Transgenic knockouts reveal a critical requirement for pancreatic β cell glucokinase in maintaining glucose homeostasis

Grupe, Andrew; Hultgren, Bruce; Ryan, Anne; Hui, Yan; Bauer, Michele; Stewart, Timothy A.

doi:10.1016/0092-8674(95)90235-x

Cited by 262 publications

(187 citation statements)

References 39 publications

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“…However, glucokinase could be replaced by other insulin-independent hexokinases, in vivo and ex vivo. In vivo, knocked out mice specifically deficient in glucokinase in liver have an almost normal glucose regulation (32), whereas deficiency in pancreas glucokinase leads to neonatal death from severe insulin-dependent diabetes mellitus (33). Ex vivo, we have shown that hepatoma cells with hexokinase 1 (2, and this paper) respond to glucose in modulating transcription of glucose-responsive genes, e.g.…”

Section: Discussionmentioning

confidence: 93%

“…In endocrine pancreas ␤ cells, the predominant glucose-sensor has been definitively identified as glucokinase by knock out of the gene in mice (32,33), and the significance of the specific GLUT 2 expression in rodent ␤ cells is still disputed, especially as the amount of the GLUT 2 isoform seems to be very low in human ␤ cells (34,35). German (36) has shown that ␤ cells overexpressing GLUT 1 do not lose their ability to sense changes in glucose concentration within the physiological range and to respond by an appropriate stimulation of the insulin gene promoter.…”

Section: Discussionmentioning

confidence: 99%

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Role of the GLUT 2 Glucose Transporter in the Response of the L-type Pyruvate Kinase Gene to Glucose in Liver-derived Cells

Antoine¹,

Lefrançois‐Martinez²,

Guillou³

et al. 1997

Journal of Biological Chemistry

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The expression of the L-PK gene in GLUT 2(؊) cells cultured in the absence of glucose was correlated with a high intracellular glucose 6-phosphate (Glu-6-P) concentration while under similar culture conditions Glu-6-P concentration was very low in GLUT 2(؉) cells. Consequently, a role of GLUT 2 in the glucose responsiveness of glucose-sensitive genes in cultured hepatoma cells could be to allow for Glu-6-P depletion under gluconeogenic culture conditions. In the absence of GLUT 2, glucose endogeneously produced might be unable to be exported from the cells and would be phosphorylated again to Glu-6-P by constitutively expressed hexokinase isoforms, continuously generating the glycolytic intermediates active on the L-PK gene transcription.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Role of the GLUT 2 Glucose Transporter in the Response of the L-type Pyruvate Kinase Gene to Glucose in Liver-derived Cells

Antoine¹,

Lefrançois‐Martinez²,

Guillou³

et al. 1997

Journal of Biological Chemistry

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“…Studies in rodents also support a critical role for GK in glucose homeostasis. 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).…”

mentioning

confidence: 99%

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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“…The pancreatic GK isoform is an absolute requirement for survival, as gk del/del (either global or b-cell specific) is lethal, whereas global or b-cell-specific heterozygous (gk del/wt ) deletion causes only modest hyperglycaemia (Bali et al 1995, Grupe et al 1995, Terauchi et al 1995. Deletion of liver GK leads to mild hyperglycaemia but decreases glucose utilisation and glycogen synthesis (Postic et al 1999).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of β-cell genes and improved function in rodent islets following chronic glucokinase activation

Gill¹,

Brocklehurst²,

Brown³

et al. 2011

Journal of Molecular Endocrinology

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Glucokinase (GK) plays a critical role in controlling blood glucose; GK activators have been shown to stimulate insulin secretion acutely both in vitro and in vivo. Sustained stimulation of insulin secretion could potentially lead to b-cell exhaustion; this study examines the effect of chronic GK activation on b-cells. Gene expression and insulin secretion were measured in rodent islets treated in vitro with GKA71 for 72 h. Key b-cell gene expression was measured in rat, mouse and global GK heterozygous knockout mouse islets (gk del/wt ). Insulin secretion, after chronic exposure to GKA71, was measured in perifused rat islets. GKA71 acutely increased insulin secretion in rat islets in a glucose-dependent manner. Chronic culture of mouse islets with GKA71 in 5 mmol/l glucose significantly increased the expression of insulin, IAPP, GLUT2, PDX1 and PC1 and decreased the expression of C/EBPb compared with 5 mmol/l glucose alone. Similar increases were shown for insulin, GLUT2, IAPP and PC1 in chronically treated rat islets. Insulin mRNA was also increased in GKA71-treated gk del/wt islets. No changes in GK mRNA were observed. Glucose-stimulated insulin secretion was improved in perifused rat islets following chronic treatment with GKA71. This was associated with a greater insulin content and GK protein level. Chronic treatment of rodent islets with GKA71 showed an upregulation of key b-cell genes including insulin and an increase in insulin content and GK protein compared with glucose alone.

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Transgenic knockouts reveal a critical requirement for pancreatic β cell glucokinase in maintaining glucose homeostasis

Cited by 262 publications

References 39 publications

Role of the GLUT 2 Glucose Transporter in the Response of the L-type Pyruvate Kinase Gene to Glucose in Liver-derived Cells

Role of the GLUT 2 Glucose Transporter in the Response of the L-type Pyruvate Kinase Gene to Glucose in Liver-derived Cells

Stimulation of Hepatocyte Glucose Metabolism by Novel Small Molecule Glucokinase Activators

Upregulation of β-cell genes and improved function in rodent islets following chronic glucokinase activation

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