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Genetic susceptibility

100M is not genetically predetermined, but an increased susceptibility to the disease may be inherited.

Identical twins

The identical twin of a patient with mOM has a 30-35% chance of developing the disease. This implies that nongenetic factors must also be involved.


The child of an insulin-dependent diabetic patient has anincreased chance of developing mOM. This risk, curiously, is greater with a diabetic father (between 1 in 20 and 1 in 40) than with a diabetic mother (1 in 40-80).
If one child in a family has IDDM, each sibling has a 1 in 20 risk of developing diabetes. If a sibling is HLAidentical, the risk rises to 1 in 6.
H LA SYSTEM. More than 90% of IDDM patients carry HLA-DR3 and/or DR4 compared with 40% of the general population. The relative risk conferred by DR3 is about 7, DR4 about 9, but the highest risk of 14 is with DR3/DR4 heterozygote. Since the risk is additive a model based on two susceptibility genes (one associated with DR3 and one with DR4) has been proposed. Stronger associations have been reported with the DQ region. Most people have two alleles with aspartic acid at position 57 on the HLADQ {3chain which confer resistance to the development of diabetes. Substitution of aspartate at position 57 by another amino acid considerably increases susceptibility to IDDM as do alleles coding for arginine at position 52 on the a chain. These DQ polymorphisms determine the degree of autoimmune response against the pancreatic islet cells but other genes, probably interacting with  environmental factors, are necessary for the development of diabetes.
In contrast, individuals with HLA-DR2 have a considerably reduced risk (0.12 times normal) of developing diabetes. The reasons for this protective effect are unclear.
THE INSULIN GENE. Associations between IDDM and other chromosomes (apart from chromosome 6) have been described. A polymorphous DNA region close to the  insulin gene on chromosome 11 has been studied, and short, intermediate and long insertions (see p. 109) have been reported. Homozygosity of the short (class 1) allele is found in some 80% of patients with IDDM as against 40% of controls.

Autoimmunity and insulin-dependent diabetes mellitus.
Several pieces of evidence suggest that autoimmune processes are involved in the pathogenesis of IDDM. ASSOCIATION WITH OTHER AUTOIMMUNE DISEASE.  Autoimmune thyroid disease, Addison’s disease and pernicious anaemia are more common in patients and their relatives.
IMMUNOGENETIC ASSOCIATIONS. The association between HLA-DR3, DR4 and diabetes, and the protective  effect of DR2 might represent idiosyncracies in theimmune process that result in increased (or reduced)  susceptibility.
THE INSULITIS PROCESS. Autopsies of patients who died soon after diagnosis are characterized by infiltration  of the pancreatic islets by mononuclear cells. A similar pattern occurs in other autoimmune diseases, e.g. thyroiditis.
IMMUNE ABNORMALITIES AT DIAGNOSIS. About 70% of newly presenting patients have islet-cell antibodies.  These react with human islets and can be detected by immunofluorescence. They usually become undetectable  within a few years of diagnosis. In such patients increased numbers of activated T lymphocytes may also be present in the circulation at diagnosis.
Of newly diagnosed patients with IDDM, 80% have antibodies to the enzyme glutamic acid decarboxylase (GAD). Pancreatic {3 cells have high levels of this enzyme and the GAD autoantigen may be critical for the initiation of {3cell destruction.
IMMUNOSUPPRESSION with agents such as cyclosporin at or soon after diagnosis prolongs {3-cell survival.

Environmental factors

A viral aetiology has been suspected for many years. This is based on the seasonal incidence of the condition, anecdotal associations, and analysis of viral antibody titres at diagnosis. IgM antibodies to Coxsackie B4 have been  reported in 20-30% of new cases. However, in view of the long prodromal period (see below), it seems likely that viruses precipitate rather than initiate the onset of diabetes.

The diabetes prodrome

Prospective study of first-degree relatives of children with diabetes has revealed that islet-cell antibodies may appear in the circulation months or even years before diagnosis. Insulin antibodies have also been reported in this period, and abnormalities of insulin secretion in response to intravenous glucose may develop. The sequence of events leading to diagnosis may be as shown. Better understanding of this sequence may in time permit strategies of prevention to be tested.

