Section 7. Endocrine system
7.2 Pituitary gland and adrenal cortex 310
7.3 Disorders of bone and bone metabolism 319
7.4 Sex hormones 322
7.5 Pregnancy 331
7.1. Endocrine pancreas and diabetes mellitus
The pancreas produces two hormones that regulate blood glucose levels. Insulin is produced by the beta cells in the islets of Langerhans and is secreted when blood glucose levels rise. The overall impact is increased utilisation of glucose and a reduction in the level of glucose in the blood. Glucagon is produced by the alpha cells in the islets when blood glucose levels are low and stimulates the conversion of glycogen stored in the liver to glucose, thus raising the level of glucose in the blood and preventing hypoglycaemia.
Diabetes mellitus is a syndrome characterised by a persistently raised blood glucose level and associated with a deficiency of or resistance to insulin. Over 2.5 million people in the UK have diabetes (Diabetes UK 2008) and more than 120 million people worldwide. In health the normal range for blood glucose is 4.0–7.0 mmol/l.
Type 1 diabetes is an autoimmune disease where the beta cells that produce insulin are destroyed. Eventually no insulin at all is secreted. Type 2 diabetes is a different disease. The patient still produces some insulin but this is either low in quantity or the cells are resistant to its action (insulin resistance). There are a great many more people with type 2 diabetes (95% of all those with diabetes) than type 1. The incidence of type 2 diabetes is increasing in this country and is linked to obesity, hypertension and heart disease.
Action of insulin
▪ Insulin secretion is dependent upon the level of glucose in the blood.
▪ A low basal level of insulin is secreted throughout the day and night, but after a meal when glucose levels rise, more insulin is secreted. There is a 7–10-fold difference in insulin concentrations between meals and following a meal. Secretion in health is about 30–40 units daily.
▪ Insulin is necessary to allow glucose to enter most body cells and so be used for energy. If there is excess glucose, insulin encourages its storage as glycogen in the liver and muscles and as fat in adipose tissue.
▪ If there is insufficient insulin the body cannot utilize its glucose which will then accumulate in the blood (hyperglycaemia) and spill over into the urine.
Effect of insulin on target cells
▪ Insulin causes the rapid uptake, storage and use of glucose by almost all tissues in the body but especially by the muscles, liver and adipose tissue.
▪ Binds with a specific membrane receptor protein on the surface of the target cell, which becomes activated and triggers the cell’s response.
▪ Within seconds of binding, about 80% of all body cells become highly permeable to glucose. This allows the rapid entry of glucose into the cells by specific carriers.
Glucose uptake by the brain is not dependent on insulin secretion.
Glucose uptake by the brain is not dependent on insulin secretion.Type 1 diabetes mellitus
▪ No insulin is produced and without insulin injections the patient would eventually die.
▪ Autoimmune disorder, the causes of which are not entirely understood. The beta cells in the pancreas are attacked by antibodies and eventually totally destroyed.
▪ Certain individuals have a genetic predisposition towards the disease but an environmental trigger factor is needed. This may be a virus.
▪ The onset of the disease has its highest incidence around 11–12 years of age, and although it can occur at any age, it is uncommon over the age of about 40 years.
Onset is reasonably acute over a period of weeks or months with polyuria (passing lots of urine), thirst, polydipsia (drinking lots), weight loss and lack of energy.
Without treatment the body has to utilise fat for energy and in doing so produces ketones. These are acidic and accumulate in the blood, being eliminated in the urine. If the person does not receive insulin therapy, a ketoacidotic coma may result. This is a medical emergency and the patient is dehydrated, suffering from electrolyte imbalance and acidotic.
Type 2 diabetes
▪ This is due to insulin resistance or deficiency. There is some insulin available but the body may not be able to utilise this adequately.
▪ The majority of people with diabetes have type 2 diabetes and the numbers are increasing worldwide.
▪ The disease is associated with obesity, and although it used to be considered a disease of middle or old age, there are now cases occurring in children.
▪ Onset is insidious and the person may have type 2 for years and not know about it.
▪ It is possible to prevent or delay the onset of type 2 diabetes by eating a healthy diet, keeping slim and exercising sufficiently.
