Diabetes mellitus is a disorder of carbohydrate metabolism in which the action of insulin is diminished or absent through altered secretion, decreased insulin activity, or a combination of both factors. There are two principal classes of diabetes (and many sub types not listed here):
Type I diabetes: Type I diabetes, also referred to as insulin dependent diabetes mellitus (IDDM), is due to a deficiency of insulin following autoimmune destruction of pancreatic beta cells. Patients with type I diabetes require administration of insulin.
Type II diabetes: Type II diabetes, also referred to as non-insulin dependent diabetes (NIDDM), is due to reduced secretion of insulin or to peripheral resistance to the action of insulin. Although patients may be controlled on diet alone, many require administration of oral antidiabetic drugs or insulin to maintain satisfactory control.
The aim of treatment is to achieve the best possible control of plasma glucose concentration and prevent or minimize complications including microvascular complications (retinopathy, albuminuria, neuropathy).
Diabetes mellitus is a strong risk factor for cardiovascular disease. Other risk factors such as smoking, hypertension, obesity and hyperlipidaemia should also be addressed.
Management of diabetes mellitus
Insulin: Insulin plays a great role in the regulation of carbohydrate, fat and protein metabolism. It is a polypeptide hormone of complex structure. There are differences in the amino acid sequence of animal insulin's, human insulin's and the human insulin analogues.
Insulin may be of beef or pork origin or it may be human insulin produced by gene technology or by modification of porcine insulin.
All insulin preparations are to a greater or lesser extent immunogenic in man but immunological resistance to insulin action is uncommon. Human and Porcine insulin are less immunogenic than bovine insulin and where possible most newly diagnosed IDDM patients are now given human insulin.
Insulin of whatever origin is formulated to provide a range of preparations offering: -
• Short duration which have a relatively rapid onset of action, namely soluble insulin, insulin lispro and insulin aspart.
• Intermediate action, e.g isophane insulin and insulin zinc suspension; and
• Long action which have a relatively slower in onset, e.g. Crystalline insulin Zinc suspension
For those who require administration of insulin, appropriate combinations of insulin therapy will have to be worked out for the individual patient. In pregnancy insulin requirements should be monitored frequently.
Examples of recommended insulin regimens
• Short - acting insulin mixed with intermediate - acting insulin: twice daily (before meals)
• Short - acting insulin mixed with intermediate acting insulin before breakfast
Short - acting insulin before evening meal
Intermediate - acting insulin: at bed time
• Short - acting insulin: three times daily (before breakfast, midday and evening meal)
Intermediate - acting insulin at bedtime
• Intermediate - acting insulin with or without short-acting insulin once daily either before breakfast or at bedtime suffices for some patients with type II diabetes who need insulin, sometimes in combination with oral hypoglycemic drugs.
Insulin is inactivated by gastro-intestinal enzymes, and must therefore be given by injection; the subcutaneous route is ideal in most circumstances. It is usually injected in to the upper arms, thighs, buttocks, or abdomen; there may be increased absorption from a limb site if the limb is used in strenuous exercise following the injection. Generally subcutaneous insulin injections cause few problems; fat hypertrophy does however occur but can be minimized by rotating the injection site. Local allergic reactions are now rare. The various types of insulin may also be given intramuscularly when the onset of action is faster than with the subcutaneous route. An even faster onset may be achieved with intravenous administration, but this route is only suitable for fast-acting or soluble insulin.
Hypoglycemia: The most frequent complications of insulin therapy is hypoglycemia and patients taking insulin should be educated about its cause, symptoms, and treatment. Most patients can recognize the early warning signs of hypoglycemia and by taking sugar immediately they can prevent more serious symptoms developing. Comatose patients should be given intravenous glucose or, if this is not practicable, subcutaneous or intramuscular glucagons.
Hypoglycemia can also develop in patients taking oral hypoglycemic, notably the sulphonylureas. Some patients may no longer be able to recognize the warning signs of hypoglycemia after transferring from animal to human insulin and these patients, if appropriate, should be transferred back to porcine insulin.
Car drivers need to be particularly careful to avoid hypoglycemia. They should check their blood glucose concentrations before driving and, on long journeys, at intervals of approximately two hours; they should ensure that a supply of sugar is always readily available. If hypoglycemia occurs the driver should switch off the ignition until recovery is complete (may be 15 minutes or longer). Driving is not permitted when hypoglycemic awareness has been lost. For sporadic physical activity departing from the patients usual daily routine extra carbohydrate may need to be taken to avert hypoglycemia. Blood glucose should be monitored before, during and after exercise.
Diabetic Ketoacidosis. Diabetic ketoacidosis results from a lack of insulin due to a number of factors and the onset may be over hours or days. It is characterized by hyperglycemia, hyperketonaemia, and acidaemia and is a medical emergency which should be treated promptly with fluid and electrolyte replacement and insulin. However, over vigorous fluid replacement without severe dehydration carries the risk of precipitating cerebral oedema.
