Impaired GK-GKRP interaction rather than direct GK activation worsens lipid profiles and contributes to long-term complications: a Mendelian randomization study.

BACKGROUND: Glucokinase (GK) plays a key role in glucose metabolism. In the liver, GK is regulated by GK regulatory protein (GKRP) with nuclear sequestration at low plasma glucose level. Some GK activators (GKAs) disrupt GK-GKRP interaction which increases hepatic cytoplasmic GK level. Excess hepatic GK activity may exceed the capacity of glycogen synthesis with excess triglyceride formation. It remains uncertain whether hypertriglyceridemia associated with some GKAs in previous clinical trials was due to direct GK activation or impaired GK-GKRP interaction. METHODS: Using publicly available genome-wide association study summary statistics, we selected independent genetic variants of GCKR and GCK associated with fasting plasma glucose (FPG) as instrumental variables, to mimic the effects of impaired GK-GKRP interaction and direct GK activation, respectively. We applied two-sample Mendelian Randomization (MR) framework to assess their causal associations with lipid-related traits, risks of metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular diseases. We verified these findings in one-sample MR analysis using individual-level statistics from the Hong Kong Diabetes Register (HKDR). RESULTS: Genetically-proxied impaired GK-GKRP interaction increased plasma triglycerides, low-density lipoprotein cholesterol and apolipoprotein B levels with increased odds ratio (OR) of 14.6 (95% CI 4.57-46.4) per 1 mmol/L lower FPG for MASLD and OR of 2.92 (95% CI 1.78-4.81) for coronary artery disease (CAD). Genetically-proxied GK activation was associated with decreased risk of CAD (OR 0.69, 95% CI 0.54-0.88) and not with dyslipidemia. One-sample MR validation in HKDR showed consistent results. CONCLUSIONS: Impaired GK-GKRP interaction, rather than direct GK activation, may worsen lipid profiles and increase risks of MASLD and CAD. Development of future GKAs should avoid interfering with GK-GKRP interaction.

Monogenic diabetes in a Chinese population with young-onset diabetes: A 17-year prospective follow-up study in Hong Kong.

AIMS: Asians have a high prevalence of young-onset diabetes, but the pattern of monogenic diabetes is unknown. We aimed to determine the prevalence of monogenic diabetes in Chinese patients with young-onset diabetes and compare the clinical characteristics and outcome between patients with and without monogenic diabetes. MATERIALS AND METHODS: We sequenced a targeted panel of 33 genes related to monogenic diabetes in 1021 Chinese patients with non-type 1 diabetes diagnosed at age ≤40 years. Incident complications including cardiovascular disease (CVD), end-stage kidney disease (ESKD) and all-cause death were captured since enrolment (1995-2012) until 2019. RESULTS: In this cohort (mean ± SD age at diagnosis: 33.0 ± 6.0 years, median[IQR] diabetes duration 7.0[1.0-15.0] years at baseline, 44.9% men), 22(2.2%, 95% confidence interval[CI] 1.4%-3.2%) had monogenic diabetes. Pathogenic (P) or likely pathogenic (LP) variants were detected in GCK (n = 6), HNF1A (n = 9), HNF4A (n = 1), PLIN1 (n = 1) and PPARG (n = 2), together with copy number variations in HNF1B (n = 3). Over a median follow-up of 17.1 years, 5(22.7%) patients with monogenic diabetes (incidence rate 12.3[95% CI 5.1-29.4] per 1000 person-years) versus 254(25.4%) without monogenic diabetes (incidence rate 16.7[95% CI 14.8-18.9] per 1000 person-years) developed the composite outcome of CVD, ESKD and/or death (p = 0.490). The multivariable Cox model did not show any difference in hazards for composite events between groups. CONCLUSIONS: In Chinese with young-onset non-type 1 diabetes, at least 2% of cases were contributed by monogenic diabetes, over 80% of which were accounted for by P/LP variants in common MODY genes. The incidence of diabetes complications was similar between patients with and without monogenic diabetes.

Association of dipeptidyl peptidase-4 inhibitor initiation at glycated haemoglobin <7.5% with reduced major clinical events mediated by low glycated haemoglobin variability.

