Determinants of the development of diabetes (maturity-onset diabetes of the young-3) in carriers of HNF-1a mutations. Evidence for parent-of-origin effect

WSTĘP. Celem pracy była ocena rozkładu wieku badanych w chwili wystąpienia cukrzycy typu MODY 3 (maturity-onset diabetes of the young-3) oraz określenie czynników determinujących ujawnienie się cukrzycy u nosicieli mutacji HNF-1a. MATERIAŁ I METODY. Przebadano rodziny (n = 104) z cukrzycą typu 2 dziedziczoną dominująco, pod kątem występowania wywołującej ją mutacji HNF-1a. WYNIKI. Mutacje HNF-1a współistniały z cukrzycą tylko w 13 rodzinach; we wszystkich przypadkach średni wiek chorych w chwili wystąpienia cukrzycy wynosił poniżej 35 lat. Obserwowano brak lub zmniejszenie wydzielania insuliny u nosicieli mutacji (n = 101). Do rozwoju cukrzycy doszło u 65% badanych w wieku do 25 lat, a u 100% do czasu ukończenia 50 lat. Jeśli cukrzyca była dziedziczona po matce, występowała w bardzo młodym wieku, zwłaszcza u osób, które zostały poddane ekspozycji na tę chorobę już w środowisku wewnątrzmacicznym; u 57 &plusmn; 8% cukrzyca ujawniła się do 15 roku życia, w porównaniu z 0,0% u osób niepoddanych tej ekspozycji (p < 7 × 10-6). U osób w wieku 25 lat różnica ta uległa zmniejszeniu (odpowiednio 85 &plusmn; 6 i 55 &plusmn; 12%; p = 0,02). Jeśli mutację odziedziczono po ojcu, cukrzyca rozwijała się u 52 &plusmn; 8% do czasu ukończenia 25 lat. Okazało się, że wiek w chwili rozpoznania jest dziedziczny (h2 = 0,47; p = 0,003). Po uwzględnieniu w analizie faktu, który z rodziców przekazał mutację, zakres udziału czynników genetycznych znacznie się zwiększał (h2 = 0,91). WNIOSKI. Mutacje HNF-1a odpowiadają za rozwój cukrzycy w niewielkim odsetku rodzin z dominującym sposobem dziedziczenia. Wiek w chwili rozwoju cukrzycy był znacznie zróżnicowany w poszczególnych rodzinach z MODY 3 i podlegał wpływowi czynników rodzinnych (łącznie z genami modyfikującymi) oraz zależał od rodzica, przekazującego mutację (czy nosiciel mutacji podlegał ekspozycji na cukrzycę w środowisku wewnątrzmacicznym).INTRODUCTION. To determine the distribution of the age at onset of diabetes (maturity-onset diabetes of the young-3 [MODY 3]and to identify determinants of the onset of diabetes in carriers of HNF-1a mutations. MATERIAL AND METHODS. Extended families (n = 104) with type 2 diabetes inherited in a dominant pattern were recruited and screened for diabetes-causing mutations in HNF-1a. RESULTS. HNF-1a mutations cosegregated with diabetes in only 13 families, all with a mean age at onset < 35 years. Insulin secretion was diminished or absent in mutation carriers (n = 101), and diabetes developed in 65% by age 25 years and in 100% by age 50 years. If the mutation was inherited from the mother, diabetes onset was very young in those exposed to diabetes in utero; 57 &#177; 8% were affected by age 15 years as compared with 0,0% in those not exposed (p < 7 × 10&#8211;6). By age 25 years, the difference was reduced (85 &#177; 6 and 55 &#177; 12%, respectively; P = 0.02). If the mutation was inherited from the father, diabetes developed in 52 &#177; 8% by age 25 years. Age at diagnosis was shown to be highly heritable (h2 = 0.47, P = 0.003). When parent of origin was included in the analyses, the magnitude of genetic contribution increased markedly (h2 = 0.91). CONCLUSIONS. Mutations in HNF-1a accounts for diabetes in a small proportion of families with a dominant pattern of inheritance. Age at onset of diabetes in MODY 3 families varied widely and was influenced by familial factors (including modifying genes) and parent of origin (whether a mutation carrier was exposed to diabetes in utero)

Toll-like receptor 2 downregulation and cytokine dysregulation predict mortality in patients with Staphylococcus aureus bacteremia

Background Staphylococcus aureus bacteremia (SAB) presents heterogeneously, owing to the differences in underlying host conditions and immune responses. Although Toll-like receptor 2 (TLR2) is important in recognizing S. aureus, its function during S. aureus infection remains controversial. We aimed to examine the association of TLR2 expression and associated cytokine responses with clinical SAB outcomes. Methods Patients from a prospective SAB cohort at two tertiary-care medical centers were enrolled. Blood was sampled at several timepoints (≤5 d, 6–9 d, 10–13 d, 14–19 d, and ≥ 20 d) after SAB onset. TLR2 mRNA levels were determined via real-time PCR and serum tumor necrosis factor [TNF]-α, interleukin [IL]-6, and IL-10 levels were analyzed with multiplex-high-sensitivity electrochemiluminescent ELISA. Results TLR2 levels varied among 59 SAB patients. On days 2–5, TLR2 levels were significantly higher in SAB survivors than in healthy controls (p = 0.040) and slightly but not significantly higher than non-survivors (p = 0.120), and SAB patients dying within 7 d had lower TLR2 levels than survivors (P = 0.077) although statistically insignificant. IL-6 and IL-10 levels were significantly higher in non-survivors than in survivors on days 2–5 post-bacteremia (P = 0.010 and P = 0.021, respectively), and those dying within 7 d of SAB (n = 3) displayed significantly higher IL-10/TNF-α ratios than the survivors did (P = 0.007). Conclusion TLR2 downregulation and IL-6 and IL-10 concentrations suggestive of immune dysregulation during early bacteremia may be associated with mortality from SAB. TLR2 expression levels and associated cytokine reactions during early-phase SAB may be potential prognostic factors in SAB, although larger studies are warranted.This study was supported by a research grant (13–2014-002) from Seoul National University Bundang Hospital (Seongnam, South Korea). The funder had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript

Beneficial Effects of Aerobic Exercise Training Combined with Rosiglitazone on Glucose Metabolism in Otsuka Long Evans Tokushima Fatty Rats

BackgroundRegular aerobic exercise is essential for the prevention and management of type 2 diabetes mellitus and may be particularly beneficial for those treated with thiazolidinediones, since it may prevent associated weight gain. This study aimed to evaluate the effect of combined exercise and rosiglitazone treatment on body composition and glucose metabolism in obese diabetes-prone animals.MethodsWe analyzed metabolic parameters, body composition, and islet profiles in Otsuka Long Evans Tokushima Fatty rats after 28 weeks of aerobic exercise, rosiglitazone treatment, and combined exercise and rosiglitazone treatment.ResultsCombined exercise with rosiglitazone showed significantly less increase in weight and epididymal fat compared to rosiglitazone treatment. Aerobic exercise alone and combined rosiglitazone and exercise treatment led to similar retention of lean body mass. All experimental groups showed a decrease in fasting glucose. However, the combined exercise and rosiglitazone therapy group showed prominent improvement in glucose tolerance compared to the other groups. Rescue of islet destruction was observed in all experimental groups, but was most prominent in the combined therapy group.ConclusionRegular aerobic exercise combined with rosiglitazone treatment can compensate for the adverse effect of rosiglitazone treatment and has benefit for islet preservation