▪ Type 2 can usually be controlled by diet alone or tablets but some patients may eventually need insulin injections.
▪ There is no cure for diabetes at present and the aim of treatment is to control the blood glucose levels and prevent long-term complications occurring.
Long-term complications of diabetes
These may affect large blood vessels such as the aorta, coronary, carotid and femoral arteries. Atheroma is deposited more readily and this results in a higher risk of cardiovascular disease.
To prevent complications blood glucose needs to be kept in as normal a range as possible. Blood pressure also needs to be tightly controlled and cardiovascular risk factors treated.
The diet in diabetes
Although the patient with type 1 diabetes will need to have insulin injections, diet is still important.
The patient will always see a dietician who will advise them and their families on the types of foods that may need to be avoided.
The diet should be a balanced diet that is low in animal fats to reduce atheroma deposition. It is the sort of healthy diet that we should all be eating.
Carbohydrate should be ‘starchy’ and long lasting such as that found in bread, rice and potatoes. Less should be eaten in the form of foods containing ‘fast’ sugar.
At least five portions of fruit and vegetables should be eaten daily but it must be remembered that fruit does contain fructose which is a fast sugar and so cannot be eaten freely.
The use of foods labelled ‘diabetic’ is not encouraged as these are unnecessary and expensive.
The patient with type 2 diabetes usually needs to lose weight and will need advice on how this may be achieved.
Exercise
It is now realised that regular exercise should be encouraged for everyone, when possible. Half an hour of moderate exercise at least five times a week is recommended. It makes people feel good and helps with weight loss as well as increasing fitness.
Insulin therapy
Insulin was first isolated from the pancreas in 1922 and immediately the outlook for the patient with type 1 diabetes changed from rapid decline and death to practically that of a healthy person.
▪ The normal production of insulin by the pancreas has to be mimicked as closely as possible by the administration of insulin by injection. Insulin requirements in the body change from minute to minute and so this is a difficult task.
▪ Insulin cannot be given orally as it is a protein and so inactivated by enzymes in the gut. It is usually given subcutaneously and the injection site is rotated on a systematic basis, using the thighs and the abdominal wall. Some patients also use the upper arms or buttocks.
▪ Injections may be up to four or even five times daily, and for some, this is the worst aspect of their illness. New, very fine insulin needles have now made the process practically painless.
▪ Insulin is a small protein and its basic structure is common to all mammalian species so allowing patients to be treated with animal insulins. Bovine insulin differs from human insulin by three amino acids and porcine only differs from human by one. Genetically engineered human insulin is now used in preference to animal insulins.
Insulin as therapy in diabetes is indicated in:
▪ type I diabetes
▪ all patients presenting with ketoacidosis, regardless of age
▪ any type of diabetes where oral therapy has failed
▪ intercurrent illness e.g. myocardial infarction
▪ pregnancy
▪ surgery.
Aims of insulin therapy
▪ Abolition of symptoms.
▪ Maintenance of ideal body weight.
▪ Optimisation of glucose control – without making the patient obsessional.
▪ Prevention of complications or delay in progress.
▪ Reduction in associated risk factors for coronary heart disease.
Close co-operation between the patient and the healthcare team is needed and the patient should be involved in decision making about their treatment. The dose of insulin needs adjustment on an individual basis.
Healthy nondiabetic fasting glucose is very close to 4.3 mmol/l. After a meal it does not rise to above 7.0 mmol/l.
In diabetes the aim is to maintain blood glucose levels as close as possible to normal physiological levels without hypoglycaemia.
Self-monitoring of blood glucose
▪ The aim is to keep blood glucose between 4 and 7 mmol/l between and before meals.
▪ Target levels of <7.8 mmol/l 2 hours postprandial (after food) in type 1. In type 2 may accept up to 9 mmol/l.
▪ The person with diabetes usually gives their own insulin injections and monitors their glucose levels.
▪ Finger prick glucose measurements are taken up to four times daily and insulin doses and physical activity may be adjusted according to these levels.
