FIGURE 1 Scheme of the hierarchical transcription factor network of the pancreatic p-cell. The diagram shows the regulation of gene expression. The arrows indicate the interaction. Genes responsible for MODY are indicated. Source: From Ref. 15.

heterozygous deficiency of HNF-1a show impaired insulin secretion and develop diabetes. HNF-4a models show impaired hepatic differentiation and reduced HNF-1a expression.

In most ethnic groups only MODY3 is next to MODY2 with the highest prevalence, whereas all other forms are rare. Up to now more than 150 HNF-1a mutations are known (21). Like patients with MODY2, patients with MODY3 first develop a mild form of diabetes mellitus type 2. It has been shown that despite a slight elevation of fasting blood glucose levels comparable with the one of MODY2 patients, in MODY3 patients the postprandial glucose levels are markedly increased 2 h after glucose load. Hyperglycemia is very progressive in MODY3 patients, and treatment with anti-diabetic agents or insulin is necessary. Patients with MODY3 show a reduced glucose re-absorption in combination with diminished nephritic barrier for glucose. Because the clinical outcome is much more aggressive, tight medical control is necessary. It has been shown that there is a direct correlation between the manifestation of diabetic complications and the appropriate treatment of the patients. MODY3 patients can develop all possible diabetes complications and the patients directly benefit from being treated as soon as possible with adequate medication to prevent or delay complications

Mutations in HNF-4a resembling MODY1 might affect the regulation of the insulin gene by HNF-4a via HNF-1a, so that the pathogenetic mechanisms for MODY1 and MODY3 are quite similar. Moreover, HNF-4a also regulates metabolic key enzymes like the glucose transporter GLUT2, glyceroaldehyd-3-phosphate dehydrogenase or pyruvate kinase. So in families with MODY1 a progressive loss of insulin secretion can be observed (24-26), whereas a compensation of the altered physiological situation does not seem to occur in MODY1 patients (27,28). Next to a defect in insulin secretion, a reduced p-cell function exists in MODY1 patients (24-26). There is also evidence for further pancreatic deficiencies in MODY1 patients as arginine-induced glucagon secretion and the pancreatic polypeptide response to hyperglycemia are deficient.

Mutations in HNF-1p are responsible for the very rare MODY5. HNF-1p can form heterodimers with HNF-1a and directly regulates HNF-4a. Heterozygote HNF-1p mutation can be associated with a broad clinical spectrum, but MODY5 has similar features to MODY1 and is characterized by diabetes mellitus, renal cysts, proteinuria, and renal failure. As a consequence of renal cysts, hypoplastic glomerulocystic kidney disease can develop in the affected patients. Female patients can exhibit malformation of the inner genitals (29-32).

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