AIM: Therapeutic inertia, hypoglycaemia and poor treatment persistence can lead to glycaemic fluctuation and poor outcomes in type 2 diabetes (T2D). We compared glycated haemoglobin (HbA1c) variability, insulin initiation, severe hypoglycaemia and clinical events in patients with T2D initiated dipeptidyl peptidase-4 inhibitors (DPP4is) at low versus high HbA1c thresholds. METHODS: Using territory-wide electronic medical records in Hong Kong, we curated a propensity score-matched cohort of patients initiated DPP4i at HbA1c <7.5% versus ≥7.5% in 2007-2019. We expressed the HbA1c variability score (HVS) as a proportion of HbA1c varied by ≥0.5% compared with preceding values. We used the Cox model to compare the risks of insulin initiation and clinical outcomes, adjusted for time-varying variables between the two groups. Mediation analysis estimated the effects of HbA1c variability on outcomes. RESULTS: Among 6874 insulin-naïve patients who initiated DPP4i, 88.7% were treated with metformin and 79.6% with sulphonylureas at baseline (54.9% men; mean age 65.2 ± 11.4 years). After a median follow-up of 4.6 years, compared with the high-threshold plus high-HVS group (≥50%), the low-threshold plus low-HVS (<50%) group had reduced hazard ratios (95% confidence interval) of insulin initiation (0.35, 0.31-0.40), severe hypoglycaemia (0.38, 0.34-0.44), major adverse cardiovascular endpoints (0.76, 0.66-0.88), heart failure (0.42, 0.36-0.49), end-stage kidney disease (0.65, 0.36-0.49) and mortality (0.45, 0.35-0.57). Reduced HbA1c variability explained 31.1%-81.2% of the effect size of DPP4i initiation at HbA1c <7.5% versus ≥7.5% on outcomes. CONCLUSIONS: In Chinese patients with T2D, avoiding therapeutic inertia with intensified glycaemic control at HbA1c <7.5% using drugs with low risk of hypoglycaemia and good tolerability, such as DPP4i, delayed insulin treatment, reduced HbA1c variability and improved clinical events.

A novel electronic health record-based, machine-learning model to predict severe hypoglycemia leading to hospitalizations in older adults with diabetes: A territory-wide cohort and modeling study.

BACKGROUND: Older adults with diabetes are at high risk of severe hypoglycemia (SH). Many machine-learning (ML) models predict short-term hypoglycemia are not specific for older adults and show poor precision-recall. We aimed to develop a multidimensional, electronic health record (EHR)-based ML model to predict one-year risk of SH requiring hospitalization in older adults with diabetes. METHODS AND FINDINGS: We adopted a case-control design for a retrospective territory-wide cohort of 1,456,618 records from 364,863 unique older adults (age ≥65 years) with diabetes and at least 1 Hong Kong Hospital Authority attendance from 2013 to 2018. We used 258 predictors including demographics, admissions, diagnoses, medications, and routine laboratory tests in a one-year period to predict SH events requiring hospitalization in the following 12 months. The cohort was randomly split into training, testing, and internal validation sets in a 7:2:1 ratio. Six ML algorithms were evaluated including logistic-regression, random forest, gradient boost machine, deep neural network (DNN), XGBoost, and Rulefit. We tested our model in a temporal validation cohort in the Hong Kong Diabetes Register with predictors defined in 2018 and outcome events defined in 2019. Predictive performance was assessed using area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC) statistics, and positive predictive value (PPV). We identified 11,128 SH events requiring hospitalization during the observation periods. The XGBoost model yielded the best performance (AUROC = 0.978 [95% CI 0.972 to 0.984]; AUPRC = 0.670 [95% CI 0.652 to 0.688]; PPV = 0.721 [95% CI 0.703 to 0.739]). This was superior to an 11-variable conventional logistic-regression model comprised of age, sex, history of SH, hypertension, blood glucose, kidney function measurements, and use of oral glucose-lowering drugs (GLDs) (AUROC = 0.906; AUPRC = 0.085; PPV = 0.468). Top impactful predictors included non-use of lipid-regulating drugs, in-patient admission, urgent emergency triage, insulin use, and history of SH. External validation in the HKDR cohort yielded AUROC of 0.856 [95% CI 0.838 to 0.873]. Main limitations of this study included limited transportability of the model and lack of geographically independent validation. CONCLUSIONS: Our novel-ML model demonstrated good discrimination and high precision in predicting one-year risk of SH requiring hospitalization. This may be integrated into EHR decision support systems for preemptive intervention in older adults at highest risk.

Comparison of ß-Cell Function and Insulin Sensitivity Between Normal-Weight and Obese Chinese With Young-Onset Type 2 Diabetes.

Normal-weight individuals with usual-onset type 2 diabetes have reduced ß-cell function and greater insulin sensitivity compared with their obese counterparts. The relative contribution of ß-cell dysfunction and insulin resistance to young-onset type 2 diabetes (YOD) among normal-weight individuals is not well established. In 44 individuals with YOD (24 with normal weight and 20 with obesity) and 24 healthy control individuals with normoglycemia (12 with normal weight and 12 with obesity), we conducted 2-h 12 mmol/L hyperglycemic clamps to measure acute (0-10 min) and steady-state (100-120 min) insulin and C-peptide responses, as well as insulin sensitivity index. Normal-weight individuals with YOD had lower acute insulin response, steady-state insulin and C-peptide responses, and a higher insulin sensitivity index compared with their obese counterparts with YOD. Compared with BMI-matched healthy control individuals, normal-weight individuals with YOD had lower acute and steady-state insulin and C-peptide responses but a similar insulin sensitivity index. The impairment of steady-state ß-cell response relative to healthy control individuals was more pronounced in normal-weight versus obese individuals with YOD. In conclusion, normal-weight Chinese with YOD exhibited worse ß-cell function but preserved insulin sensitivity relative to obese individuals with YOD and BMI-matched healthy individuals with normoglycemia. The selection of glucose-lowering therapy should account for pathophysiological differences underlying YOD between normal-weight and obese individuals.

