Phenotypic Correction of Diabetic Mice by Adenovirus-Mediated Glucokinase Expression

Desai, Urvi J.; Slosberg, Eric D.; Boettcher, Brian R.; Caplan, Shari L.; Fanelli, Barbara; Stephan, Zouhair F.; Gunther, Vicky; Kaleko, Michael; Connelly, Sheila

doi:10.2337/diabetes.50.10.2287

Cited by 59 publications

(48 citation statements)

References 34 publications

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“…In these mice, hepatic GK overexpression reduced hyperglycaemia and hyperinsulinaemia induced by a high-fat diet. Moreover, adenovirus-mediated expression of GK in the liver improves glucose tolerance and reduces hyperinsulinaemia in high-fat dietinduced diabetes in mice [10]. These results point to overexpression of GK as a possible gene therapybased approach to reduce hyperglycaemia in diabetes.…”

Section: Resultsmentioning

confidence: 84%

Long-term overexpression of glucokinase in the liver of transgenic mice leads to insulin resistance

et al. 2003

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Aims/hypothesis. Glucokinase overexpression in the liver increases glucose uptake and utilization, and improves glucose tolerance in young transgenic mice. Here, we examined the long-term effects of hepatic overexpression of glucokinase on glucose homeostasis. Moreover, we determined whether glucokinase overexpression counteracted high-fat diet-induced insulin resistance. Methods. Transgenic mice overexpressing glucokinase in liver under the control of the phosphoenolpyruvate carboxykinase promoter, fed either a standard diet or a high-fat diet, were studied. We used non-transgenic littermates as controls. Results. Transgenic mice over 6 months old developed impaired glucose tolerance. In addition, at 12 months of age, transgenic mice showed mild hyperglycaemia, hyperinsulinaemia and hypertriglyceridaemia. In spite of increased glucokinase activity, the liver of these mice accumulated less glycogen and increased triglyceride deposition. When 2-month-old glucose-tolerant mice were fed a high-fat diet, transgenic mice gained more body weight and became hyperglycaemic and hyperinsulinaemic. This was concomitant to glucose intolerance, liver steatosis and whole-body insulin resistance. Conclusion/interpretation. Long-term overexpression of glucokinase increases hepatic lipogenesis and circulating lipids, which lead to insulin resistance. Our results also suggest that the liver plays a key role in the onset of diabetes. [Diabetologia (2003) mice overexpressing GK in the liver, intracellular glucose 6-phosphate, glycogen and L-pyruvate kinase activity are increased, indicating that the activation of GK can induce glycolysis and glycogen synthesis in vivo [5]. These transgenic mice have reduced glycaemia, insulinaemia and blood glucose after an intraperitoneal glucose tolerance test, indicating that GK overexpression increased blood glucose disposal by the liver [5]. Similar results have also been obtained in transgenic mice expressing the human GK gene in the liver [6] and in mice overexpressing one or more extra copies of the entire mouse GK gene locus [7].Since the decrease in glucokinase gene expression in diabetic animals could contribute to hyperglycaemia, the effect of hepatic GK overexpression has been studied in animal models of Type 1 and Type 2 diabetes. Thus, streptozotocin-treated GK-expressing transgenic mice maintained normal levels of GK activity, Glucokinase (GK) is the main glucose-phosphorylating enzyme in the liver and pancreatic beta cells. Glucose transport and phosphorylation are the first steps in glucose utilization in the liver, where GK contributes to glucose disposal. Several studies in vitro have shown that GK activation is needed for glycolysis and glycogen synthesis [1,2,3,4]. Similarly, in transgenic

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Section: Resultsmentioning

confidence: 84%

Long-term overexpression of glucokinase in the liver of transgenic mice leads to insulin resistance

et al. 2003

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“…Hyperglycaemia is the main factor responsible for the development of diabetes-associated retinal, renal, neurological and vascular complications [25]. Overexpression of GK in the liver of transgenic mice has been shown to prevent the development of streptozotocin-induced diabetic alterations or high-fat dietinduced hyperglycaemia [15,16,17]. Moreover, mice carrying liver-specific GK gene disruption showed decreased hepatic glucose uptake and were moderately hyperglycaemic [26].…”

Section: Discussionmentioning

confidence: 99%

“…These transgenic mice showed lower fasting blood glucose concentrations, improved glucose tolerance and increased glycogen synthesis in the liver as compared to wild-type (wt) mice. More importantly, it was shown that GK overexpression in the liver prevents the development of hyperglycaemia or diabetes induced by streptozotocin or a high-fat diet [15,16,17].…”

