The material contained in this book is set out in good faith for general guidance only. Whilst every effort has been made to ensure that the information in this book is accurate, relevant and up to date, this book is sold on the condition that neither the author nor the publisher can be found legally responsible for the consequences of any errors or omissions.
Diagnosis and treatment are skilled undertakings which must always be carried out by a doctor and not from the pages of a book.
CONTENTS
CoverTitle pageMedical Advice1WHAT IS DIABETES?
The Background to Diabetes: Insulin, Glucose and the Provision of Energy
Defining and Diagnosing Diabetes
Categories of Diabetes (ADA Classification, 1997)
Impaired Fasting Glucose (IFG)
Impaired Glucose Tolerance (IGT)
Type 1 Diabetes
Type 2 Diabetes
Other Specific Forms of Diabetes Mellitus
Genetic Defects Affecting Pancreatic Beta Cells, e.g. Maturity Onset Diabetes of the Young (MODY)
Genetic Defects in Insulin Action, e.g. ‘Leprechaunism’ and Rabson-Mendenhall Syndrome
Diseases of the Exocrine Pancreas, e.g. Pancreatitis, Cystic Fibrosis, Haemochromatosis
Diabetes that Develops as a Feature of Endocrinopathies
Diabetes Caused by Drugs or Chemicals, e.g. Coticosteroids, Thiazide Diuretics and Beta-blockers
Diabetes Caused by Infections, e.g. Congenital German Measles (rubella)
Uncommon Forms of Immune-mediated Diabetes
Other Genetic Syndromes which may Confer a Greater Risk of Diabetes
Gestational Diabetes Mellitus: Diabetes First Diagnosed in Pregnancy
Conditions that Contribute to and are Closely Related to Diabetes
Insulin Resistance
Insulin Resistance Syndrome
Polycystic Ovary Syndrome and Insulin Resistance
Abdominal (or Visceral) Obesity
Hypertension
2INITIAL DIAGNOSIS AND EARLY CAREDiagnosis and ReferralInitial Consultation
Understanding and Managing Diabetes
3DIETARY AND DRUG TREATMENT
Dietary Modification or Nutrition Therapy
Dietary AdviceOral Antidiabetic Drugs
Sulphonylureas
Meglitinides: Repaglinide (Novonorm®)
Biguanides: Metformin (Glucophage®)
Alpha-glucosidase Inhibitors (Acarbose)
Injectable antidiabetic (non-insulin) drugs
GLP-1 receptor agonists (incretin mimetics)
Surgical Forms of Treatment for Diabetes: Pancreatic and Islet Cell Transplants
4INSULIN TREATMENTThe Nature of Insulin
Types of Insulin, According to Duration of Action
Very Quick-acting Insulin Analogues (Lispro and Asparte)
Quick-acting Soluble or Clear Insulin
Intermediate-acting Cloudy Insulins
Long-acting Cloudy Insulins
Insulin Mixtures
Injecting Insulin
Insulin Delivery Devices
Drawing Up Insulin (Vials and Syringes)
Insulin Treatment Regimes
Once-daily Insulin
Twice-daily Insulin
Multiple Daily Injections and the Basal Bolus Regime
Continuous Subcutaneous Insulin Infusion (CSSI)
Combined Insulin and Drug Therapy
Selecting the Insulin Regime and Starting Doses
Obtaining and Storing InsulinDisposal of ‘Sharps’Adjusting Insulin Doses
Side-effects of Insulin Treatment (other than Hypoglycaemia)
Intensive Insulin Therapy in People with
Type 1 Diabetes
Tight Control of Glycaemia in People with
Type 2 Diabetes
5MONITORING GLUCOSE LEVELSHome Blood Glucose Monitoring (HBGM)
How to Carry Out an HBGM Test
HBGM Procedure: Potential Difficulties
The Glucose Oxidase Reaction
Interpreting the Results: What is an Acceptable Range for Blood Glucose Levels?
