Insulin

Insulin is the only therapy available for patients with type 1 diabetes.  Insulin is also required in patients with type 2 diabetes who have developed sulfonylurea failure or those who are undergoing an acute infective or operative event, which has destabilized metabolic control. Insulin replacement in patients with type 1 dia­betes has been less than optimal because it is not possible to completely reproduce the normal physio­logic pattern of insulin secretion into the portal vein. The problem of achieving optimal insulin delivery remains unsolved with the present state of tech­nology. Subcutaneous injections do not reproduce the physiologic patterns of insulin secretion; how­ever, with the help of appropriate modifications of diet and exercise and careful monitoring of capil­lary blood glucose levels at home, it is possible to achieve acceptable control of blood glucose by using multiple injections. In some patients, a portable in­sulin infusion pump may be required for optimal control. With the development of highly purified hu­man insulin preparations, immunogenicity has been markedly reduced, thereby decreasing the incidence of therapeutic complications such as insulin allergy, immune insulin resistance, and localized lipoatrophy at the injection site.

Table 4: Characteristics of currently used preparations of human insulin and insulin analogues

Type of insulin	Onset of action	Peak effect	Dosing interval	Time point to monitor effect
Mealtime                                 (min)                      (min)
Lispro (rapid acting)	5-15	30-90	At meal	2 hr
Aspart(rapid acting)	5-15	60-120	At meal	2-3 hr
Regular(short acting)	30-60	120-240	30-45 min premeal	4 hr
Background                            (hrs)                     (hrs)
NPH(intermediate acting)	2-4	4-6	Twice daily	8-12 hr
Ultalente (long acting)	3-5	Limited peak	Twice daily	10-12 hr
Glargine (long acting)	2-4	Peakless	Once daily	Fasting glucose
Detemir	2-4	Peakless	Twice daily	Fasting glucose

 

Table 4 indicates commercial insulin preparations that differ with regard to their time of onset and duration of biologic action. It is important to recognize that values given for time of onset of action, peak effect, and du­ration of action are only approximate ones and that there is great variability in these parameters from pa­tient to patient and even in a given patient depending on the size of the dose, the site of injection, the de­gree of exercise, the avidity of circulating anti-insulin antibodies, and other less well defined variables.

Human insulin is now produced by recombinant DNA techniques (biosyn­thetic human insulin). Improvements in purifica­tion techniques for insulin have reduced or elimi­nated contaminating insulin precursors that were ca­pable of inducing anti-insulin antibodies. "Purified" insulin is defined as containing less than 10 ppm of proinsulin, whether extracted from animal pancreas or produced from biosynthetic proinsulin. All human and pork insulins currently available con­tain less than 10 ppm of pro insulin and are labeled as "purified." The more highly purified insulins currently in use preserve their potency quite well; therefore, refrigera­tion while in use is not necessary. During travel, re­serve supplies of insulin can be readily transported for weeks without significant loss of potency pro­vided they are protected from extremes of heat or cold. At present, insulins in the USA are available only in a concentration of 100 units/ml (U 100) while in India both U 100 and U40 are available, and dispensed in 10-mL vials. Four principal types of insulin are available: (1) Ul­trashort-acting insulin, with very rapid onset and short duration of action; (2) short-acting insulin, with rapid onset of action; (3) intermediate-acting insulin; and (4) long-acting insulin, with slow onset of action (Table 4).

Ultra-short-acting and short-acting in­sulins are dispensed as clear solutions at neutral pH. All other commercial insulins have been specifically modified to obtain more prolonged action. They are dispensed as opaque suspensions at neutral pH with either protamine (derived from fish sperm) in phos­phate buffer (NPH) or varying concentrations of zinc in acetate buffer (ultralente and lente insulins), ren­dering the insulin insoluble. These preparations are designed for subcutaneous use.

