Insulin is a protein formed by two cross-linked peptide chains. Insulin is secreted in pulses by the pancreas and reaches the liver via the portal circulation. Some 80% of the insulin reaching the liver is cleared from the circulation, which means that insulin attains much higher concentrations in the liver than in the peripheral circulation. Insulin has a short plasma half-life (3-4 minutes), and choice of the route and timing of insulin administration is a major determinant of metabolic control. Conventional insulin injections are given into the thigh, abdomen or outer side of the buttock. Standard needles range from 0.8 - 1.6 cm in length, are used with a syringe or pen device and deliver insulin into the subcutaneous fat. Too long a needle or poor injection technique can result in injection into a muscle, which is painful and results in more rapid absorption of insulin. Many alternative routes of administration have been tested, but none can match direct injection or infusion. Subcutaneous insulin injection or infusion share the disadvantages of delivery into the systemic rather than portal circulation, and rates of appearance in the blood stream which are delayed and rendered somewhat erratic by the process of absorption from subcutaneous tissues.
Characteristics of an ideal insulin administration system
Nature has placed the pancreatic beta cell inside a digestive gland and astride an arterial supply that continuously samples the rate of nutrient absorption from the gut. It responds instantaneously to these blood-borne signals by releasing insulin in synchronised pulses, a pattern of secretion that maximises its effect on liver cells. Furthermore, it matches this insulin secretion with reciprocal suppression or release of its partner hormone pancreatic glucagon, thus achieving exquisitely sensitive control of glucose output by the liver.
In the fasting state, insulin acts mainly to control the release of glucose and other metabolites from the liver, while basal levels of secretion maintain stable glucose levels in the periphery. Food ingestion produces a rapid but short-lived burst of insulin secretion. The resulting high concentrations convert the liver from an organ of glucose secretion into an organ of glucose storage, and promotes glucose uptake by peripheral insulin-sensitive tissues such as muscle and fat.
The liver thus controls the flux of glucose to the tissues in tidal fashion, absorbing glucose in times of plenty, and releasing it in times of need. Fat and muscle are able to store surplus glucose against future requirements but can also draw upon the liver to provide additional glucose when needed in the absence of food.
This finely-tuned system of supply and demand breaks down in the presence of diabetes, and it must remain a matter of wonder that our crude attempts to imitate nature by squirting insulin under the skin are as successful as they have proved to be.
Early insulin preparations were in the form of a powder, to which the user would add sterile water. The main reason was concern that the solution would become infected. Modern insulins come in solutions to which excipients (buffering, stabilizing and anti-bacterial substances) have been added, and once dispensed are stable over a wide range of temperatures and storage conditions: contamination with bacteria is exceptionally rare.
Soluble (regular) Insulin contains insulin in the form of hexamers, 6 molecules packaged together rather like the segments of an orange. These break apart following injection, very rapidly if injected directly into a vein and more slowly if injected under the skin. Short-acting insulin analogues are formulated in such a way that the insulin hexamer breaks apart more readily, allowing more rapid absorption into the circulation. Short-acting insulins can be administered intravenously or subcutaneously. Subcutaneous soluble insulin is suitable for premeal administration in basal-bolus regimens, but lacks the duration of effect needed for overnight use. Premixed soluble insulin is also available for twice daily use in combination with NPH insulin.
Longer-acting insulins are only suitable for subcutaneous use. Three different principles are used. NPH insulin uses the principle of a retarding agent. Insulin glargine contains no retarding agent, but forms microprecipitates under the skin which take time to dissolve. Occasional patients complain of soreness at the injection site. Insulin detemir contains insulin with a short fatty acyl chain which binds to circulating albumin, thus prolonging its duration of action.
Insulin is dispensed in conventional units (1 unit = 36 μg insulin). These units were initially quantified by bioassay, but this has long been superseded by physical measurement. Insulin was traditionally supplied as U40 (= 40 units per ml), but this has now been replaced by U100. U500 insulin is available for occasional patients who require very large doses of insulin.
Insulin not in use should be stored in a refrigerator, and the expiration date should be checked before use. Vials in use may safely be kept at room temperature for a month or longer, but there is a risk of diminishing potency with longer use. Extremes of temperature should be avoided. Vials should be checked for clouding of naturally transparent insulins, or clumping or other visible changes in cloudy insulins.
