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).
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.
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.
There is considerable heterogeneity in autoimmunity and β-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.
Leukocyte telomere length (LTL) is suggested to be a biomarker of biological age and reported to be associated with metabolic diseases such as type 2 diabetes. Glucose metabolic traits including ...glucose and insulin levels have been reported to be associated with LTL in adulthood. However, there is relatively little research focusing on children's LTL and the association with prenatal exposures. This study investigates the relationship between maternal and offspring glucose metabolism with offspring LTL in early life.
This study included 882 mother-child pairs from the HAPO Hong Kong Field Centre, with children evaluated at age 7.0 ± 0.4 (mean ± SD) years. Glucose metabolic traits including maternal post-load glucose during pregnancy, children's glucose and insulin levels, and their derived indices at follow-up were measured or calculated. Offspring LTL was assessed using real-time polymerase chain reaction.
Sex- and age-adjusted children's LTL was found to be associated with children's HOMA-IR (β=-0.046 ± 0.016, p=0.005). Interestingly, both children's and maternal post-load glucose levels were positively associated with children's LTL. However, negative associations were observed between children's LTL and children's OGTT insulin levels. In addition, the LTL in females was more strongly associated with pancreatic beta-cell function whilst LTL in males was more strongly associated with OGTT glucose levels.
Our findings suggest a close association between maternal and offspring glucose metabolic traits with early life LTL, with the offspring sex as an important modifier of the disparate relationships in insulin production and response.
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.
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.
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).
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.
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.
Consecutive Chinese patients with type 2 diabetes (
= 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.
Mean follow-up was 13.4 years (SD 5.5 years). rLTL was correlated inversely with age, diabetes duration, blood pressure, HbA
, and urine albumin-to-creatinine ratio (ACR), and positively with estimated glomerular filtration rate (eGFR) (all
< 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) (
< 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) (
< 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,
< 0.001), which remained significant after adjusting for age, sex, BMI, systolic blood pressure, LDL cholesterol, HbA
, eGFR, and ACR (hazard ratio 1.141 95% CI 1.084-1.200,
< 0.001).
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.
Aims/hypothesis
Few large-scale prospective studies have investigated associations between relative leucocyte telomere length (rLTL) and kidney dysfunction in individuals with type 2 diabetes. We ...examined relationships between rLTL and incident end-stage kidney disease (ESKD) and the slope of eGFR decline in Chinese individuals with type 2 diabetes.
Methods
We studied 4085 Chinese individuals with type 2 diabetes observed between 1995 and 2007 in the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data. rLTL was measured using quantitative PCR. ESKD was diagnosed based on the ICD-9 code and eGFR.
Results
In this cohort (mean ± SD age 54.3 ± 12.6 years) followed up for 14.1 ± 5.3 years, 564 individuals developed incident ESKD and had shorter rLTL at baseline (4.2 ± 1.2 vs 4.7 ± 1.2,
p
< 0.001) than the non-progressors (
n
= 3521). On Cox regression analysis, each ∆∆C
t
decrease in rLTL was associated with an increased risk of incident ESKD (HR 1.21 95% CI 1.13, 1.30,
p
< 0.001); the association remained significant after adjusting for baseline age, sex, HbA
1c
, lipids, renal function and other risk factors (HR 1.11 95% CI 1.03, 1.19,
p
= 0.007). Shorter rLTL at baseline was associated with rapid decline in eGFR (>4% per year) during follow-up (unadjusted OR 1.22 95% CI 1.15, 1.30,
p
< 0.001; adjusted OR 1.09 95% CI 1.01, 1.17,
p
= 0.024).
Conclusions/interpretation
rLTL is independently associated with incident ESKD and rapid eGFR loss in individuals with type 2 diabetes. Telomere length may be a useful biomarker for the progression of kidney function and ESKD in type 2 diabetes.
Graphical abstract
Aims/hypothesis
Accumulating evidence suggests an impact of gestational weight gain (GWG) on pregnancy outcomes; however, data on cardiometabolic risk factors later in life have not been ...comprehensively studied. This study aimed to evaluate the relationship between GWG and cardiometabolic risk in offspring aged 7 years.
Methods
We included a total of 905 mother–child pairs who enrolled in the follow-up visit of the multicentre Hyperglycemia and Adverse Pregnancy Outcome study, at the Hong Kong Centre. Women were classified as having gained weight below, within or exceeding the 2009 Institute of Medicine (IOM) guidelines. A standardised GWG according to pre-pregnancy BMI categories was calculated to explore for any quadratic relationship.
