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OBJECTIVE Several studies support associations between relative leukocyte telomere length (rLTL), a biomarker of biological aging and type 2 diabetes. This study investigates the relationship between rLTL and the risk of glycemic progression in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS In this cohort study, consecutive Chinese patients with type 2 diabetes (N = 5,506) from the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data were studied. rLTL was measured using quantitative PCR. Glycemic progression was defined as the new need for exogenous insulin. RESULTS The mean (SD) age of the 5,349 subjects was 57.0 (13.3) years, and mean (SD) follow-up was 8.8 (5.4) years. Baseline rLTL was significantly shorter in the 1,803 subjects who progressed to insulin requirement compared with the remaining subjects (4.43 ± 1.16 vs. 4.69 ± 1.20). Shorter rLTL was associated with a higher risk of glycemic progression (hazard ratio [95% CI] for each unit decrease [to ∼0.2 kilobases]: 1.10 [1.06–1.14]), which remained significant after adjusting for confounders. Baseline rLTL was independently associated with glycemic exposure during follow-up (β = −0.05 [−0.06 to −0.04]). Each 1-kilobase decrease in absolute LTL was on average associated with a 1.69-fold higher risk of diabetes progression (95% CI 1.35–2.11). Two-sample Mendelian randomization analysis showed per 1-unit genetically decreased rLTL was associated with a 1.38-fold higher risk of diabetes progression (95% CI 1.12–1.70). CONCLUSIONS Shorter rLTL was significantly associated with an increased risk of glycemic progression in individuals with type 2 diabetes, independent of established risk factors. Telomere length may be a useful biomarker for glycemic progression in people with type 2 diabetes.

Introduction: Improvements in glycemic outcomes have stalled since 20in some international surveys. We examined the latest trends in drug use and glycemic outcomes following recent introduction of newer classes of glucose lowering drugs (GLDs) in a territory-wide analysis. Methods: Using data from the Hong Kong Diabetes Surveillance Database, we estimated age-specific trends in the proportion of patients reaching different glycemic targets, and rates of severe hypoglycemia (SH) in 963,612 patients between 2002-2019. We assessed patterns of GLDs use by age, sex, presence of atherosclerotic cardiovascular disease (ASCVD) and estimated glomerular filtration rate (eGFR) . Results: HbA1c improved most markedly between 2007-2014 but plateaued since 2014, with 53.1% patients achieving HbA1c Conclusions: Following rapid improvement in 2007-2014, glycemic control and SH rates had plateaued despite the increasing use of SGLT2is and GLP-1RA in Hong Kong. Disclosure A.Yang: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. H.Wu: None. E.S.H.Lau: None. X.Zhang: None. M.Shi: None. B.Fan: None. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. A.Luk: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc.

Background: Prediabetes is associated with increased risk of cardiovascular disease (CVD) , kidney disease and death but the extent to which the risk associations between prediabetes and clinical events are modified by age is not known. Methods: We conducted a retrospective analysis of a territory-wide diabetes surveillance dataset from the Hong Kong Hospital Authority including 2,692,880 individuals with at least one glycaemic measurement between 2000 and 2019. Prediabetes was defined according to the American Diabetes Association criteria. Proportional Cox regression was used to derive hazard ratios (HR) and 95% CI of prediabetes vs. normoglycaemic for incident CVD, end-stage kidney disease (ESKD) , all-site infection and all-cause death, stratified by baseline age categories (20-39, 40-59, 60-79 and ≥80 years) . Results: Compared with people with normoglycaemia, people with prediabetes had greater hazards for clinical events in all age groups but the effect size attenuated with ascending age. In the youngest and in the oldest age categories, the respective HRs (95% CI) of prediabetes vs. normoglycaemia were 1.93 (1.71-2.17) and 1. (1.01-1.12) for CVD, 1.72 (1.42-2.08) and 1. (1.03-1.17) for ESKD, 1.48 (1.36-1.62) and 1. (1.00-1.08) for all-site infection, and, 1.52 (1.33-1.73) and 1. (1.04-1.10) for all-cause death. The associations remained after excluding people who later developed diabetes and after adjusting for metabolic factors. Conclusion: Prediabetes increases the risk of major clinical events and death independent of subsequent development of diabetes and metabolic factors. The risk relationships between prediabetes and clinical events are stronger in young than older people. Disclosure X.Zhang: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. A.Luk: None. H.Wu: None. E.S.H.Lau: None. M.Shi: None. B.Fan: None. A.Yang: None. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd.

Background: In patients with type 2 diabetes (T2D) negative for glutamic acid decarboxylase antibodies (GADA-) , the prognostic significance of insulin deficiency (ID) and insulin resistance (IR) remained uncertain. Methods: In 4590 patients with T2D consecutively enrolled to the Hong Kong Diabetes Register in 1995-2012 followed up till 2019, we measured GADA and fasting C peptide (CP) in stored samples at baseline. Using the updated homeostasis model assessment (HOMA2) , we defined below-median HOMA2-%B as ID and above-median HOMA2-IR as IR. We defined incident insulin use as the first insulin prescription of at least 28 days and used ICD-9 codes to define cardiovascular-renal diseases, severe hypoglycemia event (SHE) and all-cause mortality. We used Cox regression model to examine the associations between HOMA2 and clinical outcomes. Results: Amongst 3198 GADA- patients with available HOMA2 data, the median of HOMA2-%B was 52.4 (33.1, 60.9) and that of HOMA2-IR was 1.6 (1.1, 1.8) . The ID group was more likely to initiate insulin treatment [adjusted HR (95%CI) 1.26 (1.11-1.42) ] but less likely to progress to chronic kidney disease (CKD) , end-stage kidney disease (ESKD) and all-cause mortality than the non-ID group. The IR group had increased risks of incident insulin therapy [HR 1.13 (1.00-1.27) ], CKD, ESKD, and all-cause mortality than the non-IR group. Compared with the ID-/IR- group, the ID/IR group had the highest hazard of incident insulin use [HR 1.59 (1.30, 1.94) ], SHE and cardiovascular-renal diseases with HRs ranging from 1.45 to 2.09, although the associations for complications became insignificant after adjusting for metabolic factors and baseline treatments. Conclusions: In GADA- patients with T2D, ID and IR contributed differently to clinical outcomes with the co-existence of ID and IR associated with the highest risk of insulin requirement and adverse clinical outcomes. The assessment of ID and IR using HOMA2 improved risk stratification to identify high risk people for individualized intervention. Disclosure B.Fan: None. A.Luk: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. E.S.H.Lau: None. H.Wu: None. M.Shi: None. A.Yang: None. C.K.Lim: None. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. Funding The HKG Health Medical and Research Fund and RGC Research Impact Fund

Background: In patients with type 2 diabetes (T2D) and non-ketotic presentation, low C-peptide (CP) and positivity for glutamic acid decarboxylase antibodies (GADA+) indicate early insulin requirement. In GADA- patients, the associations of CP with insulin use, glycemic response and severe hypoglycemia event (SHE) are unknown. Methods: We measured fasting CP and GADA in 4590 Chinese patients with T2D enrolled in the Hong Kong Diabetes Register in 1995-2012 followed up till 2019. The updated homeostasis model assessment (HOMA2) was derived from fasting CP and plasma glucose. We defined incident insulin use as the first insulin prescription of at least 28 days, glycemic response as HbA1c reduction at one year after insulin initiation, and SHE using ICD-9 codes. Linear and Cox regression models were applied for association analyses. Results: At enrolment, 32% had low CP ( Conclusions: In patients with T2D, CP interacted with GADA to influence disease progressions including early insulin therapy and SHE. C-peptide might be correlated with IR in patients with GADA-. These subphenotypes allowed more precise classification of beta cell function to guide personalized treatment. Disclosure B.Fan: None. A.Luk: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. E.S.H.Lau: None. H.Wu: None. M.Shi: None. A.Yang: None. C.K.P.Lim: None. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. Funding The HKG Health Medical and Research Fund and RGC Research Impact Fund

Background: Few studies reported incidence rates of late-stage complications in people with youth-onset type 2 diabetes. We compared the clinical characteristics and incidence of cardiovascular disease (CVD) , end-stage kidney disease (ESKD) and death in a cohort of Chinese youth with type 2 and type 1 diabetes. Method: We performed a retrospective analysis of 1221 people with type 2 diabetes and 641 with type 1 diabetes diagnosed at age Result: At baseline, people with youth-onset type 2 diabetes were older at diagnosis (16 [14-18] vs. [8-15] years, p Conclusion: People with youth-onset type 2 diabetes had 2-fold increased risk of CVD and ESKD, in part driven by greater burden of obesity and other metabolic risk factors in this group. Disclosure Y.Fan: None. E.S.H.Lau: None. H.Wu: None. A.Yang: None. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. A.Luk: None.

Introduction: Whether angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) should be discontinued in advanced diabetic kidney disease (DKD) remains controversial. We examined the association of discontinuation of ACEi/ARBs when estimated glomerular filtration rate (eGFR) reached Methods: We performed a prospective analysis of a register including 11,323 patients stratified by continuation of ACEi/ARBs within 6 months of reaching eGFR Results: Of 11,323 ACEi/ARBs users with new-onset eGFR Conclusions: Discontinuation of ACEi/ARBs was associated with increased risk of cardiovascular-renal events in support of their continued use in patients with advanced DKD. Disclosure M.Shi: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. A.Yang: None. E.S.H.Lau: None. H.Wu: None. X.Zhang: None. B.Fan: None. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. A.Luk: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc.