Soluble (regular) insulins may be mixed with NPH in the syringe before use; stable premixed solutions of these insulins are widely used. Soluble insulin may also be added to insulins of the lente series, but these are no longer in general use. Other insulin mixtures should be avoided; glargine insulin, for example, should not be added to other insulins due to the uniquely low pH of its diluent.
Sites of injection
Insulin is injected into subcutaneous fat, which can be judged by pinching a fold of skin. Most people have no difficulty in locating padded areas, but there may be problems with children and lean adults. Choice of the correct length needle can help reduce the likelihood of inadvertent intramuscular injection in such individuals. See Pens and needles for more detail.
The sites of choice are the abdomen, back of the upper arm, or the outer surface of the thigh and buttocks. Insulin is absorbed more rapidly from the abdomen than the arm, and from the arm than the leg or buttocks, although absorption from the legs will be faster if the injection is followed by exercise.
Routes of administration
Intravenous insulin is used in hospitals for emergency situations, post-operative management and so forth. Only soluble insulin should be used. The advantage is that it allows very rapid adjustment to changes in blood glucose. The potential disadvantage is that the metabolic situation can deteriorate very rapidly once iv insulin is discontinued. Intravenous insulin is unsuitable for long-term use owing to the difficulty of continuous administration and increased risk of infection or thrombosis.
Subcutaneous insulin is the standard route of administration, suitable for both short and long-acting insulins. The advantages are convenience, reliability, and (as compared with iv insulin) the persistence of residual insulin under the skin, which offers some protection against rapid swings in glucose control. The disadvantages are (1) delayed and somewhat erratic absorption into the circulation (there are no truly "peakless" insulins), and (2) the insulin is administered into the systemic circulation, whereas truly physiologic replacement would be into the portal circulation.
Jet spray injectors avoid the need for use of a needle but are not pain-free; few people have opted for this means of administration.
Intraperitoneal insulin is absorbed into the portal circulation, and thus offers advantages as compared with subcutaneous insulin. It can be used in patients with renal failure treated with continuous intraperitoneal dialysis (CAPD), when it is added to the dialysis fluid. It is also used, albeit rarely, in continuous intraperitoneal insulin infusion therapy; see CIPII Intraperitoneal insulin
Other Routes of Administration
Nasal Insulin: Nasal insulin administration was actively investigated in the 1970s and 1980s, and appeared to offer the advantage of very rapid insulin delivery into the circulation coupled with the avoidance of pre-meal insulin injections. Unfortunately the problems of low bioavailability and variable absorption have limited commercial interest in this approach.
Inhaled insulin. As with intranasal insulin, Inhaled insulin potentially offers rapid absorption of needle-free insulin. The lung has a surface area of ~100 m2, and small molecules such as insulin (molecular mass 5700, diameter 2.2 nm) are readily absorbed via the alveoli. Pfizer launched an inhaled insulin under the trade name of Exubera in 2006 but withdrew it in 2008, citing poor demand.
Problems included poor bioavailability, (much of the inhaled insulin is lost in the "dead space" of the bronchial tree), and associated high costs. The inhaler proved bulky and inconvenient. Furthermore, use of inhaled insulin was associated with evidence of a mild induced restrictive lung defect. A greater concern was that 6/4,740 patients on Exubera developed lung cancer during the trial, as against 1/4,292 in the comparison group.
Despite this unpromising prologue, the FDA gave its approval for clinical use of Afrezza, a new formulation of inhaled insulin developed by MannKind .
Oral Insulin: Insulin, being a peptide chain, is rapidly broken down by acids in the stomach or digested by proteolytic enzymes. Many attempts have been made to deliver insulin in a form capable of bypassing the stomach, including liposomes, capsules and nanoparticles. Low and erratic bioavailability remain major problems, and the utility of this approach remains to be demonstrated. See Oral insulin
After 90 years of endeavour, subcutaneous insulin injection (or infusion) remains the preferred route of insulin administration. Despite the limitations of insulin delivery into the systemic circulation, this route of administration can offer substantial protection against the long-term complications of diabetes, and no better alternative seems likely to emerge in the near future.
Further reading: The ADA guidance on insulin administration can be accessed at http://care.diabetesjournals.org/content/27/suppl_1/s106.full