Drug Nomenclature
Pharmacopoeias. Most pharmacopoeias have monographs for insulin and a variety of insulin preparations.
European Pharmacopoeia, 6th ed. (Insulin, Bovine). The natural antidiabetic principle obtained from beef pancreas and purified. A white or almost white powder. Practically insoluble in water and in dehydrated alcohol. It dissolves in dilute mineral acids and, with decomposition, in dilute solutions of alkali hydroxides. Store in airtight containers. Protect from light. It should be stored at -20° until released by the manufacturer. When thawed, insulin may be stored at 2° to 8° and used for manufacturing purposes within a short period of time. To avoid absorption of humidity from the air during weighing, the insulin must be at room temperature.
European Pharmacopoeia, 6th ed. (Insulin, Porcine). The natural antidiabetic principle obtained from pork pancreas and purified. A white or almost white powder. Practically insoluble in water and in dehydrated alcohol. It dissolves in dilute mineral acids and, with decomposition, in dilute solutions of alkali hydroxides. Store in airtight containers. Protect from light. It should be stored at-20° until released by the manufacturer. When thawed, insulin may be stored at 2° to 8° and used for manufacturing purposes within a short period of time. To avoid absorption of humidity from the air during weighing, the insulin must be at room temperature.
European Pharmacopoeia, 6th ed. (Insulin, Human). A protein having the structure of the antidiabetic hormone produced by the human pancreas. It is produced either by enzymatic modification and suitable purification of insulin obtained from the pancreas of the pig or by a method based on recombinant DNA (rDNA) technology. A white or almost white powder. Practically insoluble in water and in alcohol. It dissolves in dilute mineral acids and, with decomposition, in dilute solutions of alkali hydroxides. Store in airtight containers. Protect from light. It should be stored at or below -18° or below until released by the manufacturer. When thawed, insulin is stored at 2° to 8° and used for manufacturing preparations within a short period of time. To avoid absorption of humidity from the air during weighing, the insulin must be at room temperature.
European Pharmacopoeia, 6th ed. (Insulin Aspart, Insulinum Aspartum). It is a2-chain peptide containing 51 amino acids. The A-chain is composed of 21 amino acids and the B-chain is composed of 30 amino acids. It is identical in primary structure to human insulin, except that it has aspartic acid instead of proline at position 28 of the B-chain. As in human insulin, insulin aspart contains 2 interchain di-sulfide bonds and 1 intrachain disulfide bond. It is produced by a method based on recombinant DNA (rDNA) technology. A white or almost white powder. Practically insoluble in aqueous solutions with a pH around 5.1. In aqueous solutions below pH 3.5 or above pH 6.5, the solubility is greater than or equal to 25 mg/mL. Store in airtight containers. Protect from light. It should be stored at or below -18° until released by the manufacturer. When thawed, insulin aspart may be stored at 2° to 8° and used for manufacturing purposes within a short period of time. To avoid absorption of humidity from the air during weighing, insulin aspart must be at room temperature before opening the container.
European Pharmacopoeia, 6th ed. (Insulin Lispro, Insulinum Lisprum). It is a 2-chain peptide containing 51 amino acids. The A-chain is composed of 21 amino acids and the B-chain is composed of 30 amino acids. It is identical in primary structure to human insulin, only differing in amino acid sequence at positions 28 and 29 of the B-chain. Human insulin is Pro(B28), Lys(B29), whereas insulin lispro is Lys(B28), Pro(B29). As in human insulin, insulin lispro contains 2 interchain disulfide bonds and 1 intrachain disulfide bond. It is produced by a method based on recombinant DNA (rDNA) technology. A white or almost white powder. Practically insoluble in water and in alcohol. It dissolves in dilute mineral acids and with decomposition in dilute solutions of alkali hydroxides. Store in airtight containers. Protect from light. It should be stored at or below-18°. When thawed, insulin lispro is used for manufacturing purposes within a short period of time. To avoid absorption of humidity from the air during weighing, insulin aspart must be at room temperature before opening the container.
The United States Pharmacopeia 31, 2008 (Insulin). A protein that affects the metabolism of glucose obtained from the pancreas of healthy bovine or porcine animals, or both, used for food by humans. White or practically white crystals. Soluble in solutions of dilute acids and alkalis. Store in airtight containers. Protect from light. It should be stored at -10°to -25°.
The United States Pharmacopeia 31, 2008 (Insulin Human). A protein corresponding to the active principle elaborated in the human pancreas that affects the metabolism of carbohydrate (particularly glucose), fat, and protein. It is derived by enzymatic modification of insulin from pork pancreas in order to change its amino acid sequence appropriately, or produced by microbial synthesis via a recombinant DNA process. Store in airtight containers. Protect from light. It should be stored at-10° to-25°.