Short-Acting Insulins:  Regular insulin is short-acting, soluble crystalline insulin, whose hypoglycemic effect appears within 15-30 minutes after subcutaneous injection, peaks at 1-3 hours, and lasts for about 5-7 hours when usual quantities, eg, 5-15 units, are administered. Soluble insulin hexamerizes on being injected into subcutaneous tissue, and needs to dissociate back to a monomeric state, before it can be absorbed in to the circulation and commence action.  Regular insulin is the only type that can be administered intra­venously or used in continuous subcutaneous infu­sion pumps. Regular insulin or the short acting analogues are particularly useful in the treatment of diabetic ketoacidosis and when the insulin require­ment is changing rapidly, such as after surgery or during acute infections.

Intermediate-Acting Insulin:

1. Lente insulin: This is a mixture of 30% short-acting with 70% ul­tralente insulin. Its onset of action is delayed to 2-4 hours, and its peak response is generally reached in about 8-10 hours. Because its duration of action is often less than 24 hours (with a range of 18-24 hours), most patients require at least two injections daily to maintain a sustained insulin effect. The su­pernatant of the lente suspension contains an excess of zinc ions, which may precipitate regular insulin if it is added to lente.

2. NPH (neutral protamine Hagedorn, or isophane) insulin-is an in­termediate-acting insulin in which the onset of action is delayed by combining two parts of soluble crys­talline zinc insulin with one part protamine zinc in­sulin. The mixture is reported to have equivalent con­centrations of protamine and insulin, so that neither is in excess ("isophane"). The peak action and duration of action of NPH insulin are similar to those of lente insulin, however, in contrast to lente insulin, regular insulin retains its solubility and independent rapid ac­tion when mixed with NPH. Flocculation of suspended particles may occasion­ally "frost" the sides of a bottle of NPH insulin or "clump" within bottles from which multiple small doses are withdrawn over a prolonged period. This instability is a rare phenomenon and might occur less frequently if NPH human insulin were refrigerated when not in use and if bottles were discarded after 1month of use. Patients should be vigilant for early signs of frosting or clumping of the NPH insulin, be­cause it indicates a pronounced loss of potency. Sev­eral cases of diabetic ketoacidosis have been reported in patients with type 1 diabetes who had been inadver­tently injecting this denatured insulin.

 Long-Acting Insulin: Ultralente insulin a relatively insoluble crystal of zinc and insulin sus­pended in an acetate buffer. Its onset of action is quite delayed, with peak effects at 8-14 hours and duration of action of up to 36 hours. It is generally recommended that the daily dose of Ultralente be split into two equal doses given every 12 hours. This is needed in type 1 patients to achieve basal insulin levels throughout the 24 hours, which are comparable to that achieved in normal subjects by basal endogenous se­cretion or by the overnight infusion rate programmed into insulin pumps.

Insulin Analogues

Short Acting Analogues: The first commercially available short acting analogue was insulin lispro. This analogue is synthesized by interchanging proline with lysine at positions 28 and 29 in the B chain of insulin. Another short acting analogue, insulin aspart, has been formed by substituting aspartic acid for the proline at position 28 of the B chain. These analogues appear to be similar to insulin in terms of their binding characteristics to the insulin and IGF-I receptors and equally potent in terms of glu­cose-lowering activity. The short acting analogues have a faster onset, and shorter duration of action compared with regular insulin.  They can be injected just prior to the meal (“shoot and eat”) as opposed to the recommended 30 minutes gap before meals for regular insulin.  The circulating concentration of the short acting analogues declines to undetectable levels by approximately 4 hours after the injection (25).

Long Acting Insulin Analogues:  The insulin mole­cule has also been modified in an effort to develop long­ acting insulin analogues to ensure a smooth prolonged basal control. One such analogue, insulin glargine, has a glycine substitution for asparagine at position A21 and two arginine additions at the end of the B chain. These substitutions result in a shift of the iso­electric point of human insulin from pH 5.4 toward pH 7.0, making the insulin less soluble at the neutral pH of the injection site. This insulin is administered as a clear solution at a slightly acidic pH. After injec­tion, the change to a more neutral pH causes precipi­tation of the insulin at the injection site and forms a slow-release depot. Glargine appears to provide a basal insulin level last­ing for about 24 hours. Another analogue, insulin detemir has been synthesized by removing threonine at position B30 of insulin, and acylating the e-amino group of lysine B29 with a 14-carbon myristoyl fatty acid.  The fatty acid modification allows insulin detemir  to reversibly bind albumin, resulting in delayed absorption and prolonged action. Insulin detemir needs to be injected twice a day to ensure coverage of the 24 hour period. Both the long acting analogues can be described as “peakless” insulins (26).

