Engineered enteroendocrine cells secrete insulin in response to glucose and reverse hyperglycemia in diabetic mice.
Type 1 diabetes is a metabolic disorder caused by loss of insulin-producing pancreatic beta-cells. Expression of insulin in non-beta-cells to create beta-cell surrogates has been tried to treat type 1 diabetes. Enteroendocrine K cells have characteristics similar to pancreatic beta-cells, such as a glucose-sensing system and insulin-processing proteases. In this study, we genetically engineered an enteroendocrine cell line (STC-1) to express insulin under the control of the glucose-dependent insulinotropic polypeptide promoter. We screened clones and chose one, Gi-INS-7, based on its high production of insulin. Gi-INS-7 cells expressed glucose transporter 2 (GLUT2) and glucokinase (GK) and secreted insulin in response to elevated glucose levels in vitro. To determine whether Gi-INS-7 cells can control blood glucose levels in diabetic mice, we transplanted these cells under the kidney capsule of streptozotocin (STZ)-induced diabetic mice and found that blood glucose levels became normal within 2 weeks of transplantation. In addition, glucose tolerance tests in mice that became normoglycemic after transplantation with Gi-INS-7 cells showed that exogenous glucose was cleared appropriately. These results suggest that engineered K cells may be promising surrogate beta-cells for possible therapeutic use for the treatment of type 1 diabetes.
Han
Jaeseok
J
Julia McFarlane Diabetes Research Centre, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
Lee
Hyune-Hwan
HH
Kwon
Hyokjoon
H
Shin
Seungjin
S
Yoon
Ji-Won
JW
Jun
Hee-Sook
HS
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D017690:Cell Transplantation / Q000379:methods*; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000150:complications*; D019858:Enteroendocrine Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D004797:Enzyme-Linked Immunosorbent Assay; D005941:Glucokinase / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000209:etiology / Q000601:surgery*; D007150:Immunohistochemistry; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D051379:Mice; D016688:Mice, Inbred NOD; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013311:Streptozocin
D001786:Blood Glucose; D051273:Glucose Transporter Type 2; D007328:Insulin; D013311:Streptozocin; D005941:Glucokinase; D005947:Glucose