Effect of glucose on uptake of radiolabeled glucose, 2-DG, and 3-O-MG by the perfused rat liver

1996 ◽  
Vol 271 (2) ◽  
pp. E384-E396 ◽  
Author(s):  
I. R. Sweet ◽  
L. Peterson ◽  
K. Kroll ◽  
C. J. Goodner ◽  
M. Berry ◽  
...  
Keyword(s):  
Membrane Transport ◽  
Glucose Transporter ◽  
Competitive Inhibition ◽  
Glycogen Synthesis ◽  
Glucose Production ◽  
Fed State ◽  
Glucose Levels ◽  
Hepatic Glucose Uptake ◽  
Effect Of Glucose

In the transition from the fasting to the fed state, plasma glucose levels rise, and the liver converts from an organ producing glucose to one of storage. To determine the effect of glucose on hepatic glucose uptake, radiolabeled glucose, 2-deoxyglucose, and 3-O-methylglucose were injected into perfused rat livers during different nontracer glucose levels, and the concentrations in the outflow were measured. A mathematical model was developed that described the behavior of the injected compounds as they traveled through the liver and was used to simulate and fit the experimental results. The rates of membrane transport, glucokinase, glucose-6-phosphatase, and the consumption of glucose 6-phosphate were estimated. Membrane transport for all of the tracers decreased as nontracer glucose increased, demonstrating competitive inhibition of the glucose transporter. In contrast, the consumption of injected [2-14C]glucose increased when glucose was elevated, demonstrating that glucose caused an activation of enzyme activity that overcame the competitive inhibition of transport and phosphorylation. When glucose was elevated, the rate coefficient of glucokinase did not decrease, indicating that glucokinase was stimulated by glucose. Both changes would lead to the increased glycogen synthesis and decreased glucose production rate observed in vivo during the fasted-to-fed transition.

Muscle glucose uptake during and after exercise is normal in insulin-resistant rats

1993 ◽  
Vol 264 (2) ◽  
pp. E167-E172 ◽  
Author(s):  
M. Kusunoki ◽  
L. H. Storlien ◽  
J. MacDessi ◽  
N. D. Oakes ◽  
C. Kennedy ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Glucose Transporter ◽  
Treadmill Exercise ◽  
Glycogen Synthesis ◽  
Insulin Stimulation ◽  
Adult Rats ◽  
Insulin Resistant ◽  
Glucose Levels ◽  
Hindlimb Muscles ◽  
Postexercise Recovery

It is not generally known whether impaired stimulation of muscle glucose metabolism in insulin-resistant states is specific to insulin stimulation. Our aim was to examine whether glucose uptake responded normally to exercise and postexercise recovery in insulin-resistant high-fat-fed (HFF) rats. Three-week HFF or Chow-fed [control (Con)] adult rats were studied 5 days after cannulation. Before, during, or immediately after (recovery) 50 min of treadmill exercise, bolus 2-deoxy-[3H]glucose and [14C]glucose were administered to estimate muscle glucose uptake (R'g) and glycogen incorporation rates. Mean exercise and recovery plasma glucose levels were similar in HFF and Con rats. In hindlimb muscles sampled, exercise and recovery R'g were similar in HFF and Con (e.g., red quadriceps exercise 104 +/- 13 vs. 113 +/- 8, recovery 45.3 +/- 3.9 vs. 47.7 +/- 4.5 mumol.100 g-1.min-1, respectively). Moreover, muscle glucose transporter (GLUT-4) content was not reduced in HFF rats. Glycogen resynthesis accounted almost entirely for R'g during recovery and was equivalent between groups. We conclude that impaired muscle glucose uptake and glycogen synthesis in HFF rats are characteristic of insulin but not of exercise or postexercise stimulation.

scholarly journals Arrestin domain-containing 3 (Arrdc3) modulates insulin action and glucose metabolism in liver

