Cell membrane insulin

Vincent and co-workers (496, 497) studied the insuhn-potentiating action of Cr(III) complexes at a subcellular level. The activity of tyrosine kinase (in the isolated fragment of a cell membrane insulin receptor) increased threefold to eightfold in the presence of some types of Cr(III) complexes (50-500 nM Cr) and insulin, compared with insuhn alone (Section IV.C.3). The active Cr(III) species included one isolated from the reaction of Cr(VI) with bovine liver homogenate (Section IV.C.3) (496) and a well-characterized trinuclear Cr(III) propionate complex (Section IV.D) (497). Integrity of the latter complex in the reaction medium (50 mM Tris buffer, pH 7.4) was verified by NMR spectroscopy (497). 

FIGURE 49-1. Normal glucose metabolism. Once insulin binds with receptors on the cell membrane, glucose can move into the cell, promoting cellular metabolism and energy production. 

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. 

Thirty years ago, receptors for polypeptide hormones such as insulin and GH were identified as binding activity in cells, membranes, or solubihzed membrane proteins using radiolabeled proteins... 

Osterode W, Holler C, Ulberth F (1996) Nutritional antioxidants, red cell membrane fluidity and blood viscosity in type 1 (insulin dependent) diabetes mellitus. Diabet Med 13(12) 1044-1050... 

Insulin binding to the extracellular side of cell membranes initiates the insulin cascade , a series of phosphorylation/dephosphorylation steps. A postulated mechanism for vanadium is substitution of vanadate for phosphate in the transition state structure of protein tyrosine phosphatases (PTP).267,268 In normal physiological conditions, the attainable oxidation states of vanadium are V111, Viv and Vv. Relevant species in solution are vanadate, (a mixture of HV042-/ H2VOO and vanadyl V02+. Vanadyl is not a strong inhibitor of PTPs, suggesting other potential mechanisms for insulin mimesis for this cation. 

The answer is b. (Hardman, p 1507. Katzung, pp 723-724J Three proposed mechanisms for sulfonylurea action are (1) the release of insulin from pancreatic cells, (2) reduction of serum glucagon levels, and (.3) increased binding of insulin to tissue receptors. On binding to a specific receptor that is associated with a K channel in cell membranes, sulfo-nylureas inhibit K efflux, which causes influx of Ca followed by release of preformed insulin. 

In addition to direct enhancement of channel activity, PTKs can indirectly increase GABA-evoked inhibitory current by recruiting intracellular GABAaR to the surface of postsynaptic membrane. Insulin has been shown to increase surface expression GABAaR in transfected human embryonic kidney cells. In central neurons insulin rapidly increases the expression of functional postsynaptic GABAaR in a tyrosine kinase-dependent manner, resulting in an increase in the amplitude of the miniature inhibitory postsynaptic currents. 

An important question arises about the effects of phospholipid composition and the function of membrane-bound enzymes. The phospholipid composition and cholesterol content in cell membranes of cultured cells can be modified, either by supplementing the medium with specific lipids or by incubation with different types of liposomes. Direct effects of phospholipid structure have been observed on the activity of the Ca2+-ATPase (due to changes in the phosphorylation and nucleotide binding domains) [37]. Evidence of a relationship between lipid structure and membrane functions also comes from studies with the insulin receptor [38]. Lipid alteration had no influence on insulin binding, but modified the kinetics of receptor autophosphorylation. 

One could plunge into the steric problems posed by the mechanism of protein synthesis on the ribosome 25 26)> or consider the steric fit of the hormone insulin to its acceptor in the cell membrane 27>. Or one could delve into the beautiful intricacy of terpenoid, squalene and steroid metabolism, or get lost in double bond formation, or in the steric problems posed by the branched chain fatty acids and their derivatives 28-34). 

P cells of the pancreatic islets in combination with atoms of zinc, but when required to regulate blood glucose concentration, the prohormone is cleaved and functional insulin is released into the circulation along with the C-peptide. This example of post-translational processing is mediated by peptidases which are contained in the vesicles along with the proinsulin. The fusion of the secretory vesicles with the cell membrane and activation of the peptidase prior to exocytosis of the insulin are prompted by an influx of calcium ions into the P-cell in response to the appropriate stimulus. Similarly, catecholamines are synthesized and held within the cell by attachment to proteins called chromogranins. 

The results of this TIR/FRAP study are that 80% of the nonspecific binding of fluorescein-labeled insulin to the external face of red cell membranes is reversible within <100s, and the mean residency time of the reversibly adsorbed insulin ranges from 0.4 s to 20 s. Surface diffusion of nonspecifically adsorbed insulin (as investigated by an TIR intersecting beam interference fringe pattern see Figure 7.5) was immeasurably small it is insufficient to carry a typical insulin more than 0.3 /xm before desorption. 

GLUT 4 translocation to the cell membrane in skeletal muscle is stimulated by exercise. This effect, which is independent of insulin, involves a 5 AMP-activated kinase. 

Prenylation of proteins (a posttranslational modification) that need to be held in the cell membrane by a lipid tail. An example is the p21 G protein in the insulin and growth factor pathways. 

The sulfonylureas promote insulin secretion. They block the K+ channels of the pancreatic beta cell membrane causing the beta cell to remain depolarized which promotes insulin secretion. They also antagonize the effects of glucagon and potentiate the action of insulin in target tissues. However, some pancreatic beta cell responsiveness must exist for... 

Repaglinide en nateglinide are not sulfonylurea agents but their mechanism of action is very alike. Repaglinide is the first carbamoylmethyl-benzoic acid derivative that has been registred for the treatment of diabetes mellitus. It closes ATP-dependent potassium channels in the beta cell membrane with consequent depolarization, opening of calcium channels and increased insulin release. It is rapidly absorbed with peak plasma levels after 1 hour. It has a protein binding of over 98%. 

B) Thiazolidinediones increase the number of insulin receptors on the cell membrane surface. 

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