The United States Pharmacopeia 31, 2008 (Insulin Lispro). Insulin Lispro is identical in structure to Insulin Human, except that it has lysine and proline at positions 28 and 29, respectively, of chain B, whereas this sequence is reversed in Insulin Human. It is produced by microbial synthesis via a recombinantDNA process. White or practically white crystals. Soluble in solutions of dilute acids and alkalis. Store in airtight containers. Protect from light. It should be stored at -10° to -25°.
Definitions and Terminology
Insulin is a hormone produced by the beta cells of the islets of Langerhans of the pancreas and consists of 2 chains of amino acids, the A and B chains, connected by 2 disulfide bridges. Insulin produced by different species conforms to the same basic structure but has different sequences of amino acids in the chains. Porcine insulin (C256H381N65076S6 = 5777.5) differs from human insulin (C257H383N65077S6 = 5807.6) in only one amino acid in the B chain, whereas bovine insulin (C254H377N65075S6 = 5733.5) differs from human insulin not only in this same amino acid in the B chain but also in 2 amino acids in the A chain.
The precursor of insulin in the pancreas is proinsulin which is a single polypeptide chain incorporating both the A and B chains of insulin connected by a peptide termed the C-peptide (or connecting-peptide). Although the insulins of various species may be similar in composition the proinsulins are not, in that the sequence and number of amino acids in the C-peptide may vary considerably.
Early commercial insulins were obtained by extraction from bovine or porcine or mixed bovine and porcine pancreases and were purified by recrystallisation only.
Insulins obtained by such methods were often termed ‘conventional insulins’ to distinguish them from insulins which have undergone further purification processes. An extract which has been recrystallised only once can be separated into 3 components or fractions termed the ‘a’, ‘b’, and ‘c’ components. The ‘a’ component consists of high molecular weight substances and is only usually found in very impure preparations since repeated recrystallisation will remove most of it. The ‘b’ component consists largely of proinsulin and insulin dimers, and the ‘c’ component consists of insulin, insulin esters, arginine insulin, and desamidoinsulin. Other pancreatic peptides such as glucagon, pancreatic polypeptide, somatostatin, and vasoactive intestinal peptide are also usually found in products which have not undergone further purification. Gel filtration will substantially reduce the content of proinsulin but will not significantly reduce the content of insulin derivatives or pancreatic peptides products purified by gel filtration are often termed ‘single-peak insulins’. Addition of ion-exchange chromatography to the purification methods will further reduce the proinsulin content and also reduce the contamination by insulin derivatives and pancreatic peptides. In the UK ‘highly purified insulins’ and ‘monocompo-nent insulins’ are terms sometimes applied to insulins which have undergone both gel filtration and ion-exchange chromatography. In the USA the FDA has designated the term ‘purified insulins’ for preparations similarly prepared and containing less than 10 ppm of proinsulin.
Much of the insulin now produced has an amino-acid sequence identical to that of human insulin. Human insulin (emp) is produced by the enzymatic modification of insulin obtained from the porcine pancreas it is also sometimes called semisynthetic human insulin. The term human insulin (crb) is used for insulin produced by the chemical combination of A and B chains which have been obtained from bacteria genetically modified by recombinant DNA technology. Human insulin (prb) is produced from proinsulin obtained from bacteria genetically modified by recombinant DNA technology. Human insulin (pyr) is insulin produced from a precursor obtained from a yeast genetically modified by recombinant DNA technology. Human insulin obtained by recombinant DNA technology is sometimes termed biosynthetic human insulin. Insulin or human insulin is supplied in a variety of forms in solution or suspension for injection. Crystalline insulin may be prepared for therapeutic use merely by making a solution, either of acidic or neutral pH. Soluble insulin or ‘neutral insulin‘ is a short-acting preparation that can be given intravenously if necessary to cover emergencies. Soluble formulations are sometimes referred to as ‘regular insulin‘ or ‘unmodified insulin’ these names reflect the fact that the preparation has not been formulated in order to prolong the duration of action of the insulin. In order to prolong the duration of action of insulin, preparations may be formulated as suspensions in 2 general ways. The first involves complexing insulin with a protein from which it is slowly released examples are protamine zinc insulin, which contains an excess of protamine, and isophane insulin (NPH insulin), which contains equimolecular amounts of insulin and protamine. The second method of prolonging the action of insulin is to modify the particle size and the various insulin zinc suspensions are in this category. Biphasic insulins are mixtures providing for both immediate and prolonged action. Chemical modification of the insulin molecule has resulted in insulins such as dalanated insulin (prepared by the removal of the C-terminal alanine from the B chain of insulin), insulin defalan (prepared by the removal of the terminal phenylalanine), and sulfated insulin, but these insulins have not been widely used. More recently, recombinant DNA technology has enabled production of insulin analogues with altered pharmacokinetic profiles. Insulin lispro is one such analogue, in which the B28 and B29 amino acid residues of human insulin are replaced with lysine and proline. It is available as a rapidly acting alternative to soluble insulin and as an intermediate-acting complex with protamine. Insulin aspart and insulin glulisine are other rapidly acting analogues. Insulin glargine is a long-acting form for once-daily use, and insulin de-temir is used once or twice daily. Further information on these can be found under the heading Insulin Analogues and Proinsulin, in Uses, below.
