Defect in glucokinase translocation in Zucker diabetic fatty rats

Fujimoto, Yuka; Donahue, E. Patrick; Shiota, Masakazu

doi:10.1152/ajpendo.00575.2003

Cited by 38 publications

(57 citation statements)

References 66 publications

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“…augmented by 38% when compared with that of the nondiabetic animals, strongly suggest that renal gluconeogenesis may contribute crucially to the hyperglycemia and the elevated systemic glucose production observed in these animals (49). Among the factors that potentially are involved in the probably multifactorial long-term stimulation of renal gluconeogenesis that we observed, our results suggest that both glucocorticoids and cAMP might play a substantial role by augmenting the expression of key gluconeogenic genes…”

Section: Resultssupporting

confidence: 53%

Intrinsic Gluconeogenesis Is Enhanced in Renal Proximal Tubules of Zucker Diabetic Fatty Rats

Eid

Bodin²,

Ferrier³

et al. 2006

Journal of the American Society of Nephrology

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Recent studies indicate that renal gluconeogenesis is substantially stimulated in patients with type 2 diabetes, but the mechanism that is responsible for such stimulation remains unknown. Therefore, this study tested the hypothesis that renal gluconeogenesis is intrinsically elevated in the Zucker diabetic fatty rat, which is considered to be an excellent model of type 2 diabetes. For this, isolated renal proximal tubules from diabetic rats and from their lean nondiabetic littermates were incubated in the presence of physiologic gluconeogenic precursors. Although there was no increase in substrate removal and despite a reduced cellular ATP level, a marked stimulation of gluconeogenesis was observed in diabetic relative to nondiabetic rats, with near-physiologic concentrations of lactate (38%), glutamine (51%) and glycerol (66%). This stimulation was caused by a change in the fate of the substrate carbon skeletons resulting from an increase in the activities and mRNA levels of the key gluconeogenic enzymes that are common to lactate, glutamine, and glycerol metabolism, i.e., mainly of phosphoenolpyruvate carboxykinase and, to a lesser extent, of glucose-6-phosphatase and fructose-1,6-bisphosphatase. Experimental evidence suggests that glucocorticoids and cAMP were two factors that were responsible for the long-term stimulation of renal gluconeogenesis observed in the diabetic rats. These data provide the first demonstration in an animal model that renal gluconeogenesis is upregulated by a long-term mechanism during type 2 diabetes. Together with the increased renal mass (38%) observed, they lend support to the view so far based only on in vivo studies performed in humans that renal gluconeogenesis may be stimulated by and crucially contribute to the hyperglycemia of type 2 diabetes.

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Section: Resultssupporting

confidence: 53%

Intrinsic Gluconeogenesis Is Enhanced in Renal Proximal Tubules of Zucker Diabetic Fatty Rats

Eid

Bodin²,

Ferrier³

et al. 2006

Journal of the American Society of Nephrology

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“…Previous studies have shown that glucose-induced translocation of glucokinase from the nucleus to the cytoplasm is impaired in models of insulin resistance and diabetes such as the Goto-Kakizaki, OLETF (41), and Zucker diabetic fatty rats (20,21). However, the underlying mechanisms have not been determined.…”

Section: Discussionmentioning

confidence: 98%

“…Defects in glucokinase translocation have been reported in animal models of Type 2 diabetes, including the Goto-Kakizaki rat and the Otsuka Long Evans Tokushima Fatty (OLETF) rat (41) and the Zucker diabetic fatty rat (20,21). The Zucker diabetic rat had impaired glucokinase translocation during a glucose and insulin infusion (21).…”

mentioning

confidence: 99%

Contributions of glucokinase and phosphofructokinase-2/fructose bisphosphatase-2 to the elevated glycolysis in hepatocytes from Zuckerfa/farats