Surgery: Insulin dependent diabetics who require surgery should be managed with a continuous intravenous insulin infusion. Insulin is given as normal the night before operation, and switched to either a variable rate infusion via a syringe pump, together with a 10% glucose drip, or to a combined insulin-glucose infusion, on the day of operation. Subsequent conversion back to subcutaneous insulin should be undertaken before breakfast, giving the first subcutaneous dose 30 minutes before stopping continuous infusion. Non - insulin dependent patients should have any oral treatment omitted on the day of operation, and may be given insulin by a similar regimen if control is poor or deteriorates as can happen with major surgery.
Soluble insulin is a short - acting form of insulin. When injected subcutaneouly it has a rapid onset of action (after 30 - 60 minutes), a peak action between 2 and 4 hours, and duration of action up to 8 hours when injected intravenously, soluble insulin has a very short half - life of only about 5 minutes.
When administered subcutaneous, intermediate-acting insulin's have an onset of action of approximately 1 - 2 hours, a maximal effect at 4 - 12 hours and duration of action of 16 - 24 hours. They can be given twice daily together with short - acting insulin or once daily, particularly in elderly patients. They can be mixed with soluble insulin in the syringe, essentially retaining properties of each component.
The duration of action of different insulin preparations varies considerably from one patient to another and this needs to be assessed for every individual. The type of insulin used and its dose and frequency of administration depend on the needs of each patient. For patients with acute onset diabetes mellitus, treatment should be started with soluble insulin given 3 times daily with medium acting insulin at bedtime. For those less seriously ill, treatment is usually started with a mixture of premixed short and medium acting insulin given twice daily. The proportions of soluble insulin can be increased in patients with excessive post-prandial hyperglycaemia. Patients should remain on the same insulin throughout treatment. Regimens should be developed by each country.
Insulin soluble /Neutral (HPB)*
Injection 100 units/ml in 10ml vial
* HPB stands for Human, porcine, and Bovine
Indications: - diabetes mellitus; diabetic emergencies and at surgery; diabetic ketoacidosis or coma.
Cautions: - see notes above; reduce dose in renal impairment; occasionally insulin resistance necessitating large doses; pregnancy and breastfeeding; see also interactions.
Drug interactions: - analgesics, antibacterials, antifungals, uricosurics.
Side effects: - hypoglycaemia in overdose; localized and rarely generalized, allergic reactions; lipoatrophy at injection site; insulin resistance.
Dose and Administration:
Diabetes mellitus, by subcutaneous injection, Adult and Child according to individual requirements important. Intravenous injection is contraindicated.
Storage: - Store at 2°C to 8°C. Do not allow to freeze protect from light.
Insulin Zinc suspension/Insulin Lente (HPB)*
Injection 100 units/ml in 10ml vial
* HPB stands for Human, porcine, and Bovine
Indications: - diabetes mellitus (long acting)
Cautions, Drug interactions, Side effects: see notes above and under soluble insulin.
Dose and Administrations
By subcutaneous injection, according to requirements
Storage: - store between 2°C and 8°C protect from freezing.
Isophane/NPH insulin (HPB)*
Injection, 100units/ml in 10ml vial
* BP stands for Bovine and porcine
Indications: - diabetes mellitus
Cautions, Drug interactions, Side effects; see notes above and under soluble insulin.
Protamine may cause allergic reactions
Dose and Administrations
By subcutaneous injection, according to requirements.
Intravenous injection is contraindicated.
Storage: - unopened vials of insulin should be stored at 2°C to 8°C and should not be subjected to freezing. The vial in use may be stored at room temperature; exposure to extremes in temperature or direct sunlight should be avoided.
Biphasic Insulin (BP)+
Injection (highly purified), 100 units/ml in 10ml vial
Indications: - diabetes mellitus (intermediate acting)
Cautions; Drug interactions, Side effects: see notes above and under soluble insulin.
Protamine may cause allergic reactions
Dose and Administrations
By subcutaneous injection, according to requirements
Storage: Store at 2°C to 8°C. Do not allow freezing protect from light.
Note: It should be gently shaken before use.
Biphasic Isophane Insulin (soluble/Isophane Mixture)
Injection, 50/50, 30/70, 100 units/ml in 10ml vial
Indications: diabetes mellitus (intermediate acting)
Cautions, Drug interactions, Side effects; see notes above and under soluble insulin; protamine may cause allergic reactions.
Dose and Administration
By subcutaneous injection, according to requirements
Storage: - Store at 2°C to 8°C. Do not allow freezing protect from light.
Note: It should be gently shaken before use.
Oral antidiabetic drugs. If patients with NIDDM have not achieved suitable control after about 3 months old dietary modification and increased physical activity, then oral hypoglycemic may be tried.