Fermentable oligo-, di-, monosaccharides, and polyols (FODMAPs) are fermentable short-chain carbohydrates that include fructans, galactooligosaccharides (GOS) , lactose, excess fructose, mannitol and sorbitol. Low FODMAP diets in irritable bowel syndrome were associated with reductions in metabolically beneficial, short-chain fatty acids (SCFA) - producing bacteria. We examined the interactions between FODMAP, gut microbiota and glucose tolerance in this exploratory analysis. Twenty subjects underwent oral glucose tolerance tests (OGTT) with C peptide measurements. Ten were classified as normal glucose tolerant (mean ±SD 55±years, body mass index (BMI) 22.7­±2.5 kg/m2, 2-hour plasma glucose 5.7±1.0 mmol/L) and with impaired glucose tolerance (58±­5 years, BMI 23.5±2.9 kg/m2, 2-hour glucose 9.0±0.9 mmol/L) . FODMAPs and macronutrients were assessed from 3-day food diaries. Fecal samples were collected for microbiome analysis. Total FODMAPs were positively correlated to presence of Dorea (r=0.49, p=0.027) . For individual FODMAP items, lactose was positively correlated with Akkermansia (r=0.54, p=0.013) , Bifidobacterium (r=0.42, p=0.037) and negatively correlated with Shigella (r=0.35, p=0.031) in both groups. GOS were positively correlated with Lactobacillus (r= 0.21, p=0.006) and negatively with Shigella (r=0.28, p=0.043) . In the whole group, lower insulin resistance as shown by homeostasis model assessment HOMA2-IR was associated with higher abundance of Bifidobacterium logum (r=0.48, p=0.01) . HOMA2-beta showed correlation with Dorea (r=0.43, p=0.056) . FODMAPs increased the health-promoting microbiota (e.g. Dorea, Lactobacillus, Akkermansia, and Bifidobacterium) . These SCFA promoting microbiota were associated with lower insulin resistance and improved beta-cell function while suppressing the growth of opportunistic pathogens, such as Escherichia spp. Disclosure N. Chu: None. J. He: None. R.C. Ma: Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH. A.P. Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd. Research Support; Boehringer Ingelheim. Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi. Stock/Shareholder; Aptorum Group Limited. Other Relationship; AstraZeneca, Novo Nordisk. J.C. Chan: Board Member; Asia Diabetes Foundation. Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc. Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories. Stock/Shareholder; GemVCare Ltd. E. Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc. Speaker's Bureau; Novartis AG, Sanofi. Funding Health Medical Research Fund (17180431) Hong Kong College of Physicians Young Investigator's Research Grant

BackgroundDiabetes is associated with increased risk of respiratory infections. Renin-angiotensin system (RAS) inhibition with anti-fibrotic, anti-inflammatory effects may reduce pneumonia risk. Prior studies did not account for time-varying and cumulative exposure to RAS inhibitors (RASi), with short follow-up periods, nor compared angiotensin converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) use in Asians. We investigated the association of long-term use of RASi with risk of pneumonia and related death in Chinese people with diabetes using electronic medical record (EMR) data.MethodsThis was a prospective analysis of EMR with overlap propensity-score weighting of a territory-wide cohort (n=252,616, 1.7 million person-years) and a register-based cohort (n=13,017, 0.1 million person-years) in Hong Kong. We compared new-users of RASi (ACEi/ARBs) following baseline assessment with non-RASi users and new-users of calcium-channel blockers as active comparator. The main outcome was first hospitalization and death from pneumonia. ResultsAmongst 252,616 patients with diabetes in the population-based cohort (mean age=61.0 [SD=12.2] years), 73,161 were new-ACEi-only users; 20,907 new-ARBs-only users; 38,778 ACEi/ARBs users; and 119,770 never-ACEi/ARBs users. Over a mean follow-up period of 6.7 years, 5.2% (n=13,057) of patients had pneumonia and 2.2% (n=5,480) died with pneumonia. Compared with non-RASi use, time-varying RASi exposure was associated with reduced risk of pneumonia (hazard ratio, HR, 95% CI): 0.78 (0.75-0.82) and pneumonia-related death (HR=0.49, 0.46-0.53). The respective HRs for ARBs-only were 0.70 (0.62-0.78) and 0.41 (0.33-0.52) and that of ACEi-only were 0.98 (0.91-1.05) and 0.77 (0.68-86). In the Aalen-additive hazards model, the effect of RASi use was time-invariant for pneumonia (P=0.340) and time-varying for related death (P

Patients with moderate-to-advanced diabetic kidney disease (DKD) are at high risk of hypoglycemia. There are few studies evaluating personal continuous glucose monitoring (CGM) use in this group. We investigated whether flash glucose monitoring (FGM) was effective in reducing hypoglycemia compared with standard self-monitoring of blood glucose (SMBG) in individuals with chronic kidney disease (CKD) stages 3b-5 (non-dialysis). This was a single-centre, parallel-group randomised clinical trial of 94 adults with diabetes and CKD [G3b (n=36), G4 (n=44) and G5 (n=14)] and a history of hypoglycemia. Patients were randomly assigned 1:1 to FGM or SMBG for 16 weeks. Both groups received structured education on hypoglycemia and monthly reviews by healthcare professionals. Blinded CGM was performed at baseline and end of study in both groups. Patients were aged (mean±SD) 65.4±9.0 years with estimated glomerular filtration rate (eGFR) 26.1±9.6 ml/min/1.73m2, HbA1c 7.4±0.8% and median duration of diabetes for 20 years. 93 patients had type 2 diabetes and 99% were on insulin. After 16 weeks, percentage time Disclosure J. Ling: None. J. K. Ng: None. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc. A. P. Kong: Advisory Panel; Self; Lilly Diabetes, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Sanofi, Stock/Shareholder; Self; Aptorum. A. Luk: None. C. Szeto: None. J. C. Chan: Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, MSD Corporation, Sanofi, Other Relationship; Self; Asia Diabetes Foundation, GemVCare, Research Support; Self; Applied Therapeutics, AstraZeneca, Hua Medicine, Lilly Diabetes, Merck KGaA. E. Chow: Research Support; Self; Medtronic, Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation, Sanofi-Aventis. Funding Hong Kong College of Physicians; University Grants Committee Research Matching Grant Scheme

Skin autofluorescence (SAF), a non-invasive measure of the accumulation of advanced glycation end products (AGEs) in skin collagen, is associated with baseline estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR). We aimed to investigate whether SAF can identify individuals with type 2 diabetes (T2D) at high-risk of renal function decline. A total of 3,806 Chinese with T2D had SAF measured between 2016 to 2019. The primary endpoint was incident end-stage kidney disease (ESKD) or ≥40% decline in eGFR relative to baseline. The secondary endpoint was the annual change in eGFR during follow-up. A Cox proportional hazard model was used for the primary endpoint, and linear mixed-effects model with random intercept and slope for eGFR slope and the association between SAF and rate of eGFR change. People with prevalent ESKD were excluded. Mean ± SD age was 60.4 ± 10.4 years, with mean ± SD eGFR 81.5 ± 22.9 ml/min/1.73 m2; median (interquartile range [IQR]) UACR was 2.2 (0.8-9.6) mg/mmol; and median eGFR slope was -2.18 ml/min/1.73 m2/year. During a median (IQR) 1.76 (1.13-3.13) years of follow-up, 219 experienced the primary endpoint. SAF was associated with increased risk of progression of kidney disease (adjusted hazard ratio 1.16 per SD, 95% CI [1.01, 1.33]), even after adjustment for established risk factors including eGFR and UACR. SAF was identified as an independent determinant of rate of eGFR decline (adjusted Beta coefficient -2.85 per SD, 95% CI [-3.82, -1.87]). Using the median eGFR slope as the cut-off, higher SAF was associated with faster eGFR decline (adjusted odds ratio 1.12 per SD, 95% CI [1.03, 1.22]) on multivariate logistic regression. This study demonstrates for the first time in a prospective setting that higher SAF is independently associated with increased risk of progression of kidney disease in individuals with T2D. Disclosure Q. Jin: None. A. P. Kong: Advisory Panel; Self; Lilly Diabetes, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Sanofi, Stock/Shareholder; Self; Aptorum. A. Jenkins: Advisory Panel; Self; Abbott Diabetes, Sanofi-Aventis, Other Relationship; Self; Amgen Inc., Research Support; Self; Abbott, International Diabetes Federation, JDRF, Medtronic, Mylan N. V. J. C. Chan: Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, MSD Corporation, Sanofi, Other Relationship; Self; Asia Diabetes Foundation, GemVCare, Research Support; Self; Applied Therapeutics, AstraZeneca, Hua Medicine, Lilly Diabetes, Merck KGaA. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc. E. S. Lau: None. A. Luk: None. R. Ozaki: None. E. Chow: Research Support; Self; Medtronic, Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation, Sanofi-Aventis. T. So: None. H. Yeung: None. K. Loo: n/a. C. K. Lim: Stock/Shareholder; Self; GemVCare Ltd. Funding Research Grants Council of Hong Kong (R4012-18)

The incidence of liver cancer and related mortality is increasing globally. Liver is a major site for glucose metabolism. People with type 2 diabetes (T2D) had increased risk of liver cancer. However, the association of glycemic burden (GB) with liver cancer in T2D remains unclear. We calculated GB using area under the curve above 5.7% of HbA1c (AUC_A1c) in patients with T2D enrolled in the prospective Hong Kong Diabetes Register established since 1995. Structured baseline data were linked to laboratory and hospitalization records in a territory-wide electronic medical record system with data censored in 2019. We performed Cox regression analysis to investigate the association of GB with incident liver cancer defined as first hospitalization with ICD9 code (155). We included 18,173 patients (50.93% male, age: 58.43±12.48 years, HbA1c: 7.58±1.66%, BMI: 25.51±4.06 kg/m2, disease duration: 20.68 ±7.63 years), who had ≥ 10 years of disease duration, > 3 years of observation, and ≥ 5 HbA1c measurements (21.98±12.33). During a median (IQR) follow up period of 10.62 (8.09, 15.88) years (218,381patient-years), 160 patients developed liver cancer with an incidence of 7.33 per 10,000 patient-years. We excluded 3 years of HbA1c values prior to incident liver cancer to avoid reverse causality. After adjusting for confounders, every 1 unit increase in AUC_A1c increased the hazard ratio (HR) of liver cancer by 1.22 (95% CI: 1.01-1.47), while AUC_A1c top quantile group had a HR of 1.78 (1.01-3.13) versus the lowest quantile group. In subgroup analysis, obese patients (BMI>25 kg/m2) had a HR of 1.34 (1.05-1.70) for liver cancer versus non-obese subjects. Amongst patients who developed liver cancer (n=1420) within 3 years of enrolment, one unit increase of AUC_A1c was associated with a HR of 1.49 (1.07-2.07) for liver cancer. GB and obesity independently increased the risk of liver cancer in T2D, emphasizing the importance of metabolic control for cancer risk reduction. Disclosure D. Mao: None. J. C. Chan: Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, MSD Corporation, Sanofi, Other Relationship; Self; Asia Diabetes Foundation, GemVCare, Research Support; Self; Applied Therapeutics, AstraZeneca, Hua Medicine, Lilly Diabetes, Merck KGaA. E. S. H. Lau: None. A. Yang: None. H. Wu: None. M. Shi: None. A. P. Kong: Advisory Panel; Self; Lilly Diabetes, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Sanofi, Stock/Shareholder; Self; Aptorum. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc. E. Chow: Research Support; Self; Medtronic, Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation, Sanofi-Aventis. A. Luk: None.

