Other types of diabetes mellitus

In most cases of diabetes, referred to as type 1 and type 2, no specific cause can be identified. This is referred to as primary or idiopathic diabetes. A small minority of cases, estimated at about 2%, arise as the consequence of some other well-defined disease or predisposing factor such as pancreatitis or steroid excess. This is called 'secondary diabetes'. Secondary diabetes can be sub-divided into single-gene disorders affecting insulin secretion or resistance, damage to the exocrine pancreas, other endocrine disease, drug-induced diabetes, uncommon manifestations of autoimmune diabetes, and genetic syndromes associated with diabetes. Gestational diabetes (diabetes arising for the first time in pregnancy) has a diagnostic category all to itself, but is included in this section for convenience. Secondary diabetes is often (but not always) associated with a relatively mild metabolic disturbance, but may nonetheless result in typical long-term complications such as retinopathy. Although it is relatively uncommon, the possibility of secondary diabetes should always be considered, since it may be a pointer to other disease, often requires a different approach to therapy, and is sometimes reversible.

Background

The common denominator of all the forms of diabetes discussed here is that something sets them apart from type 1 and type 2 diabetes. Since type 2 diabetes is hard to define, this implies that for most forms of diabetes in this category there is a pointer to a different pathophysiological explanation!

The current WHO classification of diabetes, adopted and regularly updated by the American Diabetes Association, identifies four main categories of diabetes, and secondary diabetes is clssified under 'other specific types' (see figures).

The common categories of secondary diabetes to consider in clinical practice are monogenic diabetes, exocrine pancreatic pathology, other endocrine disease and the unwanted effects of medications.

Monogenic (single gene) diabetes

A number of single gene disorders predisposing to diabetes have been identified in recent decades. In this group a single, usually autosomal and dominantly inherited gene defect leads to diabetes, and this can manifest itself at various ages. The first to be identified was a syndrome of early onset dominantly inherited diabetes inelegantly titled MODY (maturity onset diabetes of the young). So far, eight types of MODY have been identified, of which MODY 2 or GCK-MODY (defect in the glucokinase gene) and MODY 3 (defect in hepatocyte nuclear factor 1-alpha) are the most common.

Other single gene disorders present in the neonatal period, and may cause permanent or transient diabetes; the latter may recur in later life. About 15 gene disorders have been identified. Activating mutations in the genes which encode subunits of the potassium-ATP (KATP) channel on the beta cell membrane are responsible for approximately 40–50% of cases. Mutations in the KCNJ11 and ABCC8 genes produce a channel that cannot close in response to ATP, thus preventing depolarisation of the membrane and insulin release.

A further group of single gene disorders arises from genetic defects of insulin action. These include type A insulin resistance syndrome, lipoatrophic diabetes, leprechaunism and Rabson–Mendenhall syndrome.

Pancreatic disorders

The relationship between the pancreas and diabetes was established when Minkowski performed a pancreatectomy in the dog in 1889. Early clinicians distinguished between 'pancreatic' diabetes, due to obvious pancreatic disease, and the much more common form of diabetes in which the pancreas appeared normal. Only about 1% of human diabetes is considered to be due to overt pancreatic disease in Western societies, but subclinical pancreatic disease may be more important than previously believed.

The pancreas has a considerable reserve of islet beta cells, and investigators need to excise 70–90% from healthy animals before they will develop diabetes. Extensive pancreatic damage is therefore needed to cause human diabetes. Such damage occurs in severe cases of acute pancreatitis, in chronic pancreatitis, however caused, or following surgical excision of the pancreas. Pancreatic carcinoma predisposes to diabetes by secreting circulating factors promoting insulin resistance rather than by pancreatic destruction.

Diabetes may also result from scarring and fibrosis due to excessive iron deposition in haemochromatosis or following multiple blood transfusion.

Pancreatic diabetes results in loss of both insulin and pancreatic glucagon, but some residual function is often present, which means that diabetic ketoacidosis rarely occurs. Lack of glucagon means that patients are extra-sensitive to the action of insulin, and hypoglycaemia may be a problem. Management may be complicated by exocrine pancreatic dysfunction resulting in malabsorption. Other organs are often affected, for example in cystic fibrosis and alcohol abuse, and this may dominate the clinical picture.

Endocrine disorders

Insulin plays a central role in metabolic regulation, but its actions are modified or balanced by those of many other hormones, including glucagon, growth hormone, corticosteroids and adrenaline (epinephrine). Overproduction of these counterregulatory hormones may induce hyperglycaemia and other metabolic disturbances, particularly where insulin secretion is already deficient; conversely, failure of secretion can predispose to hypoglycaemia, especially in those treated with insulin.

Endocrine dysfunction, although uncommon, should be considered in all those with newly-diagnosed diabetes, and in those on treatment for diabetes whose control becomes unstable for unknown reasons. Since endogenous insulin is still produced, the metabolic disturbance is typically mild, and can often be reversed by treating the endocrine disord er.

Drug-induced diabetes

A number of widely used medications may affect glucose metabolism adversely, and by a wide range of possible mechanisms. Administration of other hormones, particularly corticosteroids, may antagonise insulin action, whereas thiazide agents, notably diazoxide, may inhibit insulin secretion. In most cases, standard medications serve more to unmask latent diabetes than to produce it, and their effects are relatively mild and reversible once the agent is taken away.

Uncommon forms of immune-mediated diabetes

This small category contains rare immune manifestations of diabetes, including the insulin autoimmune syndrome, disease due to anti-insulin receptor antibodies, and the 'Stiff Man' or 'Stiff Person' syndrome associated with autoreactivity to GAD.

Genetic syndromes

A number of genetic syndromes are associated with diabetes. These include chromosomal disorders such as Down's, Klinefelter's and Turner's syndromes. A distinctive form is Wolfram's syndrome, a disorder with many variants and which, when fully expressed, is known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness). The more common genetic syndromes associated with diabetes are listed in the Figure.

Gestational diabetes

This term refers to hyperglycaemia of varying severity that first presents (or is first recognised) in pregnancy. The resulting diabetes may or may not require treatment with insulin or with oral agents, and may persist after pregnancy. The term is more generally reserved for diabetes that presents in one or more pregnancies and remits following delivery.

Gestational diabetes is typically asymptomatic at presentation and diagnosis requires performance of an oral glucose tolerance test (OGTT), usually routinely performed at 24–28 weeks of gestation. The diagnosis is more likely in older or more obese women, in some ethnic groups, and in any woman with a history of glucose intolerance or big babies.

The glucose threshold for diagnosis of gestational diabetes, although established by international consensus, remains somewhat controversial. Standard criteria for the diagnosis of diabetes are based upon the ability of the OGTT to predict retinopathy, not fetal outcomes. Furthermore, the lower the glucose threshold chosen for intervention, the lower the anticipated benefit from that intervention.

Gestational diabetes strongly predicts the subsequent development of type 2 diabetes, and the diagnosis thus has implications for management during the current pregnancy, when planning future pregnancies and for the future health of the mother.

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