Payne

Arden

Lange³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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The insulin-resistant Zucker fa/fa rat has elevated hepatic glycolysis and activities of glucokinase and phosphofructokinase-2/fructose bisphosphatase-2 (PFK2). The latter catalyzes the formation and degradation of fructose-2,6-bisphosphate (fructose-2,6-P 2) and is a glucokinasebinding protein. The contributions of glucokinase and PFK2 to the elevated glycolysis in fa/fa hepatocytes were determined by overexpressing these enzymes individually or in combination. Metabolic control analysis was used to determine enzyme coefficients on glycolysis and metabolite concentrations. Glucokinase had a high control coefficient on glycolysis in all hormonal conditions tested, whereas PFK2 had significant control only in the presence of glucagon, which phosphorylates PFK2 and suppresses glycolysis. Despite the high control strength of glucokinase, the elevated glycolysis in fa/fa hepatocytes could not be explained by the elevated glucokinase activity alone. In hepatocytes from fa/fa rats, glucokinase translocation between the nucleus and the cytoplasm was refractory to glucose but responsive to glucagon. Expression of a kinase-active PFK2 variant reversed the glucagon effect on glucokinase translocation and glucose phosphorylation, confirming the role for PFK2 in sequestering glucokinase in the cytoplasm. Glucokinase had a high control on glucose-6-phosphate content; however, like PFK2, it had a relative modest effect on the fructose-2,6-P2 content. However, combined overexpression of glucokinase and PFK2 had a synergistic effect on fructose-2,6-P2 levels, suggesting that interaction of these enzymes may be a prerequisite for formation of fructose-2,6-P2. Cumulatively, this study provides support for coordinate roles for glucokinase and PFK2 in the elevated hepatic glycolysis in fa/fa rats. liver; glucose metabolism; fructose-2,6-bisphosphate THE BIFUNCTIONAL ENZYME 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK2) catalyzes both the formation of fructose-2,6-bisphosphate (fructose-2,6-P 2 ) and its degradation (26,27,35). Fructose-2,6-P 2 is a regulator of glycolysis because it is a potent activator of phosphofructokinase-1 and inhibitor of fructose-1,6-bisphosphatase-1. Various tissue-specific isoforms of PFK2 encoded by four genes are expressed in mammals. They differ in their relative kinase and bisphosphatase activities and also in their regulatory mechanisms (36). The liver isoform is regulated by phosphorylation of a serine residue at the NH 2 terminus (Ser-32) by cAMP-dependent protein kinase, which leads to an increase in the bisphosphatase-to-kinase activity ratio. This mechanism accounts for the lowering of fructose-2,6-P 2 and inhibition of glycolysis caused by glucagon (26).Recent studies by Baltrusch et al. (8) showed that PFK2 binds to glucokinase through the bisphosphatase domain. Putative roles for this heterodimeric interaction have been proposed for both the hepatocyte and pancreatic ␤-cells, which express different isoforms of PFK2 (8,31,34). In pancreatic ␤-cells, binding of PFK2 activates gluc...

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“…Functional GK activity in the liver is also allosterically regulated by its interaction with a 68-kDa GK regulatory protein (GKRP), which binds to GK and inhibits the enzyme by a decrease in the apparent enzyme affinity for glucose (58). Studies using both cultured hepatocytes (2,10,32) and performed in vivo (13,22,23) demonstrated that GK is sequestered in the nucleus by GKRP under conditions of low glucose and insulin concentrations and that in response to a rise in glucose and/or insulin concentration, GK is dissociated from GKRP and is rapidly transported to the cytoplasm. It is likely, therefore, that stimulation of GK translocation by glucose plays an important physiological role in glucose effectiveness to stimulate its own uptake and inhibit its own production by the liver in normal subjects.…”

mentioning

confidence: 99%

A defect in glucose-induced dissociation of glucokinase from the regulatory protein in Zucker diabetic fatty rats in the early stage of diabetes

