Portal Venous 5-Aminoimidazole-4-Carboxamide-1-β-<scp>d</scp>-Ribofuranoside Infusion Overcomes Hyperinsulinemic Suppression of Endogenous Glucose Output

Camacho, Raul C.; Pencek, Richard; Lacy, D. Brooks; James, Freyja D.; Donahue, E. Patrick; Wasserman, David H.

doi:10.2337/diabetes.54.2.373

Cited by 31 publications

(44 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…AICAR has been proposed as a potential therapeutic agent in relation with its hypoglycemic effects (42,43) or its putative interest to combat iatrogenic hypoglycemia (44). However, as reported here, AICAR also induced intracellular ATP depletion that could be detrimental for hepatocytes.…”

Section: Discussionmentioning

confidence: 42%

5-Aminoimidazole-4-Carboxamide-1-β-d-Ribofuranoside and Metformin Inhibit Hepatic Glucose Phosphorylation by an AMP-Activated Protein Kinase–Independent Effect on Glucokinase Translocation

et al. 2006

View full text Add to dashboard Cite

AMP-activated protein kinase (AMPK) controls glucose uptake and glycolysis in muscle. Little is known about its role in liver glucose uptake, which is controlled by glucokinase. We report here that 5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside (AICAR), metformin, and oligomycin activated AMPK and inhibited glucose phosphorylation and glycolysis in rat hepatocytes. In vitro experiments demonstrated that this inhibition was not due to direct phosphorylation of glucokinase or its regulatory protein by AMPK. By contrast, AMPK phosphorylated liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase without affecting activity. Inhibitors of the endothelial nitric oxide synthase, stress kinases, and phosphatidylinositol 3-kinase pathways did not counteract the effects of AICAR, metformin, or oligomycin, suggesting that these signaling pathways were not involved. Interestingly, the inhibitory effect on glucose phosphorylation of these well-known AMPK activators persisted in primary cultured hepatocytes from newly engineered mice lacking both liver ␣ 1 and ␣ 2 AMPK catalytic subunits, demonstrating that this effect was clearly not mediated by AMPK. Finally, AICAR, metformin, and oligomycin were found to inhibit the glucose-induced translocation of glucokinase from the nucleus to the cytosol by a mechanism that could be related to the decrease in intracellular ATP concentrations observed in these conditions. Diabetes 55: [865][866][867][868][869][870][871][872][873][874] 2006

show abstract

Section: Discussionmentioning

confidence: 42%

5-Aminoimidazole-4-Carboxamide-1-β-d-Ribofuranoside and Metformin Inhibit Hepatic Glucose Phosphorylation by an AMP-Activated Protein Kinase–Independent Effect on Glucokinase Translocation

et al. 2006

View full text Add to dashboard Cite

show abstract

“…However, enhanced glycogenolysis in muscle (32) and liver (8,22) and suppressed hepatic gluconeogenesis (31) can both be induced allosterically in vivo by raised intracellular levels of ZMP independently of a direct AMPK effect. In the most recent studies employing low-dose AICAR, HGP was enhanced in the presence of low-and high-dose insulin at eu-and hyperglycemia (8,9,38). These (8,9,38) and the earlier studies (5, 6, 26) necessitated coinfusions of insulin and glucose with AICAR, which compound the determination of in vivo glucose turnover and SkM glucose metabolism due to the direct effect of G INF on HGP independently of changes in insulin (46).…”