Circulating metabolomic markers linking diabetic kidney disease and incident cardiovascular disease in type 2 diabetes: analyses from the Hong Kong Diabetes Biobank.

AIMS/HYPOTHESIS: The aim of this study was to describe the metabolome in diabetic kidney disease (DKD) and its association with incident CVD in type 2 diabetes, and identify prognostic biomarkers. METHODS: From a prospective cohort of individuals with type 2 diabetes, baseline sera (N=1991) were quantified for 170 metabolites using NMR spectroscopy with median 5.2 years of follow-up. Associations of chronic kidney disease (CKD, eGFR<60 ml/min per 1.73 m2) or severely increased albuminuria with each metabolite were examined using linear regression, adjusted for confounders and multiplicity. Associations between DKD (CKD or severely increased albuminuria)-related metabolites and incident CVD were examined using Cox regressions. Metabolomic biomarkers were identified and assessed for CVD prediction and replicated in two independent cohorts. RESULTS: At false discovery rate (FDR)<0.05, 156 metabolites were associated with DKD (151 for CKD and 128 for severely increased albuminuria), including apolipoprotein B-containing lipoproteins, HDL, fatty acids, phenylalanine, tyrosine, albumin and glycoprotein acetyls. Over 5.2 years of follow-up, 75 metabolites were associated with incident CVD at FDR<0.05. A model comprising age, sex and three metabolites (albumin, triglycerides in large HDL and phospholipids in small LDL) performed comparably to conventional risk factors (C statistic 0.765 vs 0.762, p=0.893) and adding the three metabolites further improved CVD prediction (C statistic from 0.762 to 0.797, p=0.014) and improved discrimination and reclassification. The 3-metabolite score was validated in independent Chinese and Dutch cohorts. CONCLUSIONS/INTERPRETATION: Altered metabolomic signatures in DKD are associated with incident CVD and improve CVD risk stratification.

1-year weight change after diabetes diagnosis and long-term incidence and sustainability of remission of type 2 diabetes in real-world settings in Hong Kong: An observational cohort study.

BACKGROUND: Clinical trials have demonstrated that remission of type 2 diabetes can be achieved following sustained weight loss. However, the feasibility of achieving diabetes remission through weight management in real-world settings remains unclear. In this study, we aimed to examine the association of weight change at 1 year after diabetes diagnosis with long-term incidence and sustainability of type 2 diabetes remission in real-world settings in Hong Kong. METHODS AND FINDINGS: This was a population-based observational cohort study. The territory-wide Risk Assessment and Management Programme for Diabetes Mellitus (RAMP-DM) provides regular comprehensive assessments of metabolic control and complication screening for people with diabetes in Hong Kong. We included 37,326 people with newly diagnosed type 2 diabetes who were enrolled in the RAMP-DM between 2000 and 2017, followed until 2019. Diabetes remission was defined as 2 consecutive HbA1c <6.5% measurements at least 6 months apart in the absence of glucose-lowering drugs (GLDs) and with no record of GLDs at least 3 months before these measurements. During a median follow-up of 7.9 years, 6.1% (2,279) of people achieved diabetes remission, with an incidence rate of 7.8 (95% CI: 7.5, 8.1) per 1,000 person-years. After adjusting for age at diabetes diagnosis, sex, assessment year, body mass index, other metabolic indices, smoking, alcohol drinking, and medication use, the hazard ratio (HR) for diabetes remission was 3.28 (95% CI: 2.75, 3.92; p < 0.001) for people with ≥10% weight loss within 1 year of diagnosis, 2.29 (95% CI: 2.03, 2.59; p < 0.001) for those with 5% to 9.9% weight loss, and 1.34 (95% CI: 1.22, 1.47; p < 0.001) for those with 0% to 4.9% weight loss compared to people with weight gain. During a median follow-up of 3.1 years, 67.2% (1,531) of people who had achieved diabetes remission returned to hyperglycaemia, with an incidence rate of 184.8 (95% CI: 175.5, 194.0) per 1,000 person-years. The adjusted HR for returning to hyperglycaemia was 0.52 (95% CI: 0.41, 0.65; p < 0.001) for people with ≥10% weight loss, 0.78 (95% CI: 0.68, 0.92; p = 0.002) for those with 5% to 9.9% weight loss, and 0.90 (95% CI: 0.80, 1.01; p = 0.073) for those with 0% to 4.9% weight loss compared to people with weight gain. Diabetes remission was associated with a 31% (HR: 0.69, 95% CI: 0.52, 0.93; p = 0.014) decreased risk of all-cause mortality. The main limitation of the study is that the reliability of HbA1c used to define diabetes remission can be affected by other medical conditions. Furthermore, we did not have data on bariatric surgery. CONCLUSIONS: In this study, greater weight loss within the first year of diabetes diagnosis was associated with an increased likelihood of achieving diabetes remission and a decreased risk of returning to hyperglycaemia among those who had achieved diabetes remission. However, both the incidence of diabetes remission and the probability of its long-term sustainability were low with conventional management in real-world settings, in an era when the importance of weight loss was not fully appreciated. Our study provides evidence for policymakers to design and implement early weight management interventions and diabetes remission initiatives.

