Recent studies have shown that mutations in the transcription factor hepatocyte nuclear factor (HNF)-1 alpha are the cause of one form of maturity-onset diabetes of the young (MODY3). These studies have identified mutations in the mRNA and protein coding regions of this gene that result in the synthesis of an abnormal mRNA or protein. Here, we report an Italian family in which an A-->C substitution at nucleotide-58 of the promoter region of the HNF-1 alpha gene cosegregates with MODY. This mutation is located in a highly conserved region of the promoter and disrupts the binding site for the transcription factor HNF-4 alpha, mutations in the gene encoding HNF-4 alpha being another cause of MODY (MODY1). This result demonstrates that decreased levels of HNF-1 alpha per se can cause MODY. Moreover, it indicates that both the promoter and coding regions of the HNF-1 alpha gene should be screened for mutations in subjects thought to have MODY because of mutations in this gene.

Nicotinamide has been recently introduced, in addition to intensive insulin therapy for patients with recent-onset insulin-dependent diabetes mellitus (IDDM) to protect beta cells from end-stage destruction. However, available data are conflicting. A double blind trial in 56 newly-diagnosed IDDM patients receiving nicotinamide for 12 months at a dose of 25 mg/kg body weight or placebo was designed in order to determine whether this treatment could improve the integrated parameters of metabolic control (insulin dose, glycated haemoglobin and C-peptide secretion) in the year after diagnosis. In addition to nicotinamide or placebo, patients received three to four insulin injections daily to optimize blood glucose levels. Patients treated with nicotinamide or placebo received similar doses of insulin during follow-up and 1 year after diagnosis with comparable glycated haemoglobin levels 6.7 +/- 1.8% nicotinamide vs 7.1 +/- 0.6% placebo). Basal and glucagon stimulated C-peptide secretion detectable at diagnosis were similarly preserved in the course of 12 months follow-up both in nicotinamide and placebo treated patients. No adverse effects were observed in patients receiving nicotinamide. When age at diagnosis was taken into account, nicotinamide treated older patients ( > 15 years of age) showed significantly higher stimulated C-peptide secretion than placebo treated patients (p < 0.02). These results suggest that nicotinamide can preserve and improve stimulated beta-cell function only in patients diagnosed after puberty.(ABSTRACT TRUNCATED AT 250 WORDS)

Maturity-onset diabetes of the young (MODY), a monogenic subset of Type II (non-insulin-dependent) diabetes mellitus, is caused by mutations in at least five different genes: HNF-4a-MODY1 [1], GCK-MODY2 [2], HNF-1a-MODY3 [3], IPF-1-MODY4 [4], and HNF-1b-MODY5 [5]. MODYis an autosomal dominant disorder with an onset typically under 25 years of age, and usually accounts for 2 % to 5 % of all patients with Type II diabetes but a true estimate is challenging because patients with MODY are often wrongly diagnosed as having Type I or Type II diabetes. Late-onset Type II diabetes is a polygenic heterogeneous disorder whose pathogenesis is not clear. We regard Type II diabetes as a genetically continuous spectrum of early-onset to late-onset diabetes, partially due to mutations in the MODY genes. The prevalence of HNF-1a, GCK and HNF-4a mutations in MODY patients varies among different populations. Up to now four missense mutations in the MODY2 [6,7] and none in the MODY3 gene have been identified in Italian MODY patients. The aim of our study Diabetologia (2001) AbstractAims/hypothesis. Maturity-onset-diabetes of the young (MODY) is caused by mutations in at least five different genes. Our aim was to determine the prevalence of the most common MODY genes in Italian families with early-onset Type II (non-insulin-dependent) diabetes mellitus. Methods. We screened 28 Italian early-onset Type II diabetic families (diagnosis < 35 years) for mutations in the hepatic nuclear factor-4a, (MODY1), glucokinase (MODY2) and hepatic nuclear factor-1a (MODY3). Both strands of exons, flanking introns and minimal promoter regions of the above-mentioned genes were amplified using polymerase chain reaction and were sequenced directly. Results. We identified four different mutations, three of which are not described, (W113X, G42P43fsCC ® A, H514R) and four new polymorphisms (G184G, T513T, IVS3-nt47delG, IVS1-nt53C ® G) in the hepatic nuclear factor-1a gene, two new potential mutations (G44S, IVS4nt + 7C ® T) and three new polymorphisms (promoter-nt84C ® G, IVS9 + nt8C ® T, IVS9 + nt49G ® A) in the glucokinase gene, and a new polymorphism (IVS1c-nt11T ® G) in the hepatic nuclear factor-4a gene. Conclusion/interpretation. Mutations in the hepatic nuclear factor-1a and glucokinase are associated with Type II diabetes in 14 % and 7 % of Italian families, respectively. Our findings provide an impetus for screening Italian MODY and early-non Type II diabetic families for mutations in the above mentioned genes to identify relatives at risk who could benefit from primary prevention care. [Diabetologia (2001) 44: 1326±1329]Keywords Type II diabetes mellitus, genetics, hepatocyte nuclear factor-1a, hepatocyte nuclear factor-4a, glucokinase, MODY, Italian, mutation, polymorphism. Corresponding author: C. Gragnoli, Molecular Endocrinology, WEL 320, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA E-mail: cgragnoli@partners.org Abbreviations: HNF, hepatocyte nuclear factor; GCK, glucokinase; IPF-1, insulin promoter factor-1...

A short-term course of DFL therapy at diagnosis in addition to NCT slightly increases glucagon-stimulated but not basal beta-cell function after 1 year.

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