Free fatty acids insulin deficiency

Type 2 diabetes is characterized by tissue resistance to the action of insulin combined with a relative deficiency in insulin secretion. A given individual may have more resistance or more beta-cell deficiency, and the abnormalities may be mild or severe. Although insulin is produced by the beta cells in these patients, it is inadequate to overcome the resistance, and the blood glucose rises. The impaired insulin action also affects fat metabolism, resulting in increased free fatty acid flux and triglyceride levels and reciprocally low levels of high-density lipoprotein (HDL). 

Type 2 DM accounts for as many as 90% of DM cases and is usually characterized by the presence of both insulin resistance and relative insulin deficiency. Insulin resistance is manifested by increased lipolysis and free fatty acid production, increased hepatic glucose production, and decreased skeletal muscle uptake of glucose. )3-Cell dysfunction is progressive and contributes to worsening blood glucose control over time. Type 2 DM occurs when a diabetogenic lifestyle (excessive calories, inadequate exercise, and obesity) is superimposed upon a susceptible genotype. 

The hver produces ketone bodies by oxidizing free fatty acids to acetyl CoA, which then is converted to acetoacetate and /3-hydroxybutyrate. The initial step in fatty acid oxidation is transport of the fatty acids into the mitochondria. The essential enzyme in this process, acylcarnitine transferase, is inhibited by intramitochondrial malonyl CoA, one of the products of fatty acid synthesis. Normally, insulin inhibits Upolysis, stimulates fatty acid synthesis (thereby increasing the concentration of malonyl CoA), and decreases the hepatic concentration of carnitine these factors aU decrease the production of ketone bodies. Conversely, glucagon stimulates ketone body production by increasing fatty acid oxidation and decreasing concentrations of malonyl CoA. In patients with type 1 DM, insulin deficiency and glucagon in excess provide a hormonal milieu that favors ketogenesis and may lead to ketoacidosis. 

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. 

Insulin deficiency results in the stimulation of lipolysis, the excess free fatty acids liberated being converted to ketone bodies by the liver. This is accompanied by excess hydrogen ion production and acidosis can result. 

Long-term regulation of acetyl-CoA carboxylase involves nutritional, hormonal (e.g., insulin, thyroxine), and other factors. In animals on high-carbohydrate diets, fat-free diets, choline deprivation, or vitamin B12 deprivation, the activity is enhanced. However, fasting, high intake of fat or of polyunsaturated fatty acids, and prolonged biotin deficiency leads to decreased activity. In diabetes, the enzyme activity is low, but insulin administration raises it to normal levels. 

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