Insulin Mixtures: Since intermediate insulin require several hours to reach adequate therapeutic levels, their use in type I patients requires sup­plements of regular insulin preprandially. It is well established that insulin mixtures containing increased proportions of lente to regular insulin may retard the rapid action of admixed regular insulin. The excess zinc in lente insulin binds the soluble insulin and par­tially blunts its action, particularly when a relatively small proportion of regular insulin is mixed with lente (eg, I part regular to 1.5 or more parts lente). NPH preparations do not contain excess protamine and so do not delay absorption of admixed regular in­sulin. They are therefore preferable to lente when mixtures of intermediate and regular insulins are pre­scribed. For convenience, regular or NPH insulin may be mixed together in the same syringe and in­jected subcutaneously in split dosage before breakfast and dinner. It is recommended that the regular in­sulin be withdrawn first, then the NPH insulin. No at­tempt should be made to mix the insulins in the syringe, and the injection is preferably given immedi­ately after the syringe is loaded. Stable premixed insulins (70% NPH and 30% regular or 50% of each) are available as a convenience to patients who have difficulty mixing insulin because of visual problems or insufficient manual dexterity.

It has been demonstrated that insulin lispro can be acutely mixed with either NPH or ultralente insulin without affecting its rapid absorption. Premixed preparations of insulin lispro and NPH insulin are un­stable because of exchange of insulin lispro with the human insulin in the protamine complex. Conse­quently, the soluble component becomes over time a mixture of regular and insulin lispro at varying ratios. In an attempt to remedy this, an intermediate acting insulin composed of isophane complexes of protamine with insulin lispro has been developed and given the name NPL (neutral protamine lispro). Premixed combina­tions of NPL and insulin lispro (eg, 75:25, 50:50, and 25:75) have been tested. Pre­liminary results suggest that 25% NPL:75% insulin lispro given before each meal is effective in control­ling postprandial hyperglycemia while providing ef­fective basal coverage.


Methods of Insulin Administration

A. Insulin Syringes and Needles: Single unit syringes (those with a needle fixed to the syringe to minimize dead space) are available for injection of insulin. Their finely honed 27- or 28-gauge, and more recently even 30- gauge attached needles have greatly re­duced the pain of injections. They are light, not sus­ceptible to damage, and convenient when traveling. Two lengths of needles are available: short (8 mm) and long (12.7 mm). Long needles are preferable in obese patients to reduce the variability of insulin ab­sorption. Disposable syringes may be reused until blunting of the needle occurs (usually after three to five injections). Sterility adequate to avoid infection with reuse appears to be maintained by recapping syringes between uses. Cleansing the needle with alcohol may not be desirable, since it can dissolve the silicon coating and increase the pain of skin puncturing.

To facilitate treatment of patients who are adher­ing to a regimen of multiple preprandial injections of regular insulin that supplement a single injection of long-acting insulin delivered by a conventional syringe, portable pen injectors have been introduced. These pen-sized devices contain cartridges of U 100 regular human insulin and retractable needles, thereby eliminating the need for insulin vials and syringes during the day. Cartridges containing insulin lispro, regular insulin, NPH insulin and pre-mixed insulin are available for use with these pens.

B. Sites for Injection: Any part of the body covered by loose skin can be used as an injection site, including the abdomen, thighs, upper arms, flanks, and upper outer quadrants of the buttocks. In general, regular insulin is absorbed more rapidly from upper regions of the body such as the arm area or the ab­domen rather than from the thighs or buttocks. Exer­cise appears to facilitate insulin absorption when the injection site is adjacent to the exercising muscle. Rotation of sites continues to be recommended to avoid delayed absorption when fibrosis or lipohyper­trophy occurs owing to repeated use of a single site. However, considerable variability of absorption rates from different sites, particularly with exercise, may contribute to the instability of glycemic control in certain patients with type 1 diabetes if injection sites are rotated in­discriminately over different areas of the body. Con­sequently, diabetologists recommend limiting injec­tion sites to a single region of the body for a particular time of the day and rotating sites within that region. It is possible that some of the stability of glycemic control achieved by infusion pumps may be related to the constancy of the site of infusion from day to day. For most patients the ab­domen is the recommended site for injection, since it provides a considerable area in which to rotate sites and there may be less variability of absorption with exercise than when the thigh or deltoid areas are used. The effect of anatomic sites appears to be much less pronounced with the shorter acting insulin analogues.

