Interpretation of the results of a 75-g glucose tolerance test is presented in Table 1.2. Note that results apply to venous plasma: whole blood values are 15% lower than corresponding plasma values if the haematocrit is normal. For capillary whole blood, the diagnostic cut-offs for diabetes are ≥ 6.1 mmol/L (fasting) and 11.1 mmol/L (i.e. the same as for venous plasma). The range for impaired fasting glucose based on capillary whole blood is ≥ 5.6 and < 6.9 mmol/L. Note that marked carbohydrate deprivation can impair glucose tolerance; the subject should have received adequate nutrition in the days preceding the test.

Table 1.2 Interpretation of 75-g oral glucose tolerance test

Tip box

In the absence of symptoms, diabetes must be confirmed by a second diagnostic test (i.e. fasting, random or repeat glucose tolerance test) on a separate day.

Tip box

To get blood glucose values in mg/dl multiply the values in mmol/L by 18

Classification of diabetes mellitus

Type 1 diabetes (β-cell destruction, usually leading to absolute insulin deficiency)

Immune-mediated diabetes

The clinical presentation of type 1 diabetes in younger patients is usually acute with classical osmotic symptoms. In general, symptoms will have been present for only a few weeks with osmotic symptoms; weight loss predominates and gradually increases in intensity. Weight loss reflects:

• catabolism of protein and fat resulting from profound insulin deficiency

• dehydration if hyperglycaemia is marked.

Associated symptoms, particularly blurred vision, are not uncommon although generally less prominent. Although the islet β-cell destruction of type 1 diabetes is a process that occurs gradually over many years, it was very uncommon to detect type 1 diabetes during the early asymptomatic stages of the condition. In some patients, once symptoms appear, diagnosis may sometimes be expedited by awareness of symptoms in other family members with diabetes. Despite the presence of significant osmotic symptoms, some patients do not seek medical advice and a significant proportion (approximately 5–10%) of patients with type 1 diabetes continue to present in diabetic ketoacidosis (DKA).

Approximately 5–10% of patients with type 1 diabetes present with DKA.

Diabetic ketoacidosis

At the time of diagnosis, patients may develop rapid metabolic decompensation in the presence of an intercurrent illness, such as infection, that is likely to expose the patient’s limited, endogenous insulin reserve; an abrupt ascent in plasma glucose concentration may ensue in concert with dehydration, ketosis, acidosis and electrolyte depletion.

DKA is a life-threatening medical emergency requiring hospitalization for treatment with intravenous fluids and insulin. Patients with the features listed in Table 1.4 along with the following features should be admitted promptly to hospital for further assessment and treatment:

• heavy glycosuria

• ketonuria (++ or greater).

Table 1.4 Cardinal clinical features of diabetic ketoacidosis

• Marked polyuria and polydipsia

• Nausea and vomiting

• Dehydration

• Reduced level of consciousness

• Acidotic (Kussmaul) respiration

The diagnosis and management of DKA are considered in more detail in Section 4.

Patients with clinical features suggestive of DKA must be admitted to hospital without delay.

Type 1 accounts for only 5–10% of those with diabetes and was previously encompassed by the terms insulin-dependent diabetes or juvenile-onset diabetes. It results from a cellular-mediated autoimmune destruction of the β-cells of the pancreas. Markers of the immune destruction of the β-cell include islet cell autoantibodies, autoantibodies to insulin, autoantibodies to glutamic acid decarboxylase (GAD₆₅), and autoantibodies to the tyrosine phosphatases IA-2 and IA-2β. One or, usually, more of these autoantibodies are present in 85–90% of individuals when fasting hyperglycaemia is initially detected. In addition, the disease has strong human leukocyte antigen (HLA) associations, with linkage to the DQA and DQB genes, and it is influenced by the DRB genes. These HLA-DR/DQ alleles can be either predisposing or protective.

In this form of diabetes, the rate of β-cell destruction is quite variable, being rapid in some individuals (mainly infants and children) and slow in others (mainly adults). Some patients, particularly children and adolescents, may present with ketoacidosis as the first manifestation of the disease. Others have modest fasting hyperglycaemia that can change rapidly to severe hyperglycaemia and/or ketoacidosis in the presence of infection or other stress. Still others, particularly adults, may retain residual β-cell function sufficient to prevent ketoacidosis for many years. Immune-mediated diabetes commonly occurs in childhood and adolescence, but it can occur at any age, even in the eighth and ninth decades of life.

Autoimmune destruction of β-cells has multiple genetic predispositions and is also related to environmental factors that are still poorly defined. These patients are also prone to other autoimmune disorders such as Graves’ disease, Hashimoto’s thyroiditis, Addison’s disease, vitiligo, coeliac disease, autoimmune hepatitis, myasthenia gravis and pernicious anaemia.

Tip box

Obese patients with type 1 diabetes may present earlier in the process with milder symptoms due to increased insulin resistance.

Pluriglandular syndrome

The pluriglandular syndrome type II should be borne in mind in patients presenting with features suggesting autoimmune type 1 diabetes, particularly in those who are known to be positive for islet cell antibodies. Consideration should be given to checking for other endocrine autoantibodies in the serum, particularly:

• thyroid microsomal and thyroglobulin antibodies

• adrenal antibodies.

Antibody positivity does not predict future autoimmune disease with certainty. However, the prevalence of autoimmune thyroid disease, Addison’s disease and other non-endocrine autoimmune disorders such as pernicious anaemia, coeliac disease and premature menopause is increased in patients with type 1 diabetes. Vitiligo is a useful cutaneous marker of autoimmune disease. Periodic checks of target organ function, such as thyroid function tests or serum B₁₂ level, are indicated even in the absence of clinical features. Coexisting endocrinopathies may adversely affect metabolic stability.

Idiopathic diabetes

Some forms of type 1 diabetes have no known aetiology. Some of these patients have permanent insulinopenia and are prone to ketoacidosis, but have no evidence of autoimmunity. Only a minority of patients fall into this category and most are of African or Asian ancestry. Individuals with this form of diabetes suffer from episodic ketoacidosis and exhibit varying degrees of insulin deficiency between episodes. This form of diabetes is strongly inherited, lacks immunological evidence for β-cell autoimmunity, and is not HLA associated. An absolute requirement for insulin replacement therapy in affected patients may come and go.

Type 2 diabetes (ranging from predominantly insulin resistant with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance)

The majority of patients with type 2 diabetes are diagnosed at a relatively late stage of a long, pathological process that has its origins in the patient’s genotype (or perhaps intrauterine experience), and develops and progresses over many years.

Tip box

Type 2 diabetes represents a late stage of a complex and progressive pathological process.

The presenting clinical features of type 2 diabetes range from none at all to those associated with the dramatic and life-threatening, hyperglycaemic emergency of the hyperosmolar non-ketotic syndrome (HONK)/hyperosmolar hyperglycaemic state (HHS). In many patients with lesser degrees of hyperglycaemia, symptoms may go unnoticed or unrecognized for many years; however, such undiagnosed diabetes carries the risk of insidious tissue damage. It has been estimated that patients with type 2 diabetes have often had pathological degrees of hyperglycaemia for several years before the diagnosis is made. For example, more than 5 million people in the USA alone may have undiagnosed diabetes.

Tip box

Approximately 50% of patients in the UK with type 2 diabetes are undiagnosed.

This form of diabetes, which accounts for about 90–95% of those with diabetes, previously referred to as non-insulin-dependent diabetes, type II diabetes or adult-onset diabetes, encompasses individuals who have insulin resistance and usually have relative (rather than absolute) insulin deficiency. At least initially, and often throughout their lifetime, these individuals do not need insulin treatment to survive.

There are probably many different causes of this form of diabetes. Islet mass is reduced with deposition of islet amyloid polypeptide; the latter produces striking histological changes within the islets, yet its role in the initiation and progression of type 2 diabetes is not known. Increased plasma levels of proinsulin-like molecules indicate β-cell dysfunction; this is an early feature, being demonstrable prior to the development of diabetes in high-risk groups. Autoimmune destruction of β-cells does not occur, and patients do not have any of the other causes of diabetes listed above or below.

Most patients with type 2 diabetes are obese, and obesity itself causes some degree of insulin resistance. The absence of weight loss reflects the presence of sufficient secretion of endogenous insulin to prevent catabolism of protein and fat. Patients who are not obese by traditional weight criteria may have an increased percentage of body fat distributed predominantly in the abdominal region. Ketoacidosis seldom occurs spontaneously in this type of diabetes; when seen, it usually arises in association with the stress of another illness, such as infection. Type 2 diabetic patients are at increased risk of developing macrovascular and microvascular complications. Whereas patients with this form of diabetes may have insulin levels that appear normal or increased, the higher blood glucose levels in these diabetic patients would be expected to result in even higher insulin values had their β-cell function been normal. Thus, insulin secretion is defective and insufficient to compensate for insulin resistance. Insulin resistance may improve with weight reduction and/or pharmacological treatment of hyperglycaemia, but is seldom restored to normal. The risk of developing type 2 diabetes increases with age, obesity and lack of physical activity. It occurs more frequently in women with previous gestational diabetes mellitus (GDM) and in individuals with hypertension or dyslipidaemia. Its frequency varies in different racial/ethnic subgroups. It is often associated with a strong genetic predisposition – more so than the autoimmune form of type 1 diabetes.