Introduction: The overall evidence for the long-term exposure of metformin on cardiovascular-renal (CV) outcomes in patients with type 2 diabetes (T2D) at different stages of chronic kidney disease (CKD) remains controversial. Methods: We conducted a prospective analysis of 14,766 Chinese patients with T2D enrolled between 2000 and 2016 observed until 31 December 2019. We compared all-cause mortality and incidence of major adverse CV events (MACE) and end-stage kidney disease (ESKD) in prevalent and new metformin users versus other glucose lowering drugs (GLDs) users stratified by CKD stage. Results: During a mean follow-up of 9.6 years (141,310 person-years), we identified 1,798 deaths in metformin users (n=13,967) and 352 deaths in other-GLDs users (n=799). The mean daily dosage of metformin was 1,450 mg and duration of exposure was 7.8 years in CKD stage 1-2 (n=12,375). The respective figures were 1000 mg and 5.7 years in CKD stage 3-4 (n=1,592). Compared with other-GLDs, metformin exposure was associated with reduced risk of all-cause mortality (All: HR=0.48, 95% CI: 0.43-0.54; CKD stage 1-2: HR=0.38, 0.33-0.44; stage 3A: HR=0.53, 0.41-0.69); MACE (All: HR=0.85, 0.72-0.99; stage 1-2: HR=0.80, 0.65-0.99; stage 3-4: HR=0.97, 0.74-1.27) and ESKD (All: HR=0.65, 0.54-0.80; stage 1-2: HR=0.53, 0.33-0.85; stage 3-4: HR=0.80, 0.63-1.02). New users of metformin (n=4,013) had reduced risk of all-cause mortality across all CKD stages; MACE in stage 1-2 and ESKD in stage 1, 2 and 3 compared with users of other oral-GLDs (n=536). Increasing duration and dosage of metformin (up to 1500 mg/day) was associated with reduced or neutral risk of MACE, ESKD and all-cause mortality. The rate of metformin-associated lactic acidosis (MALA) was 5.39 per 100,000 patient-years in CKD stage 3-4. Conclusion: Long-term metformin use was associated with reduced or neutral risk of all-cause mortality, MACE and ESKD among Chinese patients with T2D at CKD stage 1-3 with low risk of MALA. Disclosure A. Yang: None. E. S. H. Lau: None. H. Wu: None. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc. A. P. Kong: Advisory Panel; Self; Lilly Diabetes, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Sanofi, Stock/Shareholder; Self; Aptorum. A. Luk: None. A. W. Fu: Research Support; Self; Merck KGaA. J. C. Chan: Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, MSD Corporation, Sanofi, Other Relationship; Self; Asia Diabetes Foundation, GemVCare, Research Support; Self; Applied Therapeutics, AstraZeneca, Hua Medicine, Lilly Diabetes, Merck KGaA. E. Chow: Research Support; Self; Medtronic, Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation, Sanofi-Aventis. Funding Asia Diabetes Foundation; Merck Pharmaceutical (HK) Limited; Chinese University of Hong Kong (to A.Y.)

Background: The roles of insulin deficiency (ID) and resistance (IR) in young patients with type 2 diabetes (T2D) are uncertain. We explored the associations of HOMA2 IR and HOMA2 %B using fasting C peptide and plasma glucose (FPG) with incident T2D and insulin use in Chinese aged 18-50 years. Methods: Cohort 1 included subjects without T2D in 1998-2002 with glycemic status ascertained in 2012-2013. Cohort 2 included patients with T2D (1995-2014) with documentation of glycemic deterioration (continuous insulin use or failure of 2 oral drugs). Results: In cohort 1, 62 subjects developed (T2D-progressors) and 285 did not develop T2D (T2D-non-progressors) during 10-year follow-up. In cohort 2 (n=737), 293 (39.8%) required insulin after a median follow-up period of 8.6 years. At baseline, T2D-non-progressors had lower HOMA2 IR [median (IQR) 0.77 (0.60, 1.06)] vs. 1.06 (0.81, 1.38)] and similar HOMA2 %B [84.3 (72, 111.5) vs. 85.1 (75.6, 100.7)] compared with T2D-progressors. Non-insulin-requiring T2D patients had lower HOMA2 IR [1.47 (1.02, 2.11) vs. 1.76 (1.19, 2.42)] and higher HOMA2 %B [62.4 (39.4, 87.4) vs. 45.4 (25.8, 71.8)] than insulin-requiring patients. When stratified by median values and using low HOMA2 %B plus low HOMA2 IR as referent, subjects with high HOMA2 %B plus high HOMA2 IR had age and sex-adjusted odds ratio (95% CI) of 2.47 (1.28, 4.93) and those with low HOMA2% B plus high HOMA2 IR had 5.27 (2.27, 12.84) of incident T2D. In the T2D cohort, using high HOMA2 %B plus low HOMA2 IR as referent, the hazard ratio (95% CI) for insulin use increased with low HOMA2 %B [2.18 (1.47, 3.23)], high HOMA2 IR [2.45 (1.64, 3.64)] and low HOMA2 %B plus high HOMA2 IR [4.25 (2.82, 6.41)] adjusted for age, sex and disease duration. These associations were attenuated after adjusting for obesity, FPG, HbA1c and TG/HDL-C. Conclusions: In young to middle-aged Chinese, progressive worsening in IR and ID contribute to onset of T2D and insulin requirement, which can be attenuated by early control of metabolic factors. Disclosure B. Fan: None. E. Chow: Research Support; Self; Medtronic, Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation, Sanofi-Aventis. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc. A. Luk: None. J. C. Chan: Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, MSD Corporation, Sanofi, Other Relationship; Self; Asia Diabetes Foundation, GemVCare, Research Support; Self; Applied Therapeutics, AstraZeneca, Hua Medicine, Lilly Diabetes, Merck KGaA. H. Wu: None. M. Shi: None. A. Yang: None. C. H. Tam: None. E. S. H. Lau: None. D. Mao: None. C. K. P. Lim: Stock/Shareholder; Self; GemVCare Ltd. A. P. Kong: Advisory Panel; Self; Lilly Diabetes, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Sanofi, Stock/Shareholder; Self; Aptorum.

Background: Diabetes predisposes to heart failure (HF). In a prospective cohort of Chinese with type 2 diabetes, we examined 1) clinical factors associated with incident HF, and 2) mortality post-HF, stratified by ejection fraction (EF). Methods: Between 1 Jun 1993 and 30 Jun 2015, 23348 patients with type 2 diabetes without history of HF were enrolled in the Hong Kong Diabetes Register, and followed for incident HF until 30 Jun 2017. HF subtypes were defined according to EF on echocardiogram: HF with reduced EF (HFrEF), EF =50%. Multivariate Cox regression was used to identify clinical factors associated with incident HF vs. no HF, by HF subtypes. 1-year and 5-year mortality rates were compared by HF subtypes. Results: Over a follow-up of 7.1 years from enrolment, 1195 patients developed HF, of whom 611 (51.1%) had an echocardiogram within 2 years of HF episode. Distribution of HF subtypes as follows: HFrEF 24.1%, HFmrEF 15.2%, HFpEF 60.7%. Old age, low GFR, albuminuria and history of coronary artery disease were associated with increased hazards for all HF subtypes. In addition, female sex, high BMI and history of neuropathy were associated with HFpEF, and low HDL cholesterol was associated with HFmrEF. Over a follow-up of 2.1 years post-HF, 760 patients (63.6%) died with a mortality rate of 189.4 per 1000 person-year. 1-year mortality rate was lower in HFpEF group (16.2%) than those with HFmrEF (vs. 26.9%, p=0.034) and HFrEF (vs. 31.3%, p Conclusions: HFpEF was the predominant HF subtype in Chinese with diabetes. Clinical factors predicting incident HF differed according to subtypes. 1-year mortality was lower in HFpEF group but mortality at 5 years were similar between HFpEF and HFrEF with a trend of higher mortality in HFmrEF group. Disclosure A. Luk: None. J. C. Chan: Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, MSD Corporation, Sanofi, Other Relationship; Self; Asia Diabetes Foundation, GemVCare, Research Support; Self; Applied Therapeutics, AstraZeneca, Hua Medicine, Lilly Diabetes, Merck KGaA. X. Zhang: None. E. Fung: None. H. Wu: None. E. S. Lau: None. A. Yang: None. E. Chow: Research Support; Self; Medtronic, Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation, Sanofi-Aventis. A. P. Kong: Advisory Panel; Self; Lilly Diabetes, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Sanofi, Stock/Shareholder; Self; Aptorum. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc.

Introduction: Angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) are renin angiotensin system inhibitors (RASi) which can reduce the proinflammatory-vasoconstricting activity of ACE/angiotensin II and enhance the anti-inflammatory-vasodilatory activity of ACE2/angiotensin 1-7. These drugs may be protective across a range of respiratory infections including bacterial and viral pneumonias. We examined long-term use of ACEi/ARBs on the risk of first pneumonia hospitalization and pneumonia-related death in Chinese patients with type 2 diabetes (T2D). Methods: Prospective analysis of 16,285 Chinese T2D patients with new RASi use observed between 2001 and 2019. Overlap weighting was performed to balance baseline characteristics. We used time-dependent Cox model to estimate the hazard ratio (HR) of outcomes while adjusting for the time-varying covariates. Results: There were 6,379 (39.2%) ACEi-users only, 4,065 (25.0%) ARBs-users and 5,841 (35.9%) non RASi-users. During a median observation of 7.6 years, 6.1% had first pneumonia hospitalization, 1.3% died during or within one month of pneumonia hospitalization and 17.6% died from other causes. No association was observed between RASi use and first pneumonia hospitalization. However, RASi-users had lower risk for pneumonia-related death (HR 0.51, 95% CI 0.35-0.76) than non-users [ACEi-users only: HR 0.53 (0.34-0.81); ARBs-users: HR 0.58 (0.32-1.04)]. We also noted reduced risk for all-cause death in RASi-users (HR 0.60, 95% CI 0.54-0.67) [ACEi-users only: HR 0.61 (0.54-0.69); ARBs-users: HR 0.67 (0.57-0.79)]. Conclusions: Long-term use of RASi was associated with reduced risk of pneumonia-related death and all-cause death, but not first pneumonia hospitalization, in Chinese patients with T2D. Relevance to other respiratory infections such as coronavirus-disease 2019 (COVID-19) merits further investigation. Disclosure M. Shi: None. E. Chow: Research Support; Self; Medtronic, Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation, Sanofi-Aventis. A. Yang: None. E. S. H. Lau: None. H. Wu: None. B. Fan: None. A. P. Kong: Advisory Panel; Self; Lilly Diabetes, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Sanofi, Stock/Shareholder; Self; Aptorum. A. Luk: None. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc. J. C. Chan: Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, MSD Corporation, Sanofi, Other Relationship; Self; Asia Diabetes Foundation, GemVCare, Research Support; Self; Applied Therapeutics, AstraZeneca, Hua Medicine, Lilly Diabetes, Merck KGaA.