Section: Discussionmentioning

confidence: 99%

“…These (8,9,38) and the earlier studies (5, 6, 26) necessitated coinfusions of insulin and glucose with AICAR, which compound the determination of in vivo glucose turnover and SkM glucose metabolism due to the direct effect of G INF on HGP independently of changes in insulin (46). It is also important to note that, in the overnight-fasted rat [as opposed to overnight-fasted dog (8,9) or 5-h-fasted rat (26)], hepatic glycogen is markedly depleted, and HGP depends mainly on gluconeogenesis, a critical factor governing the suppressive effect of AICAR (31) on HGP in rat (5).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, hepatic glycogen is markedly reduced during high-dose AICAR administration in rats (26), and glycogen phosphorylase is activated in AICAR-treated hepatocytes (45). However, more recent studies (8,9,38) indicate that, during an infusion of low-dose AICAR, insulin's action on the liver is opposed, which leads to the increase in HGP by increasing net hepatic glycogenolysis via allosteric mechanisms (8). To date, all studies employing either low-dose or high-dose AICAR infusion in vivo have simultaneously coinfused varying amounts of glucose, insulin, and somatostatin with or without basal replacement of glucagon (6,9,25,26,38), which, given the independent effect of the glucose infusion on HGP (46), may compound the interpretation of the in vivo glucose turnover data.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Impact of in vivo fatty acid oxidation blockade on glucose turnover and muscle glucose metabolism during low-dose AICAR infusion

Christopher

Rantzau²,

Chen³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

During the basal equilibrium period (0 -150 min), fasting dogs (n ϭ 8) were infused with [3-3 H]glucose followed by either 2-h saline or AICAR (1.5-2.0 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ) infusions. SkM was biopsied at completion of each study. On a separate day, the same protocol was undertaken after 48-h in vivo FA OX blockade. The AICAR and AICAR ϩ MP studies were repeated in three chronic alloxan-diabetic dogs. AICAR produced a transient fall in plasma glucose and increase in insulin and a small decline in free fatty acid (FFA). Parallel increases in hepatic glucose production (HGP), glucose disappearance (R d tissue), and glycolytic flux (GF) occurred, whereas metabolic clearance rate of glucose (MCR g) did not change significantly. Intracellular SkM glucose, glucose 6-phosphate, and glycogen were unchanged. Acetyl-CoA carboxylase (ACCϳpSer 221 ) increased by 50%. In the AICAR ϩ MP studies, the metabolic responses were modified: the glucose was lower over 120 min, only minor changes occurred with insulin and FFA, and HGP and R d tissue responses were markedly attenuated, but MCR g and GF increased significantly. SkM substrates were unchanged, but ACCϳpSer 221 rose by 80%. Thus low-dose AICAR leads to increases in HGP and SkM glucose uptake, which are modified by prior FA ox blockade.5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside; 5-aminoimidazole-4-carboxamide-1-␤-D-ribosyl monophosphate; acetyl-coenzyme A carboxylase; phosphorylation; skeletal muscle; muscle biopsy; dogs AMPK ACTIVATION PLAYS A CENTRAL ROLE in the regulation of intracellular metabolism as the master switch regulating cellular ATP energy supplies by shutting down high energy-consuming pathways, such as fatty acid synthesis and cholesterol synthesis, and by activating ATP-generating pathways such as fatty acid oxidation (42, 58). Thus, through these actions, AMPK influences fuel usage and selection in and to various tissues (42). Endogenous AMPK can be activated pharmacologically by 5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside (AICAR), which is phosphorylated in vivo to the AMP analog AICAR monophosphate (ZMP) (18). However, many of those studies employed high doses of AICAR, resulting in high tissue levels of ZMP (5,6,25,26), which might have allosterically activated glycogen phosphorylase (7), certainly in cardiac muscle (32) and in the liver (45). Nevertheless, when skeletal muscle (SkM) AMPK is activated by upstream kinases and/or by AMP allosteric effects (60), the downstream substrate acetyl-CoA carboxylase (ACC) is phosphorylated in SkM (37, 58), at Ser 221 (ACCϳpSer 221 ) (11, 52) and thereby inactivated (37, 58). Therefore, the formation of ACCϳpSer 221 represents a key sensitive marker of biological activation of AMPK in vivo (3,58). Note that the corresponding SkM site (Ser 221 ) recognized by the ACC phosphospecific rat antibody used in the assay is raised against ACC␣ϳSer 79 (11, 36, 52). The inactivation of ACC leads to reduced malonyl-CoA levels and the activation of mitochondrial carnitine palmitoyltransferase I (CPT I), which ...

