Trends in Endocrinology & Metabolism
ReviewMolecular Genetics of Maturity-onset Diabetes of the Young
Section snippets
Glucokinase Mutations and MODY2
Glucokinase (GCK) phosphorylates glucose to glucose-6-phosphate in pancreatic β cells and hepatocytes, and plays a major role in the regulation and integration of glucose metabolism16. More than 80 different GCK mutations have been found to date6, 17. Expression studies have shown that the enzymatic activity of the mutant proteins is impaired, with either a decrease of Vmax and/or a decrease of the affinity of the enzyme for glucose18. Impairment in the enzymatic activity of mutant GCK results
Mutations in Transcription Factor Genes
Positional cloning of MODY genes has led to the identification of mutations in four transcription factors: HNF-1α, HNF-1β, HNF-4α and IPF-1 (3, 8, 11, 12). The HNFs are nuclear proteins, initially found to be expressed in the liver. They were well known to modulate the expression of many hepatic genes, such as albumin and Apo C3 (Ref. 24), but their role in pancreatic islets and in the kidney was unknown until recently (Fig. 1). For a long time they have not been considered as obvious
Conclusions
The identification of GCK as a diabetes susceptibility gene has provided a major impulse for the reassessment of its physiological role as a ‘glucose sensor’ and the understanding of the patho-physiological importance of this key enzyme of glucose homeostasis. More recently, the recognition of the role of transcription factors in MODY has opened new perspectives in the understanding and treatment of Type 2 diabetes and of the mechanisms of glucose homeostasis. Only a small proportion of
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