1. What is diabetes?

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CHAPTER 1. What is diabetes?
David Matthews
Classification 2
Incidence and prevalence 6
Aetiology of diabetes 7
Type 1 diabetes 8
Type 2 diabetes 10
Insulin and its actions 13
Diabetic ketoacidosis 14
Hyperosmolar non-ketotic coma 15
The clinical differences between type 1 and type 2 diabetes 16
Conclusion 18
References 18
Diabetes mellitus is a chronic condition affecting around 171 million people worldwide; the World Health Organization (WHO) projects that this number will have more than doubled by 2030 (WHO 2005). The management of people with diabetes therefore poses a formidable challenge to the healthcare team, and to those in primary care in particular. Diabetes mellitus is a chronic condition characterised by hyperglycaemia due to deficiency or diminished effectiveness of insulin. This results in a disorder of carbohydrate metabolism; fat, protein and mineral metabolism can also be affected. Its importance as a disease is due to the irreversible tissue damage that results mainly from poor metabolic control. This irreversible tissue damage results in about 3.2 million deaths per annum from diabetes and in healthcare costs that range from 2.5 to 15% of overall budgets (WHO 2005). Diabetic retinopathy is the most common cause of blindness in persons aged less than 60 years in the UK and has an incidence of 50–65 per 100 000 of the diabetic population in Europe (Scottish Intercollegiate Guidelines Network (SIGN) 2001). One-third of people on programmes for the management of end-stage renal failure have diabetes. Having diabetes makes a person 2–3 times more likely to have a major vascular event such as myocardial infarction or stroke. Up to 15% of people with diabetes have a foot ulcer at some stage (Lancet 2005), with recurrence rates being greater than 50% after 3 years (Boulton et al 2005). Coupled with this, around 50% of people having amputations for non-traumatic reasons have diabetes. The resultant increased morbidity and mortality from diabetes is thus plain to see and explains why diabetes is a major consumer of healthcare resources world-wide.
Various classifications of diabetes were updated by the WHO in 1999 (Table 1.1). Type 2 diabetes is the most common, representing over 80% of all persons with diabetes; type 1 comprises most of the remaining 20%. Maturity onset diabetes of the young (MODY) and secondary diabetes are relatively uncommon and account for less than 5% of people. However, it is important to identify those individuals with secondary diabetes so that treatment can be directed to the underlying cause. Diabetes in association with other genetic syndromes is also very rare. In these instances, diabetes is another burden to be borne by these people.
Table 1.1 Classification of diabetes
Primary
Type 1
Type 2
MODY, maturity onset diabetes of the young
Secondary to other disorders
1. Pancreatic disease
Chronic pancreatitis
Haemochromatosis
Pancreatectomy
Carcinoma of pancreas
Cystic fibrosis
2. Endocrine disease
Acromegaly
Cushing’s syndrome
Phaeochromocytoma
Gestational
3. Drugs
Thiazide diuretics
Corticosteroids
Associated with genetic syndromes
Friedreich’s ataxia
Muscular dystrophies
Down’s syndrome
Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD)
TYPE 1 DIABETES MELLITUS
The hallmark of type 1 diabetes is a dependence on exogenously injected insulin to prevent ketosis and maintain life. Without injected insulin, people with type 1 diabetes die. This was the situation before the discovery of insulin in 1921. Some died very quickly over a matter of days. Others struggled along miserably for 3 or 4 years by eating almost starvation-type diets (Bliss 1983). In type 1 diabetes, therefore, there is an absolute deficiency of insulin.
Joseph’s case is a fairly representative example of a person newly diagnosed with type 1 diabetes presenting in diabetic ketoacidotic coma (diabetic ketoacidosis is explained later in the chapter). Before the discovery of insulin, such a presentation was lethal. Joseph will be dependent on self-injected insulin for the rest of his life. Withdrawal of insulin would rapidly cause further ketoacidosis and he must be advised never to stop his insulin injections. Joseph and his family will require further support and education to give him the necessary skills for self-management (see Chapters 3, 5, 6, 7 and 11).