The two major classes of oral hypoglycemic agents are the sulphonylureas and the biguanides. Sulphonylureas act mainly by increasing endogenous insulin secretion, whilst biguanides act chiefly by decreasing hepatic gluconeogenesis and increasing peripheral utilization of glucose. Both types of agents only function in the presence of some endogenous insulin production.
Oral treatment of NIDDM is usually begun with a sulphonylureas. Chlorpropamide has more adverse effects than the other sulphonylureas. It has a long half life and hence is considered to have an increased tendency to cause hypoglycaemia, although a recent large study reported that hypoglycaemic episodes were less frequent with chlorpropamide than Glibenclamide. Use of chlorpropamide is therefore inadvisable in the elderly; Glibenclamide is also best avoided for the same reason.
A sulphonylurea with a short half-life, such as tolbutamide, should be used instead in such patients. Unfortunately sulphonylureas can cause weight gain so severely obese patients may be treated with the biguanide metformin rather than a sulphonylurea. Metformin is as effective as the sulphonylurea in terms of blood glucose control but has a rare tendency to cause lactic acidosis in patients with renal failure and should therefore be avoided in patients at risk. Patients with NIDDM who cannot be controlled adequately by oral therapy and diet need to be given insulin either in addition to the existing treatment or in place of the oral therapy.
Contraindications: sulphonylureas should be avoided where possible in severe hepatic and renal impairment and in porphyria. They should not be used while breast feeding and insulin therapy should be substituted during pregnancy.
Insulin therapy should also be instituted temporarily during intercurrent illness (such as myocardial infarction, coma, infection, and trauma). Oral antidiabetic drugs should be omitted on the morning of surgery; insulin is often required because of the ensuing hyperglycaemia in these circumstances. Sulphonylureas are contraindicated in the presence of ketoacidosis.
Side effects: Side effects of sulphonylureas are generally mild and infrequent and include gastro-intestinal disturbances such as nausea, vomiting, diarrhoea and constipation.
They can occasionally cause a disturbance in liver function, which may rarely lead to cholestatic jaundice, hepatitis and hepatic failure. Hypersensitivity reactions can occur, usually in the first 6 - 8 weeks of therapy; they consist mainly of allergic skin reactions which progress rarely to erythema multiforme and exfoilative dermatitis, fever and jaundice; photosensitivity has rarely been reported with chlorpropamide. Blood disorders are also rare but may include leucopenia, thrombocytopenia, agranulocytosis, pancytopenia, haemolytic anaemia, and aplastic anaemia.
Chlorpropamide has appreciably more side effects, mainly because of its very prolonged duration of action and the consequent hazard of hypoglycaemia and it should generally no longer be used. It may also cause facial flushing after drinking alcohol; this effect does not normally occur with other sulphonylureas. Chlorpropamide may also enhance antidiuretic hormone secretion and very rarely cause hyponatraemia.
Glibenclamide
Tablet, 5mg
Indications: type II diabetes mellitus
Cautions, Side effects, Contraindications: see notes above
Drug interaction: - analgesics (azapropazone, phenylbutazone and possibly other NSAIDs enhance effect of sulphonylureas), antibacterial, antifungals, uricosurics.
Dose and Administrations: - Initially 5mg daily with or immediately after break fast (Elderly 2.5mg, but avoid - see notes above), adjusted according to response, maximum 15mg daily.
Chlorpropamide
Tablet, 100mg, 250mg
Indications: type II diabetes mellitus
Cautions, Contraindications, Side effects; see notes above
Drug interactions: - see under Glibenclamide.
Dose and Administrations
Initially 250mg daily with breakfast (Elderly 100 - 125 mg but avoid - see notes above), adjusted according to response; maximum 500mg daily.
Storage: - Store in a well-closed container at room temperature
Tolbutamide
Tablet, 500mg
Indications: - type II diabetes mellitus
Cautions, Contraindications; see notes above
Side effects; see notes above, also headache, and tinnitus.
Drug interactions: see under Glibenclamide.
Dose and Administrations
0.5 - 1.5g (max. 2g) daily in divided doses; with or immediately after breakfast.
Storage: - store in a well-closed container at room temperature.
Metformin
Tablet. 500mg
Indications: type 2 diabetes mellitus
Cautions: substitute insulin during severe infection, trauma, surgery; breastfeeding
Drug interactions: - alcohol, cimetidine & other cationic medication excreted by renal tubular transport (such as: amiloride, nifedipine, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, vancomycin); Furosemide; vitamin B12.
Side effects: - anorexia, nausea and vomiting, diarrhoea patients with renal failure (discontinue); decreased vitamin B12 absorption.
Contraindications: - renal impairment (withdraw if renal impairment suspected; hepatic impairment; heart failure; severe infections or trauma; dehydration; alcohol dependence; pregnancy.
Dose and Administrations
By mouth, Adult 500mg every 8 hours or 850mg every 12 hours with or after food (maximum 2g daily in divided doses).
Storage: - Store at room temperature in a light resistant container, unless otherwise specified by manufacturer.