Aetiology of type 2 diabetes

There is a strong inheritable genetic connection in type 2 diabetes: having relatives (especially first-degree relatives) with type 2 diabetes increases substantially the risk of developing type 2 diabetes. The genetics are complex and not completely understood, but presumably the disease is related to multiple genes. Only a handful of genes have been identified so far: genes for calpain-10, potassium inward-rectifier 6.2, peroxisome proliferator-activated receptor-γ and insulin receptor substrate-1. Evidence also supports inherited components for pancreatic β-cell failure and insulin resistance.

Considerable debate exists regarding the primary defect in type 2 diabetes mellitus. Most patients have insulin resistance and some degree of insulin deficiency. However, insulin resistance per se is not the sine qua non for type 2 diabetes because many people with insulin resistance (particularly those who are obese) do not develop glucose intolerance. Therefore, insulin deficiency is necessary for the development of hyperglycaemia. Insulin concentrations may be high, yet inappropriately low for the level of glycaemia. Several mechanisms have been proposed, including increased non-esterified fatty acids, inflammatory cytokines, adipokines and mitochondrial dysfunction for insulin resistance, and glucotoxicity, lipotoxicity and amyloid formation for β-cell dysfunction.

Presumably, the defects of type 2 diabetes occur when a diabetogenic lifestyle (excessive caloric intake, inadequate caloric expenditure, obesity) is superimposed upon a susceptible genotype. The body mass index (BMI) at which excess weight increases risk for diabetes varies with different racial groups. For example, compared with persons of European ancestry, persons of Asian ancestry are at increased risk for diabetes at lower levels of waist circumference/BMI. This can be seen from the adoption of the type 2 epidemiological pattern in those who have moved to a different environment in comparison with the same genetic pool of persons who have not, for instance in immigrants to Western developed countries compared with the lower incidence of countries of their origin.

Measures of insulin resistance (Table 1.5)

Homeostasis model assessment (HOMA) and quantitative insulin sensitivity check index (QUICKI) have been used to quantify degrees of insulin resistance and β-cell secretory capacity. HOMA uses fasting measurements of blood glucose and insulin concentrations to calculate indices of both insulin sensitivity and β-cell function. The principle of HOMA is that blood glucose and insulin concentrations are related by the feedback of glucose on β-cells to increase insulin secretion. The model assumes that normal-weight subjects aged less than 35 years have an insulin resistance (R) of 1 and 100% β-cell function.

Table 1.5 Measures of insulin resistance

HOMA (R) = [Insulin (mU/L) × glucose (mmol/L)]/22.5

HOMA β-cell function = [20 × insulin mU/L]/[glucose (mmol/L) − 3.5]

QUICKI employs the log of both blood insulin and glucose concentrations to quantify insulin resistance

HOMA and QUICKI measures of insulin resistance are usually in very close agreement

HOMA, homeostasis model assessment; QUICKI, quantitative proliferator-activated receptor.

Other specific types of diabetes

Genetic defects of the β-cell

Several forms of diabetes are associated with monogenetic defects in β-cell function. These forms of diabetes are frequently characterized by onset of hyperglycaemia at an early age (generally before age 25 years). They are referred to as maturity-onset diabetes of the young (MODY) and are characterized by impaired insulin secretion with minimal or no defects in insulin action. They are inherited in an autosomal dominant pattern. Abnormalities at over six genetic loci on different chromosomes have been identified to date. The most common form is associated with mutations on chromosome 12 in a hepatic transcription factor referred to as hepatocyte nuclear factor (HNF)-1α; MODY3 accounts for 70% of the MODY population A second form is associated with mutations in the glucokinase gene on chromosome 7p and results in a defective glucokinase molecule. Glucokinase converts glucose to glucose 6-phosphate, the metabolism of which, in turn, stimulates insulin secretion by the β-cell. Thus, glucokinase serves as the ’glucose sensor’ for the β-cell. Because of defects in the glucokinase gene, increased plasma levels of glucose are necessary to elicit normal levels of insulin secretion. Patients with MODY2 present with a less severe form of hyperglycaemia that can be managed with medical nutrition therapy alone. The less common forms result from mutations in other transcription factors, including HNF-4α, HNF-1β, insulin promoter factor (IPF)-1 and NeuroD1 (Table 1.6). Up to 15% of patients with MODY present with clinical characteristics of MODY, but do not have any known mutation and are classified as MODY-X until further genetic loci have been explored.

Table 1.6 Aetiological classification of diabetes mellitus

I. Type 1 diabetes (β-cell destruction, usually leading to absolute insulin deficiency)

A. Immune-mediated

B. Idiopathic

II. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance)

III. Other specific types

A. Genetic defects of β-cell function

1. Chromosome 12, HNF-1α (MODY3)

2. Chromosome 7, glucokinase (MODY2)

3. Chromosome 20, HNF-4α (MODY1)

4. Chromosome 13, insulin promoter factor-1 (IPF-1; MODY4)

5. Chromosome 17, HNF-1β (MODY5)

6. MODY7: mutation in carboxyl ester lipase

7. Mitochondrial DNA

8. Others: mutation in subunit of ATP-sensitive K channel

B. Genetic defects in insulin action

1. Type A insulin resistance

2. Leprechaunism

3. Rabson–Mendenhall syndrome

4. Lipoatrophic diabetes

5. Others

C. Diseases of the exocrine pancreas

1. Pancreatitis

2. Trauma/pancreatectomy

3. Neoplasia

4. Cystic fibrosis

5. Haemochromatosis

6. Fibrocalculous pancreatopathy

E. Drug or chemical induced

7. β-adrenergic agonists

12. Protease inhibitors

13. Others

F. Infections

1. Congenital rubella

2. Cytomegalovirus

3. Others

G. Uncommon forms of immune-mediated diabetes

1. ’Stiff man’ syndrome

2. Anti-insulin receptor antibodies

3. Others

H. Other genetic syndromes sometimes associated with diabetes

1. Down syndrome

2. Klinefelter syndrome

3. Turner syndrome

4. Wolfram syndrome

5. Friedreich ataxia

6. Huntington disease

7. Laurence–Moon–Biedl syndrome

8. Myotonic dystrophy

9. Porphyria

10. Prader–Willi syndrome

11. Others

IV. Gestational diabetes mellitus

Patients with any form of diabetes may require insulin treatment at some stage of their disease. Such use of insulin does not, of itself, classify the patient.

HNF, hepatocyte nuclear factor; IPF, insulin promoter factor; MODY, maturity-onset diabetes of the young.

Source: American Diabetes Association (2011). Reproduced with permission.

Molecular genetic testing

Knowledge of the genotype in the unaffected child of a patient with this syndrome offers the possibility of a firm diagnosis or, importantly, exclusion of the possibility of diabetes in later life. If the genetic testing is negative, no screening will be necessary and individuals and their families can be reassured. If an unaffected offspring is found to have a MODY2 mutation, then annual testing of fasting plasma glucose and, for females, awareness of the importance of excellent glycaemic control before conception and during pregnancy are required. Identification of a MODY1 or MODY3 genotype necessitates more rigorous, regular screening through childhood, adolescence and early adult life to detect the development of diabetes, as pharmacological treatment, including insulin, is likely to prove necessary. Such testing raises ethical issues and it has been suggested that it should be offered only after appropriate genetic counselling. Whether such knowledge will ultimately allow intervention to prevent or retard the appearance of diabetes is currently uncertain.

Point mutations in mitochondrial DNA have been found to be associated with diabetes mellitus and deafness. The most common mutation occurs at position 3243 in the tRNA leucine gene, leading to an A-to-G transition. An identical lesion occurs in the MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like) syndrome; however, diabetes is not part of this syndrome, suggesting different phenotypic expressions of this genetic lesion.

Genetic abnormalities that result in the inability to convert proinsulin to insulin have been identified in a few families, and such traits are inherited in an autosomal dominant pattern. The resultant glucose intolerance is mild. Similarly, the production of mutant insulin molecules with resultant impaired receptor binding has also been identified in a few families. It is associated with an autosomal inheritance and only mildly impaired or even normal glucose metabolism.

Genetic defects in insulin action

There are unusual causes of diabetes that result from genetically determined abnormalities of insulin action. The metabolic abnormalities associated with mutations of the insulin receptor may range from hyperinsulinaemia and modest hyperglycaemia to severe diabetes. Some individuals with these mutations may have acanthosis nigricans. Women may be virilized and have enlarged, cystic ovaries. In the past, this syndrome was termed type A insulin resistance. Leprechaunism and the Rabson–Mendenhall syndrome are two paediatric syndromes that have mutations in the insulin receptor gene with subsequent alterations in insulin receptor function and extreme insulin resistance. The former has characteristic facial features and is usually fatal in infancy, whereas the latter is associated with abnormalities of teeth and nails plus pineal gland hyperplasia.