Early treatment with dipeptidyl-peptidase 4 inhibitors reduces glycaemic variability and delays insulin initiation in type 2 diabetes: A propensity score-matched cohort study.

AIMS: To examine whether early treatment intensification using dipeptidyl-peptidase 4 inhibitors (DPP4i) delays insulin initiation in Chinese patients diagnosed with type 2 diabetes for less than 5 years. MATERIALS AND METHODS: In a territory-wide prospective cohort study, patients with type 2 diabetes initiating DPP4i at diabetes duration <2 years (early intensification) and 3-5 years (late intensification) were matched using 1:1 propensity-score matching (n = 908 in each arm). We used Cox regression to compare the risk of insulin initiation between the two groups. We explored the interactive and mediation effects of glycated haemoglobin (HbA1c) variability score (HVS), defined as the percentage of HbA1c varying by ≥0.5% compared with preceding values. RESULTS: Of 1816 patients (60.7% men, mean age 54.4 ± 11.9 years), 92.4% and 71.9% were treated with metformin and sulphonylureas respectively at DPP4i initiation. Early DPP4i intensification [hazard ratio (HR) 0.71, (95% CI 0.58-0.68)] and low HVS (<50%) (HR = 0.40, 0.33-0.50) were associated with delayed insulin initiation during a median 4.08 years of follow-up. Early intensification with low HVS had the lowest risk versus late intensification with high HVS (HR = 0.30, 0.22-0.40) (pinteraction  = 0.013). HVS mediated 19.5% of the total effect of early DPP4i intensification on delaying insulin initiation. The late and early intensification groups had similar HbA1c at month 0 (8.4 ± 1.3% vs. 8.4 ± 1.5%) and month 3 (7.6 ± 1.2% vs. 7.6 ± 1.3%) after DPP4i initiation. By month 12, HbA1c in the late intensification group deteriorated (7.9 ± 1.4%) but remained stable in the early intensification group (7.6 ± 1.4%, p = 0.001) with persistent between-group difference over 72 months (8.2 ± 1.7% vs. 7.7 ± 1.6%, p = 0.001). CONCLUSIONS: In type 2 diabetes, early DPP4i intensification delayed insulin initiation, partially explained by reduced glycaemic variability.

Temporal associations of diabetes-related complications with health-related quality of life decrements in Chinese patients with type 2 diabetes: A prospective study among 19 322 adults-Joint Asia Diabetes Evaluation (JADE) register (2007-2018).

BACKGROUND: Patients with type 2 diabetes (T2D) are at high risk of developing multiple complications, affecting their health-related quality of life (HRQoL). Existing studies only considered impact of complication on HRQoL in the year of occurrence but not its residual impacts in subsequent years. We investigated temporal impacts of diabetes-related complications on HRQoL in a 12-year prospective cohort of ambulatory Chinese patients with T2D enrolled in the clinic-based Joint Asia Diabetes Evaluation (JADE) Register. METHODS: HRQoL utility measures were derived from EuroQol five-dimensional three-level questionnaire (EQ-5D-3L) questionnaires completed by 19 322 patients with T2D in Hong Kong (2007-2018). Temporal EQ-5D utility decrements associated with subtypes of cardiovascular-renal events were estimated using generalized linear regression model after stepwise selection of covariates with p < .01 as cutoff. RESULTS: In this cohort (mean ± SD age:61.2 ± 11.5 years, 55.3% men, median [interquartile range] duration of diabetes:10.1 [3.0-15.0] years, glycated hemoglobin [HbA1C ] 7.5 ± 1.5%), EQ-5D utility was 0.860 ± 0.163. The largest HRQoL decrements were observed in year of occurrence of hemorrhagic stroke (-0.230), followed by ischemic stroke (-0.165), peripheral vascular disease (-0.117), lower extremity amputation (-0.093), chronic kidney disease (CKD) G5 without renal replacement therapy (RRT) (-0.079), congestive heart failure (CHF) (-0.061), and CKD G3-G4 without RRT (-0.042). Residual impacts on HRQoL persisted for 2 years after occurrence of CHF or ischemic stroke and 1 year after hemorrhagic stroke or CKD G3-G4 without RRT. CONCLUSION: This is the first comprehensive report on temporal associations of HRQoL decrements with subtypes of diabetes-related complications in ambulatory Asian patients with T2D. These data will improve the accuracy of cost-effectiveness analysis of diabetes interventions at an individual level in an Asian setting.

Comparison of beta-cell function between Hong Kong Chinese with young-onset type 2 diabetes and late-onset type 2 diabetes.

