1: Diagnosis, classification, epidemiology and biochemistry

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Section 1 Diagnosis, classification, epidemiology and biochemistry

The syndrome of diabetes mellitus

Classification of diabetes mellitus

Epidemiology

Metabolic syndrome

Haemochromatosis (’bronze diabetes’)

Polycystic ovary syndrome (PCOS)

Biochemistry of diabetes

Appendix 1.1: Prevalence estimates of diabetes, 2011–2030

The syndrome of diabetes mellitus

Diabetes mellitus is defined as a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, protein and fat metabolism resulting from defects in insulin secretion, insulin action, or both. The clinical diagnosis of diabetes is often indicated by the presence of symptoms such as polyuria, polydipsia and unexplained weight loss, and is confirmed by documented hyperglycaemia.

The clinical presentation ranges from asymptomatic type 2 diabetes to the dramatic life-threatening conditions of diabetic ketoacidosis (DKA) or hyperosmolar non-ketotic coma (HONK)/hyperosmolar hyperglycaemic state (HHS). The principal determinants of the presentation are the degrees of insulin deficiency and insulin resistance, although additional factors may also be important. In addition, pathological hyperglycaemia sustained over several years may produce functional and structural changes within certain tissues. Patients may present with macrovascular complications that include ischaemic heart disease, stroke and peripheral vascular disease, whereas the specific microvascular complications of diabetes include retinopathy, nephropathy, neuropathy.

Diagnostic criteria for diabetes mellitus

Assigning a type of diabetes to an individual often depends on the circumstances present at the time of diagnosis, and many diabetic individuals do not easily fit into a single specific type. An example is a person who has acquired diabetes because of large doses of exogenous steroids and who becomes normoglycaemic once the glucocorticoids are discontinued. In addition, some patients may present with major metabolic decompensation yet can subsequently be treated successfully with oral agents. Thus, for the clinician and patient, it is less important to label the particular type of diabetes than it is to understand the pathogenesis of the hyperglycaemia and to treat it effectively.

The American Diabetes Association (ADA, 2011) gives the following criteria for the diagnosis of diabetes:

• A1C ≥ 6.5%. The test should be performed in a laboratory using a method that is certified by the National Glycohemoglobin Standardization Program (NGSP) and standardized to the Diabetes Control and Complications Trial (DCCT) assay, or

• fasting plasma glucose (FPG) ≥ 126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 h, or

• 2-h plasma glucose ≥ 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test (OGTT). The test should be performed as described by the World Health Organization (WHO), using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water

• in a patient with classic symptoms of hyperglycaemia or hyperglycaemic crisis, a random plasma glucose ≥ 200 mg/dL (11.1 mmol/L)

• in the absence of unequivocal hyperglycaemia, the result should be confirmed by repeat testing.

The symptoms of thirst, polyuria, polyphagia and weight loss, coupled with a raised plasma glucose level, are diagnostic. In the absence of symptoms two abnormal results (i.e. two raised fasting levels) or an abnormal OGTT result is diagnostic. However, the OGTT is influenced by many factors other than diabetes, including age, diet, state of health, gastrointestinal disorders, medications and emotional stress.

Tip box

Chronic hyperglycaemia is the sine qua non of diabetes mellitus.

Categories of increased risk for diabetes (pre-diabetes): impaired fasting glucose (IFG)/impaired glucose tolerance (IGT)

The ADA criteria introduced the category of impaired fasting glucose, defined as fasting venous plasma level of 5.6–6.9 mmol/L. The diagnosis of impaired glucose tolerance can be made only using a 75-g oral glucose tolerance test; a 2-h glucose measurement points to the diagnosis of impaired glucose tolerance when the plasma glucose is found to be greater than 7.7 mmol/L but less than 11.1 mmol/L. Recently another category, impaired glycated haemoglobin, HbA1c (A1C 5.7–6.4%), has been added.

Categories of increased risk for diabetes (pre-diabetes) (ADA, 2011)

FPG 100–125 mg/dL (5.6–6.9 mmol/L): IFG

or

2 h plasma glucose in the 75-g OGTT 140–199 mg/dl (7.8–11.0 mmol/l): IGT

or

A1C 5.7–6.4%

Tip box

Impaired fasting glycaemia and glucose tolerance are usually asymptomatic.

The diagnosis of impaired glucose tolerance relies on glucose tolerance testing (see below) and denotes an intermediate stage between normality and diabetes. Patients with impaired glucose tolerance, although not at direct risk of developing chronic microvascular disease, may be detected following the development of macrovascular complications:

• ischaemic heart disease

• cerebrovascular disease

• peripheral vascular disease.

The presence of one of these conditions should therefore alert the clinician to the possibility of undiagnosed impaired glucose tolerance or type 2 diabetes, even in the absence of osmotic symptoms.

Oral glucose tolerance test

The ADA (1997) proposed measurement of fasting glucose as the principal means of diagnosing type diabetes. The WHO (1998) placed emphasis on the oral glucose tolerance test as the ’gold standard’, with both fasting and 120-min values being taken into consideration. Only when an OGTT cannot be performed should the diagnosis rely on fasting levels.

