Since the 1980s, development of recombinant DNA technology has allowed the large-scale manufacture of human insulin, either from de novo synthesis, or by 'humanisation' of animal insulin.
Insulin must be given parenterally, usually by subcutaneous injection except in treatment of emergencies. Alternative routes of administration, such as intranasal, are being investigated.
Both animal and human insulins can be formulated as soluble (short acting) and crystalline or complexed (intermediate and long acting).
Injections may be of either type alone, both, or premixed mixtures. These may be given once or more per day according to the patient's eating habits, energy expenditure and measures of glycaemic control.
Common regimes include a twice-daily biphasic mixture (which contains short- and long-acting insulins commonly in the proportion 30:70) given before breakfast and before the evening meal.
In younger, motivated, patients a more intensive regime such as the basal bolus regimen can achieve an excellent level of control. This involves a bedtime isophane insulin injection, with three injections of soluble insulin of variable dose before meals according to need during the day. Such a regimen comes closer to but cannot match the normal pattern of pancreatic insulin secretion.
Types of insulin preparations,
- Short-acting/soluble insulin
These preparations contain unmodified insulin at neutral pH and have a rapid onset, with peak action at 1-2 hours. They cover insulin requirements at meal times. - Protamine zinc insulin
Protamine and insulin, in the presence of zinc, form a poorly soluble complex with an action lasting up to 24 hours. This is now little used. - Isophane insulin
This is similar to protamine zinc insulin but the complex is formed of equimolar amounts of its constituents, with no excess protamine or zinc. The crystalline structure, and thus absorption, varies between manufacturers. The action lasts for 12-24 hours. - Lente insulin
Insulin in the presence of zinc and acetate buffer may form large crystals, (ultralente) or an amorphous type (semilente). A 70:30 mixture of these results in lente insulin. - Biphasic insulins
Several premixed insulins are available, combining varying proportions of short-acting and isophane insulins. These include 10:90, 20:80, 30:70 or 50:50 mixtures. - Insulin analogues
Pharmaceutical insulin, at neutral pH, forms hexameric complexes; once injected, it tends to dissociate. This dissociation process is thought to dictate the rate at which the insulin is absorbed into the bloodstream, as larger complexes cannot cross the capillary basement membrane. DNA and protein engineering technology has allowed the development of analogues with modified B chain sequences, such that complex formation is hindered. Lys-pro insulin contains a proline residue at B chain position 28. This insulin is quickly absorbed into the bloodstream with fast onset of action. Slow-acting analogues which would have a smoother absorption profile than the current suspensions are currently being developed
- Intensive insulin regimens have been shown to reduce the onset and progression of complications of diabetes, but have disadvantages. They increase the risk of hypoglycaemia, and are more time-consuming than standard regimens.
- Pancreatic transplantation has been performed in many thousands of patients worldwide, with 85% of patients remaining independent of insulin one year post-surgery. As well as reducing the risk or rate of progression of complications, the recipient's quality of life is usually markedly improved. However transplantation of the pancreas alone in patients without renal failure is controversial since major surgery and lifelong immunosuppression carry considerable risk.
- Combined renal-pancreas transplants are the treatment of choice in patients with diabetes who have end-stage renal failure.
- In contrast, transplantation of islet cells is minimally invasive and is capable of restoring euglycaemia and independence from insulin. It may be performed early in the course of diabetes. Initially, results were disappointing, with few patients being insulin independent at one year. Recent changes in immunosuppressive therapy have greatly improved success rates. In a recent study seven patients were independent of insulin, euglycaemic, and free of major side-effects eleven months after surgery. This approach is to be investigated on a larger scale.