Shin

Torres²,

Catlin³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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Shin J-S, Torres TP, Catlin RL, Donahue EP, Shiota M. A defect in glucose-induced dissociation of glucokinase from the regulatory protein in Zucker diabetic fatty rats in the early stage of diabetes. Am J Physiol Regul Integr Comp Physiol 292: R1381-R1390, 2007. First published January 4, 2007; doi:10.1152/ajpregu.00260.2006.-Effect of stimulation of glucokinase (GK) export from the nucleus by small amounts of sorbitol on hepatic glucose flux in response to elevated plasma glucose was examined in 6-h fasted Zucker diabetic fatty rats at 10 wk of age. Under basal conditions, plasma glucose, insulin, and glucagon were ϳ8 mM, 2,000 pmol/l, and 60 ng/l, respectively. Endogenous glucose production (EGP) was 44 Ϯ 4 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 . When plasma glucose was raised to ϳ17 mM, GK was still predominantly localized with its inhibitory protein in the nucleus. EGP was not suppressed. When sorbitol was infused at 5.6 and 16.7 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 , along with the increase in plasma glucose, GK was exported to the cytoplasm. EGP (23 Ϯ 19 and 12 Ϯ 5 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) was suppressed without a decrease in glucose 6-phosphatase flux (145 Ϯ 23 and 126 Ϯ 16 vs. 122 Ϯ 10 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 without sorbitol) but increased in glucose phosphorylation as indicated by increases in glucose recycling (122 Ϯ 17 and 114 Ϯ 19 vs. 71 Ϯ 11 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ), glucose-6-phosphate content (254 Ϯ 32 and 260 Ϯ 35 vs. 188 Ϯ 20 nmol/g liver), fractional contribution of plasma glucose to uridine 5Ј-diphosphateglucose flux (43 Ϯ 8 and 42 Ϯ 8 vs. 27 Ϯ 6%), and glycogen synthesis from plasma glucose (20 Ϯ 4 and 22 Ϯ 5 vs. 9 Ϯ 4 mol glucose/g liver). The decreased glucose effectiveness to suppress EGP and stimulate hepatic glucose uptake may result from failure of the sugar to activate GK by stimulating the translocation of the enzyme. obese-type 2 diabetes; glucokinase regulatory protein EXCESSIVE POSTPRANDIAL HYPERGLYCEMIA is a prominent and early defect in subjects with type 2 diabetes, which is the result, at least in part, from an inadequate suppression of net hepatic glucose production (NHGP) (15,34,36) and an insufficient increase in hepatic glucose uptake (HGU) (6,7,21). Glucoseinduced suppression of NHGP was associated with increased hepatic glucose phosphorylation (47) and was abolished by inhibiting hepatic glucokinase (GK) activity in normal rats (5). This suggests that increased hepatic GK flux mediates glucose's effect not only to increase HGU, but also to decrease NHGP by the opposition of glucose 6-phosphatase flux. Basu et al. (6,7) showed that in type 2 diabetic patients, lower splanchnic glucose uptake in the face of hyperglycemic hyperinsulinemia was associated with a blunted increase in glucose phosphorylation. This implies impaired activity of GK in the liver of these patients.Studies using mouse models showed a large impact of altered hepatic GK expression in regulating postabsorptive blood glucose levels and hyperglycemia-induced HGU (35). However, decreased hepatic GK activity is not always present in patients (8,...

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Defect in glucokinase translocation in Zucker diabetic fatty rats

Cited by 38 publications

References 66 publications

Intrinsic Gluconeogenesis Is Enhanced in Renal Proximal Tubules of Zucker Diabetic Fatty Rats

Intrinsic Gluconeogenesis Is Enhanced in Renal Proximal Tubules of Zucker Diabetic Fatty Rats

Contributions of glucokinase and phosphofructokinase-2/fructose bisphosphatase-2 to the elevated glycolysis in hepatocytes from Zuckerfa/farats

A defect in glucose-induced dissociation of glucokinase from the regulatory protein in Zucker diabetic fatty rats in the early stage of diabetes

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