Diseases of the exocrine pancreas

Any process that injures the pancreas diffusely can cause diabetes. Acquired processes include pancreatitis, trauma, infection, pancreatectomy and pancreatic carcinoma. With the exception of cancer, damage to the pancreas must be extensive for diabetes to occur; adrenocarcinomas that involve only a small portion of the pancreas have been associated with diabetes. This implies a mechanism other than simple reduction in β-cell mass. If sufficiently extensive, cystic fibrosis and haemochromatosis (see p. 32) will also damage β-cells and impair insulin secretion. Fibrocalculous pancreatopathy may be accompanied by abdominal pain radiating to the back and by pancreatic calcifications identified on X-ray examination. Pancreatic fibrosis and calcium stones in the exocrine ducts have been found at autopsy.

Endocrinopathies

Several hormones, such as growth hormone, cortisol, glucagon and adrenaline (epinephrine), antagonize insulin action. Excess amounts of these hormones (e.g. acromegaly, Cushing’s syndrome, glucagonoma and phaeochromocytoma, respectively) can cause diabetes. This generally occurs in individuals with pre-existing defects in insulin secretion, and hyperglycaemia typically resolves when the hormone excess is resolved.

Somatostatinoma- and aldosteronoma-induced hypokalaemia can cause diabetes, at least in part by inhibiting insulin secretion. Hyperglycaemia generally resolves after successful removal of the tumour.

Drug- or chemical-induced diabetes

Many drugs can impair insulin secretion. These drugs may not cause diabetes by themselves, but they may precipitate diabetes in individuals with insulin resistance. Certain toxins such as that in Vacor (a rat poison) and intravenous pentamidine can permanently destroy pancreatic β-cells. Such drug reactions fortunately are rare. In such cases, the classification is unclear because the sequence or relative importance of β-cell dysfunction and insulin resistance is unknown. There are also many drugs and hormones that can impair insulin action. Examples include glucocorticoids and nicotinic acid. Patients receiving interferon-α have been reported to develop diabetes associated with islet cell antibodies and, in certain instances, severe insulin deficiency. Such drug reactions fortunately are rare. The list shown in Table 1.6 is not all-inclusive, but reflects the more commonly recognized drug-, hormone- and toxin-induced forms of diabetes.

Second-generation antipsychotic agents

Epidemiological studies suggest an increased risk of hyperglycaemia-related adverse events in patients treated with the atypical antipsychotics (AAPs). Precise risk estimates for hyperglycaemia-related adverse events are not available. Assessment of the relationship between AAPs and glucose abnormalities is complicated by an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between, as well as the mechanisms involved in, AAP use and hyperglycaemia-related adverse events is not completely understood. The mechanisms involved in the development of hyperglycaemia are unclear. A meta-analysis of observational studies showed that there was a 1.3-fold increased risk of diabetes in people with schizophrenia taking second-generation antipsychotics compared with the risk in those receiving a first-generation antipsychotic agent. Studies also indicate that the hyperglycaemia is not dose-dependent, is frequently reversible on cessation of treatment with AAPs, and frequently reappears on reintroduction of these therapies. Despite discontinuation of the suspect drug, some patients require continuation of antidiabetic treatment.

Patients with an established diagnosis of diabetes mellitus who are started on AAPs should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes, hypertension) who are starting treatment with AAPs should undergo fasting blood glucose testing/HbA1c measurements at the beginning of treatment and periodically during treatment. Patients should also be monitored for the osmotic symptoms of hyperglycaemia.

Infections

Certain viruses have been associated with β-cell destruction. Diabetes occurs in patients with congenital rubella, although most of these patients have HLA and immune markers characteristic of type 1 diabetes. In addition, Coxsackievirus B, cytomegalovirus, adenovirus and mumps virus have been implicated in inducing diabetes.

Uncommon forms of immune-mediated diabetes

In this category, there are two known conditions, and others are likely to occur. The ‘stiff man’ syndrome is an autoimmune disorder of the central nervous system characterized by stiffness of the axial muscles with painful spasms. Patients usually have high titres of the GAD autoantibodies, and approximately one-third will develop diabetes.

Anti-insulin receptor antibodies can cause diabetes by binding to the insulin receptor, thereby blocking the binding of insulin to its receptor in target tissues. However, in some cases, these antibodies can act as an insulin agonist after binding to the receptor and thereby cause hypoglycaemia. Anti-insulin receptor antibodies are occasionally found in patients with systemic lupus erythematosus and other autoimmune diseases. As in other states of extreme insulin resistance, patients with anti-insulin receptor antibodies often have acanthosis nigricans. In the past, this syndrome was termed type B insulin resistance.

Ataxia telangiectasia, an autosomal recessive disorder, is found to be associated with an anti-insulin antibody-mediated insulin-resistant form of diabetes. Another form of autoimmune insulin syndrome with hypoglycaemia has been described in Japan, and is caused by polyclonal insulin-binding autoantibodies that bind to endogenously synthesized insulin. If the insulin dissociates from the antibodies several hours after a meal, hypoglycaemia ensues.

In plasma cell dyscrasias, such as multiple myeloma, the plasma cells may produce monoclonal antibodies against insulin, causing hypoglycaemia by a similar mechanism.

Other genetic syndromes sometimes associated with diabetes

Many genetic syndromes are accompanied by an increased incidence of diabetes mellitus. These include the chromosomal abnormalities of Down, Klinefelter and Turner syndromes. Wolfram syndrome is an autosomal recessive disorder characterized by insulin-deficient diabetes and the absence of β-cells at autopsy. Additional manifestations include diabetes insipidus, hypogonadism, optic atrophy and neural deafness. Other syndromes are listed in Table 1.6.

Lipodystrophic diabetes

These are enigmatic disorders that may be classified as either:

• congenital, or

• acquired (onset often in early childhood).

The principal phenotypic characteristic is partial or total absence of subcutaneous fat, variable degrees of insulin resistance, hyperlipidaemia (sometimes severe with risk of pancreatitis and atherosclerosis) and the metabolic syndrome. The paucity of adipose tissue leads to striking clinical appearances and ketosis-resistant diabetes. The molecular defects responsible await elucidation. Cirrhosis and mesangioproliferative glomerulonephritis are recognized features of some forms. Genetic forms include Berardinelli–Seip congenital lipodystrophy and Dunnigan familial partial lipodystrophy. More recently the acquired form, a human immunodeficiency virus (HIV)-related lipodystrophy in patients treated with highly active antiretroviral therapy has been recognized.

Alterations in the structure and function of the insulin receptor cannot be demonstrated in patients with insulin-resistant lipodystrophic diabetes. Therefore, it is assumed that the lesion(s) must reside in the postreceptor signal transduction pathways.

Gestational diabetes mellitus (GDM)

GDM is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. The definition applies regardless of whether only diet modification or insulin is used for treatment, or whether the condition persists after pregnancy. It does not exclude the possibility that unrecognized glucose intolerance may have antedated or begun concomitantly with the pregnancy. GDM complicates 1–14% of pregnancies in the UK, depending on the population studied. GDM represents nearly 90% of all pregnancies complicated by diabetes.

Tip box

Deterioration of glucose tolerance occurs normally during pregnancy, particularly in the third trimester.

Testing for gestational diabetes

Risk assessment for GDM should be undertaken at the first prenatal visit. Previous recommendations included screening for GDM in all pregnancies. Women with clinical characteristics consistent with a high risk of GDM (marked obesity, personal history of GDM, glycosuria, or a strong family history of diabetes) should undergo oral glucose testing (OGTT; see below) as soon as feasible. If they are found not to have GDM at that initial screening, they should be retested between 24 and 28 weeks of gestation. Women of average risk should have testing undertaken at 24–28 weeks’ gestation.

Confirmation of the diagnosis precludes the need for any glucose challenge. In the absence of this degree of hyperglycaemia, evaluation for GDM in women with average or high-risk characteristics should include a diagnostic OGTT.

Following publication of the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) trial, the International Association of Diabetes and Pregnancy Study Groups (IADPSG), an international consensus group with representatives from multiple obstetrical and diabetes organizations, including ADA, developed revised recommendations for diagnosing GDM (Table 1.7):

• Perform a 75-g OGTT, with plasma glucose measurement fasting and at 1 and 2 h, at 24–28 weeks of gestation in women not previously diagnosed with overt diabetes. The OGTT should be undertaken in the morning after an overnight fast of between 8 and 14 h, after at least 3 days of unrestricted diet (≥ 150 g carbohydrate per day) and unlimited physical activity. The subject should remain seated and should not smoke throughout the test.

• The diagnosis of GDM is made when any of the plasma glucose values in Table 1.7 are exceeded.

Table 1.7 Screening for and diagnosis of gestational diabetes mellitus (GDM)

75-g OGTT, with plasma glucose measurement fasting, 1 h and 2 hrs, at 24–28 weeks of gestation in women not previously diagnosed with overt diabetes

The OGTT should be performed in the morning after an overnight fast of at least 8 h

The diagnosis of GDM is made when any of the following plasma glucose values are exceeded:

• Fasting > 92 mg/dL (5.1 mmol/L)

• 1 h > 180 mg/dL (10.0 mmol/L)

• 2 h > 153 mg/dL (8.5 mmol/l)

OGTT, oral glucose tolerance test.

