NIDDM - GENETIC-MARKER - GLUCOSE-TRANSPORTER, GLUCOKINASE, AND MITOCHONDRIA GENE

Candidate genes for NIDDM have been screened in Japanese. Mutations in the glucokinase gene were found in apparent late-onset NIDDM patients as well as in MODY patients. Clinical characteristics in the subjects with glucokinase gene mutations are similar to those in Caucasian sub jects; diabetes mellitus is generally mild and some patients actually remain as having impaired glucose tolerance. Of great interest is that all affected subjects show blunted insulin secretion response to the glucose challenge, which is most commonly observed in Japanese NIDDM p atients. Thus, it is possible that impairment in the regulation of glu cokinase gene expression or its enzyme activity is associated with at least some Japanese NIDDM patients, though the prevalence of the mutat ions in the coding region is relatively low. In contrast, a mitochondr ial tRNA(Leu(UUR)) gene mutation at np 3243 appears to be much more co mmon, and diabetes due to this mutation has a progressive nature. Insu lin secretory capacity progressively decreases, eventually reaching an insulin-dependent state in most patients. A surprising results that t his gene mutation is often observed in ICA-positive IDDM patients who were initially non-insulin-dependent, so called slowly progressive IDD M patients. These results suggest that the mitochondrial gene mutation may cause beta cell loss in addition to defects in glucose-induced si gnaling in pancreatic beta cells, which explains that the mitochondria l gene mutation manifests a wide range of diabetic phenotypes, from NI DDM to IDDM.