Stability and Storage
Both the European Pharmacopoeia, 6th ed. and the The United States Pharmacopeia 31, 2008 recommend that insulin preparations be stored in a refrigerator at 2° to 8° and not be allowed to freeze. The European Pharmacopoeia, 6th ed. directs that insulin preparations should be protected from light, and the The United States Pharmacopeia 31, 2008 that they should be protected from sunlight. It is recognised that patients may not follow such stringent storage guidelines and most manufacturers of commercial insulin preparations consider that storage by the patient at a temperature of up to 25° would be acceptable for up to one month. Patients should still be advised not to expose their vials or cartridges to excessive heat or sunlight. It is advisable to shake suspensions gently before a dose is withdrawn.
Insulin in powder form should be stored in airtight containers and protected from light. Storage at a low temperature is also recommended. The European Pharmacopoeia, 6th ed. advises storage at a temperature of -20° for bovine and porcine insulin and at-18° or below for Human Insulin, and for Insulin Aspart and Insulin Lispro the The United States Pharmacopeia 31, 2008 requires storage at -10° to -25° for all types of insulin. It is stressed that this temperature is for the powder and not for the preparations preparations should not be subjected to storage conditions that lead to freezing.
Adsorption. The adsorption of insulin onto glass and plastics used in giving sets has been decreased by the addition of albumin or polygeline to insulin solutions but it has been stated that in practice this was unnecessary since insulin adsorption was not a major problem. However, in studies of insulin infusions used in neonatal hyperglycaemia, various methods have been investigated and found to reduce the amount of insulin lost by adsorption to the giving set. These included flushing or priming the system with the insulin infusion, or using a concentrated insulin solution to prime the tubing. A study that compared different methods found wide variation in insulin delivery depending on solution concentration, flow rate, addition of albumin, catheter type, and priming or flushing of the system.
Aggregation. For discussion of the problems of insulin aggregation, see Intensive Administration Regimens under Uses, below.
Units
One unit of bovine insulin is contained in 0.03891 mg of the first International Standard (1986). One unit of porcine insulin is contained in 0.03846 mg of the first International Standard (1986). One unit of human insulin is contained in 0.03846 mg of the first International Standard (1986).
Adverse Effects
The most frequent complication of insulin therapy is hypoglycaemia, the speed of onset and duration of which may vary according to the type of preparation and the route used. It is usually associated with an excessive dosage of insulin, the omission of a meal by the patient, or increased physical activity. Patients, especially the elderly or those with tightly controlled diabetes or diabetes of long standing, may not experience the typical early warning symptoms of a hypoglycaemic attack. There have been reports of hypoglycaemia, sometimes with decreased warning symptoms, in patients changing from animal (especially bovine) to human insulin (see under Hypoglycaemia, below). Symptoms of hypoglycaemia resulting from increased sympathetic activity include hunger, pallor, sweating, palpitations, anxiety, and tremulousness. Other symptoms include headache, visual disturbances such as blurred or double vision, slurred speech, paraesthesia of the mouth and fingers, alterations in behaviour, and impaired mental or intellectual ability. If untreated, hypoglycaemia may lead to convulsions and coma which should not be confused with hyperglycaemic coma.
Insulin, given subcutaneously, may cause either lipoatrophy or lipohypertrophy. Lipoatrophy appears to occur less frequently with purified insulins than with conventional insulins if it has occurred, it may be reversed by the injection of a purer animal insulin or human insulin into and around the atrophied site. Lipohypertrophy is usually associated with repeated injections at the same site and may usually be overcome by rotating the site of injection, although absorption of insulin may vary from different anatomical areas. Prolonged insulin therapy may result in weight gain.
Insulin occasionally causes local or systemic hypersensitivity reactions. Local reactions, characterised by erythema and pruritus at the injection site, usually disappear with continued use. Generalised hypersensitivity may produce urticaria, angioedema, and very rarely anaphylactic reactions if continued therapy with insulin is essential hyposensitisation may be needed. Again, hypersensitivity reactions occur less frequently with purified than with conventional insulins and porcine insulin is less immunogenic than bovine insulin. Although hypersensitivity reactions have been reported in patients transferred from animal to human insulins, there are only isolated reports of such reactions in patients treated exclusively with human insulin. Many patients treated with insulin, either animal or human insulin, develop antibodies but the clinical significance of this is not entirely clear.