Background and Aims. Skin autofluorescence (SAF) can non-invasively assess the accumulation of tissue AGEs. We investigated the association between SAF and kidney dysfunction in participants with T2D. Methods. Of 4,030 participants consecutively measured SAF at baseline, 3,725 participants free of end-stage kidney disease (ESKD) were included in the analyses. The association of SAF with incident ESKD or ≥30% reduction in estimated glomerular filtration rate (eGFR) was examined with Cox regression, linear mixed-effects model for the association with annual eGFR decline, and mediation analyses for the mediating roles of renal markers. Results. During a median (IQR) 1.8 (1.1-3.1) years of follow-up, 411 participants developed the outcome. SAF was associated with progression of kidney disease (hazard ratio 1.15 per SD, 95% confidence interval [CI] [1.04, 1.28]) and annual decline in eGFR (β -0.39 per SD, 95% CI [-0.71, -0.07]) after adjustment for risk factors, including baseline eGFR and urinary albumin-creatinine ratio (UACR). Decreased eGFR (12.9%) and increased UACR (25.8%) accounted for 38.7% of the effect of SAF on renal outcome. Conclusions. SAF is independently associated with progression of kidney disease. More than half of its effect is independent of renal markers. SAF is of potential to be a prognostic marker for kidney dysfunction.

Background Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and the second leading cause of cancer deaths worldwide. Driven by the epidemics of obesity and diabetes, it is anticipated that non-alcoholic fatty liver disease (NAFLD) will become the most important cause of HCC. Emerging evidence suggests that metabolic and immune dysfunction are key features of NAFLD-associated HCC, my research aim to investigate the metabolic-immune dysregulation underlying NAFLD-HCC development. Here we show that aberrant cholesterol accumulation in the liver predisposes cancer development by reprogramming the immunosurveillance microenvironment. Methods Comprehensive immune profiling in a high-fat high-carbohydrate diet-induced NAFLD murine model was performed. Results Our results revealed a specific reduction of cytolytic natural killer T (NKT) cells in the liver, which was negatively correlated with the elevated cholesterol level. Cholesterol-lowering drug Rosuvastatin reduced cholesterol level and restored NKT cell proportion and function, which subsequently suppressed the growth of orthotopically-implanted HCC tumor. Inhibition of cholesterol synthesis by an mTORC1/C2 dual kinase inhibitor Vistusertib (AZD2014), or lentiviral-mediated suppression of the mTOR pathway also showed similar effects. Notably, NKT inactivation by a specific CD1d receptor-targeting antibody abolished the anti-tumorigenic effects of both Rosuvastatin and Vistusertib, thus underscoring the casual role of NKT in cholesterol-mediated hepatocarcinogenesis. We also showed a reduction of NKT cells and its negative correlation with cholesterol elevation in obese patients undergone bariatric surgery. Conclusions Our study elucidates a new immunosuppressive role of cholesterol in establishing a pro-tumorigenic microenvironment. These findings explain why cholesterol-lowering drugs may reduce cancer incidence and provide new therapeutic strategies of revitalizing the immunosurveillant NKT cells for the intervention of NAFLD-associated HCC. This project is supported by the University Grants Committee through the Collaborative Research Fund (C4045-18W), General Research Fund (14108219, 14105419), the Li Ka Shing Foundation and the Terry Fox Foundation and the AstraZeneca Preclinical Oncology Research Program (2017).

Background Lifetime glycemic exposure and its relationship with age at diagnosis in type 2 diabetes (T2D) are unknown. Pharmacologic glycemic management strategies for young-onset T2D (age at diagnosis 3 times higher for young-onset versus usual-onset T2D (41.0 [95% confidence interval 39.1–42.8] versus 12.1 [11.8–12.3] A1C-years [1 A1C-year = 1 year with 8% average A1C]). Younger age at diagnosis was associated with faster glycemic deterioration (A1C slope over time +0.08% [0.078–0.084%] per year for age at diagnosis 20 years versus +0.02% [0.016–0.018%] per year for age at diagnosis 50 years; p-value for interaction, In a population-based cohort, Calvin Ke and colleagues investigate age at diagnosis and glycemic trajectories in Type 2 diabetes patients., Author summary Why was this study done? Young-onset type 2 diabetes (diagnosed before age 40 years) is an aggressive disease, associated with higher risks of mortality and other complications compared with usual-onset type 2 diabetes (diagnosed at age 40 years or after). Although exposure to hyperglycemia is a key risk factor for type 2 diabetes complications, the magnitude of this exposure over a lifetime has never been quantified. Because young people were excluded from randomized control trials of oral glucose-lowering drugs, it is unknown whether these drugs are effective for treating young-onset type 2 diabetes. What did the researchers do and find? Young-onset type 2 diabetes was associated with over triple the exposure to hyperglycemia from diagnosis until age 75 years compared with usual-onset type 2 diabetes. Diabetes progressed much faster in young-onset type 2 diabetes compared with usual-onset type 2 diabetes. Compared with usual-onset type 2 diabetes, people with young-onset type 2 diabetes had smaller responses to most metformin-based drug combinations and greater responses to other combinations containing sulfonylureas. What do these findings mean? Excess exposure to hyperglycemia and rapid disease progression in young-onset T2D call for better treatment strategies. The differential responses to oral glucose-lowering drugs between young- and usual-onset T2D suggest that better disease classification could guide personalized therapy.

OBJECTIVE Several studies support potential links between relative leukocyte telomere length (rLTL), a biomarker of biological aging, and type 2 diabetes. This study investigates relationships between rLTL and incident cardiovascular disease (CVD) in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Consecutive Chinese patients with type 2 diabetes (N = 5,349) from the Hong Kong Diabetes Register for whom DNA obtained at baseline was stored and follow-up data were available were studied. rLTL was measured by using quantitative PCR. CVD was diagnosed on the basis of ICD-9 code. RESULTS Mean follow-up was 13.4 years (SD 5.5 years). rLTL was correlated inversely with age, diabetes duration, blood pressure, HbA1c, and urine albumin-to-creatinine ratio (ACR), and positively with estimated glomerular filtration rate (eGFR) (all P < 0.001). Subjects with CVD at baseline had a shorter rLTL (4.3 ± 1.2 ΔΔCt) than did subjects without CVD (4.6 ± 1.2 ΔΔCt) (P < 0.001). Of the 4,541 CVD-free subjects at baseline, the 1,140 who developed CVD during follow-up had a shorter rLTL (4.3 ± 1.2 ΔΔCt) than those who remained CVD-free after adjusting for age, sex, smoking, and albuminuria status (4.7 ± 1.2 ΔΔCt) (P < 0.001). In Cox regression models, shorter rLTL was associated with higher risk of incident CVD (for each unit decrease, hazard ratio 1.252 [95% CI 1.195–1.311], P < 0.001), which remained significant after adjusting for age, sex, BMI, systolic blood pressure, LDL cholesterol, HbA1c, eGFR, and ACR (hazard ratio 1.141 [95% CI 1.084–1.200], P < 0.001). CONCLUSIONS rLTL is significantly shorter in patients with type 2 diabetes and CVD, is associated with cardiometabolic risk factors, and is independently associated with incident CVD. Telomere length may be a useful biomarker for CVD risk in patients with type 2 diabetes.

Objective: Diabetes is a leading cause of nontraumatic lower extremity amputation (LEA). We describe the secular trends in incidence rates of LEA and one-year mortality rates after LEA in people with diabetes in Hong Kong between 2001 and 2016. Methods: The Hong Kong Diabetes Surveillance Database (HKDSD) is a territory-wide population-based diabetes cohort identified from the Hong Kong Hospital Authority electronic medical system. We identified LEA events using ICD-9 procedure codes and that of one-year mortality after LEAs from the linkage to the Hong Kong Death Registry. We used Joinpoint regression models to describe the trends in incidence of LEAs from 2001 to 2016 and one-year mortality rates after LEAs from 2001 to 2015. Results: Between 2001 and 2016, a total of 390,071 men and 380,007 women with diabetes aged 20 years or older were included in the HKDSD, among whom 6,113 LEAs in men and 4,149 LEAs in women were recorded. The event rates of minor LEAs declined by 48.6% (average annual percent change [AAPC]: -3.8, 95% CI -5.7, -1.9) from 14.0 to 7.2 per 10,000 in men and by 59.5% (AAPC: -6.3, 95% CI -10.6, -1.8) from 7.9 to 3.2 per 10,000 in women. The rates of major LEAs declined by 77.9% (AAPC: -8.0, 95% CI -9.6, -6.5) from 19.5 to 4.3 per 10,000 in men and by 79.3% (AAPC: -10.4, 95% CI -13.1, -7.6) from 11.6 to 2.4 per 10,000 in women. The one-year mortality rates after both minor and major LEAs remained constant during the surveillance period in both sexes. The AAPC for one-year mortality rates was 1.5 (95% CI -3.0, 6.1) in men and 0.6 (95% CI -4.7, 6.1) in women after minor LEAs, and was -2.1 (95% CI -4.8, 0.6) in men and 2.6 (-1.4, 6.7) in women after major LEAs. Conclusions: Although the event rates of LEAs have declined overall in people with diabetes in Hong Kong, there was no improvement in one-year mortality rates after LEAs. Urgent action to improve the quality of care and ongoing surveillance after LEAs in people with diabetes is needed. Disclosure H. Wu: None. A. Yang: None. E.S. Lau: None. R.C. Ma: Advisory Panel; Self; AstraZeneca. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis, Tricida Inc. A.P. Kong: Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; AstraZeneca. Speaker’s Bureau; Self; Abbott, AstraZeneca, Sanofi. Other Relationship; Self; AstraZeneca, Novartis Pharmaceuticals Corporation, Sanofi. E. Chow: None. W. So: None. J.C. Chan: None. A. Luk: Research Support; Self; Bayer Healthcare Pharmaceuticals Inc., Roche Pharma. Other Relationship; Self; Merck Sharp & Dohme Corp.