TYPE 2 DIABETES MELLITUS
Type 2 diabetes is the most common form of diabetes world wide and there is no requirement for insulin to prevent ketosis and preserve life. Many people with type 2 diabetes can be managed by dietary means alone (see Chapters 4 and 6). Sometimes, oral hypoglycaemic drugs are required in addition to diet. Most people are over the age of 30 years when diagnosed. The main associated feature is obesity and in such people the body tissues are relatively resistant to the effects of insulin, thus causing an elevation of blood glucose. By reducing body weight many people can make carbohydrate tolerance almost normal. The management of the person with type 2 diabetes is further expanded in Chapter 4.
There is a subgroup of people, however, who are not obese and who have a relative deficiency of insulin. These people cannot secrete enough insulin to cope with the carbohydrate load they consume. The pathological process in the cells of the islets of Langerhans in the pancreas is quite different from type 1 diabetes in that these individuals do not have autoimmune damage to the pancreas. However, they might eventually require insulin therapy, although they will not be classified as having true insulin dependence.
This is an inherited form of diabetes usually arising in a person’s teenage years or in his or her early twenties and, although rare, affects about 1–2% of those with diabetes. It is passed down from one family member to another and each child has a 50% chance of inheriting the affected gene and a very high risk of developing diabetes (Shepherd 2003a).
People with MODY are usually managed with diet and/or sulphonylureas, regardless of age, for many years and ultimately will require insulin therapy. Insulin would also be required in special circumstances, such as pregnancy. Most people who have this form of diabetes have a multigenerational family history, with autosomal dominant inheritance and are usually not obese.
The molecular consequences are now well defined, with mutations in at least six genes. This means that diagnostic and predictive testing is now possible in 50–80% of families with MODY, which has implications for professional management (Shepherd 2003b). People with MODY have a mutation in the glucokinase gene, which results in mildly elevated fasting hyperglycaemia (> 5.5 mmol/L) (Barrow et al 2005). MODY 1 is due to a mutation in hepatocyte nuclear factor (HNF) 4α; MODY 2 is due to a mutation in the glycolytic enzyme glucokinase. Similarly, MODY 3 relates to HNF 1α, MODY 4 to insulin promoter factor 1, MODY 5 to HNF 1β and MODY 6 to neurogenic differentiation factor 1 (Fajans et al 2001). Genetic testing can define the subtype of diabetes as this has implications for different treatment options (Shepherd 2003a).
SECONDARY DIABETES
This type of diabetes is secondary to other disease processes that cause either pancreatic damage or production of hormones that antagonise the action of insulin (Box 1.1).
Box 1.1

Hormones that are antagonistic to the action of insulin
▪ Growth hormone
▪ Cortisol
▪ Glucagon
▪ Adrenaline
▪ Placental steroids
▪ Noradrenaline
Pancreatic disease
The pancreas can be damaged as a result of frequent bouts of pancreatitis, which is often precipitated by alcohol abuse or the presence of gallstones in the common bile duct.
The presence of carcinoma within the pancreas can also cause destruction of normal insulin-secreting cells resulting in the development of diabetes. Pancreatic disorders causing diabetes usually require treatment with insulin.
Valentina is a 73-year-old woman who presents with a 9-kg weight loss associated with nausea, polydipsia, polyuria and vulvitis. Her random blood glucose is 19.7 mmol/L and she has 2% glycosuria. Valentina is diagnosed with diabetes and is treated with dietary measures and glipizide 2.5 mg to relieve her symptoms quickly. She returns to the GP surgery 3 weeks later. Her blood glucose has fallen to 9.1 mmol/L, she has no glycosuria, but her weight has fallen by a further 2 kg.
In Valentina’s case, it is unusual to be nauseated with primary diabetes and weight loss should stop when the energy-losing glycosuria is abolished. Further investigation was thus necessary and she was found to have a carcinoma of the tail of her pancreas. Carcinoma of the pancreas can present as an apparent acute onset of diabetes and it is therefore important to think of secondary causes at the time of diagnosis, especially in elderly individuals with marked weight loss.
Endocrine disease
The secondary endocrine causes of diabetes involve excess endogenous production of hormones that are insulin antagonists (see Box 1.1):

▪ In acromegaly, growth hormone is secreted in excess by the pituitary gland.