Of patients who received intensive insulin therapy for type 1 diabetes as part of the Diabetes Control and Complications Trial, those who experienced the greatest weight gain also had increased blood concentrations of triglycerides and low-density-lipoprotein cholesterol, and lowered high-density-lipoprotein cholesterol.l These lipid changes, with higher blood pressure, increased waist-to-hip ratio, and greater insulin requirements, were held to be similar to the symptoms of insulin resistance and to indicate a possible increased risk of macrovascular disease. Results from the UK Prospective Diabetes Study indicated that type 2 diabetic patients treated with insulin had greater weight gain than those managed with other therapies, but demonstrated no evidence of harmful cardiovascular effects. For discussion of some of the specific problems associated with continuous infusion of insulin, see Intensive Administration Regimens under Uses, below.
Carcinogenicity. Primary lung malignancies have been found in a few patients receiving inhaled insulin for further details, see Administration Routes.
Effects on the liver. For a report of hepatomegaly occurring after insulin overdosage, see under Abuse, in Precautions, below.
Effects on the skin. Delayed pressure urticaria, in the form of large wheals occurring 4 to 6 hours after prolonged pressure, and lasting for up to 24 hours, was seen in a patient with type 1 diabetes within 6 months of changing from animal to human insulin. The condition improved after a switch back to insulin of animal origin, and grew worse again after a second attempt to switch to human insulin. Intermittent urticaria simultaneously affecting previous injection sites was reported in a child receiving human insulin, who had never received animal insulin.
Hypersensitivity. Hypersensitivity reactions to insulin preparations may be caused not only by the insulin itself, but also by other components of the formulation such as zinc or protamine. Hypersensitivity reactions and lipoatrophy (which is also thought to have an immune basis) have become rare since the introduction of highly purified and human insulins. Although insulin analogues have been used successfully in patients with a history of hypersensitivity to human insulin, there are also reports of both local and generalised reactions to insulin analogues.See also Adverse Effects, above and under Precautions, below.
HYPOSENSITISATION. After failure of standard hyposensitisation measures in a patient with cutaneous hypersensitivity to insulin, hyposensitisation was attempted by giving insulin by mouth. Aspirin 1.3 g three times daily by mouth was also given to antagonise vascular mediators of the reaction. After one week subsequent hyposensitisation using insulin by injection was successful. When the patient stopped taking aspirin after 6 months the original hypersensitivity reactions recurred aspirin was then given permanently in a dose of 1.3 g twice daily.
Hypoglycaemia. Hypoglycaemia is the major adverse effect of insulin treatment, with severe hypoglycaemic episodes occurring in up to a third of all insulin-treated patients at some point in their lives. Moves towards more intensive insulin therapy, in order to reduce the development of diabetic complications, increase the risk of hypoglycaemic episodes. Patients maintaining strict glycaemic control are prone to ‘hypoglycaemia unawareness’ in which the normal adrenergic counter-response to hypoglycaemia (characterised by symptoms such as pallor, sweating, and tremor) is reduced or lost, so that hypoglycaemia can develop without warning. Such a loss of awareness of impending hypoglycaemia also seems to develop as duration of diabetes increases One of the main reasons for reduced awareness of hypoglycaemia is that repeated hypoglycaemic episodes seem to trigger an adaptive conservation of glucose concentrations in the brain, resulting in higher central than peripheral blood glucose values avoidance of hypoglycaemia helps restore awareness. When recombinant human insulin became generally available in the late 1980s a number of patients complained of a loss of awareness of impending hypoglycaemia after transfer to human insulin, and there were reports of severe or even fatal hypoglycaemia occurring in patients who had been well stabilised on animal insulins.
This was, and remains, a somewhat controversial area. Despite some small studies suggesting a problem, others failed to find evidence of a difference between animal and human insulins, and a systematic review concluded that the available evidence did not support the suggestion that human insulin increased the frequency or severity of hypoglycaemia, or affected the symptoms of hypoglycaemia, compared with animal insulins. However, most commentators appear to consider that patients should continue to have access to animal insulins if desired, and that those well maintained on animal insulin should not be transferred to human insulin without appropriate clinical grounds, and then only with careful monitoring.
There has also been concern about possible long-term sequelae of hypoglycaemic episodes on the CNS. However, a report on patients participating in the Diabetes Control and Complications Trial (DCCT) suggested that the increased risk of hypoglycaemia seen with intensive therapy was not associated with neuropsychological impairment.For the treatment of insulin-induced hypoglycaemia, see below.
Oedema. Severe, acute oedema is a rare adverse effect of insulin treatment, occurring most often when starting therapy. It should be distinguished from chronic and subacute forms of oedema which may be complications of the diabetic disease process. Possible mechanisms of acute oedema are sodium retention resulting from a direct action of insulin on the renal tubule or an effect of insulin on vascular permeability. The oedema is usually self-limiting, but does respond to a decrease in insulin dosage, or diuretic therapy.