Background: There is a resurgence of interest in the role of 1-hour post-load plasma glucose (PG) in risk stratification for type 2 diabetes and a cut-off of 8.6 mmol/L has been proposed to define dysglycaemia in addition to other existing criteria of prediabetes. We examined the efficacy of 1-hour PG level in predicting future type 2 diabetes in a longitudinal community-based cohort of Hong Kong Chinese. Methods: Between 2001-2003, 489 adults without diabetes underwent 75-gram oral glucose tolerance test (OGTT). Blood samples were collected at 0, 15, 30, 60 and 120 minutes for measurement of plasma glucose and insulin levels. Between 2012-2014, progression to diabetes was ascertained either by reviewing medical records or by repeating OGTT and HbA1c. Area under the receiver-operating characteristic (ROC) curve was calculated to assess the discrimination of each parameter (fasting PG, 1-hour PG, 2-hour PG, disposition index) for development of diabetes. High 1-hour PG was defined using threshold of 8.6 mmol/L. Results: Over 12-year follow-up, 46 people (9.4%) developed diabetes. The area under ROC curve were 0.79 (95% CI 0.71, 0.86) for fasting PG, 0.84 (95% CI 0.78, 0.89) for 1-hour PG, 0.79 (95% CI 0.72, 0.86) for 2-hour PG, and 0.78 (95% CI 0.71, 0.85) for disposition index with no difference between each parameter. In multivariate logistic regression, high 1-hour PG was associated with new-onset diabetes with odds ratio (OR) 4.87 (95% CI 1.91, 14.1, p=0.002), independent of impaired fasting glucose (OR 2.19 [95% CI 0.87, 5.32, p=NA), impaired glucose tolerance (OR 3.69 [95% CI 1.67, 8.27, p=0.001]) and other clinical variables including age, sex, smoking, family history of diabetes, history of gestational diabetes, waist and blood pressure. Conclusions: One-hour PG is similar to fasting and 2-hour PG in prediction of type 2 diabetes. High 1-hour PG identifies people with high risk of diabetes independent of other criteria of prediabetes and clinical risk factors. Disclosure A. Luk: Research Support; Self; Bayer Healthcare Pharmaceuticals Inc., Roche Pharma. Other Relationship; Self; Merck Sharp & Dohme Corp. E.S. Lau: None. A.P. Kong: Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; AstraZeneca. Speaker’s Bureau; Self; Abbott, AstraZeneca, Sanofi. Other Relationship; Self; AstraZeneca, Novartis Pharmaceuticals Corporation, Sanofi. E. Chow: None. R.C. Ma: Advisory Panel; Self; AstraZeneca. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis, Tricida Inc. J.C. Chan: None.

Background: There are recent claims that high dietary BCAA may improve insulin resistance although this conflicts with the recommendation that low protein/BCAA diet may confer renoprotection in patients with chronic kidney disease (CKD) stages 3-5. Type 2 diabetes (T2D) has dysregulated energy metabolism where excessive BCAA intake can be harmful. We examined the risk association of BCAA and rate of estimated glomerular filtration rate (eGFR) decline in a prospective T2D cohort. Method: We measured serum BCAA in 2340 adults with CKD stages 1-2 at baseline with available stored sera. By using linear regression analysis, we examined the association of serum BCAA with annual change in eGFR, which was estimated from a linear mixed model using at least three eGFR measurements from baseline until the onset of CKD or data censored on June 2017. Results: In this study cohort with mean±SD follow-up of 10.0±5.3 years (age 55.2±11.2 years, BMI 25.4±4.3 kg/m2, HbA1c 7.6±1.7%, annual change in eGFR -1.37±1.28 ml/min/1.73m2), patients with incident CKD had higher serum BCAA (median [IQR]: 622.7 [540.3-730] vs. 595.8 [518.3-680.3] µM; P Conclusions: In Chinese T2D patients with CKD stages 1-2, high serum BCAA was independently associated with a modest decline in eGFR, suggesting the renoprotective effect of a low BCAA diet may be extended to early CKD with careful monitoring. Disclosure L. Lim: Research Support; Self; AstraZeneca. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc. E.S. Lau: None. H. Lee: None. C.H. Tam: None. C.K. Lim: None. A. Luk: None. E. Chow: Research Support; Self; Powder Pharmaceuticals Inc., Sanofi-Aventis. R.C. Ma: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Research Support; Self; AstraZeneca, Bayer AG, Pfizer Inc. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; AstraZeneca. J.C. Chan: Board Member; Self; Asia Diabetes Foundation. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Merck Sharp & Dohme Corp., Sanofi-Aventis. Research Support; Self; Amgen Inc., AstraZeneca, Lee Powder, Lilly Diabetes, Pfizer Inc., Sanofi-Aventis. Speaker's Bureau; Self; Ascensia Diabetes Care. Stock/Shareholder; Self; GemVCare. A.P. Kong: Advisory Panel; Self; Lilly Diabetes. Research Support; Self; AstraZeneca, Lilly Diabetes. Speaker's Bureau; Self; Abbott. Other Relationship; Self; AstraZeneca, Novartis Pharmaceuticals Corporation, Sanofi. Funding Hong Kong Society of Endocrinology, Metabolism and Reproduction; Hong Kong Association for the Study of Obesity

Aim: Risk alleles for type 2 diabetes (T2D) in the STARD10 locus, impair insulin secretion and are associated with decreased proinsulin:insulin ratios. We have shown that the T2D risk associated with variation at this locus is likely to be mediated through lowered STARD10 expression in the β cell. Here, we investigate the mechanisms by which STARD10 may regulate insulin secretion. Materials and Methods: A 3-dimensional model of STARD10 was constructed from the structure of STARD2, using the modelling tools Chimera and Modeller. Islets were isolated from StarD10fl/fl-Ins1Cre male mice (βStarD10KO). Electron Microscopy (EM) images were obtained from isolated islets after chemical fixation. Total zinc content was measured by inductively coupled plasma mass spectrometry. Pulse-chase analysis of proinsulin processing was performed using 35S-labelled amino acids. RNA-Seq was done on polyadenylated transcripts selected during the preparation of paired-end, directional RNAseq libraries, sequenced on an Illumina HiSeq 4000 machine. Results: Molecular modelling indicated that STARD10 binds either phosphatidylcholine or phosphatidylethanolamine. EM analysis of islets from βStarD10KO mice revealed a markedly altered dense core granule appearance, with a dramatic increase (Fold change = 4.3; p Conclusion: We identify STARD10 as a critical regulator of insulin granule biogenesis and β cell zinc homeostasis. Our data also suggest that increased β cell Zn2+ secretion in risk allele carriers may decrease the clearance of mature insulin to lower plasma proinsulin:insulin ratio. Disclosure G. Carrat: None. E. Haythorne: None. L. Haataja: None. P. Arvan: None. A. Tomas: None. A. Piunti: None. T.J. Pullen: None. E. Georgiadou: None. T. Stylianides: None. V. Salem: None. W. Distaso: None. A. Cakebread: None. D. Hodson: None. A.C. Fung: None. R.B. Sessions: None. F. Alpy: None. A.P. Kong: Advisory Panel; Self; Lilly Diabetes. Research Support; Self; AstraZeneca, Lilly Diabetes. Speaker's Bureau; Self; Abbott. Other Relationship; Self; AstraZeneca, Novartis Pharmaceuticals Corporation, Sanofi. I. Leclerc: None. G.A. Rutter: Consultant; Self; Sun Pharma. Funding Medical Research Council UK; UK Wellcome Trust; Royal Society; Societe Francophone du Diabete

Objective: Over two thirds of the world’s population with diabetes reside in Asia but data on time trends of diabetes incidence in this region is limited. Using population-wide data, we report trends in the incidence of type 1 and type 2 diabetes (T2D) in Hong Kong over a 14-year period. Methods: The Hong Kong Diabetes Surveillance Database (HKDSD) hosts clinical information of people with diabetes under the care of the Hong Kong Hospital Authority, a statutory body governing all public hospitals and out-patient clinics locally. Diabetes type was determined using a validated algorithm that considers both encounter codes and prescription data. Gender-specific incidence rates (per 100,000 person-year) separated by age categories were standardized to age structure of the World Health Organization population. Average annual percentage change (AAPC) was calculated using joinpoint regression analysis to describe incidence trends over time. Results: The HKDSD included 2426 cases of type 1 diabetes (T1D) and 535490 cases of T2D newly detected between 2002-2015. Among youth (age Conclusions: We observed an increase in incidence of T2D in youth and young adults and stabilization in older adults. Incidence of T1D continued to climb in youth but remained constant in adults. This study highlights the emerging problem of young-onset diabetes and calls for effective strategy for diabetes prevention in young people. Disclosure A. Luk: None. C. Ke: None. E.S. Lau: None. R.C. Ma: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Research Support; Self; AstraZeneca, Bayer AG, Pfizer Inc. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; AstraZeneca. E. Chow: Research Support; Self; Powder Pharmaceuticals Inc., Sanofi-Aventis. A.P. Kong: Advisory Panel; Self; Lilly Diabetes. Research Support; Self; AstraZeneca, Lilly Diabetes. Speaker's Bureau; Self; Abbott. Other Relationship; Self; AstraZeneca, Novartis Pharmaceuticals Corporation, Sanofi. J.C. Chan: Board Member; Self; Asia Diabetes Foundation. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Merck Sharp & Dohme Corp., Sanofi-Aventis. Research Support; Self; Amgen Inc., AstraZeneca, Lee Powder, Lilly Diabetes, Pfizer Inc., Sanofi-Aventis. Speaker's Bureau; Self; Ascensia Diabetes Care. Stock/Shareholder; Self; GemVCare. W. So: None.