Epidemiology

Diabetes is one of the most common forms of chronic diseases globally, affecting almost all ethnic groups. In 2011 it was estimated that in 366 million people worldwide suffered from diabetes, most of them living in developing nations (see appendix 1.1, figure 1.5). Globally, almost 6.6% of those aged 20–80 years were estimated to suffer from diabetes. Some 80% of people with diabetes live in low- and middle-income countries. This figure is estimated to increase to 552 million by 2030 (see appendix 1.1, figure 1.6), with the greatest increase in developing countries such as India and China; (see appendix 1.1, figure 1.7) 183 million people (50%) with diabetes are undiagnosed. Traditionally diabetes was thought to be a disease affecting people aged over 55 years. It is now increasingly appreciated that the age of onset of diabetes, especially in developing countries, is decreasing. In India it is estimated that 70% of all new-onset diabetes is in those aged less than 45 years of age.

Type 2 diabetes accounts for at least 90% of all diabetes worldwide. Rapid urbanization, increasing consumption of high-energy food, and sedentary lifestyles is leading to this rapid rise in the number of people suffering from diabetes. The increase in diabetes prevalence, especially in young adults, is likely to lead to an escalation of healthcare costs, and to increased mortality and morbidity along with loss of economic growth.

This rapid rise is occurring in parallel with the obesity epidemic. There is also a sharp rise in the number of patients with impaired glucose tolerance and impaired fasting glucose. This group of patients, with so-called pre-diabetes, is at increased risk of developing in diabetes in future and should be the target of preventive strategies.

The prevalence of type 1 diabetes is also stated to be rising, especially in Scandanavian countries. It tends to occur in genetically susceptible individuals. Some 10–20% of all newly diagnosed cases occur in those who have an affected first-degree relative. Viral infections and nutritional factors have been implicated in the development of type 1 diabetes.

Type 1 diabetes

The incidence of type 1 diabetes shows considerable geographical variation. The highest rates are in Finland, Norway, Sweden and Denmark, with Japan having the lowest incidence amongst the developed countries. In the UK, Finland and Poland the incidence has been rising in recent years; other countries have also reported increasing rates. For example, in the young in Scotland, diabetes is the most common metabolic disease, with an annual incidence of 35 per 100 000 population in 2003 with a near quadrupling of new cases in the last 40 years.

Tip box

The incidence of type 1 diabetes in persons under the age of 16 years has doubled during recent years in the UK.

Variable incidence rates between and within populations are cited as evidence of pathogenetic environmental factors (e.g. viruses, toxins). Intrauterine factors may be important and affect early development. In particular, placental transmission of viruses leading to type 1 diabetes (e.g. rubella) is widely recognized. Possibly cereals, food toxins and enteroviruses trigger islet autoimmunity through intrauterine exposure during pregnancy. Some studies have shown positive associations between diabetes and duration of breastfeeding and the early introduction of cow’s milk, whereas others have found no effect.

The peak age of presentation is 11–13 years; however, type 1 diabetes can affect any age group, even the very elderly. In some populations, up to 20% of patients diagnosed initially with type 2 diabetes prove to have evidence of autoimmune activity more typical of type 1 diabetes; such patients respond initially to oral antidiabetic agents but have an early requirement for insulin therapy. Reports of circulating antibodies directed to glutamic acid decarboxylase (GAD) in such patients point to progressive β-cell destruction. This form has been called ‘latent autoimmune diabetes in adults’ (LADA).

Tip box

Type 1 diabetes often has a long, asymptomatic, prodromal period during which β-cells are selectively destroyed.

Predicting type 1 diabetes

The increase in understanding of the pathogenesis of type 1 diabetes mellitus has made it possible to consider intervention to slow the autoimmune disease process in an attempt to delay or even prevent the onset of hyperglycaemia. Subjects who are at high risk of developing type 1 diabetes can be identified using a combination of immune, genetic and metabolic markers.

However, because only around 10% of patients have a first-degree relative with the disorder, general population screening is not feasible with present strategies. Moreover, prediction, even in higher-risk groups, is imperfect and the complex methodology is not available other than for clinical trials. For relatives of a patient with type 1 diabetes, approximate risks for developing the syndrome are as follows:

• sibling affected – 10% risk overall

• mother affected – 2–3% (risk to offspring varies with age at which mother developed diabetes – higher with younger-onset)

• father affected – 5–10%

• both parents affected – 30%.

Approximately 30–50% of identical (monozygotic) twins and up to 20% of non-identical (dizygotic) twins will ultimately develop type 1 diabetes if the other twin is affected. Experimental interventions to limit β-cell damage using potentially toxic immunosuppressive agents (e.g. ciclosporin) at diagnosis have proved to be, at best, only partially effective; this reflects the extensive and irreversible loss of β-cells by the time of presentation.

Type 2 diabetes

The clinical and biochemical features of type 2 diabetes are presented in Table 1.8.

Table 1.8 Clinical and metabolic features of type 2 diabetes

• Presentation usually in middle age or later life

• Obesity common (present in > 75%)

• Symptoms often mild, absent or unrecognized

• Relative rather than absolute insulin deficiency

• Insulin resistance common

• Ketosis-resistant

• Progressive disorder – even with antidiabetic therapy

• Insulin treatment often required to maintain long-term glycaemic control

• Other features of the ‘insulin resistance syndrome’ often present (e.g. hypertension, dyslipidaemia)

• High risk of macrovascular complications – main cause of premature death

• Tissue damage often present at diagnosis

Diabetes is one of the most common forms of chronic disease, globally affecting almost all ethnic groups. It is estimated that 285 million people worldwide suffer from diabetes, most of them living in developing nations. It is estimated that almost 6.6% of those aged 20–80 years suffer from diabetes globally. This figure is estimated to increase to 438 million by 2030, with the greatest increase in developing countries such as India and China. Traditionally diabetes was thought to be a disease affecting people aged over 55 years. It is now increasingly appreciated that the age of onset of diabetes, especially in developing countries, is decreasing. In India it is estimated that 70% of all cases of new-onset diabetes are in those aged less than 45 years.

Type 2 diabetes accounts for at least 90% of all diabetes worldwide. Rapid urbanization, increasing consumption of high-energy food and sedentary lifestyles are leading to this rapid rise in the number of patients suffering from diabetes. The increase in diabetes prevalence, especially in young adults, is likely to lead to an escalation of health-care costs and to increased mortality and morbidity rates, along with loss of economic growth.

This rapid rise is occurring in parallel with the obesity epidemic. There is also a sharp rise in the number of patients with impaired glucose tolerance and impaired fasting glucose (Table 1.9). These patients, with so-called pre-diabetes, are at increased risk of developing diabetes in the future and should be the target of preventive strategies.

Table 1.9 Diabetes and impaired glucose tolerance (IGT) for 2011 and 2030

	2010	2030
Total world population (billions)	7.0	8.3
Adult population (20–79 years, billions)	4.4	5.6
Diabetes and IGT (20–79 years)
Global prevalence (%)	8.3	9.9
Comparative prevalence (%)	8.5	8.9
No. of people with diabetes (millions)	366	552
IGT
Global prevalence (%)	6.4	7.1
Comparative prevalence (%)	6.5	6.7
No. of people with IGT (millions)	280	398

Source: International Diabetes Federation. IDF Diabetes Atlas, 5th edn. IDF, Brussels; 2011. Reproduced with permission.

The lowest prevalence (< 3%) has been reported in the least developed countries; by contrast, the highest prevalence rates (30–50% of adults) are observed in populations (e.g. North American Indians, Pacific Islanders, Australian Aborigines) that have undergone radical changes from traditional to westernized lifestyles (see below). The Pima Indians of Arizona have the highest prevalence, with over 50% of adults aged 35 years or above having diabetes. The prevalence of diabetes is also high in migrant populations; for example, South Asians in the UK have a 4-fold higher rate than the indigenous white population. Thus, type 2 diabetes represents an enormous, and rapidly expanding, global public health problem.

Global maps illustrating the projected increase from 2010 to 2030 in the prevalence of diabetes, by region, can be found in Appendix 1.1.

The increasing prevalence of type 2 diabetes depends on a number of factors:

• an increase in the levels of obesity. (Data from the Framingham study show that almost all of the increase in diabetes prevalence in the USA is due to obesity)

• demographic change – half of all people with diabetes are over 65 years old, so as the population ages the prevalence increases

• a fall in the age of onset of type 2 diabetes – people developing diabetes at an earlier age probably reflects weight gain compared with previous generations

• better survival with diabetes because of better control of blood glucose, blood pressure and hyperlipidaemia

• changes in the definition of diabetes, with the diagnosis made at a lower level of fasting

• better detection of diabetes due to opportunistic case-finding, practice-based screening and greater public awareness

• in developing countries, prevalence differs significantly owing to differences in diet, physical exercise and socioeconomic factors – the urban rate is generally assumed to be twice the rural estimate

• for the world as a whole there are more women than men with diabetes. The female excess is pronounced in the developed countries, but in developing countries the numbers are equal

• from 1995 to 2025 the adult population is predicted to increase by 64% and the prevalence of diabetes will increase by 35% (a real increase in the number of diabetic patients of 122%)

• in developed countries there will be an increase in the adult population of 11% with a 27% increase in the prevalence of diabetes

• in developing countries there will be an increase in the adult population of 82% with a 48% increase in the prevalence of diabetes (an increase in the number of diabetic patients of 170%).