The OGTT is the most robust means of establishing the diagnosis of diabetes. Glucose tolerance tests should be carried out under controlled conditions after an overnight fast.

Tip box

To avoid false-positive results, patients should receive an unrestricted diet containing adequate carbohydrate (> 150 g daily) for 3 days prior to an oral glucose tolerance test.

The patient is prepared as detailed in Table 1.1:

• Anhydrous glucose is dissolved in 300 mL water; flavouring with sugar-free lemon and chilling increases palatability and may reduce nausea. The patient should sit quietly throughout the test.

• Blood glucose is sampled before (time zero) and 120 min after ingestion of the drink, which should be completed within 5 min.

• Urinalysis may also be performed every 30 min, although this is really of interest only if a significant alteration in renal threshold for glucose is suspected.

Table 1.1 Preparation for a fasting blood test

• The subject should refrain from consuming any food or drink from midnight before the morning of the test

• Water alone is permitted for thirst

• Regular medication can generally be deferred until the sample has been taken

• The appropriate sample is taken between 0800 and 0900 hours the following morning

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

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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

Intercurrent illness

Patients under the physical stress associated with surgical trauma, acute myocardial infarction, acute pulmonary oedema or stroke may have transient increases of plasma glucose that often settle rapidly without specific antidiabetic therapy. However, such clinical situations are also liable to unmask asymptomatic pre-existing diabetes or to precipitate diabetes in predisposed individuals. Such increases, which may have short- and longer-term prognostic importance, should not be dismissed; as a minimum, appropriate follow-up and retesting is indicated following resolution of the acute illness. If there is doubt about the significance of hyperglycaemia, the blood glucose level should be rechecked 30–60 min later and the urine tested for ketones.

If hyperglycaemia is sustained, treatment with insulin may be indicated. More marked degrees of hyperglycaemia, particularly with ketonuria, demand vigorous treatment in an acutely ill patient.

Non-diabetic hyperglycaemia

As detailed above, impaired fasting glycaemia (IFG) is defined as a fasting glucose > 5.6 and < 7.0 mmol/L, whereas impaired glucose tolerance (IGT) is defined as fasting glucose < 7 mmol/L and 2-h glucose > 7.8 and < 11.1 mmol/L. IGT and IFG are both associated with an increased risk of future diabetes. However, IFG and IGT appear to have different underlying aetiologies. IFG reflects raised hepatic glucose output and a defect in early insulin secretion, whereas IGT predominantly reflects peripheral insulin resistance. IGT is also associated with an increased risk of cardiovascular disease (CVD) independently of other risk factors. The magnitude of this increased risk varies between studies, but for cardiovascular disease mortality the odds ratio was 1.34 (95% CI 1.14–1.57) in the DECODE (2003) meta-analysis. IFG appears to have only a slightly increased risk of CVD independently of other factors.

The term ‘pre-diabetes’, which is sometimes used to refer to IGT and/or IFG, is no longer the preferred term because not all patients go on to develop diabetes. A significant proportion of individuals who have impaired glucose tolerance diagnosed by an OGTT revert to normal glucose tolerance on retesting. Non-diabetic hyperglycaemia (NDH) is increasingly being used as a wider term that encompasses hyperglycaemia where the HbA1c level is raised but is below the diabetic range (Table 1.3).

Table 1.3 Diagnostic criteria for diabetes mellitus and non-diabetic hyperglycaemia

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Tip box

Testing for diabetes should be undertaken by clinical laboratories not at point of care. Bedside instruments such as glucometers should not be used to diagnose diabetes.

Glycated haemoglobin (HbA1c)

The ADA Joint Expert Committee has recommended HbA1c as a diagnostic tool with a cut-off ≥ 6.5% to diagnose diabetes. HbA1c is well established as a marker of glycaemic control in people with established diabetes as it reflects average plasma glucose over the previous 2–3 months. In addition, HbA1c has a number of advantages over fasting blood glucose or OGTT. HbA1c can be measured at any time of day and does not require special preparation such as fasting.

However, HbA1c testing is not widely available in many countries throughout the world and there are aspects of its measurement that are problematic. These include anaemia, abnormalities of haemoglobin, pregnancy and uraemia. Some of these problems may be a bigger problem in under-resourced countries owing to the high prevalence of anaemia and haemoglobinopathies.

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
7. Others

D. Endocrinopathies

1. Acromegaly
2. Cushing syndrome
3. Glucagonoma
4. Phaeochromocytoma
5. Hyperthyroidism
6. Somatostatinoma
7. Aldosteronoma

E. Drug or chemical induced

1. Vacor
2. Pentamidine
3. Nicotinic acid
4. Glucocorticoids
5. Thyroid hormone
6. Diazoxide
7. β-adrenergic agonists
8. Thiazides
9. Dilantin
10. Interferon-γ
11. Clozapine
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

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