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Objective High-density lipoproteins (HDL) comprise particles of different size, density and composition and their vasoprotective functions may differ. Diabetes modifies the composition and function of HDL. We assessed associations of HDL size-based subclasses with incident cardiovascular disease (CVD) and mortality and their prognostic utility. Research design and methods HDL subclasses by nuclear magnetic resonance spectroscopy were determined in sera from 1991 fasted adults with type 2 diabetes (T2D) consecutively recruited from March 2014 to February 2015 in Hong Kong. HDL was divided into small, medium, large and very large subclasses. Associations (per SD increment) with outcomes were evaluated using multivariate Cox proportional hazards models. C-statistic, integrated discrimination index (IDI), and categorial and continuous net reclassification improvement (NRI) were used to assess predictive value. Results Over median (IQR) 5.2 (5.0–5.4) years, 125 participants developed incident CVD and 90 participants died. Small HDL particles (HDL-P) were inversely associated with incident CVD [hazard ratio (HR) 0.65 (95% CI 0.52, 0.81)] and all-cause mortality [0.47 (0.38, 0.59)] (false discovery rate Conclusion Small HDL-P were inversely associated with incident CVD and all-cause mortality and improved risk stratification for adverse outcomes in people with T2D. HDL-P may be used as markers for residual risk in people with T2D.

Summary Hepatocyte nuclear factor 1β (HNF1B) gene is located on chromosome 17q12. It is a transcription factor implicated in the early embryonic development of multiple organs. HNF1B-associated disease is a multi-system disorder with variable clinical phenotypes. There are increasing reports suggesting that the 17q12 deletion syndrome should be suspected in patients with maturity-onset diabetes of the young type 5 (MODY5) due to the deletion of HNF1B gene. In contrast to classical 17q12 syndrome in childhood with neurological disorders and autism, patients with HNF1B-MODY deletion rarely had neuropsychological disorders or learning disabilities. The diagnosis of 17q12 deletion syndrome highlighted the phenotypic heterogeneity of HNF1B-MODY patients. In this study, we report the clinical course of a Thai woman with young-onset diabetes mellitus and hypertriglyceridemia as a predominant feature due to HNF1B deletion as part of the 17q12 deletion syndrome. Our findings and others suggest that hypertriglyceridemia should be considered a syndromic feature of HNF1B-MODY. Our case also highlights the need to use sequencing with dosage analyses to detect point mutations and copy number variations to avoid missing a whole deletion of HNF1B. Learning points Maturity-onset diabetes of the young type 5 (MODY5) may be caused by heterozygous point mutations or whole gene deletion of HNF1B. Recent studies revealed that complete deletion of the HNF1B gene may be part of the 17q12 deletion syndrome with multi-system involvement. The length of the deletion can contribute to the phenotypic variability in patients with HNF1B-MODY due to whole gene deletion. Using next-generation sequencing alone to diagnose MODY could miss a whole gene deletion or copy number variations. Specialized detection methods such as microarray analysis or low-pass whole genome sequencing are required to accurately diagnose HNF1B-MODY as a component of the 17q12 deletion syndrome. Molecular diagnosis is necessary to distinguish other acquired cystic kidney diseases in patients with type 2 diabetes which could phenocopy HNF1B-MODY. Hypertriglyceridemia is a possible metabolic feature in patients with HNF1B-MODY due to 17q12 deletion syndrome.