AIMS: We compared beta-cell function in Chinese with type 2 diabetes diagnosed at age < 40 years (young-onset diabetes, YOD) and ≥ 40 years (late-onset diabetes, LOD). METHODS: In this cross-sectional study, we selected participants from two cohorts of people with type 2 diabetes recruited in 1996-2012 (n = 4,376) and 2020-2021 (n = 794). Multivariable linear regression models were applied to compare homeostasis model assessment of beta-cell function (HOMA2-%B) and fasting plasma C-peptide across diabetes duration at enrolment between YOD and LOD. RESULTS: The YOD group (n = 1,876, mean [SD] age: 39.9 [7.5] years, median [IQR] diabetes duration: 6 [2-12] years) was more likely to have family history of diabetes (61.6 % vs 43.6 %), obesity (41.9 % vs 26.8 %), dyslipidaemia (61.7 % vs 54.4 %), and worse glycaemic control (mean HbA1c 7.7 % vs 7.4 %) than those with LOD (n = 3,294, age: 60.8 [10.6] years, diabetes duration: 5 [1-10] years). When compared to people with LOD, HOMA2-%B and fasting plasma C-peptide were lower in the YOD group, consistently among those with BMI < 27.5 kg/m2 and HOMA2-IR ≤ 1.6 (median value), adjusted for year at enrolment, sex, diabetes duration, family history of diabetes, HbA1c, weight and lipid indices (p < 0.01). Cross-sectionally, the slopes of decline in HOMA2-%B by diabetes duration were greater in YOD than LOD among individuals with BMI < 27.5 kg/m2 (p-interaction = 0.015). CONCLUSIONS: Chinese with YOD had accelerated loss of beta-cell function than those with LOD especially in non-obese individuals.

Age- and sex-specific hospital bed-day rates in people with and without type 2 diabetes: A territory-wide population-based cohort study of 1.5 million people in Hong Kong.

BACKGROUND: Type 2 diabetes affects multiple systems. We aimed to compare age- and sex-specific rates of all-cause and cause-specific hospital bed-days between people with and without type 2 diabetes. METHODS AND FINDINGS: Data were provided by the Hong Kong Hospital Authority. We included 1,516,508 one-to-one matched people with incident type 2 diabetes (n = 758,254) and those without diabetes during the entire follow-up period (n = 758,254) between 2002 and 2018, followed until 2019. People with type 2 diabetes and controls were matched for age at index date (±2 years), sex, and index year (±2 years). We defined hospital bed-day rate as total inpatient bed-days divided by follow-up time. We constructed negative binominal regression models to estimate hospital bed-day rate ratios (RRs) by age at diabetes diagnosis and sex. All RRs were stratified by sex and adjusted for age and index year. During a median of 7.8 years of follow-up, 60.5% (n = 459,440) of people with type 2 diabetes and 56.5% (n = 428,296) of controls had a hospital admission for any cause, with a hospital bed-day rate of 3,359 bed-days and 2,350 bed-days per 1,000 person-years, respectively. All-cause hospital bed-day rate increased with increasing age in controls, but showed a J-shaped relationship with age in people with type 2 diabetes, with 38.4% of bed-days in those diagnosed <40 years caused by mental health disorders. Type 2 diabetes was associated with increased risks for a wide range of medical conditions, with an RR of 1.75 (95% CI [confidence interval] [1.73, 1.76]; p < 0.001) for all-cause hospital bed-days in men and 1.87 (95% CI [1.85, 1.89]; p < 0.001) in women. The RRs were greater in people with diabetes diagnosed at a younger than older age and varied by sex according to medical conditions. Sex differences were most notable for a higher RR for urinary tract infection and peptic ulcer, and a lower RR for chronic kidney disease and pancreatic disease in women than men. The main limitation of the study was that young people without diabetes in the database were unlikely to be representative of those in the Hong Kong general population with potential selection bias due to inclusion of individuals in need of medical care. CONCLUSIONS: In this study, we observed that type 2 diabetes was associated with increased risks of hospital bed-days for a wide range of medical conditions, with an excess burden of mental health disorders in people diagnosed at a young age. Age and sex differences should be considered in planning preventive and therapeutic strategies for type 2 diabetes. Effective control of risk factors with a focus on mental health disorders are urgently needed in young people with type 2 diabetes. Healthcare systems and policymakers should consider allocating adequate resources and developing strategies to meet the mental health needs of young people with type 2 diabetes, including integrating mental health services into diabetes care.

Divergent Survival Outcomes Associated with Elevated Branched-Chain Amino Acid Levels among Older Adults with or without Hypertension and Diabetes: A Validated, Prospective, Longitudinal Follow-Up Study.

