Mechanisms of hormonal regulation of hepatic glucose metabolism

Jh, Exton

doi:10.1002/dmr.5610030108

Cited by 160 publications

(124 citation statements)

References 172 publications

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“…Increased hepatic glucose production results from the high availability of gluconeogenic precursors, such as amino acids (alanine and glutamine; as a result of accelerated proteolysis and decreased protein synthesis) (45), lactate (as a result of increased muscle glycogenolysis), and glycerol (as a result of increased lipolysis), and from the increased activity of gluconeogenic enzymes. These include PEPCK, fructose-1,6-biphosphatase, pyruvate carboxylase, and glucose-6-phosphatase, which are further stimulated by increased levels of stress hormones in DKA and HHS (46)(47)(48)(49)(50). From a quantitative standpoint, increased glucose production by the liver and kidney represents the major pathogenic disturbance responsible for hyperglycemia in these patients, and gluconeogenesis plays a greater metabolic role than glycogenolysis (46)(47)(48)(49)(50)51).…”

Section: Carbohydrate Metabolismmentioning

confidence: 99%

“…These include PEPCK, fructose-1,6-biphosphatase, pyruvate carboxylase, and glucose-6-phosphatase, which are further stimulated by increased levels of stress hormones in DKA and HHS (46)(47)(48)(49)(50). From a quantitative standpoint, increased glucose production by the liver and kidney represents the major pathogenic disturbance responsible for hyperglycemia in these patients, and gluconeogenesis plays a greater metabolic role than glycogenolysis (46)(47)(48)(49)(50)51). Although the detailed biochemical mechanisms for gluconeogenesis are well established, the molecular basis and the role of counterregulatory hormones in DKA are the subject of debate; very few studies have attempted to establish a temporal relationship between the increase in the level of counterregulatory hormones and the metabolic alterations in DKA (52).…”

Section: Carbohydrate Metabolismmentioning

confidence: 99%

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Management of Hyperglycemic Crises in Patients With Diabetes

et al. 2001

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Abbreviations: AaO 2 , alveolar-to-arteriolar oxygen; AKA, alcoholic ketoacidosis; ARDS, adult respiratory distress syndrome; BUN, blood urea nitrogen; CPT, carnitine palmitoyl-transferase; CSF, cerebrospinal fluid; DKA, diabetic ketoacidosis; FFA, free fatty acid; HHS, hyperosmolar hyperglycemic state; IRI, immunoreactive insulin; PaO 2 , arteriolar partial pressure of oxygen; RDKA, recurrent DKA.A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Management of Hyperglycemic Crises in Patients With Diabetes T E C H N I C A L R E V I E R e v i e w s / C o m m e n t a r i e s / P o s i t i o n S t a t e m e n t s 132DIABETES CARE, VOLUME 24, NUMBER 1, JANUARY 2001Technical Review noted in newly diagnosed obese type 2 diabetic patients (5,26,31). Therefore, the concept that the presence of DKA in type 2 diabetes is a rare occurrence is incorrect.The most common types of infections are pneumonia and urinary tract infection, accounting for 30-50% of cases (Table 4). Other acute medical illnesses as precipitating causes include alcohol abuse, trauma, pulmonary embolism, and myocardial infarction, which can occur both in type 1 and 2 diabetes (6). Various drugs that alter carbohydrate metabolism, such as corticosteroids, pentamidine, sympathomimetic agents, and ␣-and ␤-adrenergic blockers, and excessive use of diuretics in the elderly may also precipitate the development of DKA and HHS.The recent increased use of continuous subcutaneous insulin infusion pumps that use small amounts of short-acting insulin has been associated with an incidence of DKA that is significantly increased over the incidence seen with conventional methods of multiple daily insulin injections, in spite of the fact that most of the mechanical problems with insulin pumps have been resolved (6,(32)(33)(34). In the Diabetes Control and Complications Trial, the incidence of DKA in patients on insulin pumps was about twofold higher than that in the multipleinjection group over a comparable time period (35). This may be due to the exclusive use of short-acting insulin in the pump, which if interrupted leaves no reservoir of insulin for blood glucose control.Psychological factors and poor compliance, leading to omission of insulin therapy, are important precipitating factors for recurrent ketoacidosis. In young female patients with type 1 diabetes, psychological problems complicated by eating disorders may be contributing factors in up to 20% of cases of recurrent ketoacidosis (36,37). Factors that may lead to insulin omission in younger patients include fear of weight gain with good metabolic control, fear of hypoglycemia, rebellion against authority, and stress related to chronic disease (36). Noncompliance with insulin therapy has been found to be the leading precipitating cause for DKA in urban African-Americans and medically indigent patients (5,26). In addition, a recent study showed that diabetic patients without health insurance or with Medicaid alone had hospitali...