Clinical Monitoring of Blood Glucose Levels: Testing for HBA1c
New Developments in Blood Glucose Monitoring
Home Urine Testing (HUT)
How to Carry Out a Urine Test
Testing Urine for Ketones
6
HYPOGLYCAEMIA
The Definition of Hypoglycaemia
Immediate Causes of Hypoglycaemia
Longer-term Causes of (Recurrent) Hypoglycaemia
Events Within the Body During Hypoglycaemia
Clinical Grades of Hypoglycaemia and Symptoms
Advice and Treatment for Hypoglycaemia
Mild Hypoglycaemia
Moderate Hypoglycaemia
Severe Hypoglycaemia (in Type 1 Diabetes and Insulin-treated Type 2 Diabetes)
Severe, Sulphonylurea-induced Hypoglycaemia (in Type 2 Diabetes)
Nocturnal Hypoglycaemia
Factors that Affect Hypoglycaemia
Effect of Recurrent Hypoglycaemia and Hypoglycaemic Unawareness
Effect of Insulin Type and Species
Prevention of Hypoglycaemia
7ACUTE METABOLIC COMPLICATIONS
OF DIABETESDiabetic Ketoacidosis (DKA)
Diabetic Hyperosmolar Non-ketotic Syndrome (HONK)
Lactic Acidosis8LONG-TERM CHRONIC COMPLICATIONS:
MICROVASCULAR DISEASES
Retinopathy (Damage Affecting the Eyes)
Background Retinopathy
Pre-proliferative Retinopathy
Proliferative Retinopathy
Advanced Diabetic Eye Disease
Maculopathy
Cataracts
Glaucoma
Neuropathy (Nerve Damage)
Classification of Diabetic Neuropathy
Focal Neuropathies
Distal Symmetrical Polyneuropathy
Acute, Diffuse, Painful, Sensory Neuropathy
Motor Neuropathies
Autonomic Neuropathy
Diffuse Small Fibre Neuropathy
Charcot Neuroarthropathy
Diabetic Nephropathy (Kidney Damage)
Microalbuminuria
Proteinuria
Nephrotic Syndrome
End-stage Renal Failure
9LONG-TERM CHRONIC COMPLICATIONS:
MACROVASCULAR DISEASESGeneral Treatment and Prevention
Coronary Heart Disease
Stroke
Peripheral Vascular Disease
10DIABETES IN PREGNANT WOMEN, CHILDREN, THE ELDERLY AND ETHNIC MINORITIESDiabetes and Pregnancy
Metabolic Changes During Normal Pregnancy
Gestational Diabetes
Pre-existing Diabetes and Pregnancy
Labour and Delivery
Diabetes in ChildrenDiabetes in the Elderly
Diabetes in People from Ethnic Minority Groups
11LIVING WITH DIABETES
Psychological Aspects of Diabetes
Exercise
Exercise and Type 1 Diabetes
Exercise Advice for those with Type 1 Diabetes
Exercise and Type 2 Diabetes
Coping with Illness and Infection
Flu Vaccination
Dental Care
Travel and Holidays
Travelling at Home
Travelling Abroad
General Advice for the Journey and for While You are Away
Diabetes and Driving
Driving Insurance
Life Insurance and Other Insurances
Diabetes and Employment
Alternative Therapies Which may be Helpful in Diabetes
Scientific Research
GLOSSARYBIBLIOGRAPHYOTHER BOOKS IN THIS SERIES
A Guide To Back Pain
A Guide to Headaches and Migraines
Healing Foods
Live Longer, Extend Your Life
How to Look Great on any Budget
Positive Thinking, Positive Living
Understanding Phobias
Copyright
1
WHAT IS DIABETES?
Diabetes is a condition about which most people have a certain amount of knowledge or, at least, a set of beliefs that may or may not be true. For many, this extends no further than knowing that diabetes is caused by having too much sugar in the blood, the remedy for which is to take, on a regular basis, tablets or a substance called insulin which has to be injected. While this is broadly correct as far as it goes, other common beliefs, such as that diabetes is caused by eating too many sweets, are entirely mistaken! Most people know someone – a relative, friend, work colleague or acquaintance – who has diabetes. We may be aware that the person has to eat regularly but mostly avoids sweet foods and that he (or she) carries medication about with him. Perhaps we also know that the person sometimes has to check his sugar levels by carrying out blood glucose tests at home.
Of course, if you yourself, or a close member of your family, is already affected by diabetes, you will know a great deal more than this. However, it is vital that we should all be better informed, whether we are at present directly affected or not, for one very important reason. This is the fact that the incidence of both of the two main categories of diabetes is increasing. In particular, the number of people affected by the main form of the condition is soaring, not only in the UK but in many other countries as well. It is set to reach epidemic proportions and to rank alongside illnesses such as AIDS in presenting a huge challenge to public health on a global scale. If you or someone close to you develops diabetes, the more you understand about the condition, the better prepared you can be. The aim of this book is to try and help increase that understanding, by presenting an overview of the many aspects of this complex disorder. Of course, the first source of information and guidance for people with diabetes is the clinical diabetes team involved in their care. But it is further hoped that the information included here will support that given by medical experts and provide a useful source of reference for individuals and their families affected by diabetes.
