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Introduction
For years, it has been recognized that reasonable control of blood glucose levels reduces
the acute complications of Diabetes Mellitus. Recent studies have conclusively shown that strict glycemic control reduces the appearance and progression of chronic complications. Thus, strict glycemic control is the most salient goal of insulin therapy.
Short, intermediate and long acting insulin preparations of animal (bovine, porcine) and
human species in basal & bolus and continuous subcutaneous infusion (CS II) regimes are employed for control of fasting and postprandial hyperglycemia in diabetes mellitus. However, even with the intensive regimes, glycated hemoglobin is not fully normalized and hypoglycemia are a major limiting factor, indicating the unphysiological nature of present day insulin therapy. The major impediment is that human insulin molecule have a tendency to self associate when 2 molecules are in close proximity, a non covalent bound, creating an insulin dimmer. In the presence of zinc, as used in commercially available insulin fromulations, 3 dimmer self associate to form a hexamer. Following subcutaneous injection, the insulin hexamer must dissociate in individual molecules of insulin to get absorbed in systemic circulation. The time taken for insulin hexamer to dissociate is reflected in the time-action profile of regular human insulin & make insulin thereby un- physiological. To make more physiological search for a molecule which have reduce tendency to self associate begen & lead to development of insulin analogue.
Insulin Analogues.
Insulin analogues are type of insulin in which aminoacid sequence of insulin chains are
altered by computer assisted combinatorial chemistry which alter stability, self association characteristics and pharmaco-kinetics of insulin. Synthesis of these altered molecules is then done by DNA technology.
Types : (1) SHORT (Fast) acting analogues,
(2) BASAL (intermediate & long acting) insulin analogue.
(1) Short (fast) acting insulin analogues ;- These ae insulins with significantly reduced self
association, rapid absorption & fast and shorter duration of action & hence ideal for bolus preprandial administration.
e.g. 1) 9 ASP B 27 GLU.
2) lys (B 28) pro (B 29) (lisproi eli lilly)
Out of these lispro is well studied insulin analogue.
Insulin Lispro : It is an analogue of human insulin in which the AA proline & lysine which
normally occupy the B28 & B29 positions, respectively, are reversed. Reversion of positions of these AA causes charge repulsion and weakening of hydrophillic interaction between units thereby preventing polymerisation, which produce a analogue which has a lesser tendency to self associate than regular insulin.
Synthesis :- Insulin lispro is synthesized in a non disease producing laboratory strain of
E. Coli bacteria, which has been altered by the addition of a gene for a precursor of insulin lispro.
Pharmacokinetic :
Onset of action - 15 min (vs 30-45mm or RHI)
Peak effect - at 1 hour (vs 2-3 for RHI)
Duration of action - 3.5-4 hours (vs 5.5. - 7.5 or RHI)
Potency - Equal to RHI
Time of admistration : 15 min before meal (v/s 30mm for RHI). It provide better glycemic
control in patients receiving a high carbohydrate diet. In patients receiving a high fat content meal, postprandial administration of insulin lispro may be adequate.
Effect of Lispro in comparison to RHI
a) Post prandial glycemic control : In both type 1 & 2 DM insulin lispro significantly
improve post prandial rise in serum glucose. This improvement was seen throughout the 2 hours post prandial period.
b) Hypoglycernia :- Rata of hypoglycemia in patients with type 1 DM decreased
significantly. There were significantly less symptomatic & asymptomatic hypoglycemic episode during treatment with insulin lispro but in type II DM there is equal rate of hypoglycemia in both lispro insulin treated & RHI treated patient.
c) Over all glycemic control (glycosylated Hb) - There is no difference in end point HbAlC
level when two insulin are compared.
Indications
1) Patients with type I DM with residual pancreatic b cell function.
2) Patient with type I DM who lead an active life style.
3) It may be used with combination of long acting insulin in IDDM.
4) As a combination therapy in patient at OHA failure.
5) In patient with irregular meal time eg. Touring job personal & children, who can't wait for
half hour from injection to meal because of shortage of time.
Advantages
(1) Convenient time schedule for injecting insulin (15 min before meal)
(2) Good post prandial glucose control.
(3) Decreases incidence of Hypoglycemia.
Safety Profile : It is equivalent to regular insulin. It also causes all the side effect which
regular insulin causes e.g. hypoglycemia, local allergy, lipodystrophy.
2) Basal (intermediate & long acting) insulin analogues.
(a) Prainsulin : It was the 1st intermediate acting insulin analogue tried in clinical studies.
Though it promised to be hepatospecific & ideal for reducing fasting hyperglycemia, its weak potency, high doge requirement & increased cardiovascular deaths in initial studies led to its discontinuation in clinical studies.
(b) Diagrinyl Insulin :- It is an intermediary metabolite in bio-conversion of pro-insulin to
insulin has been synthesized by rDNA technology clinical trails are on
(c) Des 64, 65 human proinsulin (D pro) : It is also a pro insulin metabolite, which is also
intermediate acting & has hypoglycemic potency comparable to insulin.
(d) Long acting analogue :- Search is on for an ideal analogue with onset of action after 4
hours, duration of action 24 hours, consistent pharmacokinetics, chemical stability & irascibility with short acting analogue & low immunogenicity.
Novosal Basal is the prototype of this class, developed by substitutiono of threonine in
position B27 with arginine & amidation of the "C" terminal of the b chain, increasing the isoelectric point from 5.4 to 6.8. This rendered the preparation soluble in vitro at PH 3. After injection, at PH 7.4, the analogue crystallizes acting as a subcutaneous depot for slow prolonged absorption The high intra individual variation in pharmacokinetics has dampened further progress with this analogue.
Conclusion
Though there are many developed and under developing insulin analogue. Maximum
work has been done on lispro insulin and find it suitable for certain clinical situations. Insulin lispro is the only available insulin analogue in market, we may hope for certain new insulin analogues especially long acting will develop and establish themselves in future.
REFERENCES
1. Dash, Murlidharan, Newer Insulin and Insulin delivery system, Drug bullet Jan.' 98
Volume 22, No.l, Department of Pharmacology, Post graduate Institute of Medical
Education and Research, Chandigarh.
2. Selam J.L., from the concept of fasting acting analogue to property of insulin lispro,
Diabetes Metabolism 1997 September 23. Supplement 9-4529.
3. White JR, Insulin Analogue a new agent for improving glycemic control. Post
Graduate Medicine, Feb' 97 - 101 (2) 58-60, 63-65.
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