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Section: Carbohydrate Metabolismmentioning

confidence: 99%

Section: Carbohydrate Metabolismmentioning

confidence: 99%

Management of Hyperglycemic Crises in Patients With Diabetes

et al. 2001

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“…Gluconeogenesis is defined as the formation from noncarbohydrate precursors of glucose and glycogen [6,7]. Glycogen cycling has limited the interpretation of estimates of gluconeogenesis [2,8], since its contribution cannot be excluded by current methods, e.g.…”

Section: Introductionmentioning

confidence: 99%

Changes in hepatic glycogen cycling during a glucose load in healthy humans

et al. 2005

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Aims/hypothesis: Glycogen cycling, i.e. simultaneous glycogen synthesis and glycogenolysis, affects estimates of glucose fluxes using tracer techniques and may contribute to hyperglycaemia in diabetic conditions. This study presents a new method for quantifying hepatic glycogen cycling in the fed state. Glycogen is synthesised from glucose by the direct and indirect (gluconeogenic) pathways. Since glycogen is also synthesised from glycogen, i.e. glycogen→glucose 1-phosphate→glycogen, that synthesised through the direct and indirect pathways does not account for 100% of glycogen synthesis. The percentage contribution of glycogen cycling to glycogen synthesis then equals the difference between the sum of the percentage contributions of the direct and indirect pathways and 100. Materials and methods: The indirect and direct pathways were measured independently in nine healthy volunteers who had fasted overnight. They ingested 2 H 2 O (5 ml/kg body water) and were infused with [5-3 H] glucose and acetaminophen (paracetamol; 1 g) during hyperglycaemic clamps (7.8 mmol/l) lasting 8 h. The percentage contribution of the indirect pathway was calculated from the ratio of 2 H enrichments at carbon 5 to that at carbon 2, and the contribution of the direct pathway was determined from the 3 H-specific activity, relative to plasma glucose, of the urinary glucuronide excreted between 2 and 4, 4 and 6, and 6 and 8 h. Results: Glucose infusion rates increased (p<0.01) to ∼50 μmol kg −1 min −1 . Plasma insulin and the insulin : glucagon ratio rose ∼3.6-and ∼8.3-fold (p<0.001), respectively. From the difference between 100% and the sum of the direct (2-4 h, 54±6%; 4-6 h, 59±5%; 6-8 h, 63±4%) and indirect (32±3, 38±4, 36±3%) pathways, glycogen cycling was seen to be decreased (p<0.05) from 14±4% (2-4 h) to 4±3% (4-6 h) and 1±3% (6-8 h). Conclusions/interpretation: This method allows measurement of hepatic glycogen cycling in the fed state and demonstrates that glycogen cycling occurs most in the early hours after glucose loading subsequent to a fast.

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“…While increasing [cAMP] i in ß-cells via PDE4 can boost glucose-induced insulin secretion and production, 15 elevation of [cAMP] i in insulin target cells, such as adipocytes and hepatocytes, at the same time may cause mobilization of fatty acids and gluconeogenesis that could dampen the effect of augmenting in vivo insulin production. 33,34 Another aspect of this study is to note 3-MA as a "classic inhibitor of autophagy" in eukaryotic cells when used at mM concentrations. 17 In primary pancreatic ß-cells, there is an inverse relationship between autophagy and insulin production.…”

Section: Discussionmentioning

confidence: 99%

Monomethylated-adenines potentiate glucose-induced insulin production and secretion via inhibition of phosphodiesterase activity in rat pancreatic islets