HbA 1C levels
This is another means of assessing control of blood glucose. It is a measure of the percentage of haemoglobin (Hb) in the blood that is carrying glucose – glycated Hb. It is slower to change than blood glucose and monitors glucose control over a period of 2–3 months. In a person without diabetes, the normal percentage is less than 6.5%.
The National Institute for Health and Clinical Excellence (NICE) recommends that most people with diabetes should aim for between 6.5% and 7.5%.
Types of insulin available
The half-life of insulin is 5–6 minutes – it is rapidly destroyed by the liver. This is ideal in the body where it is released as needed but not ideal for an injection given for replacement therapy. Sustained-release formulations have been developed to try and overcome this. To prolong the action of insulin it is bound to zinc or proteins.
The main types of insulin are:
▪ fast acting with short duration – analogues such as aspart and soluble insulin
▪ intermediate acting e.g. isophane insulin
▪ long acting e.g. insulin zinc suspension and analogues e.g. glargine.
Types of insulin and their actions are summarised in Table 7.1.
| Types of insulin | Brand names | Following subcutaneous administration | Description | ||
|---|---|---|---|---|---|
| Quick acting | Onset | Peak | Duration | ||
| Recombinant human insulin analogues | Insulin Lispro ( Humalog®) | 5–20 min | 30–60 min | 2–5 hours | Amino acid structure slightly altered to make action faster and of shorter duration |
| Insulin Aspart ( NovoRapid®) | 2-4 hours | ||||
| Insulin Glulisine ( Apidra®) | |||||
| Soluble insulin (insulin injection; neutral insulin) | Human sequence insulins: Actrapid®, Humulin S®, Velosulin®, Insuman Rapid® | 30–60 min | 2–4 hours | 4–8 hours | Structure as in the human body |
| Highly purified animal insulins: Hypurin Bovine Neutral®, Hypurin Porcine Neutral®, Pork Actrapid® | Porcine 1 AA different to human | ||||
| Intermediate acting | |||||
| Isophane insulin (isophane protamine, isophane NPH) | Insulatard®, Humulin I®, Insuman Basal® Porcine and Bovine Isophane®, Pork Insulatard® | 1–2 hours | 5–8 hours | 12–18 hours | Soluble insulin and the protein protamine in equal amounts |
| Long acting | Onset | Peak | Duration | ||
| Insulin zinc suspension | Hipurin Bovine Lente®, Hipurin Bovine PZI® | 1–2 hours | 6–20 hours | Up to 36 hours | Combined with zinc for longer action |
| Basal insulin analogue | Glargine ( Lantus®) Detemir ( Levemir®) | 90 min | Flat profile | 24 hours | Amino acid structure changed – long action for basal level |
| Biphasic insulins | |||||
| Biphasic isophane | Human Mixtard® 10, 20, 30, 40, 50 Hypurin Pork® 30/70 Humulin® M3, Insuman Comb® 15,25,50 | Mixture of fast-acting soluble and intermediate-acting isophane Mixtard 10 is 10% soluble, 90% isophane. Reduces the number of injections. Often twice daily Usual mix is 30% soluble, 70% isophane | |||
| Biphasic insulin lispro Biphasic aspart | Humalog Mix® 25 Humalog Mix® 50 NovoMix® 30 | 25% lispro and 75% insulin lispro protamine 50% of each 30% aspart and 70% aspart protamine | |||
The action profile of insulin is also affected by:
▪ dose
▪ injection site
▪ injection technique
▪ exercise
▪ temperature
▪ insulin species (e.g. human or porcine).
Short-acting insulins
Soluble insulin (human sequence- Actrapid, Humulin S, Velosulin, Insuman Rapid. Also porcine – Hypurin Porcine Neutral, Hypurin Bovine Neutral, Pork Actrapid)
▪ The original form of insulin.
▪ Clear solution. Additive such as phenol prevents growth of micro-organisms.
▪ Injected 15–30 minutes before food.
▪ Used in medical emergencies e.g. diabetic ketoacidosis and also in surgery.
▪ Can be given intravenously and intramuscularly as well as subcutaneously.
▪ Given intravenously has half-life of only 5 minutes and duration of action only 30 minutes.