Treatment of Insulin-induced Hypoglycaemia
In the conscious and cooperative patient hypoglycaemia is treated by eating a readily absorbable form of carbohydrate, such as sugar lumps or a glucose-based drink all diabetics should always carry a suitable sugar source by way of precaution.
If the patient is drowsy or unconscious, then glucose must be given parenterally Doses of 50 mL of a 20% solution of glucose or 25 to 50 mL of glucose 50% can be given intravenously the higher concentration is more viscous and irritant to the veins. Lower concentrations are equally effective, and carry less risk of irritant effects, but larger volumes are required, e.g. up to 500 mL of glucose 5%, or 250 mL of 10%, titrated to patient response. Smaller quantities (e.g. 5 to 10 mL/kg of a 10% solution) are required in children. Bolus doses may need to be repeated, or a maintenance infusion started, to prevent persistent hypoglycaemia. If the patient has not regained consciousness within a few minutes after a bolus dose of glucose, the possibility of cerebral oedema should be considered. In situations where giving intravenous glucose is impractical or not feasible, glucagon 1 mg for adults and children above 25 kg or 0.5 mg for children below 25 kg by subcutaneous, intramuscular, or intravenous injection may arouse the patient sufficiently to allow oral glucose to be given. If the patient fails to respond to glucagon within about 10 to 15 minutes, then glucose has to be given intravenously despite any imprac-ticalities.
After a return to consciousness, oral carbohydrates may need to be given until the action of insulin has ceased, which for preparations with a relatively long duration of action such as isophane insulin, some insulin zinc suspensions, and protamine zinc insulin, may be several hours.
Carbohydrate. A comparative study of 7 different preparations of oral carbohydrate for the treatment of hypoglycaemia in the conscious patient found no significant difference in effectiveness between glucose or sucrose in solution or tablet form a hydrolysed polysaccharide solution containing glucose, maltose, and various more complex saccharides (Glucidex 19) was also roughly comparable. However, a glucose gel and orange juice were each less effective than the other formulations in treating hypoglycaemia.
Glucagon. A discussion of the relative merits of parenteral glucose and glucagon in unconscious hypoglycaemic patients suggested that glucagon should be encouraged as first-line treatment, although in practice (see above) parenteral glucose is usually preferred. The effect of glucagon relies upon the patient having adequate liver glycogen stores, which may not always be the case.
Overdose. The requirements for glucose are greater and more prolonged when hypoglycaemia is caused by insulin overdosage rather than therapeutic doses. Correction of insulin-induced hypokalaemia may also be required. Surgical excision of tissue at the site of injection has been used for massive overdose of a long-acting insulin.
Precautions
Dosage requirements of insulin may be altered by many factors. Increased doses are usually necessary during infection, emotional stress, accidental or surgical trauma, puberty, and the latter two trimesters of pregnancy. Decreased doses are usually necessary in patients with impaired renal or hepatic function or during the first trimester of pregnancy. On first stabilising therapy in newly diagnosed diabetic patients, a temporary decrease in requirements may also occur (the socalled honeymoon period).
Because of the possibility of differing responses to insulins from different species, inadvertent change from insulin of one species to another should be avoided. Reduction in insulin dosage may be required on transfer from animal (especially bovine) to human insulin. Hypoglycaemic problems associated with a change to human insulin are discussed under Adverse Effects, above. Care is also necessary during excessive exercise hypoglycaemia caused by metabolic effects and increased insulin absorption is the usual response, but hyperglycaemia may sometimes occur.
The use of insulin requires monitoring of therapy, such as testing blood or urine for glucose concentrations and the urine for ketones, by the patient.
Drugs which have an effect on blood-glucose concentrations may alter glycaemic control with consequent need for a change in insulin dose (see Interactions, below).
CAUTION. Biphasic insulin, insulin zinc suspensions, isophane insulin, protamine zinc insulin, insulin detemir, and insulin glargine should never be given intravenously and they are not suitable for the emergency treatment of diabetic ketoacidosis.
Abuse. Transient recurrent hepatomegaly associated with hypoglycaemia was associated with the surreptitious injection of additional insulin doses in an insulin-dependent diabetic. Increased storage of glycogen in the liver resulting from insulin excess was considered responsible for the hepatomegaly.
Decreased plasma C-peptide concentrations or the presence of anti-insulin antibodies may be used to confirm insulin abuse as a cause of hypoglycaemia in patients who have never been treated with insulin medically. Insulin has been abused by bodybuilders and other sportspersons severe brain damage after prolonged neuroglycopenia has resulted. There are rare reports of the misuse of insulin to induce mind-altering effects of hypoglycaemia.