2020 ◽  
Vol 117 (12) ◽  
pp. 6733-6740 ◽  
Author(s):  
Thiago M. Batista ◽  
Sezin Dagdeviren ◽  
Shannon H. Carroll ◽  
Weikang Cai ◽  
Veronika Y. Melnik ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Insulin Action ◽  
Hepatic Glucose Production ◽  
Glycogen Synthesis ◽  
Glucose Production ◽  
Hepatic Glycogen ◽  
Glycogen Accumulation ◽  
Hepatic Glucose ◽  
Glucose Output

Insulin action in the liver is critical for glucose homeostasis through regulation of glycogen synthesis and glucose output. Arrestin domain-containing 3 (Arrdc3) is a member of the α-arrestin family previously linked to human obesity. Here, we show thatArrdc3is differentially regulated by insulin in vivo in mice undergoing euglycemic-hyperinsulinemic clamps, being highly up-regulated in liver and down-regulated in muscle and fat. Mice with liver-specific knockout (KO) of the insulin receptor (IR) have a 50% reduction inArrdc3messenger RNA, while, conversely, mice with liver-specific KO ofArrdc3(L-Arrdc3KO) have increased IR protein in plasma membrane. This leads to increased hepatic insulin sensitivity with increased phosphorylation of FOXO1, reduced expression of PEPCK, and increased glucokinase expression resulting in reduced hepatic glucose production and increased hepatic glycogen accumulation. These effects are due to interaction of ARRDC3 with IR resulting in phosphorylation of ARRDC3 on a conserved tyrosine (Y382) in the carboxyl-terminal domain. Thus,Arrdc3is an insulin target gene, and ARRDC3 protein directly interacts with IR to serve as a feedback regulator of insulin action in control of liver metabolism.

scholarly journals Glucagon Deficiency Reduces Hepatic Glucose Production and Improves Glucose Tolerance In Adult Mice

2010 ◽  
Vol 31 (4) ◽  
pp. 606-606
Author(s):  
Aidan S. Hancock ◽  
Aiping Du ◽  
Jingxuan Liu ◽  
Mayumi Miller ◽  
Catherine L. May
Keyword(s):  
Glucose Homeostasis ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Postprandial Glucose ◽  
Glucagon Receptor ◽  
Glucose Levels ◽  
Adult Mice ◽  
Hepatic Glucose ◽  
Knockout Animals

Abstract The major role of glucagon is to promote hepatic gluconeogenesis and glycogenolysis to raise blood glucose levels during hypoglycemic conditions. Several animal models have been established to examine the in vivo function of glucagon in the liver through attenuation of glucagon via glucagon receptor knockout animals and pharmacological interventions. To investigate the consequences of glucagon loss to hepatic glucose production and glucose homeostasis, we derived mice with a pancreas specific ablation of the α-cell transcription factor, Arx, resulting in a complete loss of the glucagon-producing pancreatic α-cell. Using this model, we found that glucagon is not required for the general health of mice but is essential for total hepatic glucose production. Our data clarifies the importance of glucagon during the regulation of fasting and postprandial glucose homeostasis.

Decreased visceral adiposity accounts for leptin effect on hepatic but not peripheral insulin action

1999 ◽  
Vol 277 (2) ◽  
pp. E291-E298 ◽  
Author(s):  
Nir Barzilai ◽  
Li She ◽  
Lisen Liu ◽  
Jiali Wang ◽  
Meizu Hu ◽  
...  
Keyword(s):  
Insulin Action ◽  
Food Restriction ◽  
Glycogen Synthesis ◽  
Glucose Production ◽  
Sprague Dawley ◽  
Cl 316,243 ◽  
Sprague Dawley Rats ◽  
Total Fat ◽  
Contrast Reduction

