Gluconeogenesis Diabetes

Key words Zebrafish, Gluconeogenesis, Diabetes, Metabolic disease. Fasting metabolism. Small-molecule screening, Bioliuninescence, Phosphoenolpyruvate-carboxykinase, pckl. Transgenesis... 

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). 

Increased fatty acid oxidation is a characteristic of starvation and of diabetes meUims, leading to ketone body production by the Ever (ketosis). Ketone bodies are acidic and when produced in excess over long periods, as in diabetes, cause ketoacidosis, which is ultimately fatal. Because gluconeogenesis is dependent upon fatty acid oxidation, any impairment in fatty acid oxidation leads to hypoglycemia. This occurs in various states of carnitine deficiency or deficiency of essential enzymes in fatty acid oxidation, eg, carnitine palmitoyltransferase, or inhibition of fatty acid oxidation by poisons, eg, hypoglycin. 

I. Magnusson, D. L. Rothman, L. D. Katz, R. G. Shulman, and G. I. Shulman, Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study, J. Clin. Invest. 90 1323 (1992). 

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). 

Metformin Obscure Reduced hepatic and renal gluconeogenesis Decreased endogenous glucose production Type 2 diabetes Oral maximal plasma concentration in 2-3 h Toxicity Gastrointestinal symptoms, lactic acidosis (rare) cannot use if impaired renal/hepatic function congestive heart failure (CHF), hypoxic/acidotic states, alcoholism... 

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... 

Gerich, J.E., Meyer, C., Woerle, H.J., Stumvoli, M. (2001) Renal gluconeogenesis its importance in human glucose homeostasis. Diabetes Care 24, 382-391. 

Conditions that promote gluconeogenesis(untreated diabetes, severely reduced food intake) dow the citric acid cycle (by drawing off oxaloacetate) and enhance the conversion of acetyl-CoA to acetoacetate. The released coenzyme A allows continued /3 oxidation of fatty acids... 

FIGURE 23-28 Fuel metabolism in the liver during prolonged fasting or in uncontrolled diabetes mellitus. After depletion of stored carbohydrates, to proteins become an important source of glucose, produced from glucogenic amino acids by gluconeogenesis. ... 

Glucocorticoid treatment of known diabetics normally leads to deregulation, but this can be compensated for by adjusting the dose of insulin. The increased gluconeogenesis induced by glucocorticoids mainly takes place in the liver, but glucocorticoid treatment is especially likely to disturb carbohydrate metabolism in liver disease. 

Patients with type 2 diabetes have often an increased HGO [110-112]. As the glycogenolysis is decreased [111] and in all cases transient, the cause of augmented HGO is increased gluconeogenesis, mainly from lactate [111, 113]. The increased lactate production is interesting. To give a constant overproduction of lactate, glucose must be transported into cells but not oxidized, mainly because there is an increased level of FFA and therefore an increased fat oxidation [74]. The overproduction is thus caused by a mismatch between the fluxes of glucose and fat. 

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