title: Counteraction of type 1 diabetic alterations by engineering skeletal muscle to produce insulin: insights from transgenic mice.
abstract: Insulin replacement therapy in type 1 diabetes is imperfect because proper glycemic control is not always achieved. Most patients develop microvascular, macrovascular, and neurological complications, which increase with the degree of hyperglycemia. Engineered muscle cells continuously secreting basal levels of insulin might be used to improve the efficacy of insulin treatment. Here we examined the control of glucose homeostasis in healthy and diabetic transgenic mice constitutively expressing mature human insulin in skeletal muscle. Fed transgenic mice were normoglycemic and normoinsulinemic and, after an intraperitoneal glucose tolerance test, showed increased glucose disposal. When treated with streptozotocin (STZ), transgenic mice showed increased insulinemia and reduced hyperglycemia when fed and normoglycemia and normoinsulinemia when fasted. Injection of low doses of soluble insulin restored normoglycemia in fed STZ-treated transgenic mice, while STZ-treated controls remained highly hyperglycemic, indicating that diabetic transgenic mice were more sensitive to the hypoglycemic effects of insulin. Furthermore, STZ-treated transgenic mice presented normalization of both skeletal muscle and liver glucose metabolism. These results indicate that skeletal muscle may be a key target tissue for insulin production and suggest that muscle cells secreting basal levels of insulin, in conjunction with insulin therapy, may permit tight regulation of glycemia.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, and Center of Animal Biotechnology and Gene Therapy, Universitat Autonoma de Barcelona, Bellaterra, Spain.
authors.forename: Efren
authors.initials: E
authors.lastname: Riu
authors.forename: Alex
authors.initials: A
authors.lastname: Mas
authors.forename: Tura
authors.initials: T
authors.lastname: Ferre
authors.forename: Anna
authors.initials: A
authors.lastname: Pujol
authors.forename: Laurent
authors.initials: L
authors.lastname: Gros
authors.forename: Pedro
authors.initials: P
authors.lastname: Otaegui
authors.forename: Lluis
authors.initials: L
authors.lastname: Montoliu
authors.forename: Fatima
authors.initials: F
authors.lastname: Bosch
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000235:genetics / Q000628:therapy; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy*; D015870:Gene Expression; D005818:Genetic Engineering; D015316:Genetic Therapy; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D006943:Hyperglycemia / Q000628:therapy; D007328:Insulin / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics* / Q000627:therapeutic use; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000096:biosynthesis
chemical_list: D001786:Blood Glucose; D007328:Insulin; D011994:Recombinant Proteins; D005947:Glucose