Insulin gluconeogenesis

The conversion of oxaloacetate to PEP by PEP-carboxykinase (PEPCK, Eq. 14-43 Fig. 17-20) is another control point in gluconeogenesis. Insulin inhibits gluconeogenesis by decreasing transcription of the mRNA for this enzyme. Glucagon and cAMP stimulate its transcription. The activity of PEP carboxykinase " is also enhanced by Mn + and by very low concentrations of Fe +. However, the enzyme is readily inactivated by Fe " and oxygen. Any regulatory significance is uncertain. 

After a pure protein meal, the increased levels of dietary amino acids reaching the pancreas stimulate the release of glucagon above fasting levels, thereby increasing amino acid uptake into liver and stimulating gluconeogenesis. Insulin release is also stimulated, but not nearly to the levels found after a high-carbohydrate meal. 

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 dehydrogenases of the pentose phosphate pathway can be classified as adaptive enzymes, since they increase in activity in the well-fed animal and when insulin is given to a diabetic animal. Activity is low in diabetes or starvation. Malic enzyme and ATP-citrate lyase behave similarly, indicating that these two enzymes are involved in lipogenesis rather than gluconeogenesis (Chapter 21). 

In adipose tissue, the effect of the decrease in insulin and increase in glucagon results in inhibition of lipo-genesis, inactivation of lipoprotein lipase, and activation of hormone-sensitive lipase (Chapter 25). This leads to release of increased amounts of glycerol (a substrate for gluconeogenesis in the liver) and free fatty acids, which are used by skeletal muscle and liver as their preferred metabolic fuels, so sparing glucose. 

Pittner, R.A., Fears, R. and Brindley, D.N. (1985). Effects of glucocorticoids and insulin on activities of phosphatidate phosphohydrolase, tyrosine aminotransferase and glycerol kinase in isolated rat hepatocytes in relation to the control of triacyglycerol synthesis and gluconeogenesis. Biochem. J. 225 455—462. 

Answer C. Insulin increases glucose transport in only two tissues, adipose and muscle. The major site of glucose uptake is muscle, which decreases hyperglycemia. Glucose and ketone transport and metabolism are insulin independent in the brain (choice D). Insulin would slow gluconeogenesis (choice A) and fatty acid release from adipose (choice B). Insulin would inhibit glycogenolysis in the liver (choice E). 

Insulin and glucagon regulate gluconeogenesis via changes in cyclic AMP concentration. 

Insulin inhibits glycogenolysis and gluconeogenesis. Glucagon opposes the effects of insulin and therefore helps to maintain the blood glucose level so that it has the same end result as that of fatty acid oxidation (See Figure 12.14). 

Initially the level of insulin decreases, favouring increased rates of lipolysis, fatty acid oxidation, muscle protein degradation, glycogenolysis and gluconeogenesis. It soon increases, however, as a result of insulin resistance, when the stimulation of the above processes will depend on the cytokine levels. For details of endocrine hormone effects, see Chapter 12. For details of cytokines see Chapter 17. 

In relatively recent years, it has become clear that under-nntrition of mother leads to low birth weight of the baby and this can increase the risk of development of degenerative disease in later life, e.g. hypertension, obesity, type 2 diabetes. One hypothesis is that the foetus adapts meta-bolically to deficiencies by increasing the number of cells in organs that perform specific functions that can overcome the deficiency, e.g. an increase in the number of liver cells that carry out gluconeogenesis, an increase in cells in the adrenal cortex to produce more of the chronic stress hormone, cortisol. These changes are carried over into adnlthood which can lead to an inadequate response of the liver to insulin so that insulin resistance develops. So far, however, it is unclear whether deficiencies in specific nntrients or undemutrition per se are responsible for snch changes (Chapter 15). 

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