SWISS JOURNEY THROUGH THE CLINICAL AND GE NETIC FEATURES OF DIABETES IN THE YOUNG SUBJECT

The aim of this study is to understand better the genetic causes of ty pe II diabetes and the phenotypic consequences of the genetic changes. We first investigated the relative prevalence of the different forms of diabetes in young adults and their clinical features. 51 non-obese patients were identified in whom diabetes had been diagnosed before ag e 40; cases of typical insulin-dependent type I diabetes were excluded . A search for mutations of the glucokinase and HNF-1 alpha genes and for mitochondrial DNA was made, anti-islet and anti-GAD antibodies wer e determined and HLA class II genotyping was performed. Patients were subdivided on clinical grounds into a MODY (maturity onset diabetes of the young) group (n=19) and a non-MODY group (n=32). MODY is a form o f diabetes which has an a utosomal dominant inheritance for which 3 ge nes have already been implicated (MODY1, HNF-4 gene; MODY2, glucokinas e gene, and MODY3, HNF-1 alpha gene). In the MODY group we identified 3 patients with MODY2, 1 with MODY3, 1 with the 3243 mitochondrial mut ation and a further patient with autoimmune diabetes. In the non-MODY group we found 5 patients with autoimmune diabetes and 1 with MODY2. N o clinical parameter was helpful in classifying patients in one of the se subclasses of diabetes; however, glucagon stimulated C-peptide was useful in discriminating between MODY2 patients and the others. Young and lean non-insulin-dependent diabetic patients thus constitute a ver y heterogeneous group, though presenting similar clinical features. In the second study we analyzed hepatic glucose metabolism in patients w ith a mutation of the glucokinase gene expressed in both liver and isl et beta cells. We found that endogenous glucose production is inadequa tely inhibited by hyperglycemia, a fact which contributes to the patho genesis of hyperglycemia in these patients.