Insulin fasting state

In the GI tract, different hydrodynamic conditions are present, depending on the fasted or the fed state. Contraction patterns are controlled in terms of electromechanical impulses (myoelectric activity) as well as by various hormones (cholecystokinin, secretin, glucagon, motilin, and insulin, for example). In the fasted state, the motility pattern is regulated by the (interdigestive) migrating myoelectric complex [(I)... 

Details of plasma lipoproteins and their metabolism are given in Section 5.5. Most of the cholesterol in the blood is carried as part of low density lipoprotein (LDL) or high density lipoprotein (HDL), whereas most triglyceride, in the fasting state, is carried by very low density lipoprotein (VLDL). The relative concentrations of these lipoproteins constitute the lipid profile and determine CVD risk. Diabetics are more likely to show an unhealthy profile with elevated concentrations of LDL and triglyceride but reduced HDL concentration. This pattern can be partly explained by enhanced fatty acid liberation from adipocytes as a consequence of insulin resistance in that tissue and due to reduced removal from the circulation of triglycerides, which is also insulin dependent. 

CM and VLDL secreted by intestinal cells and VLDL synthesized and secreted in the liver have similar metabolic fates. After secretion into the blood, newly formed CM and VLDL take up apoprotein (apo-C) from HDL and are subsequently removed from the blood (plasma half-life of less than 1 h in humans [137]) primarily by the action of lipoprotein lipase (LPL). Lipoprotein lipase is situated mainly in the vascular bed of the heart, skeletal muscle, and adipose tissue and catalyzes the breakdown of core TG to monoglycerides and free fatty acids, which are taken up into adjacent cells or recirculated in blood bound to albumin. The activity of LPL in the heart and skeletal muscle is inversely correlated with its activity in adipose tissue and is regulated by various hormones. Thus, in the fasted state, TG in CM and VLDL is preferentially delivered to the heart and skeletal muscle under the influence of adrenaline and glucagon, whereas in the fed state, insulin enhances LPL activity in adipose tissue, resulting in preferential uptake of TG into adipose tissue for storage as fat. 

Fatty add synthetase is not controlled directly by phosphorylation however, insulin, glucagon, and thyroxine have an effect on its activity by controlling its cellular concentration. Both insulin and thyroxine increase the biosynthesis of the enzyme, whereas glucagon is inhibitory. Thyroxine and glucagon appear to regulate the biosynthesis at the transcription level, whereas insulin affects the enzyme activity at the translation level. It has no effect on cellular fatty add synthetase mRNA concentration. In summary, fatty add synthetase levels are up in the fed state and down in the fasting state. 

Because insulin normally inhibits lipolysis, a diabetic has an extensive lipolytic activity in the adipose tissue. As is seen in Table 21.4, plasma fatty acid concentrations become remarkably high. /3-Oxidation activity in the liver increases because of a low insulin/glucagon ratio, acetyl-CoA carboxylase is relatively inactive and acyl-CoA-camitine acyltransferase is derepressed. /3-Oxidation produces acetyl-CoA which in turn generates ketone bodies. Ketosis is perhaps the most prominent feature of diabetes mellitus. Table 21.5 compares ketone body production and utilization in fasting and in diabetic individuals. It may be seen that, whereas in the fasting state ketone body production is roughly equal to excretion plus utilization, in diabetes this is not so. Ketone bodies therefore accumulate in diabetic blood. 

Another observable difference between the diabetic and the fasting state is the high concentration of very low density lipoprotein (VLDL) and chylomicrons in the diabetic and their lowering in the prolonged fasting state. Insulin-dependent lipoprotein lipase is nonfunctional in the diabetic, resulting in an incomplete lipid clearance from the bloodstream. In addition, the liver may not be able to handle the enormous fatty acid influx in the diabetic, converting the excess to VLDL. 

Excessive hepatic glucose output is an important contributing factor to insulin resistance [200, 201, 280] and direct or indirect inhibition of glucose production is expected to have a favourable effect on hyperglycaemia, particularly in the fasting state. 

Fig. 10.10 Regulatory Interations of Fatty Acid Synthesis and Oxidation in Liver Note that a lack of insulin results in a release of fatty acids from adipose. Regulation of Hormone-Sensitive Lipase (Lipolysis) "Fasted" State (Fig. 10.11)...

The level of insulin in the blood increases in the fed state and promotes fuel storage the level of glucagon increases in the fasting state and promotes the release of stored fuel. 

D. Insulin causes activation of phosphatases, which dephosphorylate all of the enzymes that were phosphorylated in the fasting state. Protein kinase A is not activated by phosphorylation during fasting but by the binding of cAMP to regulatory subunits. 

In the fasting state 75% of total body glucose disposal takes place in non-insulin dependent tissues the brain and splanchnic tissues (liver and gastrointestinal tissues). In fact, brain glucose uptake occurs at the same rate during fed and fasting periods and is not altered in type 2 diabetes. 

D. The low body weight and fat mass observed in the patient are consistent with a metabolically fasted state. During such a condition, circulating insulin levels will be low, whereas counterregulatory hormones (e.g., glucagon, epinephrine, and cortisol) will be elevated. 

The clinical efficacy of fatty acid oxidation inhibitors has not yet been proven. Some beneficial effects have been noted in insulin-dependent diabetics, but no controlled clinical trials in non-insulin-dependent diabetics have been reported. Although the inhibition of fatty acid oxidation causes hypoglycaemia in the fasted state, it is unclear whether these compounds will be effective in an individual with normal eating habits. The safety and efficacy of this class of compounds can be determined only by further studies. 

There is evidence that intestinal lipoprotein production is increased in diabetes and insulin-resistant states. Intestinal lipoprotein overproduction has been suggested to be a major contributor to the fasting and postprandial lipemia observed in insulin-resistant states (M.R. Taskinen, 2003). Evidence for increased formation of intestinal apo B48-containing lipoproteins as a result of insulin resistance comes from studies in animal models (K. Adeli, 2006) as well as humans. The underlying mechanisms are currently unknown, but increased de novo lipogenesis, reduced apo B48 degradation, and higher MTP expression have been implicated. 

Thus, in addition to hormonal effects (see here), the liver senses the fed state and acts to store fuel derived from glucose. The liver also senses the fasted state and increases the synthesis and export of glucose when blood glucose levels are low. (Other organs also sense the fed state, notably the pancreas, which adjusts its glucagon and insulin outputs accordingly.)... 

Di Abietes has a ketoacidosis. When the amount of insulin she injects is inadequate, she remains in a condition similar to a fasting state even though she ingests food (see Chapters 2 and 3). Her liver continues to metabolize fatty acids to the ketone bodies acetoacetic acid and p-hydroxy-butyric acid. These compounds are weak acids that dissociate to produce anions (ace-toacetate and p-hydroxybutyrate, respectively) and hydrogen ions, thereby lowering her blood and cellular pH below the normal range. 

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