Insulin membrane transport processes

Simulation of glucose transport and glucose transporter translocation from intracellular stores to the plasma membrane in muscle cells by vanadate and peroxovan-adate involve a mechanism independent of PI-3K and protein kinase C systems utilized for stimulation of these processes by insulin. The transport of GLUT4 to the plasma membrane in muscle cells growing in culture after stimulation by vanadate, peroxovanadate, or insulin all require an intact actin network [138], Sometimes, the insulin-like action of vanadium is accompanied by overall stimulation of actual metabolic pathways. One example of this is the stimulation of the pentose phosphate pathway observed when vanadate promotes the incorporation of glucose into lipids, an antilipogenic effect [139],... 

The controlled-release micropump (Figure 2) is a recently invented device that uses the principles of membrane transport and controlled release of drugs to deliver insulin at variable rates (20,26). With a suitable supply of insulin connected to the pump, the concentration and/or pressure difference across the membrane results in diffusion or bulk transport through the membrane ). This process is the basal delivery and requires no external power source. Augmented delivery is achieved by repeated compression of the foam membrane by the coated mild-steel piston. The piston is the core of the solenoid, and compression is effected when current is applied to the solenoid coil. Interruption of the current causes the membrane to relax, drawing more drug into the membrane in preparation for the next compression cycle. 

For example, widely used protein therapeutic insulin is not transported by paracellular diffusion. It is demonstrated that insulin is transported by a process of endocytosis [5]. Some other proteins have been shown to be transported by binding to cell surface receptors and binding proteins [6]. However, only a small fraction is released at basolateral membrane and secreted into interstitial spaces in active intact form. Some reports demonstrated that therapeutic concentrations of proteins and peptides can be achieved if these compounds can withstand proteolytic enzymes in the G1 tract [7]. 

Figure 6.15 Regulation of the number of glucose transporters in the plasma membrane. The transporter affected is GLUT-4. It is unclear which translocation process is affected by insulin, physical activity or a change in the ATP/ADP concentration ratio. Effects on the translocation from within the cell to the membrane or vice versa are indicated here.

Methods of traversing the basolateral membrane include uptake systems for organic cations and anions via fadhtated diffusion and/or active transport [1]. Organic anions and cations cross the basolateral membrane via ATP-driven or secondary active processes (H -antiport) [2]. Basolateral uptake processes include the gamma-glutamyl transport system [3] and those for glycoproteins [4]. Certain proteins (insulin, epidermal growth factor (EGF)) are transcytosed across the tubular cells from the blood to the tubular lumen via receptor-mediated uptake [5]. 

Processing of insulin. Insulin is synthesized by membrane-bound polysomes in the /3 cells of the pancreas. The primary translation product is preproinsulin, which contains a 24-residue signal peptide preceding the 81-residue proinsulin molecule. The signal peptide is removed by signal peptidase, cutting between Ala (—1) and Phe (+1), as the nascent chain is transported into the lumen of the endoplasmic reticulum. Proinsulin folds and two disulfide bonds crosslink the ends of the molecule as shown. Before secretion, a trypsinlike enzyme cleaves after a pair of basic residues 31, 32 and 59, 60 then a carboxypeptidase B-like enzyme removes these basic residues to generate the mature form of insulin. 

Gins may. also contribute to the mechanism whereby insulin activates glucose transport in adipocytes and heart. This has been suggested to be a two-step process where the first step involves the recruitment of inactive glucose carriers from an internal vesicle pool to the plasma membrane and the second step involves the activation of the newly inserted carriers in the plasma membrane (vide supra). It is possible that this second step may be controlled by Gins. The reasons for thinking that this may be so are related to observations that, under certain conditions, glucagon... 

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