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Since de Meyer (1907) & Sharpey Schafer (1916) christened the secretion of islets of
Isangerhans as insulin a lot have been achieved in the field of Diabetoloty. Yet much is undone & a lot desired in the field of insulin & insulin delivery systems. The major impetus to development of new insulin delivery systems stems from three major drawbacks of contemporary insulin delivery namely
1) Peripheral unphysiologic insulin delivery : The unphysiologic subcutaneous mode of
delivery in contrast to the physiologic portal entry of insulin bypass the hepatic extraction process and leads to undesirable peripheral hyperinsulinemia.
2) Loose linking of insulin delivery to actual demand : Pancreatic insulin secretion is
pulsatile with small amplitudes in basal state & longer ones when stimulated, Glucose being the prime regulator. Even with intensive regimens of multiple subcutaneous injections (MSI) with long and short acting insulin to simulate basal and meal related insulin secretion, glycated haemoglobin is not fully normalized and hypoglycaemia is a major limiting factor, indicating the unphysiologic natureo of present day insulin therapy.
3) Quality of life issues and compliance problems - daily multiple pricks for insulin and
blood glucose monitoring, local complications and yet, a poor control, can frustrate not only the patient, but also the treating physician. Need of administration in childern, mentally retarded and physically disabled, is another problem, which remains unanswered.
Subcutaneous insulin injection devices
The MSI is associated with problems like inability to draw correct dose of insulin, difficulty
in mixing insulin, loss of insulin via the dead space and painful injection due to blunting of needle by repeated use. Progress in this area has been to improve the accuracy of dosing as well as to increase patient friendliness and compliance. Some of these measures are
i) Improvement in syringe and needle technology : By 'o' error syringes with built-in
needle, needles without hub to reduce dead space, and ultra-fine needles, some but not all, shortcomings of conventional insulin therapy, are overcome
ii) Jet injectors : This device which injects insulin without the feared needle, has not
gained much acceptance. This bulky device requires precise coordination to form a micro-jet stream of insulin under high pressure, which is deposited sub-cutaneously over a wide area. If not placed at a proper angle, laceration and bleeding can occur, and there may be reduced insulin penetration.
iii) Insulin Pen : This is the most popular, safe, accurate and convenient form of insulin
delivery device available. The idea of such a device was conceived by John Ireland and it eliminated the inconvenience of carrying insulin vials and syringes.
The pen sized syringe houses a cartridge containing insulin, the dose is set by a dial and
insulin is delivered by operating the plunger. The needles are made of vary fine gauge steel and are disposable. Premixed insulin preparations are also available. The inconvenience of drawing accurate quantity and difficulty of mixing is over. There is improvement in well-being and quality of life. The diabetic metabolic control and complication prevention is same as for MSI.
Transmucosal and oral insulin delivery
Therapeutic success of Vasopressin and Calcitonin by nasal route has provided stimulus
to studies on nasal delivery of insulin. To increase absorption, surfactants like bile salts (sodium glucocholate, sodium deoxycholate), non-toxic detergents, and sodium taurodihydrofusidate have been used. Still there is only 10-20% absorption, necessitating larger doses. There is a more rapid increase in serum insulin concentration and the absorption profile, more closely simulates that of endogenously secreted insulin. But the major impediments to this route of delivery are variability of absorption due to local factors, ambient conditions, high dose requirements and failure to eliminate need for intermediate/long acting insulin injections which cannot be delivered through nasal route.
Pulmonary administration of aerosolised insulin is an alternative method, which is
promising due to large surface area and less intra-individual variability. Larger studies for long-term are needed. Costly instrumentation is another problem.
Regarding oral administration of insulin, the major hurdle is acid and enzymatic
breakdown of the polypeptide in the gastrointestinal tract. Attempts have been made to circumvent this by packaging insulin in liposomes. With this, the fractional absorption is still very low and the technology is costly. Hence the feasibility of this route of delivery, even in the distant future is doubtful.
Insulin infusion pumps
Human desire to replace malfunctioning human organs by artificial gadgets is old. Miles
Laboratory first developed artificial pancreas in 1970. There are a variety of pumps available, with none reaching close to human pancreas.
