title: Treatment of diabetes and long-term survival after insulin and glucokinase gene therapy.
abstract: Diabetes is associated with severe secondary complications, largely caused by poor glycemic control. Treatment with exogenous insulin fails to prevent these complications completely, leading to significant morbidity and mortality. We previously demonstrated that it is possible to generate a "glucose sensor" in skeletal muscle through coexpression of glucokinase and insulin, increasing glucose uptake and correcting hyperglycemia in diabetic mice. Here, we demonstrate long-term efficacy of this approach in a large animal model of diabetes. A one-time intramuscular administration of adeno-associated viral vectors of serotype 1 encoding for glucokinase and insulin in diabetic dogs resulted in normalization of fasting glycemia, accelerated disposal of glucose after oral challenge, and no episodes of hypoglycemia during exercise for >4 years after gene transfer. This was associated with recovery of body weight, reduced glycosylated plasma proteins levels, and long-term survival without secondary complications. Conversely, exogenous insulin or gene transfer for insulin or glucokinase alone failed to achieve complete correction of diabetes, indicating that the synergistic action of insulin and glucokinase is needed for full therapeutic effect. This study provides the first proof-of-concept in a large animal model for a gene transfer approach to treat diabetes.
authors: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma Barcelona, Bellaterra, Spain.
authors: David
authors: D
authors: Callejas
authors: Christopher J
authors: CJ
authors: Mann
authors: Eduard
authors: E
authors: Ayuso
authors: Ricardo
authors: R
authors: Lage
authors: Iris
authors: I
authors: Grifoll
authors: Carles
authors: C
authors: Roca
authors: Anna
authors: A
authors: Andaluz
authors: Rafael
authors: R
authors: Ruiz-de Gopegui
authors: Joel
authors: J
authors: Montané
authors: Sergio
authors: S
authors: Muñoz
authors: Tura
authors: T
authors: Ferre
authors: Virginia
authors: V
authors: Haurigot
authors: Shangzhen
authors: S
authors: Zhou
authors: Jesús
authors: J
authors: Ruberte
authors: Federico
authors: F
authors: Mingozzi
authors: Katherine A
authors: KA
authors: High
authors: Felix
authors: F
authors: Garcia
authors: Fatima
authors: F
authors: Bosch
mesh_terms: D000818:Animals; D003131:Combined Modality Therapy; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D004285:Dogs; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005941:Glucokinase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000517:prevention & control; D007003:Hypoglycemia / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007273:Injections, Intramuscular; D007328:Insulin / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D051381:Rats; D013047:Specific Pathogen-Free Organisms; D019076:Transgenes
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D005941:Glucokinase
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