Background: Increased glycemic variability (GV) is thought to represent abnormalities of glucose homeostasis in the progression from prediabetes to diabetes. We evaluated the association between GV, beta-cell function and glucagon-like peptide 1 (GLP-1) response among individuals with prediabetes. Methods: 61 individuals with prediabetes (age Mean±SD 56±9 years, 31 male) each wore a blinded continuous glucose monitor (Medtronic iPro2) for 72 hours. Standard deviation (SD) and coefficient of variation (CV) were calculated from CGM glucose. Participants underwent a 2-hour mixed-meal tolerance test with measurement of insulin, C-peptide, GLP-1 for modelling of beta-cell function. Results: Early and late GLP-1/glucose ratio were positively correlated with CGM sensor glucose SD (r = 0.29, p=0.02 and r= 0.28 p = 0.048 respectively). Beta-cell glucose sensitivity (βCGS) was negatively correlated with SD (r = -0.28, p = 0.03). In multivariate analyses, only βCGS and GLP-1 response were significant predictors of SD, while early phase insulin and insulin secretion rate predicted average sensor glucose but not indices of GV. Conclusions: Higher GLP-1 response and reduced βCGS are associated with greater glucose fluctuations in the prediabetic range. Disclosure E. Chow: Research Support; Self; Powder Pharmaceuticals Inc., Sanofi-Aventis. A. Luk: None. J. Ling: None. A.P. Kong: Advisory Panel; Self; Lilly Diabetes. Research Support; Self; AstraZeneca, Lilly Diabetes. Speaker's Bureau; Self; Abbott. Other Relationship; Self; AstraZeneca, Novartis Pharmaceuticals Corporation, Sanofi. R.C. Ma: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Research Support; Self; AstraZeneca, Bayer AG, Pfizer Inc. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; AstraZeneca. E. Ferrannini: None. J.C. Chan: Board Member; Self; Asia Diabetes Foundation. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Merck Sharp & Dohme Corp., Sanofi-Aventis. Research Support; Self; Amgen Inc., AstraZeneca, Lee Powder, Lilly Diabetes, Pfizer Inc., Sanofi-Aventis. Speaker's Bureau; Self; Ascensia Diabetes Care. Stock/Shareholder; Self; GemVCare.

Objective: To examine how T2D onset age affects A1C trajectory and A1C lowering with insulin and other drugs. Methods: We conducted a cohort study (2000-16) in adults aged 18-75 years (y) with young-onset T2D (YOD; onset age Results: Glycemic burden was tripled in YOD versus UOD (38.8 versus 11.8 A1C-y). After accounting for drugs, YOD was associated with a higher baseline A1C (7.6%) and slope (0.05%/y) versus UOD (7.4%, 0.00%/y). Non-insulin drugs lowered A1C similarly across onset ages. The post-insulin A1C remained elevated for YOD, regardless of time to insulin start, but improved significantly for UOD. Conclusions: YOD is associated with an aggressive A1C rise and excess glycemic burden despite insulin and other drugs. More effective strategies are needed to lower A1C in people with YOD. Disclosure C. Ke: None. A. Luk: None. B.R. Shah: None. T. Stukel: None. E.S. Lau: None. R.C. Ma: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Research Support; Self; AstraZeneca, Bayer AG, Pfizer Inc. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; AstraZeneca. A.P. Kong: Advisory Panel; Self; Lilly Diabetes. Research Support; Self; AstraZeneca, Lilly Diabetes. Speaker's Bureau; Self; Abbott. Other Relationship; Self; AstraZeneca, Novartis Pharmaceuticals Corporation, Sanofi. E. Chow: Research Support; Self; Powder Pharmaceuticals Inc., Sanofi-Aventis. J.C. Chan: Board Member; Self; Asia Diabetes Foundation. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Merck Sharp & Dohme Corp., Sanofi-Aventis. Research Support; Self; Amgen Inc., AstraZeneca, Lee Powder, Lilly Diabetes, Pfizer Inc., Sanofi-Aventis. Speaker's Bureau; Self; Ascensia Diabetes Care. Stock/Shareholder; Self; GemVCare. Funding University of Toronto; Royal College of Physicians and Surgeons of Canada; Canadian Society of Endocrinology and Metabolism; Chinese University of Hong Kong; Asia Diabetes Foundation

Objective: Young-onset type 2 diabetes (YOD, defined as age Methods: We conducted a prospective cohort study measuring all-cause hospitalization in YOD and usual-onset type 2 diabetes (T2D) among adults aged 20-75 years using the Hong Kong Diabetes Register (2000-2015, n=21,779). We estimated the impacts of YOD and risk factor control on hospitalization rate after T2D diagnosis using negative binomial regression. Results: YOD hospitalization had a bimodal distribution, with a disproportionate burden of mental illness < age 40 years (35.9% of bed-days; Figure. 1). YOD was associated with a 3-fold increase in hospitalization rate vs. usual-onset T2D (adjusted rate ratio 2.8, 95% confidence interval 2.5-3.2). Intensified risk factor control (A1C Conclusions: YOD is associated with substantial excess hospitalization across the adult lifespan. Urgent efforts are required to develop aggressive management strategies, and to address the unrecognized burden of mental illness in YOD. Disclosure C. Ke: None. E.S.H. Lau: None. A. Luk: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc.. Research Support; Self; Sanofi. R.C. Ma: Research Support; Self; AstraZeneca, Bayer AG, Merck Sharp & Dohme Corp., Pfizer Inc.. Advisory Panel; Self; Boehringer Ingelheim GmbH, Nippon Boehringer Ingelheim Co. Ltd. A.P. Kong: Research Support; Self; AstraZeneca. E. Chow: Research Support; Self; Sanofi. P.M. Clarke: None. J.C. Chan: Consultant; Self; Bayer AG. Other Relationship; Self; Bayer AG. Consultant; Self; Sanofi. Other Relationship; Self; Sanofi, Eli Lilly and Company, Amgen Inc.. Consultant; Self; AstraZeneca, Merck & Co., Inc., Pfizer Inc.. Other Relationship; Self; Pfizer Inc.. Board Member; Self; Asia Diabetes Foundation. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; Merck Sharp & Dohme Corp.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis AG, Eli Lilly and Company.

Background: Obesity predicts cardiovascular(CV)-renal disease. Contrary to claims that branched-chain amino acids (BCAA)-rich diet/supplements may improve weight and insulin resistance, recent data suggest impaired oxidation of BCAA (leucine, isoleucine and valine) may contribute to CV-renal disease. We examined the associations of serum BCAA, obesity and CV-renal events in a prospective Chinese T2D cohort (1994-2007). Method: We measured serum total BCAA in 579 and 566 patients (top and lowest BMI quintiles respectively) using the colorimetric ELISA kit. Patients were monitored for clinical outcomes with data censored on May 2015. We analysed the effect of serum BCAA on incident CV-renal events using multivariate Cox regression. Results: At baseline, obese group had shorter T2D duration, worse clinical profile and higher serum BCAA than lean group. After 11 years of follow-up, obese group had higher incidence of heart failure (HF), chronic kidney and any CV disease than the lean group. In all patients, every unit increase in Ln (BCAA) elevated the risk of incident HF by 64% (hazard ratio [HR] 1.64, 95% CI 1.01-2.66). Conclusions: Serum BCAA independently predicted incident HF in T2D population even after adjustment for obesity. The associations of this biomarker with dietary patterns and clinical outcomes will provide new insights regarding the health impacts of nutrition. Model 1Model 2EventHR (95% CI)P-valueEventHR (95% CI)P-valueAny CV disease181 (21.5%)1.37 (1.01-1.85)0.044167 (21.0%)1.26 (0.88-1.79)0.206Heart failure91 (9.4%)1.59 (1.06-2.39)0.02585 (9.3%)1.64 (1.01-2.66)0.045Coronary heart disease103 (11.4%)1.19 (0.78-1.81)0.42897 (11.4%)1.05 (0.65-1.71)0.836Stroke100 (10.2%)1.42 (0.96-2.10)0.08390 (9.8%)1.35 (0.86-2.10)0.191Chronic kidney disease401 (52.0%)1.15 (0.89-1.49)0.271379 (51.6%)0.89 (0.65-1.22)0.463Model 1: adjusted for age, sex, T2D duration Model 2: Model 1 + A1c, systolic BP, LDL-cholesterol, log(triglyceride), BMI top and lowest quintiles (0,1), log(ACR), baseline eGFR, use of insulin, RAS inhibitors, oral blood glucose/lipid lowering agents, smoking status Disclosure L. Lim: Research Support; Self; AstraZeneca. Speaker's Bureau; Self; Sanofi-Aventis. E.S.H. Lau: None. A. Luk: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc.. Research Support; Self; Sanofi. E. Chow: Research Support; Self; Sanofi. H. Lee: None. R.C. Ma: Research Support; Self; AstraZeneca, Bayer AG, Merck Sharp & Dohme Corp., Pfizer Inc.. Advisory Panel; Self; Boehringer Ingelheim GmbH, Nippon Boehringer Ingelheim Co. Ltd. J.C. Chan: Consultant; Self; Bayer AG. Other Relationship; Self; Bayer AG. Consultant; Self; Sanofi. Other Relationship; Self; Sanofi, Eli Lilly and Company, Amgen Inc.. Consultant; Self; AstraZeneca, Merck & Co., Inc., Pfizer Inc.. Other Relationship; Self; Pfizer Inc.. Board Member; Self; Asia Diabetes Foundation. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; Merck Sharp & Dohme Corp.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis AG, Eli Lilly and Company. A.P. Kong: Research Support; Self; AstraZeneca.

Background We hypothesize that depression in type 2 diabetes might be associated with poor glycemic control, in part due to suboptimal self-care. We tested this hypothesis by examining the associations of depression with clinical and laboratory findings in a multicenter survey of Chinese type 2 diabetic patients. Method 2538 patients aged 18–75 years attending hospital-based clinics in four cities in China underwent detailed clinical-psychological-behavioral assessment during a 12-month period between 2011 and 2012. Depression was diagnosed if Patient Health Questionnaire-9 (PHQ-9) score ≥10. Diabetes self-care and medication adherence were assessed using the Summary of Diabetes Self-care Activities and the 4-item Morisky medication adherence scale respectively. Results In this cross-sectional study (mean age: 56.4 ± 10.5[SD] years, 53% men), 6.1% (n = 155) had depression. After controlling for study sites, patients with depression had higher HbA1c (7.9 ± 2.0 vs. 7.7 ± 2.0%, P = 0.008) and were less likely to achieve HbA1c goal of