Accelerated absorption. Factors such as a hot bath, sauna, or use of a sunbed have been reported to accelerate the absorption of subcutaneous injection, presumably by an increase in skin blood flow. There may, therefore, be a risk of hypoglycaemia
Adrenocortical insufficiency. Recurrent severe hypoglycaemia, which occurred in 2 patients with type 1 diabetes, persisted despite a reduction in insulin doses and proved to be due to Ad-dison’s disease. Insulin requirements rose again in both patients after replacement therapy with fludrocortisone and hydrocortisone.
Driving. In the UK, patients with diabetes mellitus treated with insulin or oral hypoglycaemic s are required to notify their condition to the Driver and Vehicle Licensing Agency, who then assess their fitness to drive. Patients treated with oral hypoglycaemics are generally allowed to retain standard driving licences those treated with insulin receive restricted licences which must be renewed (with appropriate checks) every 1 to 3 years. Patients should be warned of the dangers of hypoglycaemic attacks while driving, and should be counselled in appropriate management of the situation (stopping driving as soon as it is safe to do so, taking carbohydrate immediately, and quitting the driving seat and removing the ignition key from the car) should such an event occur. Patients who have lost hypoglycaemic awareness, or have frequent hypoglycaemic episodes, should not drive. In addition, eyesight must be adequate (field of vision of at least 120°) for a licence to be valid. Patients treated with diet or oral hypoglycaemics are normally allowed to hold vocational driving licences for heavy goods vehicles or passenger carrying vehicles those treated with insulin may not drive such vehicles, and are restricted in driving some other vehicles such as small lorries and minibuses. Regulations in other countries differ widely.
Exercise. Discussions of the metabolic effects of exercise and the precautions to be taken by the exercising type 1 diabetic.
Fasting. Reduction in food intake or alteration in the pattern of meal times may affect insulin requirements and predispose to the development of hypoglycaemia (above). Muslim patients who are receiving antidiabetic therapy and who fast during Ramadan have been shown to be at increased risk of severe hypoglycaemic episodes during this month. A study in 17 fasting patients with type 1 diabetes recommended reduction of the total insulin dose to 85% of that before the fasting period, and supplying 70% as long-acting ultralente insulin and 30% as a rapidly acting soluble insulin the daily dose was divided into 2 equal portions given before sunrise and after sunset. Others have made similar recommendations: 2 daily injections of an intermediate- or long-acting insulin, given before the predawn and sunset meals, together with a short-acting insulin at the meal itself or possibly a single daily injection of insulin glargine, or twice-daily insulin detemir, plus a rapidly acting analogue just before the meal.Patients with type 2 diabetes maintained on insulin may be managed similarly, by judicious use of intermediate or long-acting insulin plus a short-acting insulin given before meals. A single injection of a long-acting analogue such as insulin glargine, or two injections of isophane or lente insulin or insulin detemir before the sunset and predawn meals, may provide adequate coverage provided the dosage is appropriately individualised. However, most patients will still require a short-acting insulin to be added at the sunset meal to cover the large caloric load. Many will also require an additional dose of short-acting insulin at predawn. Studies have suggested that insulin lispro may produce good blood sugar control in fasting patients with type 2 diabetes during Ramadan.
Care is also required in patients with type 2 diabetes being treated with oral antidiabetic drugs. Patients being treated with metformin or insulin sensitisers such as the glitazones have a low risk of hypoglycaemia, although it has been suggested that the timing of metformin doses be altered so that two-thirds of the daily dose is taken just before the sunset meal and the other third before the predawn meal. Short-acting secretagogues such as repaglinide or nateglinide can also be taken twice daily before the sunset and predawn meals. However, sulfonylureas should be used with caution, and the use of chlorpropamide may be contra-indicated because of the high risk of prolonged and unpredictable hypoglycaemia.
Hypersensitivity to protamine. Retrospective surveys have indicated that patients receiving isophane insulin, which contains protamine, have an increased risk of severe anaphylactoid reactions when protamine is used to reverse systemic heparinisation after cardiac catheterisation or cardiac surgery. The degree of increase in risk is unclear, however, as it has been reported as both large and small. A review of the literature suggested that surgical patients may be at greater risk because of a higher rate of prior sensitisation to protamine and the larger doses used. A mechanism involving IgE and IgG antibodies to protamine has been proposed. See also Hypersensitivity under Adverse Effects, above.
Infections. Decreased requirements of insulin, added to the dialysate, occurred in 6 diabetic patients undergoing continuous ambulatory peritoneal dialysis for chronic renal failure during episodes of severe bacterial peritonitis. This was contrary to the increased insulin requirements of most diabetic patients during severe infections and probably resulted from increased absorption of insulin due to mesothelial damage.
