Insulin second messenger

Insulin acts by binding to insulin receptors on cell membrane. The insulin receptor complex is internalized. By phosphorylation and dephosphorylation reactions there is stimulation or inhibition of enzymes involved in metabolic actions of insulin. Second messengers like phosphatidyl inositol glycan and DAG also mediate the action of insulin on metabolic enzymes. 

Cobb, J.E. and Johnson, M.R. Synthesis of 6-0-(2-aminoethyl)-D,L-inyo-inositol-l,2-cyclic phosphate A model of a putative insulin second messenger. Tetrahedron, 1991, 47, 21-30. 

J. Insulin second messengers synthesis of 6-0-(2-amino-2-deoxy-a-D-glucopyrano-sylJ-D-chiro-inositol-l-phosphate. Tetrahedron, Lett., 1993, 34, 7869-7872. 

The preparation of the racemic cyclic phosphate (98) as a model for the putative insulin second messenger has been achieved. ... 

Family of enzymes phosphorylating phosphatidylinositol (Ptdlns), PtdIns(4)phosphate, and PtdIns(4,5)phosphate in the 3-position. The Ptdlns(3 phospholipids are second messengers in processes like cell growth, cytoskeletal rearrangement, and vesicular transport. PI 3-kinases are heterodimers composed of a catalytic and a regulatory subunit. The enzymes are activated by insulin, many growth factors, and by a variety of cytokines. Their activity can be inhibited by wortmannin and LY294002. 

Cyclic AMP (cAMP) (Figure 18-5) is formed from ATP by adenylyl cyclase at the inner surface of cell membranes and acts as an intracellular second messenger in response to hormones such as epinephrine, norepinephrine, and glucagon. cAMP is hydrolyzed by phosphodiesterase, so terminating hormone action. In hver, insulin increases the activity of phosphodiesterase. 

Some water-soluble hormones bind to receptors with intrinsic protein kinase activity (often tyrosine kinases). In this case, no second messenger is required for protein kinase activation. The insulin receptor is an example of a tyrosine kinase receptor. 

Insulin binding activates the tyrosine kinase activity associated with the cytoplasmic domain of its receptor as shown in F jure 1-9-4. There is no trimeric G protein, enzyme, or second messenger required to activate this protein tyrosine kinase activity ... 

Glucagon, a peptide of 29 amino acids, is a product of the A cells of the pancreas. It is the antagonist of insulin and, like insulin, mainly influences carbohydrate and lipid metabolism. Its effects are each opposite to those of insulin. Glucagon mainly acts via the second messenger cAMP (see p. 384). 

Leptin makes the cells of liver and muscle more sensitive to insulin. One hypothesis to explain this effect suggests cross-talk between the protein tyrosine kinases activated by leptin and those activated by insulin (Fig. 23-35) common second messengers in the two signaling pathways allow leptin to trigger some of the same downstream events that are triggered by insulin, through insulin receptor substrate-2 (IRS-2) and phos-phoinositide 3-kinase (PI-3K) (Chapter 12). 

The known regulatory effects of insulin (Table 17-3) often involve phosphorylation of serine or threonine side chains on specific proteins. The tyrosine kinase of the activated insulin receptors does not catalyze such phosphorylation. Therefore, it seems likely that one or more second messengers or mediator substances are needed. Much effort has gone into searching for... 

Glucagon and insulin are only two of the many hormones that regulate vertebrate metabolism, and cAMP is only one of several so-called second messengers that transduce the hormone signal to the inside of the cell. In the remainder of this chapter we take a comprehensive look at the hormone systems that provide the main mechanisms for regulating energy metabolism and other metabolic activities as well. 

In animals, adrenomedullin dilates resistance vessels in the kidney, brain, lung, hind limbs, and mesentery, resulting in a marked, long-lasting hypotension. The hypotension in turn causes reflex increases in heart rate and cardiac output. Adrenomedullin also acts on the kidneys to increase sodium excretion, and exerts several endocrine effects including inhibition of aldosterone and insulin secretion. Finally it acts on the central nervous system to increase sympathetic outflow. These diverse actions of adrenomedullin are mediated both by CGRP receptors and unique adrenomedullin receptors, the properties of which are incompletely defined. The major second messenger for both receptors is cAMP. 

The control of cellular kinases and phosphatases appears to be of undoubted importance to the action of insulin. Whether such effects are determined either directly or indirectly by the receptor tyrosyl kinase, Gins , the second messengers GIP and DAG and by modification of other G-proteins, perhaps even all of these, remains to be determined (Fig. 5). 

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