Defective Glycogenesis Contributes Toward the Inability to Suppress Hepatic Glucose Production in Response to Hyperglycemia and Hyperinsulinemia in Zucker Diabetic Fatty Rats

Torres, Tracy P.; Fujimoto, Yuka; Donahue, E. Patrick; Printz, Richard L.; Houseknecht, Karen L.; Treadway, Judith L.; Shiota, Masakazu

doi:10.2337/db09-1156

Cited by 22 publications

(25 citation statements)

References 29 publications

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“…GP activity is responsive to hepatic levels of glucose 6-phosphate, with a suppression of activity in response to higher glucose 6-phosphate concentrations, and thus the relative GP activities in the two groups are consistent with their relative rates of NHGU. GP activity under hyperglycemic and hyperinsulinemic conditions has previously been shown to be increased in drug-induced and genetic rodent models of obesity and/or diabetes (7,41,48), but not in high-fat-fed rats (30). In the HFD, HFrD, and HFFD groups in our previous studies (10,12), GP showed a tendency to be elevated relative to the controls.…”

Section: Liver Tissue Datamentioning

confidence: 51%

Chronic overeating impairs hepatic glucose uptake and disposition

Coate

Kraft

Shiota

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Dogs consuming a hypercaloric high-fat and -fructose diet (52 and 17% of total energy, respectively) or a diet high in either fructose or fat for 4 wk exhibited blunted net hepatic glucose uptake (NHGU) and glycogen deposition in response to hyperinsulinemia, hyperglycemia, and portal glucose delivery. The effect of a hypercaloric diet containing neither fructose nor excessive fat has not been examined. Dogs with an initial weight of Ϸ25 kg consumed a chow and meat diet (31% protein, 44% carbohydrate, and 26% fat) in weight-maintaining (CTR; n ϭ 6) or excessive (Hkcal; n ϭ 7) amounts for 4 wk (cumulative weight gain 0.0 Ϯ 0.3 and 1.5 Ϯ 0.5 kg, respectively, P Ͻ 0.05). They then underwent clamp studies with infusions of somatostatin and intraportal insulin (4ϫ basal) and glucagon (basal). The hepatic glucose load was doubled with peripheral (Pe) glucose infusion for 90 min (P1) and intraportal glucose at 4 mg·kg Ϫ1 ·min Ϫ1 plus Pe glucose for the final 90 min (P2). NHGU was blunted (P Ͻ 0.05) in Hkcal during both periods (mg·kg Ϫ1 ·min Ϫ1 ; P1: 1.7 Ϯ 0.2 vs. 0.3 Ϯ 0.4; P2: 3.6 Ϯ 0.3 vs. 2.3 Ϯ 0.4, CTR vs. Hkcal, respectively). Terminal hepatic glucokinase catalytic activity was reduced nearly 50% in Hkcal vs. CTR (P Ͻ 0.05), although glucokinase protein did not differ between groups. In Hkcal vs. CTR, liver glycogen was reduced 27% (P Ͻ 0.05), with a 91% increase in glycogen phosphorylase activity (P Ͻ 0.05) but no significant difference in glycogen synthase activity. Thus, Hkcal impaired NHGU and glycogen synthesis compared with CTR, indicating that excessive energy intake, even if the diet is balanced and nutritious, negatively impacts hepatic glucose metabolism. glycogen; glycogen phosphorylase; hypercaloric diet; liver THE LIVER IS AN ESPECIALLY IMPORTANT ORGAN in regard to glucose homeostasis because it is able to both export glucose for use by other tissues and extract glucose to reduce glycemia. Failure of the liver to make the transition from net output to uptake of glucose in the postprandial state is a major contributor to the development of impaired glucose tolerance and hyperglycemia (3,25). It is difficult to quantify hepatic glucose uptake (HGU) in the human because of the invasiveness of the hepatic portal vein catheterization required. Portal and hepatic vein catheterization is feasible in the dog, and the canine model provides a useful method for examining the liver's role in glucose disposal under postprandial conditions (31). Both high-fat and high-fructose diets and a diet with a combination of high fat and fructose are associated with marked impairment of HGU under hyperinsulinemic hyperglycemic (HIHG) clamp conditions in the dog (11,12). Under all of these circumstances, however, the modified diets were hypercaloric compared with that of the control group.The impact of excessive energy intake per se, i.e., excessive intake of foods normally viewed as nutritious, on the liver's role in glucose disposal remains unknown. The present studies were thus carried out to determine whether chronic con...

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Section: Liver Tissue Datamentioning

confidence: 51%

Chronic overeating impairs hepatic glucose uptake and disposition

Coate

Kraft

Shiota

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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“…The properties and capacity of the liver's GLUT2 are such that glucose transport across the plasma membrane depends on its concentration gradient, and therefore, it is not a regulatory step in determination of hepatic glucose flux (29,41). The catalytic activity of GK is not affected by its product (G-6-P) (32), and indeed, GK flux is not altered by a change in the G-6-P level resulting from a change in flux of the downstream pathways (44). Therefore, the improvement of the liver's ability to suppress glucose production and store glucose as glycogen in response to the rise in plasma glucose achieved by correcting hyperglycemia was due to normalized acceleration of glucose phosphorylation that might relate to maintenance of GK protein expression and normalization of GK translocation in response to hyperglycemia.…”