Leptin decreases visceral fat (VF) and increases peripheral and hepatic insulin action. Here, we generated similar decreases in VF using leptin (Lep), β3-adrenoreceptor agonism (β3), or food restriction (FR) and asked whether insulin action would be equally improved. For 8 days before the in vivo study, Sprague-Dawley rats ( n = 24) were either fed ad libitum [control (Con)], treated with Lep or β3 (CL-316,243) by implanted osmotic mini-pumps, or treated with FR. Total VF was similarly decreased in the latter three groups (Lep, 3.11 ± 0.96 g; β3, 2.87 ± 0.48 g; and FR, 3.54 ± 0.77 g compared with 6.91 ± 1.41 g in Con; P < 0.001) independent of total fat mass (by3H2O) and food intake. Insulin (3 mU ⋅ kg−1 ⋅ min−1) clamp studies were performed to assess hepatic and peripheral insulin sensitivity. Decreased VF resulted in similar and marked improvements in insulin action on glucose production (GP) (Lep, 1.19 ± 0.51; β3, 1.46 ± 0.68; FR, 2.27 ±0.71 compared with 6.06 ± 0.70 mg ⋅ kg−1 ⋅ min−1in Con; P < 0.001). By contrast, reduction in VF by β3 and FR failed to reproduce the stimulation of insulin-mediated glucose uptake (∼60%), glycogen synthesis (∼80%), and glycolysis (∼25%) observed with Lep. We conclude that 1) a moderate decrease in VF uniformly leads to a marked increase in hepatic insulin action, but 2) the effects of leptin on peripheral insulin action are not due to the associated changes in VF or β3 activation.

Protective effect of 4,6-O-ethylidene glucose against the cytotoxicity of streptozotocin in pancreatic β cells in vivo: indirect evidence for the presence of a glucose transporter in β cells

1987 ◽  
Vol 112 (3) ◽  
pp. 375-378 ◽  
Author(s):  
J. Kawada ◽  
M. Okita ◽  
M. Nishida ◽  
Y. Yoshimura ◽  
K. Toyooka ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Glucose Transporter ◽  
Indirect Evidence ◽  
Tolerance Test ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Glucose Levels ◽  
In Vivo Experiments ◽  
Glucose Transport System

ABSTRACT Ethylidene glucose (4,6-O-ethylidene glucose; EG) is known to bind the outer surface of the glucose transporter in the membranes of human erythrocytes and other mammalian cells. If a glucose transport system is present on pancreatic β cells and recognizes the glucose moiety of streptozotocin (STZ), EG should protect β cells from the cytotoxicity of STZ when it is administered with STZ. This possibility was examined in in-vivo experiments in rats. When EG and STZ were injected into rats together the animals did not become diabetic, as judged by (1) their blood glucose levels, (2) response in a glucose-tolerance test, and (3) insulin secretion in response to feeding. These results suggest that there is a glucose transporter present in β cells and also the transport of streptozotocin into β cells through this system. J. Endocr. (1987) 112, 375–378

The Role of Insulin in the Regulation of PEPCK and Gluconeogenesis In Vivo

2009 ◽  
Vol 05 (01) ◽  
pp. 34 ◽  
Author(s):  
Christopher J Ramnanan ◽  
Dale S Edgerton ◽  
Alan D Cherrington ◽  
◽  
◽  
...  
Keyword(s):  
Messenger Rna ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Hepatic Glucose Production ◽  
Glycogen Synthesis ◽  
Glucose Production ◽  
Regulatory Control ◽  
Glycolytic Flux ◽  
Large Animals

The regulation of gluconeogenesis by insulin is complex and can involve insulin-mediated events in the liver, as well as in several non-hepatic tissues. Given the complexity of this regulation, it is no surprise that there is considerable debate regarding insulin’s ability to regulate the rate of gluconeogenic formation of glucose-6-phosphate (GNG flux to G6P)in vivo. Conventional ‘textbook’ teaching (based onin vitrostudies of rat liver) depicts that insulin can inhibit this pathway by suppressing the transcription of the enzyme phosphoenolpyruvate carboxykinase (PEPCK). PEPCK is widely considered to be a ‘rate-limiting’ enzyme with high control strength. Additionally, recent data in rodents have led to the conclusion that hyperinsulinemia in the brain can inhibit GNG flux to G6P, likely through transcriptional regulation of PEPCK. Recent data from the authors’ lab have confirmed that the molecular regulation of PEPCK messenger RNA (mRNA) and protein by insulin is conserved in large animals. Acute physiological hyperinsulinemia does not alter gluconeogenic formation of G6P, however, despite substantial reductions in PEPCK protein. This indicates that PEPCK has poor regulatory control over the pathwayin vivo. A physiological rise in insulin suppresses hepatic glucose production by inhibiting glycogenolysis and promoting glycogen synthesis, stimulating glycolytic flux, and redirecting gluconeogenically derived carbon to glycogen. This review documents the relevant ways in which insulin can regulate GNG flux to G6Pin vivo.