Prediction and prevention

It is impossible accurately to predict who will develop type 2 diabetes. Major gaps in understanding of the aetiology of this heterogeneous disorder need to be filled before this will become feasible. However, it is possible to define groups at higher than average risk of developing type 2 diabetes. Factors that have been identified include:

Clinical studies have suggested that the risk of progression from a high-risk group such as impaired glucose tolerance to type 2 diabetes may be averted (or at least postponed) by measures such as dietary advice and supervised physical training (e.g. the Malmö Study in Sweden and the Diabetes Prevention Study in Finland). The US Diabetes Prevention Program showed a 58% reduction (with lifestyle changes) in risk of progression from impaired glucose tolerance to type 2 diabetes (versus 31% for metformin).

Change in lifestyle is the cornerstone of prevention:

• avoidance of obesity

• regular aerobic exercise

• avoiding smoking.

Metabolic syndrome

There are multiple definitions of the metabolic syndrome. It consists of a clustering of cardiovascular risk factors that include central obesity, hypertension and dyslipidaemia, which are all associated with insulin resistance. The presence of the metabolic syndrome is considered an important risk factor for cardiovascular disease and mortality in non-diabetic subjects and patients with type 2 diabetes. The most recent definition of the metabolic syndrome is the consensus document from the International Diabetes Federation (IDF) (Table 1.10). The IDF metabolic syndrome criteria take into account ethnic differences in body fat distribution. The WHO, National Cholesterol Education Program (NCEP) and the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel (ATP) III) have each proposed different criteria for the diagnosis.

Table 1.10 Metabolic syndrome

Metabolic syndrome is indicated where central obesity is accompanied by any two of the following four factors:

• raised TG level: > 150 mg/dL (1.7 mmol/L), or specific treatment for this lipid abnormality

• reduced HDL cholesterol: < 40 mg/dL (1.03 mmol/L*) in males and < 50 mg/dL (1.29 mmol/L*) in females, or specific treatment for this lipid abnormality

• raised blood pressure: systolic BP > 130 mmHg or diastolic BP > 85 mmHg, or treatment of previously diagnosed hypertension

• raised FPG > 100 mg/dL (5.6 mmol/L), or previously diagnosed type 2 diabetes. If > 5.6 mmol/L or > 100 mg/dL, OGTT is strongly recommended but is not necessary to define presence of the syndrome

BP, blood pressure; FPG, fasting plasma glucose; HDL, high-density lipoprotein; TG, triglycerides; OGTT, oral glucose tolerance test.

Source: International Diabetes Federation (2006). Reproduced with permission.

The international diabetes federation (IDF) definition

For a person to be defined as having the metabolic syndrome they must meet the criteria defined in Table 1.10.

Central obesity is most easily measured by waist circumference using the guidelines in Table 1.11, which are sex and ethnic group (not country of residence) specific.

Table 1.11 Ethnic specific values for waist circumference

Country/ethnic group	Waist circumference (cm)
Country/ethnic group	Male	Female
Europids	> 94	> 80
In the USA, the ATP III values (102 cm male; 88 cm female) are likely to continue to be used for clinical purposes	> 94	> 80
South Asians	> 90	> 80
Based on a Chinese, Malay and Asian–Indian population	> 90	> 80
Chinese	> 90	> 80
Japanese	> 90	> 80
Ethnic South and Central Americans	Use South Asian recommendations until more specific data are available
Sub-Saharan Africans	Use European data until more specific data are available
Eastern Mediterranean and Middle East (Arab) populations	Use European data until more specific data are available

ATP, Adult Treatment Panel.

Source: International Diabetes Federation (2006). Reproduced with permission.

The clinical value of using ’metabolic syndrome’ as a diagnosis is contentious. There are different sets of conflicting criteria in existence. Recently published studies have used different criteria and followed subjects for varied lengths of time. Thus the magnitude of risk associated with the metabolic syndrome varies across studies. Generally, the development of CVD correlates with the number of features of the metabolic syndrome at baseline. Men with three or more features at baseline are at greater risk of developing CVD than those with none. However, when confounding factors such as obesity are accounted for, diagnosis of the metabolic syndrome per se has a negligible increased association with the risk of heart disease. The metabolic syndrome probably should not be regarded as a clinical entity, but as a clustering of cardiovascular risk factors, each of which requires treatment.

The metabolic syndrome is associated with increased risk of a variety of disease outcomes including diabetes, CVD, fatty liver and non-alcoholic steatohepatosis, polycystic ovary syndrome, gallstones, asthma, sleep apnoea and some malignant diseases. The biggest impact that metabolic syndrome has on health is the increased incidence of atheromatous vascular disease. The individual components of the metabolic syndrome – hypertension, dyslipidaemia and glucose intolerance – were all known individually to be associated with increased atheromatous vascular disease.

Central to the concept of metabolic syndrome is insulin resistance, which is strongly associated with non-diabetic hyperglycaemia and type 2 diabetes. It is uncertain whether insulin resistance is the fundamental metabolic defect that links these abnormalities together. However, there is considerable epidemiological and experimental evidence that insulin resistance syndrome confers an increased risk of cardiovascular disease. Importantly, the magnitude of the risk associated with a combination of factors is greater than would be expected by simple addition (i.e. the effects are synergistic). Finally, there is evidence from longitudinal studies that these metabolic risk factors:

• worsen continuously across the spectrum of glucose intolerance

• may be present many years before the diagnosis of type 2 diabetes.

Again, depending on the study, the all-cause mortality rate is increased by 20–80% in individuals with the metabolic syndrome, with mortality from CVD increased by 60–280% and death from coronary heart disease increased by 70–330%. Presence of the metabolic syndrome confers an increased risk of death from coronary heart disease in women compared with that in men. Other studies have shown a relative risk of developing CVD for those with three or more features compared with that in those with two or fewer features of 1.3–1.7. For individuals with diabetes the relative risk is higher, with a 5-fold increased risk of CVD in those with the metabolic syndrome and diabetes versus those with diabetes without the metabolic syndrome.

Metabolic syndrome is classically associated with type 2 diabetes. However, obese patients with type 1 diabetes are also at risk of developing the metabolic syndrome. This combination is probably present in more than 30% of type 1 patients (depending on the background prevalence of metabolic syndrome). These patients:

• are more likely to develop macrovascular and microvascular complications, and have significantly higher morbidity and mortality rates

• have a higher insulin requirement

• need to be treated more aggressively (glycaemic control plus management of hypertension/dyslipidaemia)

• have a need for insulin sensitizers (e.g. metformin).

Fatty liver disease

Fatty liver disease (FLD) is considered to be part of the metabolic syndrome and is due to defects in fat metabolism. Imbalance in energy consumption and its metabolism results in increased lipid storage. Lipid storage may also be a consequence of peripheral resistance to insulin, whereby the transport of fatty acids from adipose tissue to the liver is increased. Impairment or inhibition of the receptor molecules, peroxisome proliferator-activated receptor (PPAR)-α, PPAR-γ and sterol regulatory element-binding protein (SREBP)-1, that control the enzymes responsible for the oxidation and synthesis of fatty acids also appears to contribute to the accumulation of fat. Alcohol excess is known to damage mitochondria and other cellular structures, further impairing cellular energy mechanism. Non-alcoholic FLD may begin as an excess of unmetabolized energy in liver cells. Hepatic steatosis (retention of lipid) is considered to be reversible and to some extent non-progressive if there is cessation or removal of the underlying cause.

Severe fatty liver is often accompanied by inflammation, a situation that is referred to as steatohepatitis. Progression to alcoholic steatohepatitis (ASH) or non-alcoholic steatohepatitis (NASH) depends on the persistence or severity of the inciting cause. Pathological lesions in both conditions are similar. However, the extent of inflammatory response varies widely and does not always correlate with degree of fat accumulation.

Liver with extensive inflammation and high degree of steatosis often progresses to more severe forms of the disease. Hepatocyte ballooning and hepatocyte necrosis of varying degree are often present at this stage. Liver cell death and inflammatory responses lead to the activation of stellate cells, which play a pivotal role in hepatic fibrosis. The extent of fibrosis varies widely. Perisinusoidal fibrosis is most common, especially in adults, and predominates in and around the terminal hepatic veins. The progression to cirrhosis may be influenced by the amount of lipid accumulated, the degree of steatohepatitis, and a variety of other sensitizing factors. In alcoholic FLD the transition to cirrhosis related to continued alcohol consumption is well documented, but the process involved in non-alcoholic FLD is less clear.

Cirrhosis, secondary to FLD, is now very common, and as obesity/insulin resistance becomes more common cirrhosis will become an even bigger clinical issue.