In the following pages, for convenience, topics are introduced and discussed under a series of headings. However, even medical experts and scientists have found that diabetes is not a condition that fits neatly into categories. It can be likened to the overlapping and intersecting circles of ripples that occur when pebbles are thrown into a pool of water. Inevitably one aspect overlaps with and affects another, and in addition the treatment, control and management of an individual’s diabetes change with time and circumstance. Hence, where necessary, a topic may appear under more than one heading. Finally, although there are facts, symptoms and known potential consequences associated with this condition, perhaps the most important aspect is that each person’s diabetes is unique. In the majority of cases of newly diagnosed diabetes, even the most experienced specialist would not wish to predict the future health of the person concerned. Many individual factors – physical, psychological and emotional – affect the way in which people manage and cope with their diabetes. The good news is that most are able to lead long, active and fulfilling lives, just like anyone else and the whole emphasis in modern treatment is to enable those with diabetes to do just that. The Olympic athlete Sir Steve Redgrave, winner of five gold medals for rowing, is on record as saying that he believed his career was over when he was diagnosed with diabetes. However, with the encouragement of his consultant and diabetes care team, he went on to fulfil his greatest ambition in the Sydney Olympics in the year 2000.
The Background to Diabetes: Insulin, Glucose and the Provision of Energy
Diabetes mellitus is most correctly defined as a series of disorders or a syndrome in which the body is unable to properly regulate the processing, or metabolism, of carbohydrates, fats and proteins. It is caused by an absolute or partial deficiency of the important hormone insulin, which is produced and released by specialized cells (known as beta cells) located in the pancreas. The pancreas itself is a gland that is situated between the duodenum and the spleen and behind the stomach and is about 15 cm in length. It contains two main types of cells both of which produce secretions. The first group secretes digestive enzymes involved in the breakdown of food, and the second comprises clusters of cells called the islets of Langerhans, which produce hormones. As noted above, the beta cells are the ones that produce and release insulin but others, the alpha cells, secrete a different hormone called glucagon which is also involved in the regulation of blood glucose levels. Glucagon acts principally upon processes that occur in the liver and has an important role in preventing hypoglycaemia. Hypoglycaemia is one of the main features of the form of diabetes that require insulin treatment and is described in greater detail in Chapter 6.
The function of insulin is to regulate the levels of glucose (the body’s energy source) in the blood in order to ensure that enough is made available at all times to all the various tissues and organs, so that vital life-processes can continue. Glucose is the simplest form of sugar molecule, being the end product of carbohydrate digestion and the form in which carbohydrate is absorbed from the gut into the bloodstream. Hence the main and ultimate source of glucose is carbohydrate taken in as food, but the body does not rely on this alone. When dietary glucose is in short supply, the body turns to alternative sources and processes. An understanding of the regulatory mechanisms involving insulin is important in order to comprehend what happens in diabetes, and so it is useful to look briefly at these in a little more detail.
Insulin has short-term (metabolic) and longer-term activity within the body, both of which affect other processes important to health. Returning to the analogy of ripples in a pool, when something goes wrong with the activity of insulin, as in diabetes, the effects can be far-reaching and at first sight, perhaps somewhat surprising. It is these ‘ripple effects’ that are responsible for some of the potential, LONG-TERM COMPLICATIONS OF DIABETES that are discussed in Chapters 8 and 9.
Insulin is released from the beta cells in response to certain triggers, in particular, the presence of glucose in the blood which rises following digestion of meals containing carbohydrate. Other triggers are the presence of amino acids (the end products of protein digestion) and certain hormones, including glucagon, released from the pancreatic alpha cells. Release of insulin is inhibited by the presence of certain other hormones, especially adrenaline and noradrenaline, produced by the adrenal glands, which are also known as catecholamines, and also somatostatin. Adrenaline is the hormone that prepares the body for ‘fright, flight or fight’ and is sometimes called the stress hormone, while somatostatin is produced by a third type of islet of Langerhans cells, the delta cells. In addition, it is possible that a high release of insulin may itself inhibit further secretion of the hormone.
Once released, insulin carries out its effects by acting within cells. The insulin molecules do this by each attaching to a specialized receptor site located in the cell membrane that is tailor-made to receive it. All human cells contain a number of insulin receptors but some have a particular affinity for the hormone. These are: adipocytes (fat cells); hepatocytes (liver cells); skeletal myocytes (voluntary muscle cells, i.e. those attached to bones and joints). The affinity of these target cells for insulin becomes more meaningful when the overall regulatory activity of the hormone is understood, and this is described below. The effects of insulin take place by means of a whole series of biochemical events that begin to be activated once the insulin molecules are locked into place on their receptors. These are known as post-binding or post-receptor events (because they occur after the insulin molecules are bound to their receptors). They take place within cells, that is, on the inner side of the cell membrane. They are highly complex biochemical reactions involving enzymes, transport mechanisms and even, ultimately, the expression or working of certain genes (one of the longer-term effects of insulin). While it is not necessary to know how these reactions work, a knowledge of their existence and that of insulin receptors is quite important in understanding diabetes. Insulin is the principal regulator of blood glucose and this is achieved through its actions being subjected to certain checks and balances, producing a system which in normal health is very finely tuned and controlled. The checks and balances operate mainly at post-receptor level, that is, within cells and they mainly involve counter-regulatory hormones which act antagonistically (i.e. against) the effects of insulin. The most important of these is glucagon, and also significant is growth hormone, secreted by the thyroid gland.