Genetic predisposition

Initiating event (? environmental)
Immune activation

Progressive fI cell 1055
Abnormalities of insulin secretion
7 Second trigger (7 viral)
Clinical onset
‘Remission’ (partial recovery of fI cell function)
Loss of insulin secretion

Non-insulin-dependent diabetes mellitus (type II diabetes)


Unlike IDDM this is relatively common in all populations enjoying an affluent life-style. Large differences in prevalence have been reported. The disease may be present in a subclinical form for years before diagnosis, and the incidence  increases markedly with age and degree of obesity. The onset may be accelerated by the stress of pregnancy, drug treatment or intercurrent illness. Estimates of prevalence using the WHO criteria would suggest an overall prevalence of around 2% in the UK. NIDDM is twice as prevalent in people of Afro-Caribbean ancestry and three to five times more prevalent in people from South Asia than in white Europeans.
The rates have been reported in various populations. Epidemiological surveys suggest that indolent well-fed populations are two to twenty times as likely to develop NIDDM as lean populations of the same race.



Identical twins of a patient with NIDDM have an almost 100% chance of developing diabetes and about 25% of other patients have a first-degree relative with NIDDM. Certain families exist in which diabetes appears to travel  as an autosomal dominant characteristic, but NIDDM is almost certainly a polygenic disorder. Some families show abnormalities of the gene which codes for the enzymeglucokinase on chromosome 7. The defect differs from one fam ily to another and more than 20 mutations have been described so far. Studies in other family groups have  shown linkage between the inheritance of diabetes and markers on chromosomes 3 and 20. The next decade is likely to see the identification of many of the gene abnormalities which predispose to NIDDM.


There is no evidence of immune involvement in its pathogenesis.

Prevalence of non-insulin-dependent diabetes mellitus in various populations (WHO criteria).

Prevalence of non-insulin-dependent diabetes
mellitus in various populations (WHO criteria).

Insulin secretion and action

Patients with NIDDM, unlike those with IDDM, retain about 50% of their f:l-cell mass at autopsy. Abnormalities of insulin secretion develop early in the course of the disease. Normal subjects have a biphasic  insulin response to intravenous glucose. In NIDDM the first-phase insulin response to intravenous glucose is lost, and insulin secretion in response to oral glucose is delayed and exaggerated. The majority of patients manifest reduced insulin secretion relative to the prevailing glucose concentration, and progressive f:l-cell loss occurs in many patients, although not to the extent seen in IDDM. It is not known whether this is due to ‘exhaustion’ of surviving f:lcells or to some independent process of damage. Islet amyloid deposits are commonly seen in NIDDM, destroying the cells and interfering with glucose and hormone transport. The amyloid deposits are derived  from islet amyloid polypeptide (IAPP), which may oppose the action of insulin, possibly explaining the insulin resistance that is also present. Obesity is present in 80% of patients with NIDDM, but insulin resistance may also be marked in lean individuals.

Impaired glucose tolerance

If an oral glucose tolerance test  is administered at random to a large population, 1-2% will be found to have unsuspected diabetes. A much larger group-S% or more (depending on the age, race and nutritional state of the population) – fall into an intermediate category now referred to as impaired glucose tolerance (IGT). The criteria for this category are given below. Follow-up shows that some (2-4% yearly) go on to develop diabetes, but that the abnormality does not progress in the majority. Obesity and lack of regular  physical exercise make progression to frank diabetes more likely. Classification is complicated by the poor reproducibility of the oral glucose tolerance test and the group is certainly heterogeneous. Some are obese, some have liver disease, and others are on medication that impairs glucose tolerance; individuals in this category have a risk  of cardiovascular disease that is twice that of people with normal glucose tolerance, but do not develop the specific microvascular complications of diabetes.

Tropical diabetes

A distinct variety of diabetes has been described. This is found only in developing countries on or near the equator. The following features have been described:
• Onset is before the age of 30 years.
• There is a history of severe malnutrition.
• There is insulin dependence, sometimes with severe but fluctuating insulin resistance.
• Ketoacidosis does not develop when insulin is withdrawn.
There are two main variants:
FIBROCALCULOUS PANCREATIC DIABETES. This is associated with exocrine pancreatic deficiency, pancreatic fibrosis (often leading to calcification) and the presence of stones in  the pancreatic duct. There may be a history of recurrent abdominal pain, and in 75% of cases there is evidence of pancreatic calcification on plain abdominal X-ray. Most populations in which this condition arises are subject to malnutrition and have  a diet based on cassava. Cyanates are present in the cassava root and may be a factor in the pancreatic damage.
PROTEIN-DEFICIENT PANCREATIC DIABETES. This form appears to be a direct consequence of malnutrition. The main differences from the fibrocalculous variant are that exocrine pancreatic function is unimpaired  and there is no evidence of pancreatic fibrosis or calcification. Abdominal pain is not a feature.
In both forms of tropical diabetes, insulin secretion is preserved, although impaired; this is the likely explanation for the observed resistance to ketosis. After an overnight fast, 75 g of glucose is taken in 250-350 ml of water. Blood samples are taken in the fasting state and 2 hours after the glucose has been given.
A specific enzymatic glucose assaymust be used. Note:
The concentration of glucose measured in plasma is 10% greater than that of whole blood.