Subcutaneous administration results in onset of action at approximately 30 minutes–1 hour; peak action 2–4 hours; duration of action 4–8 hours.
Recombinant human insulin analogues – the most rapid onset of action – insulin lispro (Humalog®), insulin aspart (NovoRapid®), insulin glulisine (Apidra®)
Modified soluble insulin where two amino acids have changed places.
▪ Faster onset and shorter duration of action than soluble.
▪ This results in higher preprandial glucose levels and lower postprandial levels.
▪ Hypoglycaemia occurs less frequently.
▪ Convenient as the injection is given just before eating or while eating.
▪ Can also be given intravenously and is an alternative in diabetic emergencies or surgery.
Subcutaneous administration results in onset of action in 10–20 minutes; time to peak 1 hour; duration of action 3–4 hours.
Intermediate-acting insulins
These have a slower onset and act for varying periods depending on what the insulin is combined with to increase its length of action.
Isophane insulin injection (human – Insulatard®, Humulin I®, Insuman Basal®. Animal – Hypurin®, bovine isophane, Hyperion®, porcine isophane, Pork Insulatard®)
Long-acting insulins
Insulin zinc suspension (mixed) (IZS) e.g. Hypurin®, Bovine Lente, Protamine Zinc Insulin Hypurin®, bovine protamine zinc
There is more zinc than insulin. It is crystallised and the duration of action varies by varying the size of the crystal. A smaller crystal has a proportionately larger surface area and so a faster onset of action.
Must not be mixed with soluble as there is excess zinc and this will combine with the soluble to make it longer acting.
▪ Onset 2–4 hours; time to peak 6–20 hours; duration up to 36 hours.
Long-acting analogue insulins
Insulin detemir (Levemir®), insulin glargine (Lantus®)
▪ Long-acting basal insulins usually given once daily at bedtime.
▪ Human insulins produced by recombinant DNA technology.
▪ Clear insulin. Must not be mixed with other types.
▪ When injected form a microprecipitate in the subcutaneous tissue that delays absorption and extends action.
▪ Allows a fairly constant basal insulin supply and smoothes out unwanted peak effects that are seen with other intermediate- and long-acting insulins.
▪ Low, flat profile of systemic insulin exposure over 24 hours.
Biphasic insulins
These are premixed set ratios of short-acting and isophane insulin that have been prepared in the pen/vial by the manufacturer.
The soluble or analogue component acts quickly and the isophane component last longer. This allows twice-daily administration before breakfast and evening meal.
Biphasic isophane insulin
Human Mixtard® 10, 20, 30, 40, 50; Humulin® M3, Insuman® Comb 15, 25, 50. Pork Mixtard 30®, Hypurin® porcine 30/70 mix
The figures give the percentage of soluble insulin in the combination e.g. Human Mixtard® 30 and Humulin® M3 are 30% soluble insulin and 70% isophane insulin.
All the range of mixtures that are needed is covered and so there is no need to mix.
This improves patient compliance. Available from 10% soluble, 90% isophane to 50% soluble, 50% isophane.
Biphasic insulin lispro
Humalog® Mix 25, Mix 50
25% or 50% lispro and 75 or 50% lispro protamine.
Biphasic insulin aspart Novomix® 30
30% aspart and 70% aspart protamine.
Different types of insulin are summarised in Table 7.1.
Duration of insulin action varies in individuals and each patient needs their own individual assessment.
Duration of insulin action varies in individuals and each patient needs their own individual assessment.Administration of insulin
The standard strength of insulin in the UK is 100 international units per ml.
The word units should not be abbreviated.
Small amounts can be measured accurately using special insulin syringes.
▪ Absorption after subcutaneous injection is variable and influenced by many factors e.g. site, angle and depth of injection, time of day, environmental temperature, phase of menstrual cycle, insulin species and formulation used.
▪ Absorption is slowest from the thigh – but physical activity will affect this.
▪ There is no difference in potency between human and animal insulins. Human insulin is absorbed from subcutaneous tissue slightly more rapidly than animal insulins and it has a slightly shorter duration of action. The chief reason for using human insulin is not difference in biological activity, but reduced immunogenicity.
