Glucose-regulated glucose uptake by transplanted muscle cells expressing glucokinase counteracts diabetic hyperglycemia.
Type 1 diabetic patients depend on insulin replacement therapy. However, chronic hyperglycemia due to failure to maintain proper glycemic control leads to microvascular, macrovascular, and neurological complications. Increased glucose disposal by tissues engineered to overexpress key regulatory genes in glucose transport or phosphorylation can reduce diabetic hyperglycemia. Here we report that differentiated myoblast cells expressing the glucose-phosphorylating enzyme glucokinase (GK) showed a glucose-dependent increase in glucose uptake and utilization in vitro. Transplantation of GK-expressing myotubes into healthy mice did not alter blood glucose levels and recipient mice maintained normoglycemia. After streptozotocin treatment, mice transplanted with GK-expressing myotubes counteracted hyperglycemia, polydipsia, and polyphagia, whereas mice transplanted with control myotubes developed diabetes. Similarly, diabetic mice transplanted with control myotubes remained hyperglycemic. In contrast, transplantation of GK-expressing myotubes into diabetic mice lowered hyperglycemia. These results suggest that the use of genetically engineered muscle cells to express glucokinase may provide a glucose-regulated approach to reduce diabetic hyperglycemia.
Otaegui
Pedro J
PJ
Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, and Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain.
Ontiveros
Maria
M
Ferre
Tura
T
Riu
Efren
E
Jiménez
Rocio
R
Bosch
Fatima
F
D000818:Animals; D001786:Blood Glucose / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D004742:Enhancer Elements, Genetic; D015316:Genetic Therapy; D005941:Glucokinase / Q000096:biosynthesis / Q000235:genetics*; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D032446:Myoblasts / Q000378:metabolism* / Q000637:transplantation; D011401:Promoter Regions, Genetic; D051381:Rats; D023822:Tissue Engineering
D001786:Blood Glucose; D005941:Glucokinase