The prevalence of diabetes is increasing in young adults in Asia, but little is known about metabolic control or the burden of associated complications in this population. We assessed the prevalence of young-onset versus late-onset type 2 diabetes, and associated risk factors and complication burdens, in the Joint Asia Diabetes Evaluation (JADE) cohort.JADE is an ongoing prospective cohort study. We enrolled adults with type 2 diabetes from 245 outpatient clinics in nine Asian countries or regions. We classified patients as having young-onset diabetes if they were diagnosed before the age of 40 years, and as having late-onset diabetes if they were diagnosed at 40 years or older. Data for participants' first JADE assessment was extracted for cross-sectional analysis. We compared clinical characteristics, metabolic risk factors, and the prevalence of complications between participants with young-onset diabetes and late-onset diabetes.Between Nov 1, 2007, and Dec 21, 2012, we enrolled 41,029 patients (15,341 from Hong Kong, 9107 from India, 7712 from Philippines, 5646 from China, 1751 from South Korea, 705 from Vietnam, 385 from Singapore, 275 from Thailand, 107 from Taiwan). 7481 patients (18%) had young-onset diabetes, with age at diagnosis of mean 32·9 years [SD 5·7] versus 53·9 years [9·0] with late-onset diabetes (n=33,548). Those with young-onset diabetes had longer disease duration (median 10 years [IQR 3-18]) than those with late-onset diabetes (5 years [2-11]). Fewer patients with young-onset diabetes achieved HbA1c concentrations lower than 7% compared to those with late-onset diabetes (27% vs 42%; p0·0001) Patients with young-onset diabetes had higher mean concentrations of HbA1c (mean 8·32% [SD 2·03] vs 7·69% [1·82]; p0·0001), LDL cholesterol (2·78 mmol/L [0·96] vs 2·74 [0·93]; p=0·009), and a higher prevalence of retinopathy (1363 [20%] vs 5714 (18%); p=0·011) than those with late-onset diabetes, but were less likely to receive statins (2347 [31%] vs 12,441 [37%]; p0·0001) and renin-angiotensin-system inhibitors (1868 [25%] vs 9665 [29%]; p=0·006).In clinic-based settings across Asia, one in five adult patients had young-onset diabetes. Compared with patients with late-onset diabetes, metabolic control in those with young-onset diabetes was poor, and fewer received organ-protective drugs. Given the risk conferred by long-term suboptimum metabolic control, our findings suggest an impending epidemic of young-onset diabetic complications.The Asia Diabetes Foundation (ADF) and Merck.

Objective To establish a profile of the modifiable cardiovascular disease (CVD) risk factors in the office-working population of Nanjing, China. Background With increasing modernization in China, CVD is now common among Chinese. Relevant information on the prevalence of CVD risk factors in China is, however, limited. Methods We recruited 2648 office working people aged 23–79years without history of CVD or diabetes from 7 work units of Nanjing during the years 2003 to 2005. Information from a self-reported questionnaire on lifestyle, physical examination, fasting blood for lipid profiles, and a 75-gram oral glucose tolerance test (OGTT) were obtained from each participant. We analyzed the following 7 CVD risk factors: smoking, inadequate physical activity, unhealthy dietary habit, obesity, hypertension, dyslipidemia, and hyperglycemia. Results The whole study population had an average of 2.8 risk factors, while 95.6%, 79.4% and 55.6% of them had respectively ≥1, ≥2 and ≥3 of the 7 CVD risk factors. Men had a higher proportion of smoking, hypertension, dyslipidemia, hyperglycemia, but lower in light physical activity compared with women. Number of CVD risk factors increased with age. Although risk factors in men were more common than women, they increased alarmingly in postmenopausal women. Conclusions CVD risk factors are common in office-working people in Nanjing, China. Effective interventions and treatment against risk factors should be adopted in the high risk population, which may greatly reduce the future burden of CVD in the Chinese population.

Introduction The association between sleep duration, obesity, and serum lipid profile in the youth population is under-explored. Objective To evaluate the association between sleep duration, obesity and serum lipid profile in the youth population. Methods We conducted a cross-sectional population-based study with students recruited from primary and secondary schools in Hong Kong. Anthropometric measurements, fasting lipid profiles and validated questionnaires on sleep duration were performed. A subgroup ( n = 138) was randomly selected for both questionnaires and actigraphy to assess the agreement between subjective and objective measurements of sleep duration. Results We studied 2053 healthy children and adolescents aged 6–20 years. Their mean ages were 13.0 ± 3.3 (boys) and 13.6 ± 3.3 (girls) years. The average sleep duration during schooldays, weekends, and long holidays was 8.0 ± 1.1, 9.6 ± 1.2, and 9.8 ± 1.2 h in boys and 7.7 ± 1.1, 9.9 ± 1.2, and 10.1 ± 1.2 h in girls, respectively. Using logistic regression, age, and pubertal stage were associated with obesity in secondary school students, whereas male gender and short sleep duration were associated with obesity in primary school children. In secondary school children, those with long sleep duration, as compared to those with short sleep duration, were significantly associated with reduced risk to have high TC and LDL-C levels after adjustment for age, gender, BMI, and pubertal stage. There was no significant association between sleep duration and lipid levels in primary school children. Conclusion Reduced sleep duration was associated with obesity and atherogenic dyslipidemia in young school children in Hong Kong.

Background: Type 2 diabetes (T2D) increases hospitalization risk. Young-onset T2D (YOD) (defined as onset before age 40 years) is associated with excess morbidity and mortality, but its effect on hospitalizations is unknown. Objective: To determine hospitalization rates among persons with YOD and to examine the effect of age at onset on hospitalization risk. Design: Prospective cohort study. Setting: Hong Kong. Participants: Adults aged 20 to 75 years in population-based (2002 to 2014; n = 422 908) and registry-based (2000 to 2014; n = 20 886) T2D cohorts. Measurements: All-cause and cause-specific hospitalization rates. Negative binomial regression models estimated effect of age at onset on hospitalization rate and cumulative bed-days from onset to age 75 years for YOD. Results: Patients with YOD had the highest hospitalization rates by attained age. In the registry cohort, 36.8% of YOD bed-days before age 40 years were due to mental illness. The adjusted rate ratios showed increased hospitalization in YOD versus usual-onset T2D (onset at age ≥40 years) (all-cause, 1.8 [95% CI, 1.7 to 2.0]; renal, 6.7 [CI, 4.2 to 10.6]; diabetes, 3.7 [CI, 3.0 to 4.6]; cardiovascular, 2.1 [CI, 1.8 to 2.5]; infection, 1.7 [CI, 1.4 to 2.1]; P < 0.001 for all). Models estimated that intensified risk factor control in YOD (hemoglobin A1c level

Aim Dyslipidaemia may be a risk factor for diabetic kidney disease. We examined prospectively association between the use of statins and development of renal dysfunction in type 2 diabetes. Methods A consecutive cohort of 5264 diabetic patient recruited between 1996 and 2005 underwent detailed assessments. Renal dysfunction was defined as first estimated glomerular filtration rate 2 , or, the first hospitalisation with a diagnosis of renal disease as coded by the International Classification of Disease, Ninth Revision. Drug use was quantified using the proportion of exposure time from baseline to event/death/censored time, as appropriate. Results In this cohort (male: 47.3%, median age: 55 years, median duration of diabetes: 6.0 years), none had renal dysfunction at baseline. During a median follow-up period of 4.9 (quartiles: 2.77, 7.04) years, 703 patients (13.4%) developed renal dysfunction, 1275 patients (22.2%) were exposed to statins. After controlling for baseline risk factors, multivariable adjusted hazard ratio of statin use for development of renal dysfunction was 0.32 (95% CI 0.21–0.50, p Conclusion Use of statins was associated with reduced risk of developing renal dysfunction in type 2 diabetes and this association was independent of baseline risk factors.

This cross sectional study of 290 Chinese children aged 8-18 years, evaluated a Chinese version of the self-reported Pubertal Development Scale (PDS) against both raters' and self-reported Tanner assessment of pubertal status. Children completed both the self-reported PDS and self-reported Tanner pubertal questionnaire prior to physical examination through visual depiction by a same gender rater. Puberty Category Scores (PCS) which were derived from the PDS, was used to categorize children into one of five pubertal development stages. Tanner derived composite stage (TDCS) which was derived from the Tanner pubertal questionnaires, was used to compare with PCS to obtain the inter-rater agreement. Moderately high agreements were found between raters' TDCS and PCS in girls [weighted kappa (WK) 0.57 (0.44, 0.71); Kendalltau-b 0.60 (0.51, 0.69)] and in boys [WK 0.58 (0.47, 0.69), Kendalltau-b 0.50 (0.38, 0.62)]. The correlation between self-reported PDS and rater's assessment was substantial in girls [Kendalltau-b 0.61 (0.54, 0.69)] and moderate in boys [Kendalltau-b 0.49 (0.38, 0.61)]. The Hong Kong Chinese children and adolescents were able to reliably estimate their own sexual maturation status (SMS) using a Chinese version PDS. This instrument may be useful in epidemiological studies when cost, privacy and other concerns preclude the use of other SMS assessment tools.

Multiple risk factors in type 2 diabetes may explain their high risk for ischemic stroke (IS). However, it remains unknown whether these risk factors exhibit threshold characteristics and whether these relationships are influenced by albuminuria. The study aims to investigate whether risk factors exhibit any albuminuria specific threshold for IS.This is a prospective cohort study with 6969 Chinese type 2 diabetic patients without history of stroke after a median follow-up of 5.36 years. We identified thresholds of risk factors for IS using hazard ratio plots followed by confirmation using traditional Cox regression analysis.In the non-albuminuric group (n=4008), IS risk started to increase rapidly at a body mass index threshold of 24 kg/m(2). The risk of IS declined with increasing blood hemoglobin reaching a threshold value of 14 g/dl. Using these threshold values as cutoff point, body mass indexor =24 kg/m(2) and hemoglobin14 g/dl were associated with 2-fold increased risk of IS in these subjects. In the albuminuric group (n=2961). IS risk started to increase rapidly from a systolic blood pressure threshold of 135 mmHg and declined with increasing estimated glomerular filtration rate (eGFR) reaching a trough of 115 ml/min per 1.73 m(2). Using these values as cutoff points, patients with systolic blood pressureor =135 mmHg and eGFR115 ml/min per 1.73 m(2) had 2-fold increased risk of IS.In type 2 diabetic patients, body mass index, hemoglobin, systolic blood pressure and eGFR exhibit different risk relationships and thresholds for IS contingent upon presence or absence of albuminuria.

OBJECTIVE—The purpose of this study was to compare the predictive value for coronary heart disease (CHD) of the International Diabetes Federation (IDF) definition (with Asian criteria for central obesity) of the metabolic syndrome with existing criteria of the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) in Chinese subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS—Subjects with type 2 diabetes and without macrovascular diseases or end-stage renal disease were categorized by the criteria of the IDF and the NCEP ATP III. CHD was defined as myocardial infarction, ischemic heart disease, coronary revascularization, heart failure, and death related to CHD. RESULTS—Of 4,350 patients (aged 54.4 ± 13.4 years; median follow-up period 7.1 [interquartile range 5.2–8.5] years), 65.9% had metabolic syndrome according to either IDF or NCEP ATP III criteria. The NCEP ATP III definition identified metabolic syndrome in 786 subjects (18.1%) who did not fulfill the criteria of the IDF. HDL cholesterol and systolic blood pressure were predictors of CHD after adjustment for other confounding factors. Compared with subjects without metabolic syndrome, the IDF criteria failed to predict CHD (hazard ratio 1.13 [95% CI 0.86–1.48], P = 0.374). In contrast, the NCEP ATP III definition (2.51 [1.80–3.50], P < 0.001) predicted an increased risk of CHD with the NCEP-only group having the highest risk (2.49 [1.66–3.73], P < 0.001). CONCLUSIONS—With established type 2 diabetes, the IDF definition of the metabolic syndrome failed to identify a subgroup of patients who had the highest risk for CHD. Practitioners must recognize the appropriate setting for its application.