In vivo effect of Trigonella foenum graecum on the expression of pyruvate kinase, phosphoenolpyruvate carboxykinase, and distribution of glucose transporter (GLUT4) in alloxan-diabetic rats

2006 ◽  
Vol 84 (6) ◽  
pp. 647-654 ◽  
Author(s):  
Sameer Mohammad ◽  
Asia Taha ◽  
Kamal Akhtar ◽  
R.N.K. Bamezai ◽  
Najma Zaheer Baquer
Keyword(s):  
Skeletal Muscle ◽  
Pyruvate Kinase ◽  
Plasma Glucose ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Glucose Transporter ◽  
Diabetic Rats ◽  
Altered Expression ◽  
Glucose Levels ◽  
Glucose Transporter Glut4

Plasma glucose levels are maintained by a precise balance between glucose production and its use. Liver pyruvate kinase (PK) and phosphoenolpyruvate carboxykinase (PEPCK), 2 key enzymes of glycolysis and gluconeogenesis, respectively, play a crucial role in this glucose homeostasis along with skeletal muscle glucose transporter (GLUT4). In the diabetic state, this balance is disturbed owing to the absence of insulin, the principal factor controlling this regulation. In the present study, alloxan-diabetic animals having high glucose levels of more than 300 mmol/L have been taken and the administration of Trigonella seed powder (TSP) to the diabetic animals was assessed for its effect on the expression of PK and PEPCK in liver and GLUT4 distribution in skeletal muscle of alloxan-diabetic rats. TSP treatment to the diabetic animals resulted in a marked decrease in the plasma glucose levels. Trigonella treatment partially restored the altered expression of PK and PEPCK. TSP treatment also corrected the alterations in the distribution of GLUT4 in the skeletal muscle.

Localization of the GLUT8 glucose transporter in murine kidney and regulation in vivo in nondiabetic and diabetic conditions

2005 ◽  
Vol 289 (1) ◽  
pp. F186-F193 ◽  
Author(s):  
Mario Schiffer ◽  
Katalin Susztak ◽  
Mollie Ranalletta ◽  
Amanda C. Raff ◽  
Erwin P. Böttinger ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Kidney Disease ◽  
Plasma Glucose ◽  
Glucose Transporter ◽  
Apoptotic Cell ◽  
Major Complication ◽  
Distal Portion ◽  
Glucose Levels ◽  
Transporter Family

Kidney disease is a major complication of diabetes, and poor glycemic control is associated with the development of diabetic nephropathy. The precise mechanisms that lead to diabetic kidney disease still remain largely unknown and are under current investigation. Because glucose transporters in the kidney play an important role in the local maintenance of intracellular glucose and plasma glucose homeostasis, the tissue distribution and regulation of glucose transporter GLUT8, a new member of the glucose transporter family with important functions in cellular survival, were examined. To understand the normal regulation of GLUT8 expression in response to metabolic signals, fasting and feeding conditions were studied. Additionally, GLUT8 expression was studied using two different models of insulin resistance, GLUT4−/− and db/db mice. GLUT8 was localized to glomerular podocytes and tubular epithelial cells in the distal portion of the nephron. Expression of GLUT8 in the kidney was influenced by plasma glucose levels in vivo. Podocytes in kidneys of diabetic db/db mice express higher levels of GLUT8 compared with nondiabetic db/m mice. Because podocytes play an important role in glomerulosclerosis development and high levels of glucose have been shown to induce apoptotic cell death in various kidney cells, these data may provide further insight into the pathogenesis of glomerulosclerosis and diabetic nephropathy.