Haemochromatosis (’bronze diabetes’)

Haemochromatosis is usually defined as iron overload with a hereditary/primary cause, or originating from a metabolic disorder. However, the term has often also been used more broadly to refer to any form of iron overload. The term haemosiderosis is generally used to indicate the pathological effect of iron accumulation in any given organ, which occurs mainly in the form of haemosiderin.

Hereditary haemochromatosis is the most common of several ’iron overload’ diseases. It is the most common single-gene inherited disorder in Caucasians, with 1 in 10 persons carrying an abnormal gene. Haemochromatosis is caused by mutations in the HFE gene, inherited in an autosomal recessive manner. The two mutations identified in the HFE gene are C282Y and H63D.

As many as 1 in 200 Americans are believed to carry both markers of the gene for haemochromatosis, and it is estimated that about half will eventually develop complications. This will give a prevalence similar to that of type 1 diabetes but, as in type 2 diabetes, the condition appears to be relatively underdiagnosed.

Haemochromatosis causes the body to absorb excessive amounts of iron from the diet. The body lacks an efficient means of excreting this excess iron, and as a result excess iron is deposited in organs, mainly the liver, but also the pancreas, heart, endocrine glands and joints.

Haemochromatosis is characterized by the four main features:

• Increased pigmentation (slate-grey or brownish bronze) is seen in more than 90% of patients; it is often one of the first signs of the disease and may precede other signs by many years. Hyperpigmentation is most evident on sun-exposed skin, particularly the face. There may also be skin thinning and/or ichthyosis-like changes (scaling) with partial loss of body hair (pubic region most affected)

• Enlarged liver occurs in more than 95% of patients and is often accompanied by cirrhosis and liver failure

• Diabetes mellitus, often requiring insulin therapy, is seen in 30–60% of patients

• Heart failure due to cardiomyopathy.

Symptoms

The condition is 10 times more common in males than in females, and usually presents between 40 and 60 years of age. Symptoms tend to occur in men between the ages of 30 and 50 years, and in women over the age of 50 years, with joint pain being the most common presentation:

• joint pain – commonly in the second and third metacarpophalangeal joints, and the interphalangeal and carpal joints

Investigations

• Measurement of serum iron levels has no value in making the diagnosis.

• Transferrin saturation corresponds to the ratio of serum iron and total iron-binding capacity. Similar to iron, it is influenced by liver disease (other than haemochromatosis) and inflammation; therefore, it has limitations in the diagnostic workup.

• Haemochromatosis is suggested by persistently raised transferrin saturation in the absence of other causes of iron overload. It is the initial test of choice.

• The screening threshold for haemochromatosis is a fasting transferrin saturation of 45–50%.

• Approximately 30% of women younger than 30 years who have haemochromatosis do not have increased transferrin saturation.

• High transferrin saturation is the earliest evidence of haemochromatosis. A value greater than 60% in men and 50% in women is highly specific.

• Serum ferritin levels raised above 200 μg/L in premenopausal women and 300 μg/L in men and postmenopausal women indicate primary iron overload due to haemochromatosis, especially when associated with high transferrin saturation and evidence of liver disease.

• Ferritin concentration can be high in other conditions, such as infections, inflammations and liver disease.

• Ferritin concentration higher than 1000 μg/L suggests liver damage with fibrosis or cirrhosis.

• Ferritin levels are less sensitive than transferrin saturation in screening tests for haemochromatosis.

• Genetic testing for the HFE mutation is indicated in patients with evidence of iron overload (e.g. raised transferrin saturation, high serum ferritin levels, excess iron staining or iron concentration on liver biopsy samples) and also in all first-degree relatives of patients with haemochromatosis. This is indicated particularly in patients with known liver disease and evidence of iron overload, even if other causes of liver disease are present.

Liver biopsy:

• is useful to identify liver disease and to determine the presence or absence of cirrhosis, which directly affects prognosis.

• is indicated in the following cases:

• raised liver enzymes in combination with hereditary haemochromatosis

• serum ferritin level above 1000 μg/L.

Management

It is important to detect haemochromatosis as early as possible so that venesection can be instituted to prevent the build-up of iron and potential complications. Tiredness and abdominal pain should diminish, and increased pigmentation of the skin should fade. Once complications such as diabetes and cirrhosis have developed, they cannot be reversed. In addition, arthritis may fail to improve with venesection.

Haemochromatosis cannot be treated with a low iron diet alone. However, some foods affect the way the body absorbs iron. The following dietary tips may play a small part in reducing the symptoms of the disease:

• Minimize alcohol intake, particularly with meals – alcohol may lead to increased iron absorption and increase the risk of liver disease

• Reduce intake of liver, kidney and red meat – iron absorption from red meat is 20–30% compared with 1–20% for vegetables and grains

• Avoid vitamin supplements or tonics containing iron or vitamin C – vitamin C enhances the absorption of iron from the diet.

Treatment of haemochromatosis consists of regular venesection. Depending on the degree of iron overload, the procedure may initially be performed once weekly or once monthly. This regularity of treatment continues until serum ferritin levels return to normal; this may take up to 2 years. After this, lifelong maintenance therapy needs to be set in place as excess iron continues to be absorbed. On average, venesection is required every 3–4 months to prevent build-up and maintain normal levels. Regular monitoring of serum ferritin, transferrin saturation, haematocrit and haemoglobin is necessary throughout the treatment process.

Acquired haemochromatosis may be the result of blood transfusions, excessive dietary iron, or secondary to other disease.

• Alcoholic liver disease – patients include those who are heavy drinkers, perhaps of iron-containing fortified wines, and who have cirrhosis. Liver biopsy in these patients may show a modest increase in iron; however, contrary to patients with haemochromatosis, the hepatic iron levels are relatively normal.

• Ineffective erythropoiesis with marrow hyperplasia – patients with hyperplastic erythroid marrow absorb an increased amount of iron to the point where they may have clinical iron overload. Examples include the hereditary sideroblastic anaemias, severe α- and β-thalassaemia, and the myelodysplastic syndrome variants, such as refractory anaemia with ringed sideroblasts (RARS).

• Iron overload associated with chronic anaemia – examples include hereditary spherocytosis and acquired sideroblastic anaemia, where patients have increased effective erythropoiesis and increased iron absorption.

• Multiple transfusions – hypertransfusion is performed in patients with β-thalassaemia major, sickle cell anaemia, refractory aplastic anaemia and myelodysplastic syndrome. Such patients may receive as much as 100 units of red cells.

• Porphyria cutanea tarda (PCT) – this is primarily a skin and liver disease that occurs in familial and sporadic forms. The cause of liver siderosis in sporadic PCT has not been established, but may be related to a mutation in the HFE gene.

Polycystic ovary syndrome (PCOS)

PCOS is one of the most common female endocrine disorders, affecting approximately 5–10% of females of reproductive age (12–45 years). A majority of patients with PCOS have insulin resistance and/or are obese. Their raised insulin levels contribute to or cause the abnormalities seen in the hypothalamic–pituitary–ovarian axis that lead to PCOS.

Hyperinsulinaemia increases the gonadotropin-releasing hormone (GnRH) pulse frequency, luteinizing hormone (LH) over follicle-stimulating hormone (FSH) dominance, which increases ovarian androgen production, decreases follicular maturation, and decreases sex hormone-binding globulin (SHBG) binding; all of these steps lead to the development of PCOS. Insulin resistance is a common finding among patients of normal weight as well as overweight patients.

Hyperinsulinaemia in patients with PCOS has been found to be associated with an increased 17,20-lyase activity, leading to excess androgen production.

Adipose tissue possesses aromatase, an enzyme that converts androstenedione to oestrone, and testosterone to oestradiol. The excess adipose tissue in obese patients creates the paradox of having both excess androgens (which are responsible for hirsutism and virilization) and oestrogens (which inhibits FSH via negative feedback).

The principal features are:

• obesity

• anovulation – oligomenorrhoea, amenorrhoea (irregular, few, or absent menstrual periods)

• hirsutism – excessive mild symptoms of hyperandrogenism, such as acne or hyperseborrhoea, are frequently seen in adolescent girls and are often associated with irregular menstrual cycles. In most instances, these symptoms are transient and reflect only the immaturity of the hypothalamic–pituitary–ovarian axis during the first years following menarche.

Tip box

Not all women with PCOS have polycystic ovaries, nor do all women with ovarian cysts have PCOS.

The diagnosis is straightforward using the Rotterdam criteria (Table 1.12), even when the syndrome is associated with a wide range of symptoms.

Table 1.12 Diagnosis of polycystic ovary syndrome

In 2003 a consensus workshop sponsored by ESHRE and ASRM in Rotterdam indicated PCOS to be present when 2 of the following 3 criteria are met:

• oligo-ovulation and/or anovulation

• excess androgen activity

• polycystic ovaries (by gynaecological ultrasonography)

• exclusion of other endocrine disorders

ESHRE, European Society of Human Reproduction and Embryology; ASRM, American Society for Reproductive Medicine.

History-taking should enquire specifically about:

• the menstrual pattern

• history of obesity

• hirsutism

• absence/presence of breast discharge.

These four questions can diagnose PCOS with a sensitivity of approximately 80% and a specificity of about 90%.