In normal health, insulin is produced at a low level throughout any 24-hour period, accounting for about half of the total amount released. However, as mentioned above, this increases markedly when blood glucose levels rise following digestion of a carbohydrate-containing meal, and insulin then goes to work to remove this from the circulation. It does this by promoting the uptake of glucose by all cells to fulfil their immediate energy needs. Also, and most important, it promotes the removal of glucose to liver and skeletal muscle cells, where it is converted to glycogen. Glycogen or animal starch is a complex carbohydrate molecule and is the body’s main reserve energy store, which can be drawn upon in times of need. Additionally, insulin stimulates the uptake of surplus glucose by fatty tissue where it is converted to triglyceride (a type of fat) molecules and stored. Insulin has other effects as well but in order to understand these, it is necessary to look at what happens in the liver. We also need to examine the chain of events that occurs when carbohydrate and food in general are in short supply. If food is unavailable, there is no need for high levels of insulin to be released, but the body still requires glucose to supply its energy needs. In these circumstances, for example after the nightly fast, a process called glycogenolysis takes place in the liver in which glycogen is broken down into glucose and released into the circulation. The hormone which stimulates this process is glucagon. In addition, and especially when glycogen stores have themselves been depleted and there is still a lack of food, another mechanism called gluconeogenesis is activated. In this process, stored fats and eventually proteins are broken down and the molecules released are used by the liver to manufacture glucose. Breakdown (or lipolysis) of triglycerides also takes place in fatty tissues and releases fatty acids. In the liver these are utilized to make glucose, but another process called ketogenesis (which has potentially serious consequences in diabetes) also occurs as a result of this process. Ketogenesis produces molecules called ketone bodiesor ketones which, in normal conditions as described above, provide energy for outlying tissues such as muscles. A familiar ketone body and one which is important in diabetes, is acetone, which has a characteristic ‘fruity’, ‘peardrops’ aroma. One of the most important functions of insulin, and one which is critical in diabetes, is to suppress both the breakdown of triglycerides and ketogenesis. The body’s normal energy stores – glycogen and then triglycerides – are used first when food is unavailable. But if fasting continues, proteins derived from tissues such as the muscles eventually have to be utilized and converted, by gluconeogenesis, into glucose. Glycogenolysis and gluconeogenesis occur when insulin levels are low because the body has not received an intake of food. In normal circumstances, the body has enough reserves of stored energy to ‘fuel’ its daily activity, and protein does not need to be utilized for this purpose. Any protein eaten can therefore be used for its normal purposes of tissue growth and repair. Insulin indirectly regulates the fate of protein through its effects upon carbohydrates and fats. The processes described above determine what happens when a person embarks upon a weight-loss diet or a ‘fad’ diet such as a protein-only regime and, as we shall see, are highly significant in diabetes. In normal health, insulin and its counter-regulatory system are so finely tuned that they maintain blood glucose levels within an extremely narrow range of 3–8 mmol/l (millimols per litre).
Defining and Diagnosing Diabetes
The information given above is designed to provide a better understanding of diabetes and the reasons behind its symptoms and manifestations. As noted previously, diabetes is caused by a complete or partial deficiency of insulin or a lack of its effects. Hence the defect may be in the production and release of the hormone or it may occur at receptor or post-receptor level. The second situation is known as INSULIN RESISTANCE and the problem may lie with the receptors themselves or with post-receptor events. If the receptors themselves are involved, it may be because they are too few in number or because they have lost some of their ability to bind to insulin. Defects in insulin receptors can sometimes be corrected with treatment, but in very rare cases they may be a part of a severe, inherited condition. Malfunction in post-receptor events preventing insulin from performing its normal metabolic actions is quite common. Usually, there is a degree of impairment, so that the actions of insulin are rendered less effective, rather than a complete breakdown of the system. Post-receptor defects are highly complex, may not be reversible, and are a prominent feature in the most common form of diabetes, TYPE 2 DIABETES. The other main reason for insulin deficiency has to do with defects in the pancreatic beta cells of the islets of Langerhans.