▪ In Cushing’s syndrome, the adrenal cortex makes excess cortisol due either to a primary tumour within the adrenal gland or to excess adrenocorticotrophic hormone (ACTH) production.
▪ In phaeochromocytoma there is excess secretion of adrenaline or noradrenaline by a tumour of the adrenal medulla or sympathetic plexus.
Hypertension, which is seen in acromegaly, Cushing’s syndrome and phaeochromocytoma, commonly accompanies type 2 diabetes. When faced with an obese, hypertensive person with an elevated blood glucose it is important to consider the possibility of an underlying endocrine disorder before accepting a diagnosis of type 2 diabetes
The exceedingly rare glucagonoma results in diabetes because glucagon also antagonises insulin.
Gestational diabetes occurs in about 4% of women with normal pregnancies and is due to the insulin-antagonising effects of placental steroids and human placental lactogen. Gestational diabetes has been defined as carbohydrate intolerance of variable severity with onset during pregnancy, although there is no consensus about its diagnosis, treatment or management (SIGN 2001). Some women with gestational diabetes might need insulin treatment towards the end of pregnancy. Postnatally, the diabetes goes into remission but these women will enter the ‘at risk’ category for developing type 2 diabetes in later years (see Chapter 2).
Drug therapy
The thiazide diuretics, which are commonly used to treat essential hypertension, have a blood-glucose-raising effect by their inhibitory action on insulin secretion. Other drugs, such as corticosteroids (e.g. prednisolone), also make tissues relatively resistant to the effects of insulin and thus unmask diabetes.
GENETIC SYNDROMES
The genetic syndromes in Table 1.1 are rare but can be associated with diabetes mellitus, although the mechanisms are unknown. The syndrome comprising diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) is a well-recognised entity that can present with varying clinical features of the syndrome. Acanthosis nigricans, a rare skin condition sometimes associated with hirsutism and polycystic ovaries, is associated with a very insulin-resistant type of diabetes.
INCIDENCE AND PREVALENCE
The incidence of a disease is the number of new cases arising each year. The prevalence is the number of people with a disease in the population at any one time. The incidence of diabetes varies from country to country and area to area within countries (Hjelm et al 2003, Yach et al 2006). In the UK, the prevalence of diabetes is now around 3% and rising.
TYPE 1 DIABETES MELLITUS
The incidence varies between population groups and in the UK the cumulative risk of developing type 1 diabetes in persons aged under 20 is now 0.3–0.4%, with the peak between 10 and 14 years. This is increasing in all age groups being most marked in the 0–4 years.
TYPE 2 DIABETES MELLITUS
Accurate figures of the incidence of type 2 diabetes are difficult to establish, despite this being the more frequent type, because of inconsistent diagnostic criteria. The diagnosis of diabetes is addressed in Chapter 2.
The true prevalence is also difficult to determine accurately because of the relatively large population of people with type 2 diabetes who remain undiagnosed. There is, however, gathering evidence of a worldwide epidemic (Hjelm et al 2003). The prevalence of type 2 diabetes varies from country to country and population to population. A main feature is the low prevalence among Europeans who remain within Europe; there is a high prevalence among the Pima Indians, urban New Guineans and the Nauru (Diamond 2003, Knowler et al 1981, WHO 2005, Zimmet et al 1990). The population groups with the projected greatest increase are in Asia and Africa (Hjelm et al 2003).
Type 2 diabetes becomes more common with increasing age, with over 50% of people attending diabetes services in the UK aged over 60 years. There are now a growing number of younger people acquiring type 2 diabetes in the Western world, although it is still rare (Ehtisham et al 2004). The prevalence within the UK is only 2 in every million children. These young people tend to present later than young people with type 1 diabetes, are overweight, are usually female and a greater proportion are of ethnic minority origins. It is thought that this is due to more sedentary lifestyles and consuming more processed foods that are high in fat content.
AETIOLOGY OF DIABETES
TYPE 1 DIABETES
There is good evidence that type 1 diabetes is a T-cell-mediated autoimmune disorder and that affected persons are born with the tendency to destroy their own insulin-producing beta cells in the islets of Langerhans. There is evidence of familial clustering but there must also be some environmental trigger, as twin studies have shown that in only around 50% of identical twin pairs does the other twin develop diabetes (Devendra et al 2004).
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