Accelerated glycogenolysis in uremia and under sucrose feeding: role of phosphorylase alpha regulators

1997 ◽  
Vol 273 (1) ◽  
pp. E17-E27
Author(s):  
Z. Bakkour ◽  
D. Laouari ◽  
S. Dautrey ◽  
J. P. Yvert ◽  
C. Kleinknecht
Keyword(s):  
Hepatic Glucose Production ◽  
Glycogen Synthesis ◽  
Glucose Production ◽  
Glycogen Storage ◽  
Hepatic Insulin Resistance ◽  
Hepatic Glycogen ◽  
Glycogen Depletion ◽  
Sucrose Feeding

To understand the mechanism of hepatic glycogen depletion found in uremia and under sucrose feeding, we examined net hepatic glycogenolysis-associated active enzymes and metabolites during fasting. Liver was taken 2, 7, and 18 h after food removal in uremic and pair-fed control rats fed either a sucrose or cornstarch diet for 21 days. Other uremic and control rats fasted for 18 h were refed a sucrose meal to measure glycogen increment. Glycogen storage in uremia was normal, suggesting effective glycogen synthesis. During a short fast, sucrose feeding and uremia enhanced net glycogenolysis through different but additive mechanisms. Under sucrose feeding, there were high phosphorylase alpha levels associated with hepatic insulin resistance. In uremia, phosphorylase alpha levels were low, but the enzyme was probably activated in vivo by a fall of inhibitors (ATP, alpha-glycerophosphate, fructose-1,6-diphosphate, and glucose) and a rise of Pi, as verified in vitro. Enhanced gluconeogenesis was also suggested, but excessive hepatic glucose production was unlikely in uremia. During fasting, hypoglycemia occurred in uremia due to reduced glycogenolysis, inefficient hepatic gluconeogenesis, and impaired renal gluconeogenesis. This may be relevant to poor fasting tolerance in uremia, which could be aggravated under excessive sucrose intake.

scholarly journals A physiological increase in the hepatic glycogen level does not affect the response of net hepatic glucose uptake to insulin

2009 ◽  
Vol 297 (2) ◽  
pp. E358-E366 ◽  
Author(s):  
Jason J. Winnick ◽  
Zhibo An ◽  
Mary Courtney Moore ◽  
Christopher J. Ramnanan ◽  
Ben Farmer ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Glycogen Synthesis ◽  
Control Period ◽  
In Vivo Studies ◽  
Hepatic Glycogen ◽  
Glycogen Level ◽  
Hepatic Glucose ◽  
Glycogen Deposition ◽  
Hepatic Glucose Uptake

To determine the effect of an acute increase in hepatic glycogen on net hepatic glucose uptake (NHGU) and disposition in response to insulin in vivo, studies were performed on two groups of dogs fasted 18 h. During the first 4 h of the study, somatostatin was infused peripherally, while insulin and glucagon were replaced intraportally in basal amounts. Hyperglycemia was brought about by glucose infusion, and either saline ( n = 7) or fructose ( n = 7; to stimulate NHGU and glycogen deposition) was infused intraportally. A 2-h control period then followed, during which the portal fructose and saline infusions were stopped, allowing NHGU and glycogen deposition in the fructose-infused animals to return to rates similar to those of the animals that received the saline infusion. This was followed by a 2-h experimental period, during which hyperglycemia was continued but insulin infusion was increased fourfold in both groups. During the initial 4-h glycogen loading period, NHGU averaged 1.18 ± 0.27 and 5.55 ± 0.53 mg·kg−1·min−1 and glycogen synthesis averaged 0.72 ± 0.24 and 3.98 ± 0.57 mg·kg−1·min−1 in the saline and fructose groups, respectively ( P < 0.05). During the 2-h hyperinsulinemic period, NHGU rose from 1.5 ± 0.4 and 0.9 ± 0.2 to 3.1 ± 0.6 and 2.5 ± 0.5 mg·kg−1·min−1 in the saline and fructose groups, respectively, a change of 1.6 mg·kg−1·min−1 in both groups despite a significantly greater liver glycogen level in the fructose-infused group. Likewise, the metabolic fate of the extracted glucose (glycogen, lactate, or carbon dioxide) was not different between groups. These data indicate that an acute physiological increase in the hepatic glycogen content does not alter liver glucose uptake and storage under hyperglycemic/hyperinsulinemic conditions in the dog.

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