Investigations should include:

• Gynaecological ultrasonography – in PCOS there is ’follicular arrest’, whereby several follicles develop to a size of 5–7 mm (pre-ovulatory size is 16 mm or more). According to the Rotterdam criteria, 12 or more small follicles (2–9 mm) should be seen in an ovary on ultrasound examination and/or the ovarian volume should be > 10 cm³ on either side.

• Serum (blood) levels of androgens including androstenedione, testosterone and dehydroepiandrosterone sulphate may be raised. The free testosterone level is considered to be the best measure.

• Other blood tests are suggestive but not diagnostic. The ratio of LH : FSH is greater than 1 : 1, as tested on day 3 of the menstrual cycle. This pattern is not specific and is present in less than 50%.

Common assessments for associated conditions or risks include:

• fasting biochemical screen and lipid profile

• frank diabetes can be seen in 65–68% of women with this condition.

For exclusion of other disorders that may cause similar symptoms:

• prolactin to rule out hyperprolactinaemia

• thyroid-stimulating hormone (TSH) to rule out hypothyroidism

• 17-hydroxyprogesterone to rule out 21-hydroxylase deficiency (congenital adrenal hyperplasia).

Women with PCOS are at risk of the following:

• type 2 diabetes

• hypertension

• dyslipidaemia

• cardiovascular and cerebrovascular disease

• miscarriage

• acanthosis nigricans

• endometrial hyperplasia and increased risk of endometrial cancer. This appears to be due to over-accumulation of the uterine lining and also lack of progesterone, resulting in prolonged stimulation of uterine cells by oestrogen. It is, however, unclear whether this increased risk is directly due to PCOS or to the associated obesity, hyperinsulinaemia and hyperandrogenism

• [autoimmune thyroiditis].

Differential diagnosis

Other causes of irregular or absent menstruation and hirsutism, include congenital adrenal hyperplasia, Cushing syndrome, hyperprolactinaemia and androgen-secreting neoplasms, as well as other pituitary or adrenal disorders.

PCOS has been reported in other insulin-resistant situations, such as acromegaly.

Medical treatment of pcos is tailored to the patient’s goals

In each of these areas, there is considerable debate as to the optimal treatment. One of the major reasons for this is the lack of large-scale clinical trials comparing different treatments. Broadly, these may be considered under four categories:

1 Lowering of insulin levels

Successful weight loss is the most effective method of restoring normal ovulation/menstruation. Reducing insulin resistance by improving insulin sensitivity through medications such as metformin and/or thiazolidinediones is often helpful.

2 Treatment of hirsutism or acne

The standard contraceptive pill may be effective in reducing hirsutism. A common choice of contraceptive pill is one that contains cyproterone acetate; in the UK/USA the available brand is Dianette/Diane. Cyproterone acetate is a progestogen with antiandrogen effects.

Other drugs with antiandrogen effects include flutamide and spironolactone, both of which can give some improvement in hirsutism. Spironolactone is probably the most commonly used drug in the USA. Metformin may reduce hirsutism, perhaps by reducing insulin resistance, and is often used when there are other features such as insulin resistance, diabetes or obesity that should also benefit from metformin. Eflornithine (Vaniqa) is a drug that is applied to the skin in cream form, often to the face. It is an irreversible inhibitor of ornithine decarboxylase, the enzyme that catalyses the rate-limiting step in folliculogenesis. Hence it inhibits hair growth directly. Individuals may vary in their response to different therapies, and it is usually worth trying other drug treatments if one does not work, but drug treatments do not work well for all individuals. For removal of facial hair, electrolysis or laser treatments are faster, more efficient, although expensive alternatives.

3 Restoration of fertility

Of course, not all women with PCOS have difficulty becoming pregnant. Treatment of infertility is not within the scope of this book.

4 Restoration of regular menstruation, and prevention of endometrial hyperplasia and endometrial cancer

If fertility is not the primary aim, menstruation can usually be regulated with a contraceptive pill. The purpose of regulating menstruation is essentially for the woman’s convenience and perhaps sense of well-being; there is no medical requirement for regular periods, so long as they occur sufficiently often (at least every 3 months). Most brands of contraceptive pill result in a withdrawal bleed every 28 days if taken in 3-week intervals. Dianette is also beneficial for hirsutism, and is therefore often prescribed for PCOS.

If a regular menstrual cycle is not desired, then therapy for an irregular cycle is not necessarily required – if a menstrual bleed occurs at least every 3 months, the endometrium is being shed sufficiently often to prevent increased risk of endometrial abnormalities or cancer. If menstruation occurs less often or not at all, some form of progestogen replacement is recommended. Some women prefer a uterine progestogen implant such as the intrauterine system (Mirena) coil, which provides simultaneous contraception and endometrial protection for many years, although often with unpredictable minor bleeding. An alternative is an oral progestogen taken at intervals (e.g. every 3 months) to induce a predictable menstrual bleed.

Biochemistry of diabetes

Insulin

The hormone insulin is a primary regulatory signal in animals, suggesting that the basic mechanism is old and central to animal life (Figs 1.1 & 1.2). β-cells in the islets of Langerhans release insulin in two phases. In the first phase insulin release is triggered rapidly in response to increased blood glucose levels. The second phase is a sustained, slow release of newly formed vesicles that are triggered independently of glucose.

Figure 1.1 Primary structure (amino acid sequence) of human insulin.

Figure 1.2 Regulation of glucose metabolism by insulin.

During the first phase of insulin release, glucose enters the β-cells through the glucose transporter (GLUT-2), and through glycolysis and the respiratory cycle multiple high-energy adenosine triphosphate (ATP) molecules are produced, leading to the ATP-controlled potassium channels (K⁺) closing and the cell membrane depolarizing. On depolarization, voltage-controlled calcium channels (Ca^2 +) open. An increased calcium level causes activation of phospholipase C, which cleaves the membrane phospholipid, phosphatidylinositol 4,5-bisphosphate, into inositol 1,4,5-triphosphate and diacylglycerol. Inositol 1,4,5-triphosphate (IP3) binds to receptor proteins in the membrane of endoplasmic reticulum (ER), which allows the release of Ca^2 + from the ER via IP3 gated channels, and further raises the cell concentration of calcium. The increased amount of calcium in the cells causes release of previously synthesized insulin, which has been stored in secretory vesicles.

Evidence of early impaired first-phase insulin release can be seen in the oral glucose tolerance test, demonstrated by a substantially raised blood glucose level at 30 min, a marked drop by 60 min, and a steady climb back to baseline levels over the following hourly time points.

Insulin secretion from the pancreas is not continuous, but oscillates within a period of 3–6 min, changing from generating a blood insulin concentration of more than about 800 pmol/L to less than 100 pmol/L. This is thought to avoid downregulation of insulin receptors in target cells and to assist the liver in extracting insulin from the blood.

Other substances known to stimulate insulin release include amino acids from ingested proteins and acetylcholine, released from vagus nerve endings (parasympathetic nervous system). Glucagon-like peptide (GLP) and glucose-dependent insulinotropic peptide (GIP), released by enteroendocrine cells of intestinal mucosa, also stimulate insulin release. Acetylcholine triggers insulin release through phospholipase C, whereas GLP and GIP act through adenylate cyclase. The three amino acids, alanine, glycine and arginine, which stimulate insulin secretion, act similarly to glucose by altering the membrane potential of β-cells.

The sympathetic nervous system (via α₂-adrenergic stimulation as demonstrated by the agonists clonidine or methyldopa) inhibits the release of insulin. However, circulating adrenaline (epinephrine) will activate β₂-receptors on the β-cells in the pancreatic islets to promote insulin release. This is important, as muscle cannot benefit from the raised blood sugar resulting from adrenergic stimulation (increased gluconeogenesis and glycogenolysis from the low blood insulin : glucagon state) unless insulin is present to allow for GLUT-4 translocation into the tissue.

When the glucose level comes down to the usual physiological value, insulin release from the β-cells slows or stops. If blood glucose levels drop lower, release of hyperglycaemic hormones (most prominently glucagon from islet of Langerhans’ α-cells) forces release of glucose into the blood from cellular stores, primarily liver cell stores of glycogen. By increasing blood glucose levels, the hyperglycaemic hormones prevent or correct life-threatening hypoglycaemia. Release of insulin is strongly inhibited by the stress hormone noradrenaline (norepinephrine), leading to increased blood glucose levels during stress. The many roles of insulin are summarized in Table 1.13.

Table 1.13 Main physiological actions of insulin

• Increased glycogen synthesis – increases hepatic (and skeletal muscle/adipose tissue) storage of glucose cells in the form of glycogen; lowered levels of insulin cause liver cells to convert glycogen to glucose and excrete it into the bloodstream

• Increased fatty acid synthesis – increased uptake of plasma lipids by adipose tissue; lack of insulin causes the reverse

• Increased esterification of fatty acids – increased adipose tissue production of triglycerides from fatty acid esters; lack of insulin causes the reverse

• Decreased proteolysis

• Decreased lipolysis – reduction in conversion of fat cell lipid stores into free fatty acids; lack of insulin causes the reverse

• Decreased gluconeogenesis – decreased production of glucose from non-sugar substrates; lack of insulin causes glucose production from assorted substrates in the liver and elsewhere

• Increased amino acid uptake – increased uptake of circulating amino acids; lack of insulin inhibits absorption

• Increased potassium uptake – increased cellular uptake of plasma potassium; lack of insulin inhibits absorption. Insulin’s increase in cellular potassium uptake lowers potassium levels in blood

• Arterial muscle tone – induces arterial wall muscle relaxation, increasing blood flow, especially in microarteries; lack of insulin reduces flow by allowing these muscles to contract

Tip box

Hepatic glucose production is the principal determinant of the fasting blood glucose concentration.

