Insulin Adipose tissue

The first hormonal signal found to comply with the characteristics of both a satiety and an adiposity signal was insulin [1]. Insulin levels reflect substrate (carbohydrate) intake and stores, as they rise with blood glucose levels and fall with starvation. In addition, they may reflect the size of adipose stores, because a fatter person secretes more insulin than a lean individual in response to a given increase of blood glucose. This increased insulin secretion in obesity can be explained by the reduced insulin sensitivity of liver, muscle, and adipose tissue. Insulin is known to enter the brain, and direct administration of insulin to the brain reduces food intake. The adipostatic role of insulin is supported by the observation that mutant mice lacking the neuronal insulin receptor (NDRKO mice) develop obesity. 

GLUT 4 Heart and skeletal muscle, adipose tissue Insulin-stimulated uptake of glucose... 

Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M (2006) MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Qin Invest 116 1494-1505 Kaul M, Garden GA, Lipton SA (2001) Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410 988-994... 

In adipose tissue, insulin stimulation suppresses triglyceride hydrolysis (to free fatty acids and glycerol) by activating cAMP phosphodiesterase (cAMP PDE). Cyclic AMP, (3, 5 cAMP), is required to stimulate hormone sensitive lipase (HSL), the enzyme which hydrolyses triglyceride within adipocytes PDE converts active 3, 5 cAMP to inactive 5 AMP thus preventing the stimulation of HSL. The net effect of insulin on lipid metabolism is to promote storage. 

As it does in adipose tissue, insulin promotes increased glucose uptake by skeletal muscle. 

Insulin also stimulates the storage of excess fuel as fat (Fig. 23-26). In the liver, insulin activates both the oxidation of glucose 6-phosphate to pyruvate via glycolysis and the oxidation of pyruvate to acetyl-CoA. If not oxidized further for energy production, this acetyl-CoA is used for fatty acid synthesis in the liver, and the fatty acids are exported as the TAGs of plasma lipoproteins (VLDLs) to the adipose tissue. Insulin stimulates TAG synthesis in adipocytes, from fatty acids released... 

The uptake of glucose by brain, liver, kidneys, erythrocytes, and the islets of Langerhans is unaffected by insulin. However, in muscle and adipose tissues insulin stimulates glucose uptake. Part of this effect results from insulin-induced translocation of molecules of the 509-residue glucose transport protein GLUT4 (Chapter 8) from the cytosol into the plasma membrane where it can function.354-3563 Insulin apparently also increases the rate of synthesis of the transporters. 

Q4 In type 2 diabetes there is a reduction in the responsiveness of beta-cells (/1-cells) to plasma glucose levels (which might be due to a reduction in the number of (6-cells or their abnormal function) and an increase in the secretion of glucagon. Many patients with this condition show resistance insulin. Insulin resistance is defined as a suboptimal response to insulin in insulin-sensitive tissues (liver, muscle and adipose tissues). Insulin resistance is increased by obesity, inactivity and age. Obesity and insulin resistance coexist in approximately 60% to 80% of patients with type 2 diabetes in the West. In approximately 10% to 40% of patients with type 2 diabetes, amyloid deposits have been found in the islet tissues of the pancreas. Interestingly, the presence of amyloid correlates positively with the age of the patient and the duration and severity of the disease. 

In muscle and adipose tissue, insulin promotes transport of glucose and other monosaccharides across cell membranes it al.so facilitates tran.sport of amino icids, potassium ion.s. nucleosides, and ionic phosphate. Insulin also activates certain enzymes—kinases and glycogen. synthetase in muscle und adipose tissue. In adipose tissue, insulin decreases the release of fatty acids induced by epinephrine or glucagon. cAMP promotes fatty acid release from adipose ti.ssue therefore. it is pos.sible that insulin decreases fatty acid release by reducing tissue levels of cAMP. Insulin also facilitates the incorporation of intracellular amino acids into protein. 

GLUT4 (muscle) Skeletal muscle, cardiac muscle, and adipose tissue Insulin-stimulated glucose transport... 

In some tissues, the phosphatase is regulated by hormones. In liver, epinephrine binds to the a-adrenergic receptor to initiate the phosphatidyl inositol pathway (p. 388), causing an increase in Ca" concentration that activates the phosphatase. In tissues capable of fatty acid synthesis, such as the liver and adipose tissue, insulin, the hormone that signifies the fed state, stimulates the phosphatase, increasing the conversion of pyruvate into acetyl Co A. Acetyl CoA is the precursor for fatty acid synthesis (p. 635). In these tissues, the pyruvate dehydrogenase complex is activated to funnel glucose to pyruvate and then to acetyl CoA and ultimately to fatty acids. 

Fig. 36.7. Regulation of the storage of triacylglycerols (TG) in adipose tissue. Insulin stimulates the secretion of LPL from adipose cells and the transport of glucose into these cells. ApoCii activates LPL. FA = fatty acids.

The fed state is also an opportunity to lay down storage triglycerides in adipose tissue. Insulin therefore switches on lipoprotein lipase, which downloads fatty acids from chylomicrons it switches on the enzymes that resynthesise triglyceride inside the adipocytes it switches off hormone-sensitive lipase, the one that releases fatty acids into the blood when the stores are mobilised. 

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. 

Raven GM. The pathophysiological consequences of adipose tissue insulin resistance. In Insulin Resistance The Metabolic Syndrome X (Reaven GM and Laws A, eds). Humana Press, Totowa, NJ, 1999 233-246. 

Insulin is the only hormone known to reduce the blood sugar level. It is secreted by the -cells of the islets of Langerhans in the pancreas in response to an elevated level of blood glucose. The overall action of insulin is to promote storage pathways. More specifically it stimulates the transport of glucose across the plasma membrane of certain cells, especially of muscle and adipose tissue, but not of liver. In this way it promotes the synthesis of glycogen in the liver and fatty acids in both liver and adipose tissue. Insulin also stimulates protein synthesis. 

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