Insulin substitutes

Around 40 years ago, the short-lived use of synthalin (II) as a hypoglycaemic drug [2] led to numerous studies on guanidines as potential insulin substitutes [3]. Synthalin itself was withdrawn when it was reported that it can cause liver damage [4], and the widespread interest in guanidines eventually lapsed until the introduction of guanethidine nearly 30 years later. 

Yet treatment of diabetes today is far from complete. In spite of insulin, cardiovascular, renal, eye, and nervous system complications still occur. In spite of sulfonylureas, many primary and secondary failures occur and there is yet no oral insulin substitute for the juvenile or labile diabetic. 

Sahu, A., Sninsky, C.A., Kalra, P.S. Kalra, S.P. (1990) Neuropeptide-Y concentration in microdissected hypothalamic regions and in vitro release from the medial basal hypothalamus-preoptic area of streptozotocin-diabetic rats with and without insulin substitution therapy. Endocrinology 126, 192-198. 

Sekae N, Li j and Shechtee Y (1996) Vanadium salts as insulin substitutes mechanisms of action, a scientific and therapeutic tool in diabetes meUitus research. Crit Rev Biochem Mol Biol 31 339—359. Shechtee Y and Kaelish SJD (1980) Insulin-like stimulation of glucose oxidation in rat adipocytes by vanadyl (IV) ions. Nature 284 556-558. 

Markussen, J., Diers, I., Hougaard, P., Langkjrer, L., Norris, K, Snel, L., Sorensen, A. R., Sorensen, E., and Voigt, H. O., 1988, Soluble, prolonged-acting insulin derivatives. HI. Degree of protraction, crystallizability and chemical stabihty of insulins substituted in position A21, B13, B23, B27 and B30, Protein Eng., 2 157-166. 

The compound 1-fluoro-2,4-dinitrobenzene is exceedingly reactive toward nucleophilic aromatic substitution and was used in an imaginative way by Frederick Sanger (Section 27.11) in his determination of the structure of insulin. 

BENZENESULFONIC ACID DERIVATIVES As has been discussed previously, substituted -alkylbenzene-sulfonylureas often possess the property of releasing bound insulin, thus sparing the requirement for insulin injections in adult-onset diabetes. A pyrimidine moiety, interestingly, can serve as a surrogate for the urea function. 

Insulin is ordered by die generic name (insulin zinc suspension, extended) or the trade (brand) name (Humulin U) (see the Summary Drug Table Insulin Preparations). The nurse must never substitute one brand of insulin for anodier unless the substitution is approved by the health care provider because some patients may be sensitive to changes in brands of insulin. In addition, it is important never to substitute one type of insulin for anodier. For example, do not use insulin zinc suspension instead of die prescribed protamine zinc insulin. 

This drug is not oral insulin and cannot be substituted for insulin. 

Recommendations in this section may change based on results from the recent GLUCONTROL trial and the Volume Substitution and Insulin Therapy in Severe Sepsis Study. Both trials where stopped early due to lack of efficacy and safety concerns. 

Three rapid-acting insulins have been approved in the United States lispro, aspart, and glulisine. Substitution of one or two amino acids in regular insulin results in the unique pharmacokinetic properties characteristic of these agents. Onset of action of rapid-acting insulins varies from 15 to 30 minutes, with peak effects occurring 1 to 2 hours following administration. 

All RTKs contain between one and three tyrosines in the kinase activation loop, which is composed of subdomains VII and VIII of the protein kinase catalytic core. Phosphorylation of these tyrosines has been shown to be critical for stimulation of catalytic activity and biological function for a number of RTKs, including insulin receptor, FGF receptor, VEGF receptor, PDGF receptor, Met (hepatocyte growth factor receptor), and TrkA (NGF receptor). A major exception is the EGF receptor, for which autophosphorylation of a conserved tyrosine in the activation loop does not seem to be involved in signaling. Substitution of tyrosine with phenylalanine has no effect on RTK activity or downstream signals. 

Deeb SS, Fajas L, Nemoto M, Pihlaja-maki J, Mykkanen L, Kuusisto J et al. A Prol2Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nature Genet 1998 20[3] 284—287. 

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. 

Fast-acting insulins Amino acid substitutions generate products that enter the bloodstream more quickly from the site of injection, facilitating product co-administration with a meal rather than administration 30-45 min prior to a meal 11... 

Reverse-phase HPLC (RP-HPLC) separates proteins on the basis of differences in their surface hydophobicity. The stationary phase in the HPLC column normally consists of silica or a polymeric support to which hydrophobic arms (usually alkyl chains, such as butyl, octyl or octadecyl groups) have been attached. Reverse-phase systems have proven themselves to be a particularly powerful analytical technique, capable of separating very similar molecules displaying only minor differences in hydrophobicity. In some instances a single amino acid substitution or the removal of a single amino acid from the end of a polypeptide chain can be detected by RP-HPLC. In most instances, modifications such as deamidation will also cause peak shifts. Such systems, therefore, may be used to detect impurities, be they related or unrelated to the protein product. RP-HPLC finds extensive application in, for example, the analysis of insulin preparations. Modified forms, or insulin polymers, are easily distinguishable from native insulin on reverse-phase columns. 

A number of studies have also focused upon the generation of longer-acting insulin analogues. The currently used Zn-insulin suspensions, or protamine-Zn-insulin suspensions, generally display a plasma half-life of 20-25 h. Selected amino acid substitutions have generated insulins which, even in soluble form, exhibit plasma half-lives of up to 35 h. 

Failure of initial therapy should result in addition of another class of drug. Substitution of a drug from another class should be reserved for drug intolerance. Metformin and an insulin secretagogue are often first- and second-line therapy. 

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