Insulin deficiency (ID) and resistance (IR) contribute to progression from normal glucose tolerance to diabetes to insulin requirement although their relative contributions in young-onset diabetes is unknown.We examined the associations of HOMA2 using fasting plasma glucose and C-peptide in Chinese aged 20-50 years with (1) progression to type 2 diabetes (T2D) in participants without diabetes in a community-based cohort (1998-2013) and (2) glycaemic deterioration in patients with T2D in a clinic-based cohort (1995-2014). We defined ID as HOMA2-%B below median and insulin IR as HOMA2-IR above median.During 10-year follow-up, 62 (17.9%) of 347 community-dwelling participants progressed to T2D. After 8.6 years, 291 (48.1%) of 609 patients with T2D had glycaemic deterioration. At baseline, progressors for T2D had higher HOMA2-IR, while in patients with T2D, progressors for glycaemic deterioration had higher HOMA2-IR and lower HOMA2-%B than non-progressors. The non-ID/IR group and the ID/IR group had an adjusted odds ratios of 2.47 (95% CI: 1.28, 4.94) and 5.36 (2.26, 12.79), respectively, for incident T2D versus the ID/non-IR group. In patients with T2D, 50% of the ID/IR group required insulin at 6.7 years versus around 11 years in the non-ID/IR or ID/non-IR, and more than 15 years in the non-ID/non-IR group. Compared with the latter group, the adjusted hazard ratios were 2.74 (1.80, 4.16) in the ID/non-IR, 2.73 (1.78, 4.19) in the non-ID/IR and 4.46 (2.87, 6.91) in the ID/IR group (p-interaction = 0.049).In young Chinese adults, IR and ID contributed to progression to T2D and glycaemic deterioration.

Context Leukocyte telomere length (LTL) is a biomarker of biological aging and is associated with metabolic diseases such as type 2 diabetes. Insufficient maternal vitamin D was associated with increased risk for many diseases and adverse later life outcomes. Objective This study investigates the relationship between vitamin D levels and offspring LTL at early life. Methods This observational, longitudinal, hospital-based cohort study included eligible mother-child pairs from the HAPO Hong Kong Field Centre, with 853 offspring at age 6.96 ± 0.44 (mean ± SD) years. LTL was measured using real-time polymerase chain reaction while serum vitamin D metabolites 25(OH)D2, 25(OH)D3, and 3-epi-25(OH)D3 were measured in maternal blood (at gestation 24-32 weeks) and cord blood by liquid chromatography–mass spectrometry. Results LTL at follow-up was significantly shorter in boys compared with girls (P Conclusion Our findings suggest 25(OH)D3 and 3-epi-25(OH)D3 in utero may impact on childhood LTLs, highlighting a potential link between maternal vitamin D and biological aging.

We aim to assess the long-term impact of acute kidney injury (AKI) on progression of diabetic kidney disease (DKD) and all-cause mortality and investigate determinants of AKI in Chinese patients with type 2 diabetes (T2D). A consecutive cohort of 9,096 Chinese patients with T2D from the Hong Kong Diabetes Register was followed for 12 years (mean ± SD age 57 ± 13.2 years; 46.9% men; median duration of diabetes 5 years). AKI was defined based on the Kidney Disease: Improving Global Outcomes (KDIGO) criteria using serum creatinine. Estimated glomerular filtration rate measurements were used to identify the first episode with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Polygenic risk score (PRS) composed of 27 single nucleotide polymorphisms (SNPs) known to be associated with serum uric acid (SUA) in European populations was used to examine the role of SUA in pathogenesis of AKI, CKD, and ESRD. Validation was sought in an independent cohort including 6,007 patients (age 61.2 ± 10.9 years; 59.5% men; median duration of diabetes 10 years). Patients with AKI had a higher risk for developing incident CKD (hazard ratio 14.3 [95% CI 12.69–16.11]), for developing ESRD (12.1 [10.74–13.62]), and for all-cause death (7.99 [7.31–8.74]) compared with those without AKI. Incidence rate for ESRD among patients with no episodes of AKI and one, two, and three or more episodes of AKI was 7.1, 24.4, 32.4, and 37.3 per 1,000 person-years, respectively. Baseline SUA was a strong independent predictor for AKI. A PRS composed of 27 SUA-related SNPs was associated with AKI and CKD in both discovery and replication cohorts but not ESRD. Elevated SUA may increase the risk of DKD through increasing AKI. The identification of SUA as a modifiable risk factor and PRS as a nonmodifiable risk factor may facilitate the identification of individuals at high risk to prevent AKI and its long-term impact in T2D.