C. Insulin Delivery Systems: Efforts to ad­minister insulin by "closed loop" systems (glucose­controlled insulin infusion systems [Biostator] have been successful in acute situations such as diabetic ketoacidosis or during surgery. However, chronic use is precluded by the bulkiness of the computerized pump and by the need for continuous aspiration of blood for the external glucose sensor that activates the appropriate insulin or glucose infusion.

Several small portable "open loop" devices for the delivery of insulin are in the market. These devices contain an insulin reservoir and a pump programmed to deliver regular insulin subcutaneously; they do not contain a glucose sensor. With improved methods for self-monitoring of blood glucose at home (see below), these pump systems are becoming increas­ingly popular. These pumps are small (about the size of a pager) and easy to program. They have many features, including the ability to record a number of different basal rates throughout a 24-hour period and adjust the time over which bolus doses are given. They are able also to detect pressure build-up if the catheter is kinked. Im­provements have also been made in the infusion sets. The catheter connecting the insulin reservoir to the subcutaneous cannula can be disconnected so the pa­tient can remove the pump temporarily (eg, for bathing). The great advantage of continuous subcu­taneous insulin infusion (CSII) is that it allows for establishment of a basal profile tailored to the patient. The patient therefore is able to eat with less regard to timing because the basal insulin infusion -should maintain a constant blood glucose level between meals.

CSII therapy is appropriate for patients who are motivated, mechanically adept, educated about dia­betes (diet, insulin action, treatment of hypo- and hy­perglycemia), and willing to monitor their blood glu­cose, four to six times a day. Known complications of CSII include ketoacidosis, which can occur when in­sulin delivery is interrupted, and skin infections. An­other major disadvantage is the cost and the time de­manded of physicians and staff in initiating therapy. Patients use either regular insulin or short-acting analogues in the pumps. Reports suggest that subjects using insulin lispro have lower HbAlc values and improved postprandial glucose control with the same frequency of hypoglycemia. There does remain a concern that in the event of pump failure, insulin lispro could result in more rapid onset of hyperglycemia and ketosis. The published results suggest that insulin requirements are lower and there is less hypoglycemia with this form of insulin de­livery compared with intensive insulin therapy by injections.

Intranasally administered soluble insulin is rapidly absorbed when given along with a detergent sub­stance to facilitate adsorption. Preliminary clinical trials have demonstrated its efficacy in reducing post-prandial hyperglycemia in subjects with type 1 diabetes. However, its absorption is limited to less than 10% of the administered nasal dose. This reduces its cost-effectiveness, and most manufacturers have dis­continued clinical trials until more progress is made in improving its bioavailability. Inhalers that can provide more precise delivery of drugs have been de­veloped, and inhaled insulin is currently in phase III trials.

Pancreatic islet cells have been successfully transplanted in genetically similar strains of rodents with experimental diabetes; however, this approach has not yet been successful in humans because of dif­ficulties in preparing and maintaining viable islets and because of immunologic rejection of the tissue. Pancreas transplantation at the time of renal trans­plantation is becoming more widely accepted. Pa­tients undergoing simultaneous pancreas and kidney transplantation have a 74% chance of pancreatic graft survival and a 92% chance of renal graft survival after I year. Routine use of pancreatic transplantation in the absence of a need for renal transplantation should only be considered in those rare patients who fail all other insulin therapeutic approaches and who have life-threatening complications related to their lack of metabolic control.  Islet cell transplant has also been tried with success especially for patients with brittle type 1diabetes.  The limited availability of donor tissue limits the utility of these procedures.