Menstruation. Changes in glycaemic control associated with the menstrual cycle have been recorded in women with type 1 diabetes mellitus. In a retrospective review of 124 women, 61% reported perimenstrual changes in glucose concentrations and 36% made adjustments to their insulin dose, usually a small increase in the premenstrual insulin dose followed by a small decrease at the onset of menstruation. Based on mean glycosylated haemoglobin measurements, there was no evidence of improved glycaemic control in women adjusting their insulin dose compared with those leaving it unchanged despite changes in capillary glucose measurements. Changes in appetite and food consumption associated with the menstrual cycle may affect variations in glucose concentrations and insulin requirements.
Morning hyperglycaemia. Morning hyperglycaemia may be the result of mere waning of subcutaneously injected insulin. It may also be rebound hyperglycaemia (posthypoglycaemic hyperglycaemia or the Somogyi phenomenon) occurring after an episode of nocturnal hypoglycaemia. Morning hyperglycaemia has also been observed without antecedent hypoglycaemia even during constant intravenous infusion of insulin, when the waning of previously injected insulin would not be a factor and this is commonly referred to as the dawn phenomenon. Clinically, it is important to distinguish between the dawn phenomenon, simple waning of previously injected insulin, and rebound hyperglycaemia as a cause of early-morning hyperglycaemia because their treatment differs. Management of the dawn phenomenon and insulin waning generally consists of adjusting the evening dose of insulin to provide additional coverage between 4 a.m. and 7 a.m. Management of rebound hyperglycaemia consists of reducing insulin doses or providing additional late-evening carbohydrate, or both, to avoid nocturnal hypoglycaemia. Mistaking rebound hyperglycaemia for the dawn phenomenon or mere waning of injected insulin could result in more serious nocturnal hypoglycaemia, if evening doses of insulin were increased.
Pregnancy. For discussion of the precautions necessary in the management of diabetes mellitus during pregnancy, see p.431. There has been a report of 2 cases of fetal malformation in the offspring of well-controlled diabetic women who received insulin lispro However, the incidence of fetal malformation is increased in infants of women with diabetes. At that time the manufacturers were aware of 19 live births among women treated with insulin lispro, 1 of which exhibited a congenital abnormality. Since then, a number of retrospective studies” have looked at the rates of fetal malformations in the offspring of women treated with insulin lispro, for either pre-existing diabetes mellitus or gestational diabetes. These have included groups ranging in size from 62 to 496 women, and none have found any evidence of an increase in the incidence of abnormalities with insulin lispro compared with rates published for women treated with other insulins.
There is less information available about the use of other insulin analogues, but a few cases and studies of insulin glargine use during pregnancy have been described. It was started in one woman during the fourteenth week of gestation, and continued until delivery with no apparent adverse effect on the baby. In another report, insulin glargine was inadvertently continued by 5 women during the first 6 to 12 weeks of unplanned pregnancies. In these cases, therapy was changed from insulin glargine to isophane insulin, and no fetal malformations were detected. The use of insulin glargine during the entire pregnancy, without adverse effect, has also been described, and successful pregnancies were reported in 4 women given insulin glargine for gestational diabetes. Furthermore, a small case-control study found no significant difference in neonatal outcomes for insulin glargine and human insulin in women with type 1 or gestational diabetes, and another study found no unexpected adverse effects in the babies of 115 women given insulin glargine. A single-dose study has reported that insulin aspart was effective in reducing postprandial glucose concentration in gestational diabetes. Randomised studies in women with type 1 diabetes or gestational diabetes have also found no indication of an increase in congenital malformations with insulin aspart compared with human insulin.
Prion disease transmission. Studies of cattle with proven bovine spongiform encephalopathy (BSE) have not detected infec-tivity in the pancreas, from which bovine insulin is derived.
Renal impairment. See under Infections, above.
Smoking. Smoking has been reported to decrease the absorption of insulin and dosage adjustment may be necessary, although glycaemic control does not seem to be significantly affected.
Surgery. For a discussion of the management of diabetes mellitus during surgery.
Travelling. Advice for the diabetic patient when travelling, including adjustment of insulin dosage when crossing time zones. Since insulin solution or suspension must not be frozen, it should not be carried in the luggage hold of an aircraft.
Interactions
Many drugs have an effect on blood-glucose concentrations and may alter insulin requirements. Drugs with hypoglycaemic activity or which may decrease insulin requirements include ACE inhibitors, alcohol, anabolic steroids, aspirin, beta blockers (which may also mask the warning signs of hypoglycaemia), disopyramide, fenfluramine, guanethidine, some MAOIs, mebendazole, octreotide, some tetracyclines, and the tricyclic antidepressant amitriptyline. On the other hand, increased requirements of insulin may possibly be seen with chlordiazepoxide, chlorpromazine, some calcium-channel blockers such as diltiazem or nifedipine, corticosteroids, diazoxide, lithium, thiazide diuretics, and thyroid hormones. Both increased and decreased requirements may occur with cyclophosphamide, isoniazid, and oral contraceptives.
