Insulin Glucose-6-phosphatase

The effects of stimulation of the insulin receptors include activation of glucokinase and glucose phosphatase. Insulin also increases glucose transport... 

Metformin restrains hepatic glucose production principally by suppression of gluconeogenesis. The mechanisms involve potentiation of insulin action and decreased hepatic extraction of certain gluconeogenic substrates such as lactate. In addition, metformin reduces the rate of hepatic glycogenolysis and decreases the activity of hepatic glucose-6-phosphatase. Insulin-stimulated glucose uptake and glycogenesis by skeletal muscle is increased by metformin mainly by increased... 

Both phosphorylase a and phosphorylase kinase a are dephosphorylated and inactivated by protein phos-phatase-1. Protein phosphatase-1 is inhibited by a protein, inhibitor-1, which is active only after it has been phosphorylated by cAMP-dependent protein kinase. Thus, cAMP controls both the activation and inactivation of phosphorylase (Figure 18-6). Insulin reinforces this effect by inhibiting the activation of phosphorylase b. It does this indirectly by increasing uptake of glucose, leading to increased formation of glucose 6-phosphate, which is an inhibitor of phosphorylase kinase. 

Glucose-6-phosphatase T T Glucocorticoids, glucagon, epinephrine (cAMP) Insulin ... 

Interconversion processes (see p. 120) also play an important role. They are shown here in detail using the example of the PDH complex (see p. 134). The inactivating protein kinase [la] is inhibited by the substrate pyruvate and is activated by the products acetyl-CoA and NADH+H. The protein phosphatase [Ibj—like isodtrate dehydrogenase [3] and the ODH complex [4j-is activated by Ca. This is particularly important during muscle contraction, when large amounts of ATP are needed. Insulin also activates the PDH complex (through inhibition of phosphorylation) and thereby promotes the breakdown of glucose and its conversion into fatty acids. 

Transporters in the plasma membrane of hepatocytes allow insulin-independent transport of glucose and other sugars in both directions. In contrast to muscle, the liver possesses the enzyme glucose-6-phosphatase, which can release glucose from glucose-6-phosphate. 

Diabetes - insulin dependent Methyl malonic, propionic or isovaleric acidaemias Pyruvate carboxylase and multiple carboxylase deficiency Gluconeogenesis enzyme deficiency glucose-6-phosphatase, fructose-1,6-diphosphatase or abnormality of glycogen synthesis (glycogen synthase) Ketolysis defects Succinyl coenzyme A 3-keto acid transferase ACAC coenzyme A thiolase... 

This phosphatase converts phosphorylase a to phosphorylase b, sharply reducing the activity of phosphorylase and slowing glycogen breakdown in response to high blood glucose. Insulin also acts indirectly to stimulate PP1 and slow glycogen breakdown. 

A 73 year old Japanese woman, weight 33.5 kg, took nateglinide 270 mg/day and pioglitazone 15 mg/day for 6 months (105). Her HbAic concentration was 8.6% and fasting glucose 11.4 mmol/1. Metformin 250 mg bd was added and 3 weeks later she developed jaundice and fatigue. A few months before her liver function tests had been normal. Aspartate transaminase activity was 689 IU/1, alanine transaminase 772 IU/1, alkaline phosphatase 639 IU/1, and bilirubin 6.5 mg/dl. All oral therapy was withdrawn and insulin started. Her liver function improved over the next few weeks. 

Ilyin, V.S. and Titova, G.V. (1963). In vitro effect of insulin on the activity of liver glucose-6-phosphate dehydrogenase and glucose-6-phosphatase (In Russian). Biochimika 28,987-991. 

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