Whatever the reason, or combination of reasons, behind the deficiency of insulin, the effect is to cause a sustained rise in the level of blood glucose or hyperglycaemia. An elevated level of blood sugar is the defining feature of diabetes mellitus but this does not always produce a clear-cut set of symptoms. The syndrome ranges from producing no symptoms at all to severe illness due to acute and potentially fatal metabolic complications. In general, severity of symptoms is related to the degree of insulin deficiency, although there are other factors which may influence this. One of the functions of insulin is regulation of the normal salts/water balance. Hyperglycaemia may result in glucose entering the urine and disruption of the body’s normal electrolytes (salts) to water ratios in the tissues. A feature of this imbalance is that the person passes an abnormally large quantity of urine ( polyuria), and this may be particularly the case during the night (nocturia). Excessive urination leads to further loss of salts such as sodium and potassium and an increased thirst, so that the person drinks excessively. Increased urination, thirst and excessive drinking in diabetes may be medically referred to as osmotic symptoms. The presence of sugar in the urine quite commonly encourages opportunistic infections by yeast organisms (thrush), with irritation and itching around the external opening of the urethra. High glucose levels in the blood can affect the lens of the eye which may become swollen, causing inability to focus and a blurring of vision. This is a temporary and reversible situation which is rectified with treatment for the diabetes, as distinct from DIABETIC RETINOPATHY which is a potential LONG-TERM COMPLICATION of the syndrome. Other symptoms that are quite common in diabetes include recurrent infections such as boils, mood swings and irritability, and a tingling ‘pins and needles’ sensation in the feet and hands.
If deficiency in insulin continues to be severe, the mechanisms described in the previous section accelerate as fat and protein are broken down in the liver’s attempt to provide the body with energy. As a result, blood glucose levels rise even higher, but the continuing lack of insulin means that the body remains deprived of energy. Symptoms of this include extreme tiredness and rapid weight loss. In serious cases, as a result of ketogenesis, ketosis or acidosis occurs and there is a build up of ketones in the blood, from which they pass into the urine (ketonuria). There may be a detectable smell of acetone from the person’s breath. In extreme and severe untreated cases, there may be a progression to a serious and potentially fatal condition called DIABETIC KETOACIDOSIS (DKA), which is described in Chapter 7.
Many people are newly diagnosed with diabetes each day in the UK. Although some will have gone to their doctor feeling unwell or with symptoms that have indicated diabetes, for many others the diagnosis comes as a complete surprise. This is because it is quite common for diabetes to be detected during a routine health check or during a period of hospitalization for some other problem. Quite often, initial suspicion of diabetes is raised when sugar is found to be present in a urine sample. However, further testing of blood samples is needed for the diagnosis to be confirmed. It is estimated that 50 per cent of those with the commonest form of diabetes – as many as one million people – are at present undiagnosed and unaware that they have the syndrome. It is probable that many of these people either have no symptoms or that symptoms have developed so slowly and insidiously that they have not recognized that anything is amiss. Ultimately, diagnosis is usually made by testing one or more samples of venous blood (from veins) or plasma. Samples may need to be given on more than one day, depending, to some extent, on whether the person is exhibiting any other symptoms of diabetes. In Britain the diagnostic criteria established by the World Health Organization (WHO) in 1980 and 1985 are still in use, although these have since been challenged and revised by the American Diabetes Association (ADA) through their Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 1997. These criteria are as follows.
•WHO: A level of glucose at or exceeding 11.1 mmol/l in the plasma of venous blood sampled at random. (Or 10.1 mmol/l if whole venous blood is sampled.)
OR
A fasting glucose level at or exceeding 7.8 mmol/l in the plasma of venous blood. (Or 6.7 mmol/l if whole venous blood is sampled.)•ADA: A level of glucose at or exceeding 11.1 mmol/l in the plasma of venous blood sampled at random, plus symptoms of diabetes.
OR
A fasting glucose level at or exceeding 7.0 mmol/l in the plasma of a venous blood sample. (Fasting is defined as no food or drink containing calories for the previous 8 to 10 hours, usually overnight.)
With both sets of criteria, repeat testing is usually carried out on consecutive days and the diagnosis is confirmed if abnormal readings continue to be obtained. A further test which may be carried out is the Oral Glucose Tolerance Test (OGTT). This has been used for some time and in revised WHO guidelines (1988) continues to be considered very important, especially in cases where the initial results are not clear cut. The OGTT has to be carried out under carefully controlled conditions and requires the person to follow a set of guidelines, summarized below.
•For at least 3 days before the test, the person must eat three meals a day containing plenty of starchy foods such as cereals, bread, pasta, and potatoes.•An overnight fast, lasting from 10 to 16 hours, is required immediately before the test when only plain water may be drunk.•The person must refrain from smoking and exercising immediately before and during the test.•The test must be performed between 8 and 9 a.m. on the morning following the fast.•A blood sample is taken to obtain a venous plasma glucose level before the test. The person is then given a flavoured drink containing 75 g of glucose dissolved in 250 ml of water, which must be consumed within 5 minutes. A second blood sample is obtained and tested after 120 minutes.•Urine samples may occasionally require to be tested, every 30 minutes.
The OGTT has been found to be useful in identifying two intermediate states between normality and diabetes, called IMPAIRED FASTING GLUCOSE (IFG) and IMPAIRED GLUCOSE TOLERANCE (IGT). In the OGTT, a normal result for venous plasma glucose levels is at or less than 6.0 mmol/l in the fasting state and less than 7.8 mmol/l from the second sample taken at 120 minutes. The result for diabetes is at or greater than 7.8 mmol/l during fasting and greater than 11.1 mmol/l after 120 minutes.