▪ Some sources report that there may be less warning of a hypoglycaemic attack after human than animal insulin.
▪ The rate of absorption may be affected by smoking, alcohol intake (vasodilation) and drugs such as propranolol (peripheral vasoconstriction) and nifedipine (vasodilation).
▪ It has been said that the problem in type I diabetes is not the insulin deficiency but the insulin therapy. This is because getting the correct type of insulin and the regimen right can be difficult.
Insulin regimens
The number of available insulins, injection devices and pumps produces a daunting array of choices.
The overall aim is to produce as near a normal glycaemic profile as is achievable in the individual.
In the young person with type 1 diabetes we need to emulate the body’s secretion patterns, where there is a sharp rise in available insulin following meals and snacks with a rapid return to the low basal rate between meals and at night.
To acquire a similar profile with injected insulin would need continuous blood glucose monitoring, together with minute-by-minute insulin regulation. This is not yet available.
Common insulin regimens
1. Twice-daily short-acting mixed with intermediate-acting insulins
Commonest split is 30% soluble and 70% isophane.
Injections should be no closer than 8 hours apart and preferably more than 10.
If postprandial hyperglycaemia is a problem, the percentage of soluble insulin in the mixture can be increased.
2. Twice-daily isophane
Provides good control with minimum risk of hypoglycaemia.
▪ Particularly effective in older people with type 2, changing to insulin from oral hypoglycaemic agents.
▪ Some patients with type 2 diabetes may receive just once-daily insulin before breakfast or at bedtime.
3. Basal/bolus regimen
This is usually the regimen of choice for those with acute-onset diabetes.
Short-acting insulin (soluble insulin or insulin analogue such as aspart) is given before meals, three times daily and isophane or a long-acting insulin analogue (e.g. glargine) at bedtime to provide a 24 hour basal level.
This regimen emulates the body’s basal insulin secretion with mealtime boluses.
▪ Advantages – flexibility of lifestyle, mealtimes, meal sizes and when exercising.
▪ Disadvantage – need four injections daily.
Basal insulin is usually best given in the late evening. This reduces overlap with the action of the evening soluble.
▪ Most people need more soluble with breakfast than other meals.
▪ Most people need less soluble with lunch.
▪ May vary according to individual lifestyles.
▪ May not necessarily achieve better control than twice-daily insulin.
Sometimes fast-acting analogue insulins may be given before eating up to five times daily with long-acting insulin at night.
4. Continuous subcutaneous insulin infusion pump
Continuous supply of preprogrammed basal insulin with addition of boluses whenever food is taken. A small pump is attached to the abdomen via a cannula.
This has been approved by NICE for certain patients. It provides the best control and is well tolerated by some.
Advantages:
▪ Most closely matches normal functioning.
▪ Flexibility of lifestyle.
▪ Can make adjustments for exercise more easily.
Disadvantages:
▪ Cost of equipment and disposables.
▪ Inconvenience of wearing pump.
▪ Can cause problems on abdominal site.
Adverse effects of insulin therapy
Hypoglycaemia
The risk of hypoglycaemia is highest before meals and during the night.
Causes include too high a dose of insulin, irregular eating habits, unusual levels of exercise or excessive alcohol intake (Table 7.2).
It is important not to let glucose levels fall below 4 mmol/l.
It is important not to let glucose levels fall below 4 mmol/l.The saying is ‘four is the floor’.
| Increased insulin requirements | Decreased insulin requirements |
|---|---|
| Stress | Renal or hepatic impairment |
| Accidental or surgical trauma Puberty | Some endocrine disorders e.g. Addison’s disease, hypopituitrism |
| Second and third trimesters of pregnancy | Coeliac disease |
Signs and symptoms of hypoglycaemia
The brain is totally reliant on the blood glucose for its energy and so is the first organ to suffer when glucose levels are low.
▪ At first there may be just a headache, but as the glucose levels fall, thinking processes are disrupted. Confusion follows and the person may behave strangely, often becoming aggressive.
▪ Some symptoms of hypoglycaemia are due to adrenaline (epinephrine) release and these include tremor, pallor and sweating.