Branched-chain amino acids are critical metabolic intermediates that can indicate increased risk of cardiometabolic disease when levels are elevated or, alternatively, suggest sufficient mitochondrial energy metabolism and reserve in old age. The interpretation of BCAA levels can be context-dependent, and it remains unclear whether abnormal levels can inform prognosis. This prospective longitudinal study aimed to determine the interrelationship between mortality hazard and fasting serum BCAA levels among older men and women aged ≥65 years with or without hypertension and diabetes mellitus. At baseline (0Y), fasting serum BCAA concentration in 2997 community-living older men and women were measured. Approximately 14 years later (14Y), 860 study participants returned for repeat measurements. Deaths were analysed and classified into cardiovascular and non-cardiovascular causes using International Classification of Diseases codes. Survival analysis and multivariable Cox regression were performed. During a median follow-up of 17Y, 971 (78.6%) non-cardiovascular and 263 (21.4%) cardiovascular deaths occurred among 1235 (41.2%) deceased (median age, 85.8 years [IQR 81.7-89.7]). From 0Y to 14Y, BCAA levels declined in both sexes, whereas serum creatinine concentration increased (both p < 0.0001). In older adults without hypertension or diabetes mellitus, the relationship between mortality hazard and BCAA level was linear and above-median BCAA levels were associated with improved survival, whereas in the presence of cardiometabolic disease the relationship was U-shaped. Overall, adjusted Cox regression determined that each 10% increment in BCAA concentration was associated with a 7% (p = 0.0002) and 16% (p = 0.0057) reduction in mortality hazard estimated at 0Y and 14Y, respectively. Our findings suggested that abnormally high or low (dyshomeostatic) BCAA levels among older adults with hypertension and/or diabetes mellitus were associated with increased mortality, whereas in those with neither disease, increased BCAA levels was associated with improved survival, particularly in the oldest-old.

Cold-Induced Reprogramming of Subcutaneous White Adipose Tissue Assessed by Single-Cell and Single-Nucleus RNA Sequencing.

Adipose browning has demonstrated therapeutic potentials in several diseases. Here, by conducting transcriptomic profiling at the single-cell and single-nucleus resolution, we reconstituted the cellular atlas in mouse inguinal subcutaneous white adipose tissue (iWAT) at thermoneutrality or chronic cold condition. All major nonimmune cells within the iWAT, including adipose stem and progenitor cells (ASPCs), mature adipocytes, endothelial cells, Schwann cells, and smooth muscle cells, were recovered, allowing us to uncover an overall and detailed blueprint for transcriptomes and intercellular cross-talks and the dynamics during white adipose tissue brown remodeling. Our findings also unravel the existence of subpopulations in mature adipocytes, ASPCs, and endothelial cells, as well as new insights on their interconversion and reprogramming in response to cold. The adipocyte subpopulation competent of major histocompatibility complex class II (MHCII) antigen presentation is potentiated. Furthermore, a subcluster of ASPC with CD74 expression was identified as the precursor of this MHCII+ adipocyte. Beige adipocytes are transdifferented from preexisting lipid generating adipocytes, which exhibit developmental trajectory from de novo differentiation of amphiregulin cells (Aregs). Two distinct immune-like endothelial subpopulations are present in iWAT and are responsive to cold. Our data reveal fundamental changes during cold-evoked adipose browning.

Incident cardiovascular-kidney disease, diabetic ketoacidosis, hypoglycaemia and mortality in adult-onset type 1 diabetes: a population-based retrospective cohort study in Hong Kong.

Background: Type 1 diabetes can occur at any age. The majority of literature on type 1 diabetes were reported in children whereas adult-onset type 1 diabetes is less well characterised. This study aims to compare the risk of diabetes-related complications and mortality in Chinese with adult-onset type 1 diabetes versus those with youth-onset type 1 diabetes and adult-onset type 2 diabetes. Methods: Between 2000 and 2018, 2738 people with type 1 and 499,288 with type 2 diabetes underwent metabolic and complication assessment in Hong Kong Hospital Authority. They were followed for incident diabetic ketoacidosis (DKA), severe hypoglycaemia, end-stage kidney disease (ESKD), cardiovascular disease (CVD) and all-cause mortality until 2019. Findings: In multivariable Cox regression adjusted for sex, diabetes duration and calendar year, people with type 1 diabetes diagnosed aged ≥40 years had a lower hazard of DKA (hazard ratio HR [95% CI] 0.47 [0.32-0.70]) but higher hazards of severe hypoglycaemia (HR 1.37 [1.13-1.67]), ESKD (HR 4.62 [2.90-7.37]), CVD (HR 11.44 [6.92-18.91]) and mortality (HR 16.22 [11.43-23.02]) versus those diagnosed aged <20 years. Compared with peers with type 2 diabetes presenting at comparable age, people with type 1 diabetes diagnosed aged ≥40 years had higher age-, sex- and diabetes duration-adjusted hazards of DKA (HR 19.87 [13.95-28.31]), severe hypoglycaemia (HR 3.26 [2.81-3.80]), ESKD (HR 1.58 [1.20-2.09]) and mortality (HR 2.26 [1.96-2.60]), and a similar hazard of CVD (HR 1.11 [0.87-1.43]). These associations remained constant after adjustment for metabolic indices. Interpretation: People with type 1 diabetes diagnosed in late adulthood had elevated risks of a broad range of complications and mortality compared with people with youth-onset type 1 diabetes and people with type 2 diabetes presenting at same age bands. Funding: This study did not receive any specific funding.