Section: Discussionmentioning

confidence: 96%

“…We measured glycogen synthase activity and phosphorylase activity, glycogen and glucose 6-phosphate (G-6-P) in liver, plasma levels of glucose, free fatty acids (FFAs), triglyceride, insulin, and glucagon, corticosterone, blood levels of hemoglobin A1c, lactate, and alanine, urinary glucose, specific activities of [ (15,16,44). Triglyceride content in liver, soleus muscle, and gastrocnemius muscle were determined according to the method of Carr et al (9).…”

Section: Methodsmentioning

confidence: 99%

“…Rates of glucose appearance (R a) and disappearance (Rd), endogenous glucose production (EGP), glucose cycling (GC), G-6-Pase flux, GS in liver and skeletal muscle, and percent contribution of plasma glucose and PEP to form UDPG in liver were calculated as described previously (44).…”

Section: Methodsmentioning

confidence: 99%

“…The catalytic properties of human GK and its inhibition by human GKRP are similar to that of rat GK (7). In Zucker diabetic fatty (ZDF) rats, a widely used genetic model of obese T2DM (39), defective suppression of NHGP and failure to increase flux from glucose to glycogen in response to a rise in plasma glucose and insulin are associated with defective augmentation of glucose phosphorylation (GK flux) resulting from impaired dissociation of GK from GKRP and subsequent decreased translocation of the enzyme from the nucleus to the cytoplasm in the early diabetic stage (15,16,36), abnormal relocation of GKRP to the cytoplasm in the presence of hyperglycemia during the middle stage (44), and a progressive reduction of hepatic GK protein levels in the later stage of the disease (43). Therefore, defective glucose effectiveness on hepatic glucose flux in T2DM is likely associated with impaired GK activity.…”

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confidence: 99%

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Glucotoxicity targets hepatic glucokinase in Zucker diabetic fatty rats, a model of type 2 diabetes associated with obesity

Ueta¹,

O’Brien²,

McCoy³

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Ueta K, O'Brien TP, McCoy GA, Kim K, Healey EC, Farmer TD, Donahue EP, Condren AB, Printz RL, Shiota M. Glucotoxicity targets hepatic glucokinase in Zucker diabetic fatty rats, a model of type 2 diabetes associated with obesity. Am J Physiol Endocrinol Metab 306: E1225-E1238, 2014. First published April 8, 2014 doi:10.1152/ajpendo.00507.2013.-A loss of glucose effectiveness to suppress hepatic glucose production as well as increase hepatic glucose uptake and storage as glycogen is associated with a defective increase in glucose phosphorylation catalyzed by glucokinase (GK) in Zucker diabetic fatty (ZDF) rats. We extended these observations by investigating the role of persistent hyperglycemia (glucotoxicity) in the development of impaired hepatic GK activity in ZDF rats. We measured expression and localization of GK and GK regulatory protein (GKRP), translocation of GK, and hepatic glucose flux in response to a gastric mixed meal load (MMT) and hyperglycemic hyperinsulinemic clamp after 1 or 6 wk of treatment with the sodiumglucose transporter 2 inhibitor (canaglifrozin) that was used to correct the persistent hyperglycemia of ZDF rats. Defective augmentation of glucose phosphorylation in response to a rise in plasma glucose in ZDF rats was associated with the coresidency of GKRP with GK in the cytoplasm in the midstage of diabetes, which was followed by a decrease in GK protein levels due to impaired posttranscriptional processing in the late stage of diabetes. Correcting hyperglycemia from the middle diabetic stage normalized the rate of glucose phosphorylation by maintaining GK protein levels, restoring normal nuclear residency of GK and GKRP under basal conditions and normalizing translocation of GK from the nucleus to the cytoplasm, with GKRP remaining in the nucleus in response to a rise in plasma glucose. This improved the liver's metabolic ability to respond to hyperglycemic hyperinsulinemia. Glucotoxicity is responsible for loss of glucose effectiveness and is associated with altered GK regulation in the ZDF rat. glucotoxicity; hepatic glucose flux; glucokinase; type 2 diabetes; sodium-glucose cotransporter 2 inhibitor

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Measurement of Glucose Homeostasis In Vivo: Combination of Tracers and Clamp Techniques

Shiota

2012

Methods in Molecular Biology

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A tracer technique referred to as "pancreatic-blood glucose clamp" allows assessment in response to a change in blood glucose, insulin, and/or glucagon of whole body glucose disposal, endogenous glucose production, speci fi c tissue/organ glucose uptake and storage, and insulin secretion. This technique is currently considered the optimal method for measurement of insulin sensitivity and glucose effectiveness. We describe here, for use in conscious-unrestrained mice and rats, the pancreatic-blood glucose clamp technique and its associated methods; which include catheterization of blood vessels; a clamp of plasma insulin, glucagon, and glucose; analyses of metabolites and tracers; and calculations.

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Defective Glycogenesis Contributes Toward the Inability to Suppress Hepatic Glucose Production in Response to Hyperglycemia and Hyperinsulinemia in Zucker Diabetic Fatty Rats

Cited by 22 publications

References 29 publications

Chronic overeating impairs hepatic glucose uptake and disposition

Chronic overeating impairs hepatic glucose uptake and disposition

Glucotoxicity targets hepatic glucokinase in Zucker diabetic fatty rats, a model of type 2 diabetes associated with obesity

Measurement of Glucose Homeostasis In Vivo: Combination of Tracers and Clamp Techniques

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