Tip box

Stimulation of glucose uptake (and subsequently metabolism or storage as glycogen) requires higher plasma insulin concentrations than are necessary for suppression of hepatic glucose production.

Insulin degradation

Once an insulin molecule has docked on to the receptor and effected its action, it may be released back into the extracellular environment or it may be degraded by the cell. Degradation normally involves endocytosis of the insulin–receptor complex followed by the activation of the insulin degrading enzyme. Most insulin molecules are degraded by liver cells. It has been estimated that a typical insulin molecule is finally degraded approximately 70 min after its initial release into the circulation.

Glucagon

Glucagon is an important hormone involved in carbohydrate metabolism. Glucagon is synthesized and secreted from the α-cells of the islets of Langerhans. It is released when blood glucose levels start to fall too low, causing the liver to convert stored glycogen into glucose and release it into the bloodstream, raising blood glucose levels and ultimately preventing the development of hypoglycaemia. The action of glucagon is thus opposite to that of insulin. However, glucagon also stimulates the release of insulin, so that newly available glucose in the bloodstream can be taken up and used by insulin-dependent tissues (Tables 1.14 & 1.15).

Table 1.14 Causes of increased and decreased secretion/inhibition of glucagon

Increased secretion of glucagon is caused by:	Decreased secretion/inhibition of glucagon is caused by:
• Decreased plasma glucose

• Somatostatin

• Increased catecholamines – noradrenaline (norepinephrine) and adrenaline (epinephrine)

• Insulin

• Increased plasma amino acids (to protect from hypoglycaemia if an all-protein meal is consumed)

• Increased free fatty acids and keto acids in the bloodstream

• Sympathetic nervous system

• Increased urea production

• Acetylcholine

• Cholecystokinin

Table 1.15 Metabolic actions of insulin and glucagon

	Insulin	Glucagon
Fatty acid uptake and release in fat	Stimulates synthesis TG from FFA; inhibits release of FFA from TG	Stimulates release of FFA from TG
Liver glycogen	Increases synthesis and thereby glucose uptake and storage	Stimulates glycogenolysis and glucose release
Liver gluconeogenesis	Inhibits; saves amino acids	Stimulates; glucose synthesized and released
Glucose uptake, skeletal muscle	Stimulates uptake, storage as glycogen and use in energy metabolism	No receptors, no effect
Glycogen, skeletal muscle	Stimulates synthesis	No receptors, no effect
Amino acid uptake	Stimulates and is necessary for protein synthesis	No receptors, no effect
Brain (hypothalamus)	Reduces hunger through hypothalamic regulation	No effect

FFA, free fatty acids; TG, triglycerides.

The insulin receptor

The insulin receptor is a transmembrane receptor belonging to the large class of tyrosine kinase receptors (Fig. 1.3). Two α-subunits and two β-subunits make up the receptor. The β-subunits pass through the cellular membrane and are linked by disulphide bonds. Receptor activity is mediated by tyrosines phosphorylation within the cell. The ‘substrate’ protein for insulin receptor substrate (IRS)-1 is phosphorylated, leading to an increase in the high-affinity glucose transporter (GLUT-4) molecules on the outer membrane of insulin-responsive tissues. These tissues include muscle cells, adipose tissue and hepatocytes. This process leads to an increase in the uptake of glucose from blood into these tissues and a cascade of post-receptor signalling events still not fully elucidated. GLUT-4 is transported from cellular vesicles to the cell surface, where it mediates the transport of glucose into the cell. Other isoforms of glucose transporters (e.g. GLUT-1 at the blood–brain and blood–retinal barriers, GLUT-2 in islet β-cells) do not require insulin to transfer glucose into cells.

• Receptor defects – there may be a reduced number of insulin receptors or a reduction in their affinity for insulin. This may occur in response to chronic hyperinsulinaemia (so-called downregulation). Lesser degrees of obesity and glucose intolerance are associated with receptor defects that are largely reversible with treatment. Inherited severe receptor defects are rare.

• Post-receptor defects – defects in intracellular events distal to the binding of insulin account for insulin resistance in most patients with type 2 diabetes; the maximal response to insulin is impaired and is usually only partially reversible, even with insulin-sensitizing drugs. The precise nature of these defects has not yet been identified.

Figure 1.3 Cellular binding of insulin to its receptor and post-binding events. GLUT-4, glucose transporter-4; GRB, growth factor receptor-bound protein; PI3-kinase, phosphatidylinositol-3 kinase.

Tip box

Insulin receptor downregulation and post-receptor defects frequently coexist.

Lipolysis

Lipolysis is the hydrolysis of lipids (Fig. 1.4). Metabolically it is the breakdown of triglycerides into free fatty acids within cells. When fats are broken down for energy, the process is known asβ-oxidation: ketones are produced and are found in large quantities in ketosis (a state in metabolism occurring when the liver converts fat into fatty acids and ketone bodies, which can be used by the body for energy). Lipolysis testing strips such as Ketostix are used to recognize urinary ketones.

Figure 1.4 Regulation of lipolysis and ketone body metabolism by insulin (+ ve = increased by insulin; − ve = decreased by insulin).

The following hormones induce lipolysis: noradrenaline (epinephrine), noradrenaline (norepinephrine), glucagon, growth hormone and cortisol (although cortisol’s actions are still unclear). These trigger G-protein-coupled receptors, which activate adenylate cyclase. This results in increased production of cAMP, which activates protein kinase A, which subsequently activate lipases found in adipose tissue.

Triglycerides are transported through the blood to appropriate tissues (adipose, muscle, etc.) by lipoproteins such as chylomicrons. Triglycerides present on the chylomicrons undergo lipolysis by the cellular lipases of target tissues, which yield glycerol and free fatty acids. Free fatty acids released into the blood are then available for cellular uptake. Free fatty acids not immediately taken up by cells may bind to albumin for transport to surrounding tissues that require energy. Serum albumin is the major carrier of free fatty acids in the blood. The glycerol also enters the bloodstream and is absorbed by the liver or kidney where it is converted to glycerol 3-phosphate by the enzyme glycerol kinase. Hepatic glycerol 3-phosphate is converted mostly to dihydroxyacetone phosphate (DHAP) and then glyceraldehyde 3-phosphate (GA3P), to rejoin the glycolysis and gluconeogenesis pathway.

While lipolysis is triglyceride hydrolysis, the process by which triglycerides are broken down, esterification is the process by which triglycerides are formed. Esterification and lipolysis are essentially reversals of one another.

Glucose toxicity

Importantly, from a therapeutic standpoint, there is evidence that hyperglycaemia per se may adversely affect both insulin action and endogenous insulin secretion. These effects have been termed ‘glucose toxicity’. The clinical implication is that reducing the level of hyperglycaemia (by non-pharmacological measures, oral agents or insulin) may produce secondary improvements in intermediary metabolism.

Lipotoxicity

Disturbed fatty acid metabolism has been documented in patients with type 2 diabetes and lesser degrees of glucose intolerance. Experimental data indicate that raised fatty acid concentrations may:

• impair insulin-mediated glucose disposal and oxidation (via the glucose–fatty acid or Randle cycle)

• accelerate hepatic glucose production

• inhibit endogenous insulin secretion

• contribute to hypertriglyceridaemia.

These effects may be regarded as evidence for a toxic effect of fatty acids. Under experimental conditions, fatty acids may induce apoptosis in islet β-cells. Tumour necrosis factor-α produced by adipocytes has also been implicated in the production of insulin resistance in glucose metabolism via inhibitory effects on insulin signalling. In addition, increased circulating fatty acid concentrations have been implicated in the pathogenesis of hypertension.

Appendix 1.1: Prevalence estimates of diabetes, 2011–2030

Figure 1.5 Prevalence (%) estimates of diabetes (20–79 years), 2010.

(Source: International Diabetes Federation/IDF Diabetes Atlas, 5th edn. IDF, Brussels. © International Diabetes Federation 2011. Reproduced with permission.)

Figure 1.6 Prevalence (%) estimates of diabetes (20–79 years), 2030.

(Source: International Diabetes Federation/IDF Diabetes Atlas, 5th edn. IDF, Brussels. © International Diabetes Federation 2011. Reproduced with permission.)

Figure 1.7 International Diabetes Federation regions and global projections for the number of people with diabetes (20–79 years), 2010–2030.

(Source: International Diabetes Federation/ IDF Diabetes Atlas, 5th edn. IDF, Brussels. © International Diabetes Federation 2011. Reproduced with permission.)