Insulin lipolysis inhibition

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. 

Insulin normally inhibits lipolysis by decreasing the lipolytic activity of HSL in the adipocyte. Individuals such as Di Abietes, who have a deficiency of insulin, have an increase in lipolysis and a subsequent increase in the concentration of free fatty acids in the blood. The liver, in turn, uses some of these fatty acids to synthesize triacylglycerols, which then are used in the hepatic production of VLDL. VLDL is not stored in the liver but is secreted into the blood, raising its serum concentration. Di also has low levels of LPL because of decreased insulin levels. Her hypertriglyceridemia is the result, therefore, of both overproduction of VLDL by the liver and decreased breakdown of VLDL triacylglycerol for storage in adipose cells. 

Increased lipid synthesis/inhibi-tion of lipolysis Activation of lipoprotein lipase (LPL)/induc-tion of fatty acid synthase (FAS)/inactivation of hormone sensitive lipase (HSL) Facilitated uptake of fatty acids by LPL-dependent hydrolysis of triacylglycerol from circulating lipoproteins. Increased lipid synthesis through Akt-mediated FAS-expression. Inhibition of lipolysis by preventing cAMP-dependent activation of HSL (insulin-dependent activation of phosphodiesterases )... 

As to be expected from a peptide that has been highly conserved during evolution, NPY has many effects, e.g. in the central and peripheral nervous system, in the cardiovascular, metabolic and reproductive system. Central effects include a potent stimulation of food intake and appetite control [2], anxiolytic effects, anti-seizure activity and various forms of neuroendocrine modulation. In the central and peripheral nervous system NPY receptors (mostly Y2 subtype) mediate prejunctional inhibition of neurotransmitter release. In the periphery NPY is a potent direct vasoconstrictor, and it potentiates vasoconstriction by other agents (mostly via Yi receptors) despite reductions of renal blood flow, NPY enhances diuresis and natriuresis. NPY can inhibit pancreatic insulin release and inhibit lipolysis in adipocytes. It also can regulate gut motility and gastrointestinal and renal epithelial secretion. 

The rate of mitochondrial oxidations and ATP synthesis is continually adjusted to the needs of the cell (see reviews by Brand and Murphy 1987 Brown, 1992). Physical activity and the nutritional and endocrine states determine which substrates are oxidized by skeletal muscle. Insulin increases the utilization of glucose by promoting its uptake by muscle and by decreasing the availability of free long-chain fatty acids, and of acetoacetate and 3-hydroxybutyrate formed by fatty acid oxidation in the liver, secondary to decreased lipolysis in adipose tissue. Product inhibition of pyruvate dehydrogenase by NADH and acetyl-CoA formed by fatty acid oxidation decreases glucose oxidation in muscle. 

Insulin stimulates lipogenesis by several other mechanisms as well as by increasing acetyl-CoA carboxylase activity. It increases the transport of glucose into the cell (eg, in adipose tissue), increasing the availability of both pyruvate for fatty acid synthesis and glycerol 3-phosphate for esterification of the newly formed fatty acids, and also converts the inactive form of pyruvate dehydrogenase to the active form in adipose tissue but not in liver. Insulin also—by its ability to depress the level of intracellular cAMP—inhibits lipolysis in adipose tissue and thereby reduces the concentration of... 

Figure 16.3 Effects of insulin on the glucose/fatty acid cycle. Insulin enhances glucose metabolism by stimulating glucose uptake by muscle and adipose tissue and by inhibiting lipolysis in adipose tissue (see Chapter 12 for the mechanism of these effects). The effect of glucose metabolism on lipolysis is via stimulation of fatty acid esterification via glycerol 3-phosphate.

Glucocorticoids inhibit the uptake of glucose by fat cells, resulting in increased lipolysis. The increased insulin secretion in response to hyperglycaemia also stimulates lipogenesis and ultimately increase in fat deposition. 

Glucocorticoids increase serum glucose levels and thus stimulate insulin release and inhibit the uptake of glucose by muscle cells, while they stimulate hormone sensitive lipase and thus lipolysis. The increased insulin secretion stimulates lipogenesis and to a lesser degree inhibits lipolysis, leading to a net increase in fat deposition combined with increased release of fatty acids and glycerol into the circulation. 

Fig. 21.2 Major effects of AMPK activation on numerous tissues. AMPK plays a key role in regulating whole body energy storage and expenditure. In hypothalamus, AMPK is involved in regulation of satiety and food intake. Activation of AMPK in the hypothalamus increases food intake, whereas inhibition decreases intake. In peripheral tissues such as skeletal muscle and liver, activation of AMPK increases energy expenditure by stimulating mitochondrial genesis and energy substrate utilization. AMPK also regulates lipolysis in adipose tissue and insulin secretion in pancreas.

In the -in vivo situation, the ketogenic action of glucagon is most prominent in states of insulin deficiency. This can be explained because insulin normally suppresses the effect of glucagon on hepatic cAMP levels [170] and inhibits the action of the hormone on lipolysis, i.e., fatty acid release in adipose tissue [171]. 

In addition, there are numerous effects of insulin, generally anabolic, not mediated through its well-known effects on glucose transport. For example, in muscle, insulin decreases glycogenolysis and proteolysis. Lipolysis is inhibited by insulin in adipocytes. The effect of insulin on hepatic tissue is to promote increased glycogen production and protein synthesis and to inhibit glycogenolysis, proteolysis, lipolysis, and gluconeogenesis (Fig. 10-1). 

Insulin is an antilipolytic hormone, and its effect on adipose tissue is to increase the transport of glucose into the fat cell, to stimulate lipogenesis and inhibit lipolysis. Thus, pyruvate dehydrogenase and acetyl-CoA carboxylase are activated, and the hormone-sensitive lipase is inactivated. In the normal, well-fed state insulin stimulates the deposition of fat. 

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