This is present when the fasting blood glucose is over 6.7 mmol litre-I and/or when the 2-hour value is over 10 mmol litre’ Corresponding values for plasma glucose are 7.8 mmol litre-I and 11.1 mmol litre:

Impaired glucose tolerance

This is present when the fasting blood glucose is below 6.7 mmol litre ” and when the 2-hour value is between 6.7 and 10 mmol litre I. Corresponding values for plasma glucose are 7.8 and 11.1 mmol litre-I. Impaired glucose tolerance can only be diagnosed using the oral glucose tolerance test. Intermediate sampling times (e.g. 30 min and 60 min) are not needed for the diagnosis of diabetes by WHO criteria. However, simultaneous blood and urine glucose measurements can be used to define a low renal threshold for glucose. Diabetes can usually be diagnosed on the basis of fasting or random blood glucose measurements (see text). The glucose tolerance test should be reserved for borderline casesonly.


Acute presentation

Young people often present with a brief 2-4 week history and report the classic triad of symptoms:
POLYURIA, due to the osmotic diuresis that results when blood glucose levels exceed the renal threshold THIRST, due to the resulting loss of fluid and electrolytes WEIGHT LOSS, due to fluid depletion and the accelerated breakdown of fat and muscle secondary to insulin deficiency. Ketoacidosis may be the presenting feature if these early symptoms are not recognized and treated.

Subacute presentation

The clinical onset may be over several months, particularly in older patients. Thirst, polyuria and weight loss are usual features but medical attention is sought for such symptoms as lack of energy, visual blurring due to glucose-  induced changes in refraction, or pruritus vulvae or balanitis due to Candida infection .

Complications may be the presenting feature. These include:
• Staphylococcal skin infections
• Retinopathy noted during a visit to the optician
• A polyneuropathy causing tingling and numbness in the feet
• Impotence
• Arterial disease, resulting in myocardial infarction or peripheral gangrene

Asymptomatic diabetes

Glycosuria or a raised blood glucose may be detected on routine examination (e.g. for insurance purposes) in individuals who have no symptoms of ill health.

Physical examination

This is often unrewarding in younger patients, but evidence of weight loss and dehydration may be present, and the breath may smell of ketones. Older patients may present with established complications, and the presence of the characteristic retinopathy is diagnostic of diabetes.


The diagnosis is usually simple. Blood glucose is so closely controlled by the body that even small deviations become important.
1 In symptomatic patients, a single elevated blood glucose, measured by a reliable method, indicates diabetes.
2 In asymptomatic or mildly symptomatic patients, the diagnosis is made on:
(a) One, preferably two, fasting venous blood glucose levels above 6.7 mmol litre-I (120 mg dI-I); the equivalent venous plasma level is 7.8 mmol litre”” (140 mg dI-I), or (b) One, preferably two, random values above 10 mmol litre-I (180 mg dr ‘) in venous whole blood or ILl mmol litre-I (200 mg dI-l) in venous plasma.
3 A glucose tolerance test (GTT) is unnecessary when thecriteria above are satisfied, and should be reserved for  true borderline cases.
4 Glycosuria is measured using sensitive glucose-specific dipstick methods. Glycosuria is not diagnostic of diabetes  but indicates the need for further investigation. About 1% of the population have renal glycosuria. This is an inherited low renal threshold for glucose, transmitted either as a Mendelian dominant or recessive trait.

Other investigations

No further tests are needed to diagnose diabetes. Other routine investigations include screening the urine for proteinuria, a full blood count, urea and electrolytes, liver biochemistry and a fasting blood sample for cholesterol and triglycerides. The latter test is useful to exclude an associated hyperlipidaemia but should only be performed after blood glucose has been brought under control. It is important to remember that diabetes may be secondary to other conditions, may be precipitated by underlying illness and be associated with autoimmune disease or hyperlipidaemia. Hypertension is present in one-third of European patients with NIDDM and 50% of Afro-Caribbeans.

Posted by: brianna

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