Background Puberty is associated with a clustering of cardiometabolic risk factors (CMRFs) during adolescence that are manifested in later life. Although anthropometric variables such as body mass index (BMI) can predict cardiometabolic risk in children and adolescents, it is not clear whether there is an interaction between pubertal stage and BMI associated with cardiometabolic risk in this age group. This paper examines the association of pubertal stage and BMI with CMRFs in Hong Kong Chinese children. Methods A cross-sectional school-based study was conducted among 1985 (95.1 %) students aged 6 to 18 years. Fasting lipid profile and plasma glucose, blood pressure, body weight, body height and waist circumference were measured. A self-reported pubertal stage questionnaire was used to assess pubertal stage of participants. Two cardiometabolic risk scores, alpha and beta, were constructed to quantify cardiometabolic risk. Cardiometabolic risk score alpha refers to the sum of z-scores of sex-specific, age-adjusted waist circumference, height-adjusted systolic and diastolic blood pressure, fasting plasma glucose, triglyceride and low-density lipoprotein cholesterol, and minus z-score of sex-specific age-adjusted high-density lipoprotein cholesterol. Cardiometabolic risk score beta includes all components of risk score alpha except waist circumference. Results The interaction of BMI z-score (ZBMI) and pubertal stage demonstrated a further increase in variance explained in both the cardiometabolic risk scores alpha and beta (0.5 % and 0.8 % respectively) in boys and (0.7 % and 0.5 % respectively) in girls. Conclusions Pubertal stage has an interaction effect on the association of cardiometabolic risk by BMI in boys and may have a similar but lesser effect in girls.

Background: Pharmacoepidemiologic analysis can confirm whether drug efficacy in a randomized controlled trial (RCT) translates to effectiveness in real settings. We examined methods used to control for immortal time bias in an analysis of renin–angiotensin system (RAS) inhibitors as the reference cardioprotective drug. Methods: We analyzed data from 3928 patients with type 2 diabetes who were recruited into the Hong Kong Diabetes Registry between 1996 and 2005 and followed up to July 30, 2005. Different Cox models were used to obtain hazard ratios (HRs) for cardiovascular disease (CVD) associated with RAS inhibitors. These HRs were then compared to the HR of 0.92 reported in a recent meta-analysis of RCTs. Results: During a median follow-up period of 5.45 years, 7.23% (n = 284) patients developed CVD and 38.7% (n = 1519) were started on RAS inhibitors, with 39.1% of immortal time among the users. In multivariable analysis, time-dependent drug-exposure Cox models and Cox models that moved immortal time from users to nonusers both severely inflated the HR, and time-fixed models that included immortal time deflated the HR. Use of time-fixed Cox models that excluded immortal time resulted in a HR of only 0.89 (95% CI, 0.68–1.17) for CVD associated with RAS inhibitors, which is closer to the values reported in RCTs. Conclusions: In pharmacoepidemiologic analysis, time-dependent drug exposure models and models that move immortal time from users to nonusers may introduce substantial bias in investigations of the effects of RAS inhibitors on CVD in type 2 diabetes.

Objective: Diabetes is associated with impaired health-related quality of life (HRQoL) which predicts adverse clinical outcome. To examine clinical factors associated with HRQoL in a cross-sectional cohort of 14,826 Hong Kong Chinese patients with type 2 diabetes receiving outpatient care. Methods: Adult patients with type 2 diabetes who underwent comprehensive assessment of risk factors and complications using the web-based Joint Asia Diabetes Evaluation (JADE) Program also completed the EuroQol-5D (EQ-5D) questionnaire and visual analogue scale (VAS) for evaluation of HRQoL. Multiple linear regression analysis was used to identify clinical correlates with EQ-5D index and the association was expressed using β-coefficient whereby β>0 indicates positive correlation and β

Aims/Introduction: Type 2 diabetes is characterized by dysregulation of immunity, oxidative stress and reduced incretin effects. Experimental studies suggest that glucagon-like peptide (GLP-1) might have immunomodulating effects. We hypothesize that GLP-1 receptor agonist, exendin-4, might reduce inflammatory response in type 2 diabetes. Materials and Methods: Using peripheral blood mononuclear cells (PBM C) sampled from 10 type 2d iabetes and 10 sex- and age-matched control subjects and supernatants from PBMC culture, the expression of phospho-mitogen activated protein kinase (MAPK) signaling pathways in CD4+ T helper lymphocytes and monocytes was analyzed using flow cytometry. Cytokines/chemokines and superoxide anion before and after treatment with exendin-4 were measured by cytometric bead array and chemiluminesence assay, respectively. Results: Compared with control subjects, PBMC from type 2 diabetes patients showed activated MAPK (P38, c-Jun NH2-terminal protein kinase and extracellular signal-regulated kinase) signaling pathway, elevated superoxide anion, increased pro-inflammatory cytokines (tumor necrosis factor-a ,i nterleukin-1b, interleukin-6) and chemokines (CCL5/regulated on activation normal T-cell expressed and secreted and CXCL10/interferon-c-induced protein 10). These changes were attenuated by exendin-4, possibly through the suppression of p38 MAPK. Conclusions: These results suggest that exendin-4 might downregulate pro-inflammatory responses and reduce oxidative stress by suppressing MAPK signaling pathways in type 2 diabetes. (J Diabetes Invest, doi: 10.1111/jdi.12063, 2013)

Renal dysfunction can be evaluated by increased intra-renal arterial resistance index (RI). We evaluated 113 Chinese men with type 2 diabetes on their RI. Results suggest that RI is associated with chronic kidney disease and subclinical arteriosclerosis. RI may help monitoring the deterioration of intra-renal hemodynamics.

BackgroundChildhood and adolescence are critical periods of habit formation with substantial tracking of lifestyle and cardiovascular risk into adulthood. There are various guidelines on recommended levels of physical activity in youth of school-age. Despite the epidemic of obesity and diabetes in China, there is a paucity of data in this regard in Chinese youth. We examined the association of self-reported level of physical activity and cardiovascular risk in Hong Kong Chinese youth of school-age.MethodsThis was a cross-sectional study conducted in 2007-8 in a school setting with 2119 Hong Kong Chinese youth aged 6-20 years. Physical activity level was assessed using a validated questionnaire, CUHK-PARCY (The Chinese University of Hong Kong: Physical Activity Rating for Children and Youth). A summary risk score comprising of waist circumference, blood pressure, fasting plasma glucose and lipids was constructed to quantify cardiovascular risk.ResultsIn this cohort, 21.5% reported high level of physical activity with boys being more active than girls (32.1% versus 14.1%, p < 0.001). Regression analysis showed physical activity level, sex and pubertal stage were independently associated with cardiovascular risk score.ConclusionSelf-reported level of physical activity is associated with cardiovascular risk factors in Chinese youth after adjusting for sex and pubertal stage.

Adiponectin is an adipocytokine with insulin sensitizing effect while chronic inflammation damages pancreatic beta-cells leading to reduced insulin response. We aimed to prove the hypothesis that adiponectin levels and inflammatory markers (white blood cell counts [WCC], Helicobacter pylori [HP] titers, high sensitivity C-reactive protein [hs-CRP]) may interact to affect risk of diabetes. We studied 288 Chinese men (age-median: 41.0 years, IQR: 35.3-46.0 years) being recruited from the community in Hong Kong. The mean adiponectin level was 5.39+/-2.81 microg/ml and 40.9% (n=107) had low adiponectin level (4 microg/ml). On multiple regression analysis, adiponectin was negatively associated with diabetes, HOMA insulin resistance top quartile, plasma glucose (PG) and 2h insulin; and positively associated with HOMA insulin sensitivity index. WCC was independently associated with PG and 15' insulin, and negatively associated with HOMA insulin sensitivity top quartile. HP titre was associated with 30' PG level and diabetes. hs-CRP did not enter the multivariable model. In conclusion, adiponectin, WCC and HP titer are independent predictors for hyperglycemia and reduced insulin sensitivity in Chinese men. These findings may explain the high risk for diabetes in Chinese population despite their relatively low adiposity.

Background: A recently halted clinical trial showed that intensive treatment of type 2 diabetes mellitus was associated with increased mortality. Given the phenotypic heterogeneity of diabetes, therapy targeted at insulin status may maximize benefits and minimize harm. Methods: In this longitudinal cohort study, we followed 503 patients with type 2 diabetes who were free of cardiovascular disease from 1996 until data on mortality and cardiovascular outcomes were censored in 2005. Phenotype-targeted therapy was defined as use of insulin therapy in patients with a fasting plasma C peptide level of 0.2 nmol/L or less and no insulin therapy in patients with higher C peptide levels. Results: The mean age of the cohort was 54.4 (standard deviation 13.1) years, and 56% were women. The mean duration of diabetes was 4.6 years (range 0–35.9 years). Of the 503 patients, 110 (21.9%) had a low C peptide level and 111 (22.1%) were given insulin. Based on their C peptide status, 338 patients (67.2%) received phenotype-targeted therapy (non-insulin-treated, high C peptide level [ n = 310] or insulin-treated, low C peptide level [ n = 28]), and 165 patients (32.8%) received non-phenotype-targeted therapy (non-insulin-treated, low C peptide level [ n = 82] or insulin-treated, high C peptide level [ n = 83]). Compared with the insulin-treated, low-C-peptide referent group, the insulin-treated, high-C-peptide group was at a significantly higher risk of cardiovascular events (hazard ratio [HR] 2.85, p = 0.049) and death (HR 3.43, p = 0.043); the risk was not significantly higher in the other 2 groups. These differences were no longer significant after adjusting for age, sex and diabetes duration. Interpretation: Patients with low C peptide levels who received insulin had the best clinical outcomes. Patients with normal to high C peptide levels who received insulin had the worst clinical outcomes. The results suggest that phenotype-targeted insulin therapy may be important in treating diabetes.