▪ The blood pressure will be normal or even raised slightly.
▪ If the condition is not corrected, consciousness will be lost.
▪ Warning signs of hypoglycaemia may be less in those who have had diabetes for many years.
Treatment of hypoglycaemia
Oral glucose or sugar in any form may be given if the patient is fully conscious and co-operative. The person with diabetes should always carry some form of glucose with them in case they feel hypoglycaemic. At first 10–20 g of glucose should be given. 10 g of glucose is found in about 3 sugar cubes or 2 teaspoons of sugar. Nondiet forms of Lucozade, Coca-cola, Ribena or sparkling glucose drink may be used.
Glucose is available as a gel for buccal administration in the form of Glucogel®.
Hypoglycaemia causing unconsciousness is an emergency. It may be treated by the administration of glucagon, 1 mg, intramuscularly. Glucagon is the hormone produced by the alpha cells in the islets of Langerhans. Its action is the reverse of insulin and glucagon is secreted when glucose levels are low. It stimulates the conversion of glycogen stores in the liver to glucose and so raises blood glucose levels.
As soon as possible the patient should be given some longer-lasting carbohydrate e.g. toast.
Intravenous glucose may be used to treat hypoglycaemia when the patient is unconscious – 50 ml of 20% glucose is given into a large peripheral vein. Glucose is irritant, especially if the needle comes out of the vein and enters the tissues.
Lipohypertrophy
Changes in the fat deposits beneath the skin may occur at injection sites after they have been used repeatedly. The fat becomes lumpy and may be unsightly but is otherwise harmless. The site should not be used further as absorption may be erratic.
Drug interactions with insulin
The most important interactions are those that result in a rise or fall in blood glucose levels.
Drugs that may increase the action of insulin
▪ Beta blockers may increase the hypoglycaemic effects of insulin and may also mask the symptoms of hypoglycaemia e.g. tremor. Recovery from hypoglycaemia is slower. Normally we release adrenaline (epinephrine) in hypoglycaemia and this increases blood glucose. Beta blockers block the adrenergic receptor and so interfere with this. There is greatest risk with nonselective drugs such as propranolol and less risk with cardioselective agents such as atenolol.
▪ Angiotensin converting enzyme( ACE) inhibitors may increase sensitivity in some patients. Three times the incidence of hypoglycaemia has been reported in one trial.
▪ Alcohol gives enhanced hypoglycaemic effect.
▪ Some antidepressants – monoamine oxidase inhibitors (MAOIs) enhance hypoglycaemic effect. Moclobemide appears not to do this (see section 4.5).
▪ Anabolic steroids e.g. nandrolone and testosterone may possibly enhance blood glucose lowering effects of insulin in some patients. An average reduction of insulin dose of one third is needed in about one third of patients (Stockley 2005). The reason is uncertain.
▪ Quinine given as an antimalarial or sometimes when used for cramp has been associated with hypoglycaemia in patients without diabetes and thus not receiving insulin. The effect in diabetes has not been studied.
▪ Aspirin in large doses can lower blood sugar levels.
Drugs that antagonise the action of insulin or impair glucose tolerance
▪ Levothyroxine.
▪ Furosemide may occasionally raise blood glucose levels. Thiazide diuretics (e.g. bendroflumethiazide) do raise blood glucose and can impair the control of diabetes.
▪ Oral contraceptives and hormone replacement therapy may occasionally require adjustment of insulin.
▪ Calcium channel blockers e.g. nifedipine – occasional reports only. No precautions appear necessary but just to monitor the effects on glucose control.
▪ Lithium may occasionally impair glucose tolerance.
▪ Antipsychotics such as chlorpromazine, clozapine, risperidone and olanzapine are associated with an increased risk of glucose intolerance.
▪ Studies have shown that those who smoke require more insulin. This may be due to reduced absorption of insulin due to peripheral vasoconstriction and a rise in hormones that oppose the action of insulin.
Oral antidiabetic drugs
These are used in type 2 diabetes that is not controlled by diet alone. Dietary and lifestyle changes will be tried for at least 3 months. If there is no response, tablets may be needed.
