Other Types Of Diabetes

Maturity-onset diabetes of the young (MODY) is inherited as an autosomal dominant and, to date, abnormalities at six genetic loci on different chromosomes have been identified. The most common form of MODY is associated with mutations on chromosome 12 in hepatic nuclear factor (HNF)-la and hence this is referred to as transcription-factor MODY. Other mutations affect such transcription factors as HNF-ip, HNF-4a, insulin promoter factor-1 and NEUROD 1. Transcription factor mutations alter insulin secretion in the mature p-cell as well as altering p-cell development, proliferation and cell death.

Glucose tolerance is normal at birth, but progressive p-cell dysfunction ensues until the emergence of frank diabetes. Patients with transcription-factor mutations tend to be lean and insulin-sensitive rather than obese and insulin-resistant. Microvascular complications are frequent.

The first gene implicated in MODY was the glu-cokinase gene. Mutations on the glucokinase gene on chromosome 7p result in a defective glucokinase molecule. As glucokinase converts glucose to glucoses-phosphate, the metabolism of which stimulates insulin secretion by the p-cell, glucokinase serves as a 'glucose sensor'. With defects in the glucokinase gene, increased plasma levels of glucose are necessary to elicit normal levels of insulin secretion. Over 100 glu-cokinase gene mutations have now been found in families from several different countries. Fasting hyper-glycemia is present from birth and worsens very slowly with age. Subjects are usually detected by screening, e.g. in pregnancy or during coincidental illness or by family studies. The mild hyperglycemia of this type of MODY rarely needs any treatment other than diet, and microvascular complications are rare.

Other specific genetic defects leading to diabetes include point mutations in mitochondrial DNA, genetic abnormalities leading to the inability to convert proinsulin to insulin and to the production of mutant insulin molecules and mutations of the insulin receptor.

As previously described, diabetes may result from overt diseases of the exocrine pancreas, secondary to specific endocrinopathies and due to drugs or chemicals. Certain viruses have been associated with p-cell destruction (Coxsackievirus B, cytomegalovirus, adenovirus, mumps, congenital rubella), although in most cases the precise nature of the association remains unclear. Many other genetic syndromes are accompanied by an increased incidence of diabetes (Down's syndrome, Klinefelter's syndrome, Turner's syndrome, Wolfram's syndrome).

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