Blood samples taken at a doctor’s surgery, clinic or hospital are normally subjected to laboratory analysis to obtain readings of blood glucose levels. People subsequently diagnosed with diabetes have to continue to monitor their blood glucose levels as part of management of the condition. There is no need to worry that this requires setting up a laboratory in the home! As described later, home testing is quite a simple procedure which does not take up a great deal of time.
Categories of Diabetes
(ADA Classification, 1997)
As well as revising the diagnostic criteria for diabetes, the ADA also proposed changes of name for the two main forms of the syndrome and these terms are now in general use. Hence the former Insulin-Dependent Diabetes Mellitus or IDDM may now be called TYPE 1 DIABETES and Non-Insulin Dependent Diabetes Mellitus (NIDDM) may be termed TYPE 2 DIABETES. On a worldwide basis, Type 2 diabetes accounts for over 85 per cent of cases, although incidence varies between different ethnic groups. In the UK, more than 1.4 million people are known to have diabetes and about 80 per cent of this is Type 2.
IFG is a state which is most accurately identified by means of the Oral Glucose Tolerance Test described above. It is considered to be an intermediate state, falling short of diabetes, but may be a pre-diabetic stage in some cases. It is identified when an abnormally high level of fasting glucose of 6.1 to 6.9 mmol/l is obtained from a venous plasma sample before the glucose drink is given, but a normal reading, of less than 7.8 mmol/l, exists after 120 minutes. (In normality, the fasting glucose level is at, or less than, 6.0 mmol/l.) IFG does not usually produce symptoms and the clinical implications are not, at present, fully established. A person identified with this condition may receive advice on diet, if appropriate, and further monitoring of blood glucose levels so that any changes can be identified.
IGT is a second intermediate state, falling in between normality and diabetes and is one which can only be diagnosed by means of the OGGT. For IGT to exist, an abnormally high reading for fasting glucose, of 6.1 to 6.9 mmol/l, is obtained from a venous plasma sample, as in IFG. However, 120 minutes into the test, after the glucose drink has been taken, the reading remains abnormally high in the second plasma sample, at 7.8 to 11.0 mmol/l. This distinguishes IGT form both IFG and normality, in which the second reading is less than 7.8 mmol/l, and from diabetes, in which it is greater than 11.1 mmol/l. People with IGT usually do not have any symptoms but they may eventually develop Type 2 diabetes (2 to 5 per cent of those diagnosed). However, IGT can also be transitory (for example it can develop during : ) and some people return to normal levels of glucose tolerance with the passage of time. Defects in insulin receptors may be the cause of IGT in some cases and this may be reversible with treatment. Those with long-term, stable IGT are considered to be at greater risk both of Type 2 diabetes and also of the of the syndrome (such as heart disease, stroke, and conditions affecting the circulation in the legs). It is quite common for IGT (or Type 2 diabetes) to be diagnosed after a person has developed macrovascular disease, with this being the presenting condition for which the person is receiving treatment. Also, sometimes a misdiagnosis of Type 2 diabetes is made when, in fact, the person has IGT. People at a greater risk of heart disease, because of the existence of high blood pressure (hypertension), elevated levels of triglycerides, in blood plasma, high pulse rate and/or obesity, are also considered to be at high risk of IGT and/or Type 2 diabetes. In addition, the incidence of IGT is associated with ageing.
Type 1 diabetes (formerly Insulin-Dependent Diabetes Mellitus or IDDM) is the less common of the two main forms of diabetes and, in some ways, is easier to understand. This is because in the vast majority of cases, the diabetes arises because of a gradual and progressive autoimmune destruction of the beta islet cells of the pancreas which produce insulin. An autoimmune response can be thought of as a form of self-destruction. For some reason, the body’s immune system fails to recognize some component or substance that belongs to itself and produces antibodies to attack and destroy that element, as though it were foreign or invading. In the case of Type 1 diabetes, it is the all-important insulin-producing cells that are attacked, but it takes some time for the situation to become critical. In fact, it is only after most (about 90 per cent) of the beta cells have been destroyed that the person begins to show classical symptoms of diabetes. These may include any of those described under above, but in particular, marked osmotic symptoms, weight loss and tiredness. When tests are carried out, they reveal ketonuria and significant hyperglycaemia. Usually, the symptoms are sufficiently noticeable to prompt the person to seek medical help, but this is not always the case. Unfortunately, about 5 to 10 per cent of people with Type 1 diabetes are not diagnosed until they are admitted to hospital in the emergency stage of (DKA). The key feature of Type 1 disease is that those affected need insulin replacement therapy for life in order to ensure survival.