There are several groups of drugs:
▪ Biguanides e.g. metformin.
▪ Sulphonylureas e.g. gliclazide.
▪ Glitazones e.g. rosiglitazone.
▪ Prandial glucose regulators e.g. nateglinide.
▪ Enzyme inhibitors e.g. acarbose.
Some patients may be taking more than one type of antidiabetic drug.
The majority of patients with type 2 diabetes are overweight and the main problem is insulin resistance. For this group a drug that increases the body’s sensitivity to insulin is need. Metformin and the glitazones are insulin sensitisers.
If the person with type 2 is not overweight the problem is likely to be insufficient insulin secretion, and now a drug that stimulates the pancreas to produce more insulin is needed. Sulphonylureas and prandial glucose regulators work this way.
Insulin sensitisers
These act directly against insulin resistance.
Biguanides – metformin
Originated from a plant remedy, French lilac, in the 1950s.
Metformin is the only drug available at the moment. Phenformin was discontinued in the 1970s due to high incidence of lactic acidosis.
Metformin is the most extensively used oral agent for type 2 diabetes worldwide.
Metformin is the most extensively used oral agent for type 2 diabetes worldwide.Pharmacokinetics
▪ Quickly absorbed and quickly eliminated unchanged in the urine.
▪ Time to peak plasma concentration is 1–2 hours, half-life is 2–5 hours. Effect lasts about 5 hours.
▪ Not metabolised and is eliminated unchanged in the urine (90% in 12 hours).
▪ Gastrointestinal absorption is complete within 6 hours of ingestion.
Contraindications
Need sufficient renal function to avoid accumulation of the drug. Tubular secretion is more important than glomerular filtration.
Lactic acidosis may occur with other chronic conditions and metformin is contraindicated in renal failure or impairment, hepatic impairment, cardiac or respiratory insufficiency and alcohol dependence.
Adverse effects
▪ Side effects are less troublesome if small doses are used at first.
▪ 5% of patients are not able to tolerate the drug due to gastrointestinal side effects.
▪ Unpleasant metallic taste.
▪ Lactic acidosis is a very rare but potentially fatal complication. The risks are greatly reduced if metformin is avoided in the presence of hepatic, renal, chest or cardiac disease. Most cases are due to bad prescribing.
▪ On its own is extremely unlikely to cause hypoglycaemia.
▪ Does not result in weight gain. Useful in the obese patient.
▪ With long-term use it may interfere with the absorption of vitamin B 12 and folic acid.
Efficacy
▪ Long-term blood glucose lowering effects are similar to sulphonylureas although mechanism of action is different.
▪ Reduces fasting plasma glucose by about 2–4 mmol/l and HbA 1c by 1–2%.
▪ Action is dependent on presence of insulin but is independent of weight, age and duration of diabetes.
▪ Has been shown to delay the onset of type 2 in those with impaired glucose tolerance.
▪ If used alongside insulin in type 2 diabetes, it decreases the amount of insulin the patient needs (Box 7.1).
Box 7.1
Advantages of monotherapy with metformin
Unlikely to cause hypoglycaemia
Improves insulin sensitivity
Reduction or stabilisation of body weight
Improved blood lipid profile
Reduced risk of myocardial infarction of 39% (UK Prospective Diabetes Study Group 1998) after 10 years
Increased fibrinolysis and reduced clotting tendency
Thiazolidinediones (glitazones)
Pioglitazone (Actos®), rosiglitazone (Avandia®)
▪ These drugs were introduced in the late 1990s and reduce insulin resistance. They are known as insulin sensitisers and require the presence of insulin to work.
Mechanism of action
▪ Combine with a receptor inside the cell nucleus – peroxisome proliferators-activated receptor-gamma (PPARγ). Known as PPARγ agonists.
▪ May take several weeks for effect to be seen on blood glucose levels because the drugs act by increasing gene transcription in the nucleus. Full expression of the drug may not occur for 2–3 months after first administration.
▪ They enhance the response of the tissues to insulin and so target insulin resistance. Aid insulin action by promoting glucose utilisation in the tissues.