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confidence: 99%

Improved metabolic disorders of insulin receptor-deficient mice by transgenic overexpression of glucokinase in the liver

et al. 2002

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Aims/hypothesis. Insulin receptor null mutant mice develop severe diabetes, ketoacidosis and liver steatosis and die within 1 week after birth. Since the liver plays an essential role in the control of glucose homeostasis, we examined in this work whether the metabolic disorders of insulin receptor-deficient mice could be improved upon restoration of hepatic glucose metabolism by transgenic constitutive overexpression of glucokinase selectively in the liver. Methods. We first generated transgenic mice overexpressing rat glucokinase cDNA under control of the liver-specific phenylalanine hydroxylase gene promoter. These transgenic mice were crossed with heterozygous insulin-receptor-null mutants to produce homozygous insulin-receptor-null mice overexpressing glucokinase in the liver. Results. The transgenic mice overexpressing glucokinase in the liver showed improved glucose tolerance and were mildly hypoglycaemic and hyperlipidaemic under starved conditions. The introduction of the glucokinase transgene in insulin receptor null mice did not prevent the development of glycosuria. However, ketoacidosis was delayed by more than 1 week and survival was prolonged to 10 to 16 days in 16% of the pups. In these longer surviving pups, serum glucose and triglyceride concentrations were lowered, hepatic glycogen stores were reconstituted and liver steatosis was absent as compared with the pups which had developed strong ketoacidosis and died earlier.Conclusions/interpretation. These results show that overexpression of hepatic glucokinase can compensate, in part, for the metabolic disorders developed by insulin receptor-deficient mice. This shows the importance of improving hepatic function in diabetes and must revive interest in enhancement of glucokinase activity as a therapeutic strategy for the treatment of diabetes. [Diabetologia (2002[Diabetologia ( ) 45:1292[Diabetologia ( -1297

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“…Mice that are homozygous for disruption of the GK gene die from diabetes within days of birth, whereas the heterozygotes are hyperglycemic (10,11). Liver-specific GK overexpression in nondiabetic mice improved glucose tolerance (12,13), and in high-fat dietinduced diabetic mice, adenoviral overexpression of GK improved glucose tolerance and decreased fasting blood glucose with concomitant decreased insulin secretion (14).…”

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Stimulation of Hepatocyte Glucose Metabolism by Novel Small Molecule Glucokinase Activators

et al. 2004

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Glucokinase (GK) has a major role in the control of blood glucose homeostasis and is a strong potential target for the pharmacological treatment of type 2 diabetes. We report here the mechanism of action of two novel and potent direct activators of GK: 6-[(3-isobutoxy-5-isopropoxybenzoyl)amino]nicotinic acid (GKA1) and 5-({3-isopropoxy-5-[2-(3-thienyl)ethoxy] benzoyl}amino)-1,3,4-thiadiazole-2-carboxylic acid (GKA2), which increase the affinity of GK for glucose by 4-and 11-fold, respectively. GKA1 increased the affinity of GK for the competitive inhibitor mannoheptulose but did not affect the affinity for the inhibitors palmitoylCoA and the endogenous 68-kDa regulator (GK regulatory protein [GKRP]), which bind to allosteric sites or to N-acetylglucosamine, which binds to the catalytic site. In hepatocytes, GKA1 and GKA2 stimulated glucose phosphorylation, glycolysis, and glycogen synthesis to a similar extent as sorbitol, a precursor of fructose 1-phosphate, which indirectly activates GK through promoting its dissociation from GKRP. Consistent with their effects on isolated GK, these compounds also increased the affinity of hepatocyte metabolism for glucose. GKA1 and GKA2 caused translocation of GK from the nucleus to the cytoplasm. This effect was additive with the effect of sorbitol and is best explained by a "glucose-like" effect of the GK activators in translocating GK to the cytoplasm. In conclusion, GK activators are potential antihyperglycemic agents for the treatment of type 2 diabetes through the stimulation of hepatic glucose metabolism by a mechanism independent of GKRP. Diabetes 53:535-541, 2004

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Phenotypic Correction of Diabetic Mice by Adenovirus-Mediated Glucokinase Expression

Cited by 59 publications

References 34 publications

Long-term overexpression of glucokinase in the liver of transgenic mice leads to insulin resistance

Long-term overexpression of glucokinase in the liver of transgenic mice leads to insulin resistance

Improved metabolic disorders of insulin receptor-deficient mice by transgenic overexpression of glucokinase in the liver

Stimulation of Hepatocyte Glucose Metabolism by Novel Small Molecule Glucokinase Activators

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