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...

No abstract

The genes causing type 2 diabetes (T2D), a complex heterogeneous disorder, differ and/or overlap in various populations. Among others there are two loci in linkage to T2D, the chromosomes 20q12-13.1 and 12q15. These two regions harbor two genes, C/EBPbeta and CHOP, which are excellent candidate genes for T2D. In fact, C/EBPbeta protein cooperates with HNF4alpha (MODY1, monogenic form of diabetes) and 1alpha (MODY3, monogenic form of diabetes). C/EBPbeta mediates suppression of insulin gene transcription in hyperglycemia and may contribute to insulin-resistance. It interacts in a complex pathway with the CHOP protein. CHOP may play a role in altered beta-cell glucose metabolism, in beta-cell apoptosis, and in lack of beta-cell replication. Thus, both C/EBPbeta and CHOP genes may independently and interactively contribute to T2D. The chromosomal regions targeting C/EBPbeta and CHOP genes have never been previously explored in T2D. We planned to identify their potential contribution to T2D in Italians. We have genotyped a group of affected siblings/families with both late- and early-onset T2D around the C/EBPbeta and the CHOP genes. We have performed non-parametric linkage analysis in the total T2D group, in the late-onset and the early-onset group, separately. We have identified a suggestive linkage to T2D in the CHOP gene locus in the early-onset T2D group (P = 0.04). We identified the linkage to T2D in the chromosome 12q15 region in the early-onset T2D families and specifically target the CHOP gene. Our next step will be the identification of CHOP gene variants, which may contribute to the linkage to T2D in Italians.

The economic burden of Type 2 Diabetes Mellitus (T2DM) is a challenge for sustainability. Psychological factors, healthy behaviors, and stressful conditions are predictive and prognostic factors for T2DM. Focusing on psychological factors can reduce costs and help ensure the sustainability of diabetes care. The study aimed to support an integrated medical-psychological approach in the care of patients with T2DM. A group of patients undergoing usual healthcare treatment was compared to patients who received a psychotherapeutic intervention in addition to standard treatment. The study’s outcomes were: physical health (blood glucose, glycated hemoglobin, blood lipids, blood pressure); lifestyle (cigarettes, alcoholic drinks, physical activity, body mass index); mental health (anxiety, depression, stress, coping styles, alexithymia, emotion regulation, locus of control); costs (number of referrals to a specialist, standard cost of each visit). We examined the change from baseline to 24-week follow-up. Compared to the Standard Group, the Integrated Group reported a reduction in blood lipids and triglycerides, chronic depressive and anxious mood states, patient emotional coping, and the number of specialist visits and diagnostic tests. Close collaboration between diabetologists and psychologists is feasible, and it is worth considering integrated care as an option to contain and make healthcare spending more sustainable.