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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.

Additional file 1: Supplementary methods: 1) Hong Kong Diabetes Register TRS Study Group Members; 2) Hong Kong Diabetes Biobank Study Group Members; and 3) Cohort descriptions. Figure S1. Principal component analysis (PCA). Figure S2. Pooled correlations of each candidate polygenic risk scores with measured lipid traits. Figure S3. Proportion of phenotypic variance in lipid traits explained by each candidate polygenic risk scores. Figure S4. Geometric means of measured lipid traits stratified by the quintile of polygenic risk score with the best performance. Figure S5. Geometric means of measured lipid traits at baseline and follow-up, and three-year changes in lipid traits stratified by quintile of polygenic risk scores in adolescents.

Background Type 2 diabetes (T2D) is a progressive disease whereby there is often deterioration in glucose control despite escalation in treatment. There is significant heterogeneity to this progression of glycemia after onset of diabetes, yet the factors that influence glycemic progression are not well understood. Given the tremendous burden of diabetes in the Chinese population, and limited knowledge on factors that influence glycemia, we aim to identify the clinical and genetic predictors for glycemic progression in Chinese patients with T2D. Methods and findings In 1995–2007, 7,091 insulin-naïve Chinese patients (mean age 56.8 ± 13.3 [SD] years; mean age of T2D onset 51.1 ± 12.7 years; 47% men; 28.4% current or ex-smokers; median duration of diabetes 4 [IQR: 1–9] years; mean HbA1c 7.4% ± 1.7%; mean body mass index [BMI] 25.3 ± 4.0 kg/m2) were followed prospectively in the Hong Kong Diabetes Register. We examined associations of BMI and other clinical and genetic factors with glycemic progression defined as requirement of continuous insulin treatment, or 2 consecutive HbA1c ≥8.5% while on ≥2 oral glucose-lowering drugs (OGLDs), with validation in another multicenter cohort of Hong Kong Diabetes Biobank. During a median follow-up period of 8.8 (IQR: 4.8–13.3) years, incidence of glycemic progression was 48.0 (95% confidence interval [CI] 46.3–49.8) per 1,000 person-years with 2,519 patients started on insulin. Among the latter, 33.2% had a lag period of 1.3 years before insulin was initiated. Risk of progression was associated with extremes of BMI and high HbA1c. On multivariate Cox analysis, early age at diagnosis, microvascular complications, high triglyceride levels, and tobacco use were additional independent predictors for glycemic progression. A polygenic risk score (PRS) including 123 known risk variants for T2D also predicted rapid progression to insulin therapy (hazard ratio [HR]: 1.07 [95% CI 1.03–1.12] per SD; P = 0.001), with validation in the replication cohort (HR: 1.24 [95% CI 1.06–1.46] per SD; P = 0.008). A PRS using 63 BMI-related variants predicted BMI (beta [SE] = 0.312 [0.057] per SD; P = 5.84 × 10−8) but not glycemic progression (HR: 1.01 [95% CI 0.96–1.05] per SD; P = 0.747). Limitations of this study include potential misdiagnosis of T2D and lack of detailed data of drug use during follow-up in the replication cohort. Conclusions Our results show that approximately 5% of patients with T2D failed OGLDs annually in this clinic-based cohort. The independent associations of modifiable and genetic risk factors allow more precise identification of high-risk patients for early intensive control of multiple risk factors to prevent glycemic progression., Author summary Why was this study done? There is marked heterogeneity in the rate of progression to insulin requirement in patients with type 2 diabetes (T2D). Whereas some patients can maintain optimal glycemic control with oral glucose-lowering drugs for prolonged periods, others experience rapid deterioration in glycemia, requiring early insulin treatment. It is important to gain insight into what factors are associated with glycemic progression. Previous studies identified baseline HbA1c, young age, and weight gain as independent clinical predictors for glycemic progression in White populations, but there is a paucity of data in Asians. Besides environmental and lifestyle factors including obesity, it is well known that genetic factors play a pivotal role in the onset of diabetes. However, it remains unclear whether genetic variants of body mass index (BMI) and T2D predicts glycemic progression once T2D develops. Moreover, genetic variants associated with response to oral glucose-lowering drugs might also predict glycemic progression. What did the researchers do and find? We investigated glycemic progression among 7,091 Chinese patients with T2D from the Hong Kong Diabetes Register enrolled between 1995 and 2007. We explored the associations of clinical variables and different polygenic risk scores (PRSs) of obesity, T2D, and response to oral glucose-lowering drugs with glycemic progression and validated the associations of PRSs in another multicenter prospective cohort of Hong Kong Diabetes Biobank (HKDB). We found that there was an approximately 1.3-year delay of insulin use after oral glucose-lowering drug failure in real-world practice. We observed a U-shape association between BMI and glycemic progression and found that young age of diagnosis, high HbA1c and triglyceride, use of tobacco, and presence of microvascular complications also predicted rapid glycemic progression. We found that the PRS derived from 123 known risk variants for T2D was associated with early age of diagnosis and rapid glycemic progression, with validation in the replication cohort of HKDB, whereas the PRS derived from 63 BMI-related variants was associated with BMI but not glycemic progression. What do these findings mean? This study highlighted the delay in insulin treatment after oral glucose-lowering drug failure, which represents an important treatment gap in clinical practice. This work emphasized the importance of both genetic and modifiable risk factors, notably lipo-glucotoxicity, obesity, and tobacco use on glycemic progression, which enables identification of high-risk patients for optimal control of risk factors to improve glycemic durability. This study provides novel insights toward the underlying pathophysiology underlining glycemic progression, highlighting some overlap with pathogenesis of T2D. Our work highlights the potential utility of incorporating PRSs for drug response to guide clinical management of T2D.