Identification of a Common Variant for Coronary Heart Disease at PDE1A Contributes to Individualized Treatment Goals and Risk Stratification of Cardiovascular Complications in Chinese Patients With Type 2 Diabetes.

OBJECTIVE: In this study we aim to unravel genetic determinants of coronary heart disease (CHD) in type 2 diabetes (T2D) and explore their applications. RESEARCH DESIGN AND METHODS: We performed a two-stage genome-wide association study for CHD in Chinese patients with T2D (3,596 case and 8,898 control subjects), followed by replications in European patients with T2D (764 case and 4,276 control subjects) and general populations (n = 51,442-547,261). Each identified variant was examined for its association with a wide range of phenotypes and its interactions with glycemic, blood pressure (BP), and lipid controls in incident cardiovascular diseases. RESULTS: We identified a novel variant (rs10171703) for CHD (odds ratio 1.21 [95% CI 1.13-1.30]; P = 2.4 × 10-8) and BP (ß ± SE 0.130 ± 0.017; P = 4.1 × 10-14) at PDE1A in Chinese T2D patients but found only a modest association with CHD in general populations. This variant modulated the effects of BP goal attainment (130/80 mmHg) on CHD (Pinteraction = 0.0155) and myocardial infarction (MI) (Pinteraction = 5.1 × 10-4). Patients with CC genotype of rs10171703 had >40% reduction in either cardiovascular events in response to BP control (2.9 × 10-8 < P < 3.6 × 10-5), those with CT genotype had no difference (0.0726 < P < 0.2614), and those with TT genotype had a threefold increase in MI risk (P = 6.7 × 10-3). CONCLUSIONS: We discovered a novel CHD- and BP-related variant at PDE1A that interacted with BP goal attainment with divergent effects on CHD risk in Chinese patients with T2D. Incorporating this information may facilitate individualized treatment strategies for precision care in diabetes, only when our findings are validated.

Asia-Pacific consensus recommendations for application of continuous glucose monitoring in diabetes management.

Glucose monitoring has evolved from self-monitoring of blood glucose to glycated hemoglobin, and the latest continuous glucose monitoring (CGM). A key challenge to adoption of CGM for management of diabetes in Asia is the lack of regional CGM recommendations. Hence, thirteen diabetes-specialists from eight Asia-Pacific (APAC) countries/regions convened to formulate evidence-based, APAC-specific CGM recommendations for individuals with diabetes. We defined CGM metrics/targets and developed 13 guiding-statements on use of CGM in: (1) people with diabetes on intensive insulin therapy, and (2) people with type 2 diabetes on basal insulin with/without glucose lowering drugs. Continual use of CGM is recommended in individuals with diabetes on intensive insulin therapy and suboptimal glycemic control, or at high risk of problematic hypoglycemia. Continual/intermittent CGM may also be considered in individuals with type 2 diabetes on basal insulin regimen and with suboptimal glycemic control. In this paper, we provided guidance for optimizing CGM in special populations/situations, including elderly, pregnancy, Ramadan-fasting, newly diagnosed type 1 diabetes, and comorbid renal disease. Statements on remote CGM, and stepwise interpretation of CGM data were also developed. Two Delphi surveys were conducted to rate the agreement on statements. The current APAC-specific CGM recommendations provide useful guidance for optimizing use of CGM in the region.

Higher incidence of cardiovascular-kidney complications in Chinese with youth-onset type 2 diabetes versus youth-onset type 1 diabetes attenuated by control of cardio-metabolic risk factors: A population-based prospective cohort study in Hong Kong.

AIMS: To determine and compare the incidence of diabetes complications in Chinese with youth-onset type 2 and type 1 diabetes. METHODS: We conducted a population-based prospective cohort study, including 1,260 people with type 2 diabetes and 1,227 with type 1 diabetes diagnosed at age < 20 years who underwent metabolic and complication assessment in Hong Kong Hospital Authority between 2000 and 2018. They were followed for incident cardiovascular disease (CVD), end-stage kidney disease (ESKD) and all-cause death until 2019. Multivariable Cox regression analysis was applied to compare the risks of these complications in type 2 versus type 1 diabetes. RESULTS: People with type 1 diabetes (median age: 20 years, median diabetes duration: 9 years) and type 2 diabetes (median age: 21 years, median diabetes duration: 6 years) were followed for a mean period of 9.2 and 8.8 years respectively. The risks of CVD (HR [95 % CI] 1.66 [1.01-2.72]) and ESKD (HR 1.96 [1.27-3.04]) but not death (HR 1.10 [0.72-1.67]) were higher in type 2 versus type 1 diabetes, adjusted for age at diagnosis, diabetes duration and sex. The association became nonsignificant with further adjustment for glycaemic and metabolic control. Youth-onset type 2 diabetes conferred mortality excess (standardized mortality ratio 4.15 [3.28-5.17]) to age- and sex-matched general population. CONCLUSIONS: People with youth-onset type 2 diabetes had higher incidence rates of CVD and ESKD than type 1 diabetes. The excess risks in type 2 diabetes were removed after adjusted for cardio-metabolic risk factors.