Results
Independent of pre-pregnancy BMI, gestational hyperglycaemia and other confounders, women who gained more weight than the IOM recommendations had offspring with a larger body size and increased odds of adiposity, hypertension and insulin resistance (range of
p
values of all the traits: 4.6 × 10
−9
<
p
< 0.0390) than women who were within the recommended range of weight gain during pregnancy. Meanwhile, women who gained less weight than outlined in the recommendations had offspring with increased risks of hypertension and insulin resistance, compared with those who gained weight within the recommended range (7.9 × 10
−3
<
p
< 0.0477). Quadratic relationships for diastolic blood pressure, AUC for insulin, pancreatic beta cell function and insulin sensitivity index were confirmed in the analysis of standardised GWG (1.4 × 10
−3
<
p
quadratic
< 0.0282). Further adjustment for current BMI noticeably attenuated the observed associations.
Conclusions/interpretation
Both excessive and inadequate GWG have independent and significant impacts on childhood adiposity, hypertension and insulin resistance. Our findings support the notion that adverse intrauterine exposures are associated with persistent cardiometabolic risk in the offspring.
Per- and polyfluoroalkyl substances (PFAS) are persistent chemicals that have been linked to increased risk of gestational diabetes mellitus (GDM) and may affect glucose metabolisms during pregnancy. ...We examined the associations between maternal PFAS exposure and maternal glucose metabolisms and GDM risk among 1601 mothers who joined the Hyperglycaemia-and-Adverse-Pregnancy-Outcome (HAPO) Study in Hong Kong in 2001–2006. All mothers underwent a 75 g-oral-glucose-tolerance test at 24–32 weeks of gestation. We measured serum concentrations of six PFAS biomarkers using high-performance liquid-chromatography-coupled-with-tandem-mass-spectrometry (LC-MS-MS). We fitted conventional and advanced models (quantile-g-computation qgcomp and Bayesian-kernel machine regression BKMR) to assess the associations of individual and a mixture of PFAS with glycaemic traits. Subgroup analyses were performed based on the enrollment period by the severe-acute-respiratory-syndrome (SARS) epidemic periods in Hong Kong between March 2003 and May 2004. PFOS and PFOA were the main components of PFAS mixture among 1601 pregnant women in the Hong Kong HAPO study, with significantly higher median PFOS concentrations (19.09 ng/mL), compared to Chinese pregnant women (9.40 ng/mL) and US women (5.27 ng/mL). Maternal exposure to PFAS mixture was associated with higher HbA1c in the qgcomp (β = 0.04, 95 % CI: 0.01–0.06) model. We did not observe significant associations of PFAS mixture with fasting plasma glucose (PG), 1-h and 2-h PG in either model, except for 2-h PG in the qgcmop model (β = 0.074, 95 % CI: 0.01–0.15). PFOS was the primary contributor to the overall positive effects on HbA1c. Epidemic-specific analyses showed specific associations between PFAS exposure and the odds of GDM in the pre-SARS epidemic period. The median concentration of PFOS was highest during the peri-SARS epidemic (21.2 14.5–43.6 ng/mL) compared with the pre-SARS (12.3 9.2–19.9 ng/mL) and post-SARS (20.3 14.2–46.3 ng/mL) epidemic periods. Potential interactions and exposure-response relationships between PFOA and PFNA with elevated HbA1c were observed in the peri-SARS period in BKMR model. Maternal exposure to PFAS mixture was associated with altered glucose metabolism during pregnancy. SARS epidemic-specific associations call for further studies on its long-term adverse health effects, especially potential modified associations by lifestyle changes during the COVID-19 pandemic.
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•PFAS mixture and its individual components were associated with higher maternal HbA1c.•PFOS was the primary contributor to the positive effects on HbA1c in the HAPO study in Hong Kong (n=1,601).•There were interactions and dose-response relationships between PFOA and PFNA with higher HbA1c in the peri-SARS period.
Aim
Levels of branched‐chain amino acids (BCAAs, namely, isoleucine, leucine, and valine) are modulated by dietary intake and metabolic/genetic factors. BCAAs are associated with insulin resistance ...and increased risk of type 2 diabetes (T2D). Although insulin resistance predicts heart failure (HF), the relationship between BCAAs and HF in T2D remains unknown.
Methods
In this prospective observational study, we measured BCAAs in fasting serum samples collected at inception from 2139 T2D patients free of cardiovascular‐renal diseases. The study outcome was the first hospitalization for HF.
