Dr. Th. Premchand Singh
Professor of Medicine, RIMS, Imphal
The quest for a treatment for diabetes has a history as long as the disease itself, dating back to Ebers Papyrus in1500 B.C. The discovery of Insulin on the 30th July 1921 when Frederick Grant Banting and Charles Herbert Best injected 4 c.c. of extract of degenerated pancreas to a dog and the dog’s blood sugar found dropped, was thought to be the ultimate end for the search of treatment of diabetes. However, the presently available insulins can not control the diabetes as good as the insulin of a normal pancreas. The search for a better insulin thus continues.
The available insulin preparations differ with respect to the animal species from which they are obtained, their purity, solubility and the time of onset and duration of action. Insulin is a two-chain polypeptide having 51 amino acids and molecular weight of 6000. The A chain has 21, while B chain has 30 amino acids. The bovine and pork insulins are derived from the respective animals, the human insulins are produced by recombinant DNA technology. There are major differences between amino acid sequence in human, pork and bovine insulins.
Species A chain B chain
______________________________ _______
8th AA 10th AA 30th AA
Human Threonine Isoleucine Threonine
Pork Threonine Isoleucine Alanine
Bovine Alanine Valine Alanine
It is seen that pork insulin is more homologous to human insulin than bovine insulin. With the development of highly purified insulin preparations immunogenecity has been markedly reduced. However, the aim of achieving optimal insulin delivery and thereby reproducing the physiological patterns of insulin secretion is not yet feasible with the presently available insulins. The challenge for the insulin chemist has been to develop two insulin analogues, one type to provide insulin needs in response to meals and another type for a constant delivery of about 1 unit of insulin per hour to meet the needs of the basal state.
Insulin Analogues
The importance of intensive treatment regimens to control blood glucose can not be overemphasized to reduce microvascular and macrovascular complications of diabetes. Ideally, glycaemic control should be as near normal as practicable for each patient(1,2). Pursuit of tighter glycaemic control has encouraged introduction of newer insulins. Insulin analogues represent the latest evolutionary milestone in the more than 80 years history of insulin therapy. Modifications in the structure of insulin using recombinant DNA technology have contributed to understanding the importance of individual and sequences of amino acids in the molecular assembly of insulin, its biological activity and therapeutic properties. The rationale for the design of biosynthetic insulin analogues is, by directed engineering of the primary structure of the protein, to minimize the unwanted properties of insulin while retaining its biological activities. These insulin analogues are attempted to replicate normal insulin secretion both in fasting and fed states following subcutaneous injections. These newer designer insulins allow a customized treatment plan for individualized patients, as individuals suffering from diabetes have different habits and lifestyle needs. With the introduction of newer insulins, a new classification of insulin has been proposed based on speed of onset and duration of action.
Classification of Insulins:
Category Type Onset of action
(mins) Duration of action (mins)
Rapid
Aspart,
Lispro 0 -20 2 -5
Rapid-Intermediate Aspart-Protaminated aspart mixture 10 -20 8 -16
Short Regular 15 -60 4 – 8
Short- Intermediate Regular-Isophane (NPH)
Mixture 15 – 60 8 – 16
Intermediate Isophane (NPH) 60 120 8 -16
Long Lente 120 – 240 16 – 30
Very Long
Glargine 60 120 24
Rapid acting insulin analogues:
Insulin Lispro is a new insulin analogue produced by recombinant technology, where two amino acids near the terminal end of the B chain have been reversed in position. After subcutaneous injection, insulin Lispro quickly dissociates into monomers and absorbed rapidly reaching peak serum values as early as one hour. It can be given 15 minutes before meals in contrast to the regular insulin which should be given preferably half an hour before food. The duration of action lasts for 3 to 4 hours only. This closely mimics the normal physiological insulin production in the body and reduce the incidence of hypoglycaemia in between meals. Insulin Aspart is another short acting insulin analogue which is identical to that of native human insulin except for the substitution of aspartic acid for proline at position B28 of insulin amino acid sequence. This prompts more rapid dissociation from hexamers and dimers leading to rapid release from subcutaneous injection sites.
These new rapid acting insulin analogues, lispro and aspart have quickly established themselves as suited for meal-time injection to boost circulating insulin concentrations to coincide with the period of meal digestion. These insulin analogues are structurally modified for quick absorption into the circulation and have a rapid onset and short duration of action when given just before meals than having to anticipate a meal 15-30 minutes in advance before a meal. These reduce the risk of inter-prandial hypoglycaemia.
Long acting insulin analogues:
These short acting insulins are exciting and control the post prandial hyperglycaemia, however to mimic the physiological insulin secretion, a truly long acting depot insulin to cover the basal requirement in between the foods is also required. This will control blood glucose between meals and during the night. The long acting insulins available now have peaks and valleys, and does not maintain the same level of insulin throughout the 24 hours. Insulin Glargine is a long acting insulin analogue introduced in August 2002, where aspargine is replaced by glycine at amino acid 21 and two arginine residues to the C-terminus of the B chains slowing down its release and reducing its solubility in the blood. The onset of action of insulin Glargine is late, the duration of action is longer lasting for more than 24 hours and there is no pronounced peak and closely matches the basal component of normal insulin release. A lower incidence of hypoglycaemia has been reported with insulin Glargine.
Detemir is another long-acting “basal” insulin analogue, which is linked to a fatty acid, myristic acid. The fatty acid side chain promotes aggregation of detemir in intestinal fluid and delays dissociation and release into the circulation. On entering the blood, the fatty acyl group binds to albumin and a dynamic dissociation from the albumin gives a constant slow rate of release of active monomeric detemir. Studies to-date indicate a predictable effect of detemir on glycaemic control with fewer hypoglycaemias and less weight gain than NPH(10,11).
Biphasic Premixed Insulin formulations:
“Biphasic” premixed formulations of a rapid-acting analogue with protaminated rapid-acting insulin analogue have provided a convenient new means to combine mealtime and basal insulin delivery. These premixed insulin formulations are the combinations of lispro and aspart with isopahane complexes of protamine with lispro and aspart. Biphasic lispro and biphasic aspart are now available and they facilitate mealtime glycaemic control with faster insulin peaks and a flat basal insulin concentrations for inter-prandial glycaemic control.
Conclusion
The newer designer insulins truly mimics the insulin secretion of a normal person, where there are peaks of insulin secretion with every meals with a flat basal secretion to control the blood glucose levels between the meals with little risk of developing hypoglycaemia. Both the fasting and postprandial hyperglycaemias are taken care of by these analogues. With these newer insulins, physicians can design different modalities of treatment for different individual diabetic patients, and diabetic patients may be more liberal with the food timings. These analogues also promise to be the best weapon yet for really tight control of diabetes and thereby preventing or delaying the complications of diabetes mellitus.
References:
1. Cambell IW. Need fir intensive, early glycaemic control in patients with type 2 diabetes. Br J Cardiol 2000; 7: 625-31
2. Baily CJ, Day C. Antidiabetic drugs. Br J Cardiol 2002; 10: 128-36
1. Owen DR and Luzia SD. Designer Insulins. J. Diab Ass Ind. 1997; 37: 77-80
2. Lee W, Zirman B. From insulin to insulin analogues, progress in the treatment of type 1 diabetes. Diabetes Rev. 1998; 6: 73-88
3. Marks J. Diabetes management in the future: a whiff and a long shot? Clin Diabetes 1998; 16;3