Fatty acid metabolism insulin

Insulin resistance occurs when the normal response to a given amount of insulin is reduced. Resistance of liver to the effects of insulin results in inadequate suppression of hepatic glucose production insulin resistance of skeletal muscle reduces the amount of glucose taken out of the circulation into skeletal muscle for storage and insulin resistance of adipose tissue results in impaired suppression of lipolysis and increased levels of free fatty acids. Therefore, insulin resistance is associated with a cluster of metabolic abnormalities including elevated blood glucose levels, abnormal blood lipid profile (dyslipidemia), hypertension, and increased expression of inflammatory markers (inflammation). Insulin resistance and this cluster of metabolic abnormalities is strongly associated with obesity, predominantly abdominal (visceral) obesity, and physical inactivity and increased risk for type 2 diabetes, cardiovascular and renal disease, as well as some forms of cancer. In addition to obesity, other situations in which insulin resistance occurs includes... 

These agents activate PPAR-y a nuclear transcription factor important in fat cell differentiation and fatty acid metabolism. PPAR-yagonists enhance insulin sensitivity in muscle, liver, and fat tissues indirectly. Insulin must be present in significant quantities for these actions to occur. 

The prevalence of Type 2 Diabetes (T2D) is increasing world-wide and considered one of the main threats to human health in the 21st century. In 2010, 221 million patients are expected to be diabetic (compared to 151 million in the year 2000). The increase in diabetes prevalence is considered to be secondary to changes in human lifestyle accompanied by physical inactivity and unlimited food supply. Skeletal muscle insulin resistance, defined as the reduced response of skeletal muscle to a given dose of insulin, is a common finding in patients with type 2 diabetes mellitus and can be found before the onset and predict the development of the disease. Several factors determine skeletal muscle insulin sensitivity and among others alterations in fatty acid metabolism have been proposed. ... 

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.

Peterson et al. found an increase in intramyocellular lipid content and reduction in mitochondria phosphorylation (mitochondrial rates of ATP production) in insulin-resistant subjects versus insulin-sensitive subjects. They concluded that their results supported the h) othesis that insulin resistance is due to dysregulation of intramyocellular fatty acid metabolism, which maybe caused by an inherited defect in mitochondrial oxidative phosphorylation. 

The vital role of insulin is best appreciated when we look at the consequences of a lack of insulin and/or a lack of insulin response, leading to excess blood glucose. Hyperglycaemia is responsible for many manifestations of the disease, because it leads to non-enzymic glycation of proteins, as shown by Anthony Cerami (of course, there are other important manifestations of the disease, such as the dysfunction of fatty acid metabolism and the formation of ketone bodies, which have not been considered here see P. J. Randle et... 

Groop, L. C., Bonadonna, R. C., DelPrato, S., Ratheiser, K, Zyck, K Ferrannini, E., and DeFronzo, R A. (1989). Glucose and free fatty acid metabolism in non-insulin-depend-eni diabetes mellitus. . Clin, invest. Hi, 205-213. 

S.E. Meek, et al.. Insulin regulation of regional free fatty acid metabolism. Diabetes, 1999, 48, 10-14. 

Insulin is released after carbohydrate intake. Describe two ways insulin acts to influence fatty acid metabolism. 

Although the effects of insulin on postprandial metabolism are profound, other factors (e.g., substrate supply and allosteric effectors) also affect the rate and degree to which these processes occur. For example, elevated levels of fatty acids in blood promote lipogenesis in adipose tissue. Regulation by several allosteric effectors further ensures that competing pathways do not occur simultaneously for example, in many cell types fatty acid synthesis is promoted by citrate (an activator of acetyl-CoA carboxylase), whereas fatty acid oxidation is depressed by malonyl-CoA (an inhibitor of carnitine acyltransferase I activity). The control of fatty acid metabolism is described in Section 12.1. 

Involvement of PI3K/PKB Signalling in Insulin Effects on Fatty Acid Metabolism... 

Recent studies strongly suggest a role of PKB in governing some aspects of hepatic fatty acid metabolism in response to insulin. The detailed mechanisms by which these regulations occur are not fully understood but increasing evidence suggests a cross-talk with both SREBP-lc and PPARa. 

Between meals, a decreased insulin level and increased levels of insulin counter-regulatory hormones (e.g., glucagon) activate hpolysis, and free fatty acids are transported to tissues bound to serum albumin. Within tissnes, energy is derived from oxidation of fatty acids to acetyl CoA in the pathway of -oxidation. Most of the enzymes involved in fatty acid oxidation are present as 2-3 isoenzymes, which have different but overlapping specificities for the chain length of the fatty acid. Metabolism of unsaturated fatty acids, odd-chain-length fatty acids, and medium-chain-length fatty acids requires variations of this basic pattern. The acetyl CoA produced from fatty acid oxidation is principally oxidized in the TCA cycle or converted to ketone bodies in the liver. 

Turner, N Cooney, GJ Kraegen, EW Bruce, CR. Fatty acid metabolism, energy expenditure and insulin resistance in muscle. J Endocrinol, 2014 220 T61-79. 

C24H38N7O19P3S 853.587 Involved in control of hepatic fatty acid synthesis and oxidation. Acts as a metabolic coupling factor in pancreatic p-cell signal transduction mechanisms linking insulin secretion and fatty acid metabolism. 236 (H2O). 

The mechanism of action of insulin is discussed below. Insulin deficiency interferes with the adequate utilization of glucose. The sugar accumulates in the blood, and hyperglycemia, glucosuria, dehydration, increased diuresis, loss of electrolytes, and polydypsia ensue. By a mechanism that may or may not be related to the primary defect in carbohydrate metabolism observed in diabetes, fatty acid metabolism is also affected. A critical phenomenon is the accumulation of 2-carbon compounds that condense to form 4-car-bon compounds, generating ketosis and acidosis. These symptoms will now be reviewed individually. 

In adipose tissues, insulin accelerates the dissimilation of glucose to CO2 through the Embden-Meyerhof pathway and the hexose monophosphate shunt and increases its utilization for glycogen and fatty acid synthesis. Insulin is without effect on fatty acid uptake and lipogenesis when glucose is absent from the medium. And the studies of Fain and Loken [132] have established that the antilipolytic effect of insulin is blocked by trypsin. Trypsin does not affect its inhibition through other metabolic interferences. A protein factor, possibly a receptor, probably is needed for insulin s action on adipose tissue. 

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