Insulin properties

Hinds, K. and Kim, S. 2002. Effects of PEG conjugation on insulin properties. Advanced Drug Delivery Reviews 54(4), 505-530. 

Much uncertainty reigned over the nature of proteins, the best known of which were hemoglobin, the digestive enzymes, and later, insulin. Properties of individual amino acids and the peptide bond were studied early in this century, but it was not until urease was crystallized by Sumner1 in 1926, followed by the isolation of other pure enzymes, that it was finally accepted in the 1930s that enzymes were proteins and that their catalytic properties were not the function of some adsorbed low molecular weight entity. Somewhat later, towards the end of the 1930s, coenzymes were isolated and their roles established. 

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. 

BAYK8644 is a DHP with Ca2+ channel activating properties. Although some therapeutic effects can be envisaged for such drugs (such as stimulation of glucose-dependent insulin secretion, positive inotropy), severe side effects are also predicted from animal studies (dystonic neurobehavioral syndrome, hypertension, arrhythmias), which currently prevents their clinical development. 

Disorders of lipoprotein metabolism involve perturbations which cause elevation of triglycerides and/or cholesterol, reduction of HDL-C, or alteration of properties of lipoproteins, such as their size or composition. These perturbations can be genetic (primary) or occur as a result of other diseases, conditions, or drugs (secondary). Some of the most important secondary disorders include hypothyroidism, diabetes mellitus, renal disease, and alcohol use. Hypothyroidism causes elevated LDL-C levels due primarily to downregulation of the LDL receptor. Insulin-resistance and type 2 diabetes mellitus result in impaired capacity to catabolize chylomicrons and VLDL, as well as excess hepatic triglyceride and VLDL production. Chronic kidney disease, including but not limited to end-stage... 

Onset, peak, and duration are three properties of insulin diat are of clinical importance... 

The entry rate of glucose into red blood cells is far greater than would be calculated for simple diffusion. Rather, it is an example of facilitated diffiision (Chapter 41). The specific protein involved in this process is called the glucose transporter or glucose permease. Some of its properties are summarized in Table 52-3-The process of entry of glucose into red blood cells is of major importance because it is the major fuel supply for these cells. About seven different but related glucose transporters have been isolated from various tissues unlike the red cell transporter, some of these are insidin-dependent (eg, in muscle and adipose tissue). There is considerable interest in the latter types of transporter because defects in their recruitment from intracellular sites to the surface of skeletal muscle cells may help explain the insulin resistance displayed by patients with type 2 diabetes mellitus. 

DPP-4 is a serine protease that inactivates GLP-1. GLP-1 stimulates insulin secretion and suppresses glucagon release. The inhibition of DPP-4 prolongs the half-life of GLP-1 and brings about beneficial effects on glucose levels and glucose tolerance in type 2 diabetics. Backes et al. [64] report on the parallel optimization of enzyme binding affinity and inhibition, selectivity, ADME properties, and PK (Scheme 19). 

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. 

Some flavonoids, such as procyanidins, have antidiabetic properties because they improve altered glucose and oxidative metabolisms of diabetic states (Pinent and others 2004). Extract of grape seed procyanidins (PE) administered orally to streptozotocin-induced diabetic rats resulted in an antihyperglycemic effect, which was significantly increased if PE administration was accompanied by a low insulin dose (Pinent and others 2004). The antihyperglycemic effect of PE may be partially due to the insuli-nomimetic activity of procyanidins on insulin-sensitive cell lines. 

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