show abstract

“…AICAR is converted to the AMP analog AICA-riboside (ZMP) upon entering the cell and thus mimics an increase in cellular stress. In previous studies, AICAR has been shown to increase energy-producing pathways in the liver relative to energy-consuming pathways (14)(15)(16). The regulatory potential of the hepatic energy state is powerful, considering the key role of the liver in whole-body carbohydrate, lipid, and protein metabolism.…”

Section: Introductionmentioning

confidence: 99%

Hepatic energy state is regulated by glucagon receptor signaling in mice

et al. 2009

Self Cite

View full text Add to dashboard Cite

The hepatic energy state, defined by adenine nucleotide levels, couples metabolic pathways with energy requirements. This coupling is fundamental in the adaptive response to many conditions and is impaired in metabolic disease. We have found that the hepatic energy state is substantially reduced following exercise, fasting, and exposure to other metabolic stressors in C57BL/6 mice. Glucagon receptor signaling was hypothesized to mediate this reduction because increased plasma levels of glucagon are characteristic of metabolic stress and because this hormone stimulates energy consumption linked to increased gluconeogenic flux through cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) and associated pathways. We developed what we believe to be a novel hyperglucagonemic-euglycemic clamp to isolate an increment in glucagon levels while maintaining fasting glucose and insulin. Metabolic stress and a physiological rise in glucagon lowered the hepatic energy state and amplified AMP-activated protein kinase signaling in control mice, but these changes were abolished in glucagon receptor-null mice and mice with liver-specific PEPCK-C deletion. 129X1/Sv mice, which do not mount a glucagon response to hypoglycemia, displayed an increased hepatic energy state compared with C57BL/6 mice in which glucagon was elevated. Taken together, these data demonstrate in vivo that the hepatic energy state is sensitive to glucagon receptor activation and requires PEPCK-C, thus providing new insights into liver metabolism. IntroductionThe energy state in the cell is defined by adenine nucleotide levels and is critically coupled to nearly all metabolic processes (1). In the cell, the adenine nucleotides ATP, ADP, and AMP are tied directly or indirectly to all energetic pathways and allosterically control numerous regulatory enzymes (2-6). Changes in adenine nucleotides typically occur such that ATP and AMP deviate in reciprocal directions, while ADP remains constant (1). Such changes are the basis for using the ratio AMP/ATP (1, 7) or the equation for cellular energy charge ([ATP + (0.5 × ADP)] / [ATP + ADP + AMP]) (8, 9) as indices of the metabolic environment. Metabolic stress is thus characterized by a rise in AMP paired with a fall in ATP levels, reflecting a decrease in energy state. A fall in energy state is of considerable importance, in part due to the regulatory role of AMP/ATP ratios on AMPK activity (10). AMPK is a metabolic switch sensitive to high AMP/ATP ratios and functions to protect the energy state by inhibiting ATP-consuming processes while stimulating ATP-producing processes. (10).In most tissues, the environment is controlled to maintain a high energy state (low AMP/ATP ratio). In skeletal muscle, for example, creatine kinase limits reductions in ATP during conditions such as exercise, when energy utilization is accelerated (11,12). The liver, in contrast, lacks creatine kinase, and exercise has been shown to markedly decrease the hepatic energy state and increase the phosphorylation of AMPK (11, 13). The regulatory...

show abstract

Portal Venous 5-Aminoimidazole-4-Carboxamide-1-β-d-Ribofuranoside Infusion Overcomes Hyperinsulinemic Suppression of Endogenous Glucose Output

Cited by 31 publications

References 61 publications

5-Aminoimidazole-4-Carboxamide-1-β-d-Ribofuranoside and Metformin Inhibit Hepatic Glucose Phosphorylation by an AMP-Activated Protein Kinase–Independent Effect on Glucokinase Translocation

5-Aminoimidazole-4-Carboxamide-1-β-d-Ribofuranoside and Metformin Inhibit Hepatic Glucose Phosphorylation by an AMP-Activated Protein Kinase–Independent Effect on Glucokinase Translocation

Impact of in vivo fatty acid oxidation blockade on glucose turnover and muscle glucose metabolism during low-dose AICAR infusion

Hepatic energy state is regulated by glucagon receptor signaling in mice

Contact Info

Product

Resources

About