▪ Decrease hepatic glucose production.
▪ Overall cause a decrease in circulating insulin and triglycerides in type 2 diabetes.
▪ Reduce insulin resistance and preserve beta cell function when added to metformin or sulphonylureas.
▪ Lower incidence of hypoglycaemia than sulphonylureas.
▪ Give an additional decrease in HbA 1C of about 1–1.2% that is sustained for at least 2 years.
▪ Do not increase the risk of hypoglycaemia.
▪ Do not cause gastrointestinal side effects.
Cardiovascular safety
Patients with diabetes are at an increased risk of heart disease. The use of these drugs may be associated with weight gain and fluid retention that may make some heart conditions worse. They are contraindicated in heart failure.
Only licensed for use in combination with metformin or sulphonylureas and not recommended with insulin as this combination has precipitated heart failure.
Rosiglitazone may be associated with an increased risk of myocardial infarction and so caution is advised in those with ischaemic heart disease.
Safety has been reviewed by a European Commission in 2007 that advised the benefits of glitazones in type 2 outweighed the risks, but individual risk should be evaluated.
Adverse reactions
▪ Liver function tests should be done as a precautionary measure before commencement of treatment. Liver function monitored every 2 months for 12 months and then occasionally while still taking the drug.
▪ Increased risk of fracture mainly of the foot and arm in women.
▪ Worsening of macula oedema in some patients with decreased vision.
▪ May cause ovulation to resume and so may be a risk of pregnancy.
▪ Anaemia.
▪ Can be used in the elderly if no contraindications.
Efficacy
Monotherapy may reduce fasting glucose by 3 mmol/l.
▪ Not all patients respond. If no response after 3 months it is likely the patient is a nonresponder.
▪ Efficacy enhanced if combined with other drugs.
Secretagogues
These drugs stimulate the release of preformed insulin from the pancreas.
There are two classes:
▪ Sulphonylureas.
▪ Prandial regulators.
Sulphonylureas
The oldest class of antidiabetic drugs that are derived from sulphonamide antibiotics originally.
▪ Stimulate insulin secretion to lower blood glucose concentration.
▪ Second-generation drugs have been developed and display greater potency e.g. glibenclamide, gliclazide, glipizide, gliquidone.
▪ There is now a third-generation drug that acts on a different part of the sulphonylurea receptor, glimepiride.
▪ May be given as monotherapy or in combination with any differently acting oral antidiabetic agent.
Mechanism of action
▪ Stimulate insulin secretion by binding to a receptor on the beta cell in the pancreas and allowing an influx of calcium into the cell. This stimulates the release of preformed insulin and results in a fall in plasma glucose levels.
▪ They are of no use in type 1 diabetes where the beta cells are largely destroyed.
▪ The drugs have different potencies according to their ability to bind to receptors on the beta cells and stimulate insulin release.
▪ Usually reduce fasting plasma glucose (FPG) by 2–4mmol/l.
▪ Associated with a fall in HbA 1c of 1–2%.
▪ Action dependent on adequate beta cell function but independent of age and body weight.
▪ As the disease progresses there is a deterioration in beta cell function and insulin may then be required. Insulin resistance remains essentially unchanged.
▪ There appears to be a lower secondary failure rate with gliclazide and this is the most commonly prescribed drug in this group.
Pharmacokinetics
The drugs are well absorbed orally and reach their peak plasma concentration after 2–4 hours.
Should be taken at least half an hour before food. This is because they are not absorbed until they reach the duodenum.
Their duration of action varies and this determines the number of doses needed daily.
Sulphonylureas are mostly excreted in the urine and so action is increased in the elderly (whose renal function is impaired) and in those with renal disease.
Cross the placenta and so may cause hypoglycaemia in the newborn.
Adverse effects
Hypoglycaemia
As these drugs increase the release of insulin, hypoglycaemia may occur with their use. The incidence is related to the potency of the drug and its duration of action.
▪ More likely on the longer-acting preparations and in those with irregular eating habits. Also more likely in patients with good control.
▪ The hypoglycaemia may be prolonged, as the drug will still be exerting its action for some time.