More than 80 per cent of people with diabetes in Britain have this form (formerly Non-Insulin Dependent Diabetes Mellitus or NIDDM), as do the estimated ‘missing million’ who are currently undiagnosed. Type 2 diabetes is regarded as being a heterogeneous disorder, that is, one in which there may be two contributing defects and other associated adverse factors. One defect or adverse factor may have a relatively greater impact upon one person with the syndrome compared to another and this underlines the need for an individual approach when it comes to treatment. In contrast to Type 1 diabetes, in Type 2 disease people have a relative, rather than an absolute, loss of insulin. However, the disorder is a progressive one and in many cases the situation, both with regard to insulin secretion and the effectiveness of its action, may worsen with time. Type 2 diabetes has a long, ‘silent’, asymptomatic period lasting many years, and usually people are not diagnosed until they are over the age of 40. During this time, enough insulin is produced or is effective to prevent ketosis but not enough to ensure a normal disposal of glucose. Hence there is sustained hyperglycaemia and very often the development of resultant tissue damage and diabetic .
This is an unusual form of diabetes, which has been the subject of considerable research in recent years. Although it superficially resembles Type 2 diabetes, there are a number of important differences. MODY appears in childhood or young adulthood, before the age of 25 years, and in most cases at least one or even two other members of the immediate family are affected. It has an entirely genetic origin and the defects (or mutations) in the genes involved have been identified. Environmental factors do not contribute to MODY and those affected are of normal weight and rarely obese. Five sub-groups of MODY have been identified (MODY 1, 2, 3, 4, 5 – depending upon the precise mutations in the genes involved) which produce diabetes of varying degrees of severity. Hence treatment also varies accordingly, with one form usually managed by diet alone while others require drug or insulin therapy. The risk of complications likewise varies between the different forms of MODY. In one in five families affected by this syndrome, the genetic defect involved is not one that has been previously identified. Hence it is likely that further sub-groups of MODY will emerge in the future when further mutations are identified. The pattern of inheritance involved in MODY is called ‘autosomal dominance’ and there is a 50 per cent risk of diabetes in the child of an affected parent. It has been suggested that genetic screening of the offspring of a MODY parent might be helpful but there is also concern that this might raise more problems than it solves. Although ‘at risk’ children with the genetic defect for MODY can be identified, it is far from certain that any preventive treatment that may be attempted will be effective.
There are a number of rare, genetic abnormalities affecting the insulin receptors, resulting in severe disruption of their structure and function. Severe insulin resistance and diabetes are characteristic of these syndromes, along with various other metabolic features.
The pancreas is vulnerable to a number of conditions and disorders which, if severe, may cause secondary diabetes. (inflammation of the pancreas) may be acute (and usually transient), or chronic and long-lasting (often caused by alcoholism). People with the chronic condition are at risk of diabetes, as are those with cancer of the pancreas and patients who have undergone surgical removal (pancreatectomy) of the whole or part of the gland as a method of treatment. Cystic fibrosis is a condition that affects all the glands of the body, including the pancreas. Improved treatment for sufferers and increased survival times mean that diabetes is a common complication, usually appearing in the teenage years or young adulthood and eventually requiring insulin therapy. Haemochromatosis is a rare metabolic, genetic disorder which is characterized by iron being deposited in various organs, including the liver and pancreas. Diabetes requiring insulin treatment develops in about half of those affected. It is sometimes called ‘bronzed diabetes’ due to an unusual pigmentation of the skin which is a feature of haemochromatosis. The disorder causes a number of serious complications, of which diabetes is only one and sufferers require intensive treatment.
Endocrinopathies (diseases due to disorders of the ) and in particular autoimmune conditions, such as , acromegaly, and , primarily affect hormone-secreting glands, causing hormone imbalances which affect the production and action of insulin. It has also been found that people with Type 1 diabetes run an increased risk of developing other autoimmune disorders. People suffering from these conditions are likewise at greater risk of developing diabetes which may require insulin treatment or or .
Quite a number of drug treatments are associated with the development of glucose intolerance, insulin resistance or diabetes. Also, when these drugs are taken by people with existing diabetes, they may lead to a lowering of glycaemic control so that someone with Type 2 syndrome that had been managed with tablets may then require insulin. It may be that some patients are in a higher risk group for glucose intolerance, insulin resistance or diabetes, or are undiagnosed for these conditions at the start of drug treatment. Many of the drugs are used to treat serious conditions with a known link to diabetes such as hormonal disorders, and heart and circulatory disease.
Various viral infections have been implicated in the development of Type 1 diabetes. Infection of a developing foetus with rubella leads to a 20 to 40 per cent risk of autoimmune diabetes in the child.
This is a group of rare disorders, such as Stiff Man syndrome, which are associated with the development of diabetes.
A number of inherited, chromosomal abnormalities carry an increased risk of diabetes. Their number include , , , , neonatal diabetes, and mitochondrial syndromes passed through the maternal line.
