Association between serum ALT levels and incidence of new-onset diabetes in general population of Japanese: a longitudinal observational study (ISSA-CKD)

Objective We aimed to clarify the relationship between serum alanine transaminase (ALT) levels and incidence of new-onset diabetes in a Japanese general population.Setting Population-based retrospective cohort study using annual health check-up data for residents of Iki City, Nagasaki Prefecture, Japan.Participants A total of 5330 Japanese individuals (≥30 years old) without diabetes at baseline were analysed.Primary and secondary outcome measures Serum ALT levels were determined using an enzymatic method and were classified into gender-specific quartile groups as follows: group 1 (3–16 U/L in men and 3–13 U/L in women), group 2 (17–21 U/L in men and 14–16 U/L in women), group 3 (22–29 U/L in men and 17–22 U/L in women) and group 4 (30–428 U/L in men and 23–268 U/L in women). The study outcome was the incidence of diabetes (fasting glucose ≥7.0 mmol/L, non-fasting glucose ≥11.1 mmol/L, glycated haemoglobin ≥6.5% or use of glucose-lowering therapies).Results After an average follow-up period of 5.0 years, 279 individuals developed diabetes. The incidence rate of diabetes increased with elevation of serum ALT levels (0.7% per 100 person-years in group 1, 0.9% in group 2, 0.9% in group 3 and 1.7% in group 4) (p<0.001 for trend). This association was significant after adjustment for other risk factors including age, sex, obesity, hypertension, dyslipidaemia, smoking, current daily alcohol intake and regular exercise (p<0.001 for trend). Comparable associations were observed between men and women (p=0.459 for interaction).Conclusion Serum ALT levels were associated with future development of diabetes in the general Japanese population

A Challenging Synthesis of the Highly Functionalized Echinocandin ASP9726: A Successor of Micafungin

Here, we describe a practical, scalable, and challenging synthesis of the highly functionalized novel echinocandin ASP9726 (<b>1</b>) starting from the natural product FR901379 (<b>3</b>), which is a starting material of micafungin (<b>2</b>). The synthesis includes transformations that address significant synthetic challenges due to the need to control the chemoselectivity of the reactions during modification of the highly functionalized peptide core. In the present study, we discovered an efficient, high-yielding route to ASP9726 (<b>1</b>) that is suitable for large-scale production. Namely, dehydration of carboxamide (<b>14</b>) to nitrile (<b>15</b>) was accomplished by use of EDC·HCl with pyridine. Further, the transformation of nitrile (<b>15</b>) to primary amine (<b>17</b>) was conducted via hydrogenation with Sponge Nickel catalyst without decomposition, followed by one-pot debenzylation with Pd/C. Reductive amination between primary amine (<b>17</b>) with dihydroxyacetone (DHA) was accomplished using 2-picoline/borane complex as a reducing agent in MeOH, yielding 66.6 kg of peptide core unit (<b>18</b>). After the C₁₅H₃₁ chain cleavage by bioconversion, reductive amination between the core peptide unit (<b>4</b>) and side chain (<b>10</b>) was achieved in high yield by making use of <i>tert</i>-butyl amine/borane complex as a reducing agent. Consequently, highly pure ASP9726 (<b>1</b>) was obtained in a practical manner without using silica gel or ODS column chromatography purification in any step. Overall yield was drastically increased from 0.71% to 13.8% compared to that of the prior synthetic method