Team-Based Diabetes Care in Ontario and Hong Kong: a Comparative Review.

PURPOSE OF REVIEW: There are gaps in implementing and accessing team-based diabetes care. We reviewed and compared how team-based diabetes care was implemented in the primary care contexts of Ontario and Hong Kong. RECENT FINDINGS: Ontario's Diabetes Education Programs (DEPs) were scaled-up incrementally. Hong Kong's Multidisciplinary Risk Assessment and Management Program for Diabetes Mellitus (RAMP-DM) evolved from a research-driven quality improvement program. Each jurisdiction had a mixture of non-team and team-based primary care with variable accessibility. Referral procedures, follow-up processes, and financing models varied. DEPs used a flexible approach, while the RAMP-DM used structured assessment for quality assurance. Each approach depended on adequate infrastructure, processes, and staff. Diabetes care is most accessible and functional when integrated team-based services are automatically initiated upon diabetes diagnosis within a strong primary care system, ideally linked to a register with supports including specialist care. Structured assessment and risk stratification are the basis of a well-studied, evidence-based approach for achieving the standards of team-based diabetes care, although flexibility in care delivery may be needed to meet the unique needs of some individuals. Policymakers and funders should ensure investment in skilled health professionals, infrastructure, and processes to improve care quality.

Differential Associations of GAD Antibodies (GADA) and C-Peptide With Insulin Initiation, Glycemic Responses, and Severe Hypoglycemia in Patients Diagnosed With Type 2 Diabetes.

OBJECTIVE: We examined the associations of GAD antibodies (GADA) and C-peptide (CP) with insulin initiation, glycemic responses, and severe hypoglycemia in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: In 5,230 Chinese patients (47.6% men) with T2D (mean ± SD age: 56.5 ± 13.9 years; median diabetes duration: 6 [interquartile range 1, 12] years), enrolled consecutively in 1996-2012 and prospectively observed until 2019, we retrospectively measured fasting CP and GADA in stored serum and examined their associations with aforementioned outcomes. RESULTS: At baseline, 28.6% (n = 1,494) had low CP (<200 pmol/L) and 4.9% (n = 257) had positive GADA (GADA+). In the low-CP group, 8.0% had GADA+, and, in the GADA+ group, 46.3% had low CP. The GADA+ group had an adjusted hazard ratio (aHR) of 1.46 (95% CI 1.15-1.84, P = 0.002) for insulin initiation versus the GADA- group, while the low-CP group had an aHR of 0.88 (0.77-1.00, P = 0.051) versus the high-CP group. Following insulin initiation, the GADA+ plus low-CP group had the largest decrements in HbA1c (-1.9% at month 6; -1.5% at month 12 vs. -1% in the other three groups). The aHR of severe hypoglycemia was 1.29 (95% CI 1.10-1.52, P = 0.002) in the low-CP group and 1.38 (95% CI 1.04-1.83, P = 0.024) in the GADA+ group. CONCLUSIONS: There is considerable heterogeneity in autoimmunity and ß-cell dysfunction in T2D with GADA+ and high CP associated with early insulin initiation, while GADA+ and low CP, increased the risk of severe hypoglycemia. Extended phenotyping is warranted to increase the precision of classification and treatment in T2D.

Young-onset diabetes in women with Polycystic Ovary Syndrome: A territory-wide retrospective analysis in Hong Kong.

AIM: To ascertain the risk of progression to diabetes among Chinese women with PCOS. METHODS: Women with PCOS (n = 3978) were identified from the Hong Kong Diabetes Surveillance Database based on the ICD-9 code for PCOS diagnosis and women without PCOS served as controls (n = 39780), matched 1:10 by age. RESULT(S): The mean follow-up was 6.28 ± 4.20 and 6.95 ± 4.33 years in women with PCOS and controls, respectively. The crude incidence rate of diabetes was 14.25/1000 person-years in women with PCOS compared with 3.45 in controls. The crude hazard ratio of diabetes in women with PCOS was 4.23 (95 % CI: 3.73-4.80, p < 0.001). Further stratified by age group, the risk of developing diabetes decreased with increasing age but it remained significantly higher in women with PCOS across all age groups. It also suggested that the incidence rate of diabetes in women with PCOS aged 20-29 is highly comparable to that in healthy women aged ≥ 40. More than half of the incident diabetes captured during the follow-up in women with PCOS cohort were young-onset diabetes. CONCLUSION: Women diagnosed with PCOS at a younger age have the highest relative risk of developing diabetes, suggesting frequent glycemic status screening is required to detect diabetes at an early stage.