Case Study

A 19 year old woman, of normal weight, with positive family history of DM in her father and grandfather (with onset of the disease at a young age in both)

manifests, at a medical check up, mild hyperglycaemia (blood sugar: 155 mg/dl [8.6 mmol/L]). This is confirmed in repeated measurements. No ketoacidosis is ever present. What type of DM does this patient have?

The positive family history of DM, with a young age at onset in two generations, implies the presence of some hereditary type of DM. The age of disease onset in this patient, the mildness of hyperglycaemia, with no ketoacidosis, are also in favour of the view that this is not a classic Type 1 DM case. It is very likely that this is one of the autosomally inherited syndromes of DM (type MODY [Maturity Onset Diabetes of the Young]), which account for around 1-5 percent of cases of Type 2 DM. Up to date, six different types of MODY have been described, which are due to mutations of specific genes (see Chapter 1, Table 1.2). The clinical characteristics that separate MODY patients from those with classic Type 2 DM, are the positive family history of DM in two, or rather, three generations back (with disease onset at a young age, usually less than 25 years), the young age at disease onset of the affected person and lack of obesity. Diabetes mellitus is caused by a b-cell dysfunction, due to a mutation of a gene that alters b-cell function (insulin levels are frequently normal, but lower for the level of the patient's hyperglycaemia). The most common cause of MODY is a mutation in the transcription factor hepatocyte nuclear factor-la (HNF-la, MODY 3), which accounts for around 69 percent of MODY cases. The second most frequent cause is a mutation in the glucokinase gene (MODY 2, frequency 14 percent). The rest of the mutations of the transcription factors (see Chapter 1, Table 1.2) are rarer (up to 3 percent of MODY cases). Treatment of patients with these syndromes is usually with dietary advice or oral antidiabetic medications (due to the usually mild hyperglycaemia), and only very rarely is insulin needed.

The practical approach to the present patient would be either to send a specimen for DNA analysis in a specialized laboratory for possible genetic diagnosis of one of these syndromes or better - which will be necessary anyhow - to place the patient under close monitoring, with self measurements of blood glucose at home and frequent office visits. This is necessary in order to monitor the course of the disease and decide the need for intervention or not (with medicines, insulin or diet alone), given the fact that the various MODY syndromes have a variable severity and course.

58 Diabetes in Clinical Practice Further reading

Creutzfeldt, W. (2001) The entero-insular axis in type 2 diabetes - incretins as therapeutic agents. Exp Clin Endocrinol Diabetes, 109(Suppl 2), S288-S303.

Fajans, S.S., Bell, G.I., Polonsky, K.S. (2001) Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med, 345, 971-80.

Yki-Jarvinen, H. (2003) Insulin resistance in type 2 diabetes, in Textbook of Diabetes, 3rd edn (eds J. Pickup and G. Williams) Blackwell Science Ltd, Oxford, 22, pp. 1-19.

Gerich, J.E. and Smith. T.S. (2003) B-cell defects and pancreatic abnormalities in type 2 diabetes, in Textbook of Diabetes, 3rd edn, (eds J. Pickup and G. Williams) Blackwell Science Ltd, Oxford, 23, pp. 1-11.

Matthews, D.R., Cull, C.A., Stratton, I.M., Holman, R.R., Turner, R.C. (1998) UK Prospective Diabetes Study (UKPDS) Group. UKPDS 26: sulphonylurea failure in non-insulin-dependent diabetic patients over six years. Diabet Med, 15, 297-303.

Vionnet, N., Stoffel, M., Takeda, H. et al. (1992) Nonsense mutation in the glucokinase gene causes early onset non-insulin-dependent diabetes mellitus. Nature, 356, 721-22.

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