Results
During 29 103 person‐years of follow‐up, 115 primary events occurred (age: 54.8 ± 11.2 years, 48.2% men, median interquartile range diabetes duration: 5 years 1‐10). Patients with incident HF had 5.6% higher serum BCAAs than those without HF (median 639.3 561.3‐756.3 vs 605.2 524.8‐708.7 μmol/L; P = .01). Serum BCAAs had a positive linear association with incident HF (per‐SD increase in logarithmically transformed BCAAs: hazard ratio HR 1.22 95% CI 1.07‐1.39), adjusting for age, sex, and diabetes duration. The HR remained significant after sequential adjustment of risk factors including incident coronary heart disease (1.24, 1.09‐1.41); blood pressure, low‐density lipoprotein cholesterol, and baseline use of related medications (1.31, 1.14‐1.50); HbA1c, waist circumference, triglyceride, and baseline use of related medications (1.28, 1.11‐1.48); albuminuria and estimated glomerular filtration rate (1.28, 1.11‐1.48). The competing risk of death analyses showed similar results.
Conclusions
Circulating levels of BCAAs are independently associated with incident HF in patients with T2D. Prospective cohort analysis and randomized trials are needed to evaluate the long‐term safety and efficacy of using different interventions to optimize BCAAs levels in these patients.
Leukocyte telomere length (LTL) is a biomarker of biological aging and is associated with metabolic diseases such as type 2 diabetes. Insufficient maternal vitamin D was associated with increased ...risk for many diseases and adverse later life outcomes.
This study investigates the relationship between vitamin D levels and offspring LTL at early life.
This observational, longitudinal, hospital-based cohort study included eligible mother-child pairs from the HAPO Hong Kong Field Centre, with 853 offspring at age 6.96 ± 0.44 (mean ± SD) years. LTL was measured using real-time polymerase chain reaction while serum vitamin D metabolites 25(OH)D2, 25(OH)D3, and 3-epi-25(OH)D3 were measured in maternal blood (at gestation 24-32 weeks) and cord blood by liquid chromatography-mass spectrometry.
LTL at follow-up was significantly shorter in boys compared with girls (P < 0.001) at age 7. Childhood LTL was negatively associated with childhood BMI (β ± SE = -0.016 ± 0.007)(P = 0.02) and HOMA-IR (β ± SE = -0.065 ± 0.021)(P = 0.002). Multiple linear regression was used to evaluate the relationship between 25(OH)D and LTL, with covariate adjustments. Childhood LTL was positively correlated with total maternal 25(OH)D (0.048 ± 0.017) (P = 0.004) and maternal 3-epi-25(OH)D3 (0.05 ± 0.017) (P = 0.003), even after adjustment for covariates. A similar association was also noted for cord 3-epi-25(OH)D3 (0.037 ± 0.018) (P = 0.035) after adjustment for offspring sex and age.
Our findings suggest 25(OH)D3 and 3-epi-25(OH)D3 in utero may impact on childhood LTLs, highlighting a potential link between maternal vitamin D and biological aging.
ABSTRACT
Aims/Introduction
To determine the population health burden attributable to the development of diabetes among women with a history of gestational diabetes mellitus (GDM).
Materials and ...Methods
We conducted a retrospective analysis of women with a history of GDM attending the Hong Kong Hospital Authority between 2000 and 2019. The time‐varying population attributable fraction was calculated.
Results
A total of 76,181 women with a history of gestational diabetes mellitus were included, 6,606 of them developed diabetes during a median follow‐up of 8.6 years. The respective hazard ratios (95% confidence interval) among women with GDM who developed diabetes vs those with GDM only were 2.8 (2.2, 3.7) for cardiovascular disease (CVD), 4.8 (3.0, 7.7) for end‐stage kidney disease (ESKD), 2.2 (1.9, 2.6) for infection‐related hospitalization, and 1.8 (1.3, 2.4) for all‐cause mortality. The development of diabetes was associated with 1.3 (0.8, 1.7), 0.6 (0.3, 0.8), 3.2 (2.4, 4.0), and 0.5 (0.2, 0.9) additional incident cases per 1,000 person‐years, accounting for 24.0% (13.2%, 35.9%), 42.0% (22.5%, 58.8%), 10.8% (7.1%, 14.9%), and 6.0% (−3.1%, 16.1%) of absolute number of CVD, ESKD, infection‐related hospitalization, and all‐cause mortality over 20 years after GDM, respectively.
Conclusions
Diabetes is a significant contributor to the population health burden of some clinical outcomes in women with a history of gestational diabetes mellitus, but other risk factors need to be considered.
In this population‐based cohort of Chinese women with a history of gestational diabetes mellitus, we found that the subsequent development of diabetes in women with GDM increased the hazards of cardiovascular and kidney diseases by 3‐ to 5‐fold, infection‐related hospitalization and all‐cause mortality by 2‐fold, and cancer by 20%. By 20 years post‐GDM, diabetes accounted for close to one half of the new cases of end‐stage kidney disease and one quarter of cardiovascular disease. Our results indicate that diabetes is an important contributor to selected clinical events in women with a history of gestational diabetes mellitus although other risk factors need to be considered.
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