The commercial availability of insulin in 1923 was the beginning of a succession of improvements in the treatment of diabetes mellitus that continuous to this very day. While it is unlikely that any new therapy for diabetes will have the dramatic impact of Banting and Best's discovery, the synergy of information which is burgeoning from several disciplines, including physiology, pathology, molecular biology and chemistry, is expected to catalyze the development of important new treatment modalities in the foreseeable future.

The development of the extended action insulins, purified pork insulin, human insulin & DNA insulin pumps and pen injectors represents only incremental developments. The latest development is that of the analogs of insulin prepared by people synthesis.

The commercial insulins presently available have some inherent limitations, which reduce their ability to control glycemia without risk of significant hypoglycetica, hyper insulinemia and weight gain.

Interventions

(a) Fast - Acting Analogs:
Normal insulin secretion has two phases stimulated and basal. The function of the stimulated phase is to promote disposal of ingested nutrients, principally glucose, into the periphery (peripheral glucose disposal, PGD). An essential component of this phase of insulin secretion is the synchronization of the rise in serum insulin concentration in relation to the ingestion of food. The peak serum concentration and glucodynamic effects of neutral soluble human insulin occur two hours after subcutaneous injection and may persist for up to eight hours.

Scientists have demonstrated that the inappropriate post prandial hyper glycemia that occurs with neutral soluble human insulin is related to the propensity of insulin to self association into dimmers, hexamers and larger aggregates. Since the rate of absorption of insulin is largely a function of molecular size strategies for enhancing absorption involve changing the molecule in ways that reduce self association An example fat acting analogy is Lys (B 28,), Pro (B 29).

Insulin analogs are useful tools in under standing insulin-receptor dynamics. Single or di-substituted farms of human insulin behave quite differently in various invitro systems. For instance, Asp (B10) insulin (where in the naturally occurring histidine at the 10 position of the B-chain is replaced by aspartic acid) has relative affinities for the insulin and IGF-1 receptors which are approximately 3-4 times that of human insulin and a relative potency in a fat - cell assay twice that of human insulin on the other hand Asp (B25), insulin has animal activity in all three of these invitro test systems. These differences are may be due to internalization and degradation as well as in mitogenicity.

Slow-Acting Analogs

The target of simulation by insulin analog development programs is the low insulin concentration (5-20 MU/L (30-120 Pmol/L) which normally occurs in the basal, or post absorptive, state. The physiological function of this component of insulin secretion is to restrain hepatic glucose production (HGP). To date, clinicians have had to relay on ultralente beef, mixed beef-pork or human insulins as "basal" insulins because these are the only ones that have been commercial available.

Another approach in developing an intermediate or long acting insulin is that of the study of human diagnosis insulin (Arg [B31],Arg [B32]).

Pharmacodynamic Interventions

Four peptides fall in to the category of pharmacodynamic interventions: Human proinsulin (HPI), biosynthetic human C-peptide (BHCP), Glucagon-like peptide-1 (amide) or GLIP, and IGF-1. While development of first was suspended because of possible toxicity and the evaluation of the others is preliminary all represent unique examples of the user of recombinant technology and/or solid-phase peptide chemistry to produce peptides that have the potential for improving glycaemic control in patients with diabetes.

The pharmacokinetics of HPI were found to be virtually identical to those of pork proinsulin. The availability of BHCP as a by product from the production of insulin via human proinsulin has made possible the evaluation of this substance as replacement in C-peptide negative patients. GLIP or glucagons-like peptide-1 (amide), is powerful insulinotropic agent that in processed in the L-cells of the upper intestine form a glucagons precursor molecule, proglucagon.

Safety Issues With Insulin Analogs

Issues about the safety of insulin analogs derive primarily from three sources.
- Increased incidence of cardiovascular events in one multicenter study described above comparing HPI & human insulin in insulinnaive patients.
- Findings that certain analogs have IGF-1 effects invitro.
- The unexpected observation that one insulin analog, Asp (B10), physiological Concentrations of HPI invivo stimulate plasminogen activator inhibitor type - a concentrations in porcine aortic endothelial cells.

Conclusion

It has now been established unequivocally that excellent glycemic control is forestalling the microvascular complications of diabetes mellitus. It is also know that existing insulins are incapable of normalizing glycemia without a risk of hypoglycemia, which for most patients in un-acceptable. Assuming that the best method of improving glycemic control is by simulating normal insulin secretion with basal bolus insulins, it appears that progress is at least being made towards the development of bolus insulins with fast-acting analogs. The advantages of these is rapid onset and decline of effect, leading to the more efficient disposal of meals without between-meal hyper-insulinemia, a putative atherogenic risk factor, and hypoglycemia.

Additionally, the fast-acting analogs may improve quality of life by permitting the patient to take his or her insulin close to meals. Unresolved issues with the fast-acting insulin analogs include whether they will truly meet the specifications for bolus treatment and their safety. With respect to "basal insulin", progress has been slow. Nonetheless, given the importance of suitable basal treatment, there is every reason to hope that suitable analogs to meet this need will be available in the foreseeable future.

-- The authors are with SCS College of Pharmacy, Harapanahalli, Karnataka