Continuous subcutaneous insulin infusion (CSI1) or open loop insulin delivery system or
insulin pumps
This is an externally worn device which delivers insulin at a basal predetermined rate
through a tubing leading to a subcutaneous inserted needle. An additional dose is delivered before each meal. The patient has to monitor his blood-glucose and set the pump infusion dose based on the same type of algorithms as used in MSI regimes. The initial enthusiasm with external pumps waned due to practical problems like unwieldy size, pump malfunction, infection, DKA (pump failure, catheter blockade) and hypoglycemia {run-away pump). With refinement in technology and better patient selection (motivated and knowledgeable), the advantage of CSII are precise bolus insulin delivery and removal of adverse variables in conventional injection techniques such as depth of injection, exercise of limb and lagre subcutaneous deposit. The Oslo study has shown improvement in moor conduction velocity, reduction in the increased GFR, and arrest in progression of retinopathy. The Steno Hospital Group studu and Kroc Collaborative study showed worsening of the retinal lesions, but the albumin secretion declined in both studies.
Implantable insulin pumps
These are miniature forms of external insulin pumps. They are implanted in the upper left
quadrant of abdomen for intraperitoneal route or in pectoral position for Venacaval delivery of insulin. This provides a precise continuous dosing, and physiologic (portal) delivery of insulin. An external telemetry unit controls the pump function. The insulin reservoir is refilled periodically by piercing a rubber septum with a standard hypodermic needle. The high cost, need for surgical implantation, and risk of catheter blockade routine use of this system outside a research setting. These pumps may be particularly useful in those rare patients who have resistance to subcutaneous insulin and who respond to intravenously administered insulin.
Closed loop insulin delivery systems or artificial pancreas or biostator or gciis (glucose
controlled insulin infusion system)
The instrumentation required for artificial pancreas is of the size of a haemodialysis unit. It
consists of following parts :
a) Glucose sensor to detect blood-glucose level constantly.
b) A computer to determine the amount of insulin required to be infused.
c) Infuser to inject the amount of insulin or glucose required.
A continuous intravenous access is made for glucose sensing and insulin administration. It
is costly equipment, sparsely available for research purpose. It can be used for controlling blood glucose rapidly in patients requiring major surgery or for treatment of ketoacidosis.
Lectin and polymer bound insulin delivery systems
Insulin bounded to lectin (concanavalin A) can be competitively displaced by glucose. This
has the potential to act as a closed loop system in which as glucose concentration rises, more insulin will be released. Similar implants consisting of compressed mixture of 15% insulin in palmitic acid and polycyanoacrylate nano capsules, containing insulin, can slowly release insulin. None of these approaches has so far reached clinical applicability due to unreliable link of delivery to demand.
REFERENCES
1. Dahl-Jorgensen K, Brinchmann Hausen O, et al. Effect of near normoglycemia for 2
years on progression of early diabetic retinopathy, nephropathy and neuropathy. The
Osio Study, BMJ 1986; 293: 1195-9.
2. Hagmuller G, Kritz H, Varco RL, et al. Treatment of type II diabetic by a totally
implantable insulin infusion device. Lancet 1981; 1 : 1233-5.
3. Hornquist IO, Wikby A, Anderson PO, Dufwa AM. Insulin Pen Treatment Quality of
Life and Metabolic Control: Retrospective Intragroup Evaluations. Diabetes Research
and Clinical Practice 10; 221-230,1990
4. The KROC Study Group : Blood Glucose control and the evolution of diabetic
retinopathy and albuminuria. NEIM 1984; 311: 365-72.
5. Moses AC, Gordon GS, Carey MC, Flier JS, Insulin administered intranasally as an
insulin-bite salt aerosol. Effectiveness and reproducibility in normal and diabetic
subject. Diabetes 1983;32:1040-7.
6. Pickup 1C, Keen H, Vibert GC,et al. Continous subcutaneous insulin infusion in the
treatment of diabetes mellitus. Diabetes Care 1980; 2:290-300.
7. Spangler, RS. Insulin administration of via liposomes. Diabetes Care 1990;9:911-22.
8. Walters DP, Smith PA, Marteau TM, Brimble A, Brothwick LJ. Experience with
Novopen an injection Device using Insulin for Diabetic Patients. Diabetic Medicine
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