This is regarded as a special category which includes and transient diabetes, both precipitated and diagnosed in pregnancy but resolving after the birth, and diabetes that has been pre-existing but first comes to light during pregnancy. While transient diabetes and IGT usually disappear after delivery, affected women have a greater risk of eventually developing Type 2 diabetes. Women with pre-existing but formerly unsuspected diabetes are usually older mothers who are overweight or obese, and in almost all cases they are affected by Type 2 syndrome. These women continue to need treatment for their diabetes following delivery. A small number of, usually young, women diagnosed with gestational diabetes are discovered to have Type 1 syndrome. It is thought that the metabolic changes that occur during pregnancy (which for all women are pro-diabetic) may exacerbate or at least reveal the existence of diabetes that had previously not reached a stage of producing symptoms.
The conditions described below are often a component of diabetes (especially of Type 2 syndrome) and may themselves contribute to the existence of the condition.
We have already seen that resistance to the effects of insulin, which usually appears to act at the level beyond the receptor sites, is of major significance in Type 2 diabetes. Insulin resistance is defined as a reduced response or sensitivity to a physiological amount of insulin (i.e. a quantity which would be expected to have an identifiable effect). Its existence is suspected when a test of a venous blood plasma sample after a fast reveals an abnormally high level of insulin (hyperinsulinaemia) in the presence of a normal or raised level of blood glucose. Sensitivity to insulin can be determined using a laboratory technique called the hyperinsulinaemic glucose clamp. A certain quantity of insulin is infused and at the same time, dextrose (a form of sugar) is also given. The more sugar that is required to maintain a normal blood glucose level during the period of elevated insulin caused by the infusion, the greater the person’s sensitivity to insulin. Studies suggest that there is considerable variation in the degree of insulin sensitivity in apparently healthy people, and insulin resistance as such does not cause any symptoms. Indeed, about one quarter of those surveyed have degrees of insulin resistance comparable with those in people diagnosed with glucose intolerance or Type 2 diabetes. It is known that sustained hyperinsulinaemia, as occurs in insulin resistance, increases the risk of the development of cardiovascular complications. Insulin resistance naturally increases during puberty and pregnancy, but in normal health this is compensated for by an increased production of insulin. Sensitivity returns to normal once these states are past. Insulin resistance can also be caused by drugs and is also much more likely to occur in people who are obese, especially in those who have upper body, abdominal fat deposits. This type of obesity is similarly closely linked with the incidence of Type 2 diabetes. It is further believed that lack of exercise and cigarette smoking may make insulin resistance worse in some cases.
This syndrome was first described in 1988 and has a number of alternative names (Reaven’s syndrome, metabolic syndrome, syndrome X). It has several components and usually more than one is present in those affected. The key features, identified in 1988, are:
In women, the relatively common condition called polycystic ovary syndrome, in which the follicles of the ovaries fail to produce eggs to maturity and develop multiple small cysts, may in some cases be linked with insulin resistance, in some cases. Polycystic ovary syndrome is caused by a hormonal imbalance which results in a greater than normal availability of male sex hormones (, mainly ) which may stimulate a masculine pattern of hair growth in some women. The ovaries normally produce minute quantities of androgens which are ‘mopped up’ by proteins called It is thought that hyperinsulinaemia in insulin resistance may stimulate the production of testosterone by the ovaries and also inhibit the production of globulin. This allows more testosterone to be available, producing the symptoms of polycystic ovary syndrome. It has been found that affected women may have a greater susceptibility to Type 2 diabetes. Also, women affected by run a greater risk of developing polycystic ovary syndrome.
As has been noted, there is a close connection between obesity and Type 2 diabetes and it is thought that upper body or abdominal fat may be particularly important. However, although men are more likely to show this pattern of fat distribution than women (who more frequently lay down fat below the waist), there is no apparent sex difference in the incidence of Type 2 diabetes. The main function of abdominal adipocytes (fat cells) is to store triglycerides as an energy reserve in times of need. ( ). These fat cells have been shown to have a different metabolic activity compared to other fat cells elsewhere, particularly with regard to their sensitivity to certain hormones. They have been found to be more resistant to insulin but show greater sensitivity to catecholamines (counter-regulatory hormones) which act in opposition to insulin. Hence it is felt by some experts that abdominal obesity promotes the type of insulin resistance that is often a feature of Type 2 diabetes, although it is probably only one contributory factor and may not be enough to cause diabetes in itself.
High blood pressure can occur on its own but it is often a feature of Type 2 diabetes and the insulin resistance syndrome. Less commonly, it may also be associated with Type 1 syndrome as well. It is believed that the physiological and metabolic consequences of insulin resistance and Type 2 diabetes promote the development of hypertension and that the two are closely linked ( Chapter 9).
