Transplantation, Heterologous
D002096:C-Peptide; D007328:Insulin; D011498:Protein Precursors; D014157:Transcription Factors; C013737:preproinsulin; D011384:Proinsulin; D005947:Glucose