ACE inhibitors. Although ACE inhibitors are favoured for use in diabetic patients with hypertension or evidence of incipient nephropathy or both, they may increase insulin sensitivity and thus decrease insulin requirements. A study of hospital admissions found that ACE inhibitors increased the risk of severe hypoglycaemia in patients receiving insulin. However, an analysis of pharmacovigilance data and a case-control study have both found no such increase in risk.
Alcohol. Severe hypoglycaemic episodes have been reported in type 1 diabetics after heavy drinking episodes. Alcohol inhibits gluconeogenesis, and its effects are therefore likely to be greatest if taken without food however, it seems to be generally agreed that diabetics need not abstain from a moderate alcohol intake with meals.
Aspirin. Aspirin produces a modest decrease in blood-glucose concentrations but a significant interaction at conventional analgesic doses appears to be unlikely. One study in children with type 1 diabetes found an average 15% decrease in blood glucose values following treatment with aspirin 1.2 to 2.4 g daily for 3 days, but there were no significant changes in insulin requirements. However, high doses of aspirin can reduce or even replace the insulin dose required. Other salicylates might be expected to have similar properties.
Beta blockers. There are a few reports of severe hypoglycaemia in patients, including insulin-treated diabetics, who were given propranolol or plndolol, there is also a report of an interaction with timolol given as eye drops. Some evidence exists of an interaction with metoprolol, but little evidence for some of the more selective beta blockers. Because of the effects of beta blockers on the sympathetic nervous system the usual premonitory signs of hypoglycaemia may not occur, allowing a severe episode to develop before the patient is aware and able to counter it.
Calcium-channel blockers. Diabetes worsened in an insulin-treated diabetic when given diltiazem. The resultant intractable hyperglycaemia improved when the drug was withdrawn, and recurred, although at a more manageable level, when diltiazem was restarted at a lower dose. There are also reports of a diabetogenic effect of nifedipine. However, reports of significant disturbances of metabolic control appear to be uncommon.
Interferons. Markedly increased insulin requirements developed in a previously well controlled diabetic after treatment with Interferon alfa 2a. Insulin requirements rapidly fell once interferon therapy was stopped.
Oral contraceptives. Both increases and decreases (mainly the former) in insulin requirements have been reported in insulin-dependent diabetics given various oral contraceptives. However, it appears that in most cases the effects of a hormonal contraceptive on diabetic control are modest or insignificant: limited data suggest that progestogenonly and combined oral contraceptives in general have little effect.
Pharmacokinetics
Insulin has no hypoglycaemic effect when given by mouth since it is inactivated in the gastrointestinal tract.
It is fairly rapidly absorbed from subcutaneous tissue on injection and although the half-life of unmodified insulin in blood is very short (being only a matter of minutes), the duration of action of most preparations is considerably longer because of their formulation (for further details see Uses and Administration, below). The rate of absorption from different anatomical sites depends on local blood flow, with absorption from the abdomen being faster than that from the arm, and that from the arm faster than from buttock or thigh. Absorption may also be increased by exercise. The absorption of insulin after intramuscular injection is more rapid than that after subcutaneous doses. Human insulin may be absorbed slightly faster from subcutaneous tissue than porcine or bovine insulin.
Insulin is rapidly metabolised, mainly in the liver but also in the kidneys and muscle tissue. In the kidneys it is reabsorbed in the proximal tubule and either returned to venous blood or metabolised, with only a small amount excreted unchanged in the urine.
For discussion of factors which may affect the absorption of insulin, see under Precautions, Accelerated Absorption, above, and Uses, Administration Routes, below.
Resistance to Insulin
The term insulin resistance has traditionally been used to describe a state in which diabetic patients exhibit considerably increased insulin requirements. It is now used in a much wider sense, and is for instance also applied to patients in whom a subnormal biological response to insulin can be demonstrated, although many of these patients do not apparently present difficulties in their clinical management. Insulin resistance is found particularly in obese patients resistance to endogenous insulin is thought to be linked to the development of type 2 diabetes in such patients. Insulin resistance is frequently associated with lipid disorders, hypertension, and ischaemic heart disease, a complex sometimes described as the metabolic syndrome. In women, it may also be linked to polycystic ovary syndrome.
Insulin resistance of the type manifested by greatly increased insulin requirements may be due to factors including antibody formation and inadequate absorption of insulin from subcutaneous sites. A few patients with severe insulin resistance have responded to insulin lis-pro (see Insulin Analogues and Proinsulin under Uses, below).
Mecasermin (insulin-like growth factor I) has been observed to improve insulin sensitivity in insulin resistance.