Boland

Alarcón

Ali

et al. 2015

Islets

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(2015) Monomethylated-adenines potentiate glucose-induced insulin production and secretion via inhibition of phosphodiesterase activity in rat pancreatic islets, Islets, 7:2, e1073435, DOI: 10.1080DOI: 10. /19382014.2015 To link to this article: https://doi.org/10. 1080/19382014.2015 Abbreviations: 3-MA, 3-methyladenine; N6-MA, N6-methyladenine; 9-MA, 9-methyladenine; 1-MA, 1-methyladenine; 7-MA, 7-methyladenine; PKA, protein kinase-A; CREB, cAMP-response element binding protein; 9-CPA, 9-cylopentyladenine; PDE, phosphodiesterase; IBMX, 3-isobutyl-1-methylxanthine; GPR-40, G-protein coupled receptor-40; PLC, phospholipase-C; DAG, diacylglycerol; PKC, protein kinase-C; GLP-1, glucagon-like peptide-1; GIP, gastric inhibitory peptide; MMPX, 8-Methoxymethyl-3-isobutyl-1-methyl xanthine; EHNA, Erythro-9-(2-hydroxy-3-nonyl) adenine; KRBH, Krebs-Ringer bicarbonate buffer; PMSF, phenylmethylsulfonyl fluoride; TLCK, Tosyl-lysyl chloromethylketone; RIA, radioimmunoassay; BCA, bicinchoninic acid; LC3, Microtubule-associated protein-1 light chain-3; mTOR, mammalian Target of Rapamycin; PI3 0 K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PDK-1, Phosphoinositide dependent kinase-1; AMPK, AMP-activated protein kinase.Monomethyladenines have effects on DNA repair, G-protein-coupled receptor antagonism and autophagy. In islet û-cells, 3-methyladenine (3-MA) has been implicated in DNA-repair and autophagy, but its mechanism of action is unclear. Here, the effect of monomethylated adenines was examined in rat islets. 3-MA, N6-methyladenine (N6-MA) and 9-methyladenine (9-MA), but not 1-or 7-monomethylated adenines, specifically potentiated glucose-induced insulin secretion (3-4 fold; p 0.05) and proinsulin biosynthesis (»2-fold; p 0.05). Using 3-MA as a 'model' monomethyladenine, it was found that 3-MA augmented [cAMP] i accumulation (2-3 fold; p 0.05) in islets within 5 minutes. The 3-, N6-and 9-MA also enhanced glucose-induced phosphorylation of the cAMP/protein kinase-A (PKA) substrate cAMP-response element binding protein (CREB). Treatment of islets with pertussis or cholera toxin indicated 3-MA mediated elevation of [cAMP] i was not mediated via G-protein-coupled receptors. Also, 3-MA did not compete with 9-cyclopentyladenine (9-CPA) for adenylate cyclase inhibition, but did for the pan-inhibitor of phosphodiesterase (PDE), 3-isobutyl-1-methylxanthine (IBMX). Competitive inhibition experiments with PDE-isoform specific inhibitors suggested 3-MA to have a preference for PDE4 in islet û-cells, but this was likely reflective of PDE4 being the most abundant PDE isoform in û-cells. In vitro enzyme assays indicated that 3-, N6-and 9-MA were capable of inhibiting most PDE isoforms found in û-cells. Thus, in addition to known inhibition of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3 0 K)/m Target of Rapamycin (mTOR) signaling, 3-MA also acts as a pan-phosphodiesterase inhibitor in pancreatic û-cells to elevate [cAMP] i and then potentiate glucose-induced insulin secretion and production in parallel.

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Mechanisms of hormonal regulation of hepatic glucose metabolism

Cited by 160 publications

References 172 publications

Management of Hyperglycemic Crises in Patients With Diabetes

Management of Hyperglycemic Crises in Patients With Diabetes

Changes in hepatic glycogen cycling during a glucose load in healthy humans

Monomethylated-adenines potentiate glucose-induced insulin production and secretion via inhibition of phosphodiesterase activity in rat pancreatic islets

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