Glucokinase activators (GKAs) are an emerging class of glucose lowering drugs that activate the glucose-sensing enzyme glucokinase (GK). Pending formal cardiovascular outcome trials, we applied ...two-sample Mendelian randomisation (MR) to investigate the impact of GK activation on risk of cardiovascular diseases.
We used independent genetic variants in or around the glucokinase gene meanwhile associated with HbA
at genome-wide significance (P < 5 × 10
) in the Meta-Analyses of Glucose and Insulin-related traits Consortium study (N = 146,806; European ancestry) as instrumental variables (IVs) to mimic the effects of GK activation. We assessed the association between genetically proxied GK activation and the risk of coronary artery disease (CAD; 122,733 cases and 424,528 controls), peripheral arterial disease (PAD; 7098 cases and 206,541 controls), stroke (40,585 cases and 406,111 controls) and heart failure (HF; 47,309 cases and 930,014 controls), using genome-wide association study summary statistics of these outcomes in Europeans. We compared the effect estimates of genetically proxied GK activation with estimates of genetically proxied lower HbA
on the same outcomes. We repeated our MR analyses in East Asians as validation.
Genetically proxied GK activation was associated with reduced risk of CAD (OR 0.38 per 1% lower HbA
, 95% CI 0.29-0.51, P = 8.77 × 10
) and HF (OR 0.54 per 1% lower HbA
, 95% CI 0.41-0.73, P = 3.55 × 10
). The genetically proxied protective effects of GKA on CAD and HF exceeded those due to non-targeted HbA
lowering. There was no causal relationship between genetically proxied GK activation and risk of PAD or stroke. The estimates in sensitivity analyses and in East Asians were generally consistent.
GKAs may protect against CAD and HF which needs confirmation by long-term clinical trials.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
In Asia, diabetes-associated death due to cardiorenal diseases were 2–3 times higher in women than men which might be due to gender disparity in quality of care and health habits.
Adults with type 2 ...diabetes (T2D) from 11 Asian countries/areas were assessed using the same protocol (2007–2015). We compared treatment target attainment (HbA1c < 7%, blood pressure BP < 130/80 mmHg, risk-based LDL-cholesterol, lack of central obesity waist circumference <90 cm in men or <80 cm in women), use of cardiorenal-protective drugs (renin-angiotensin system RAS inhibitors, statins), and self-reported health habits including self-monitoring blood glucose (SMBG) by gender. Analyses were stratified by countries/areas, age of natural menopause (<50 vs. ≥50 years), and comorbidities (atherosclerotic cardiovascular disease ASCVD, heart failure, kidney impairment eGFR < 60 mL/min/1.73 m2).
Among 106,376 patients (53.2% men; median (interquartile range) diabetes duration: 6.0 (2.0–12.0) years; mean ± SD HbA1c 8.0 ± 1.9%; 27% insulin-treated), women were older and less likely to receive college education than men (28.9% vs. 48.8%). Women were less likely to smoke/drink alcohol and were physically less active than men. Women had lower BP (<130/80 mmHg: 29.4% vs. 25.7%), less general obesity (54.8% vs. 57.8%) but more central obesity than men (77.5% vs. 57.3%). Women were less likely to have ASCVD (12.8% vs. 17.0%) or heart failure (1.3% vs. 2.3%), but more likely to have kidney impairment (22.3% vs. 17.6%) and any-site cancer than men (2.5% vs. 1.6%). In most countries/areas, more men attained HbA1c <7% and risk-based LDL-cholesterol level than women. After adjusting for potential confounders including countries and centres, men had 1.63 odds ratio (95% CI 1.51, 1.74) of attaining ≥3 treatment targets than women.
Asian women with T2D had worse quality of care than men especially in middle-income countries/areas, calling for targeted implementation programs to close these care gaps.
Asia Diabetes Foundation.
Nil.
Type 2 diabetes (T2D)-associated end-stage kidney disease (ESKD) is a global burden, while the renoprotective effects of metformin remain controversial. In a population-based cohort (2002–2018) ...including 96,643 patients with T2D observed for 0.7 million person-years, we estimated the risk association of metformin and its dose-relationship with ESKD in a propensity-score overlap-weighting (PS-OW) cohort by eGFR categories. Amongst 96,643, 83,881 (86.8%) had eGFR-G1/G2 (≥60 mL/min/1.73 m2), 8762 (9.1%) had eGFR-G3a (≥45–60 mL/min/1.73 m2), 3051 (3.2%) had eGFR-G3b (≥30–45 mL/min/1.73 m2), and 949 (1.0%) had eGFR-G4 (≥15–30 mL/min/1.73 m2). The respective proportions of metformin users in these eGFR categories were 95.1%, 81.9%, 53.8%, and 20.8%. In the PS-OW cohort with 88,771 new-metformin and 7872 other oral glucose-lowering-drugs (OGLDs) users, the respective incidence rates of ESKD were 2.8 versus 22.4/1000 person-years. Metformin use associated with reduced risk of ESKD (hazard ratio (HR) = 0.43 95% CI: 0.35–0.52 in eGFR-G1/G2, 0.64 0.52–0.79 in eGFR-G3a, 0.67 0.56–0.80 in eGFR-G3b, and 0.63 0.48–0.83 in eGFR-G4). Metformin use was associated with reduced or neutral risk of major adverse cardiovascular events (MACE) (7.2 versus 16.0/1000 person-years) and all-cause mortality (14.6 versus 65.1/1000 person-years). Time-weighted mean daily metformin dose was 1000 mg in eGFR-G1/G2, 850 mg in eGFR-G3a, 650 mg in eGFR-G3b, and 500 mg in eGFR-G4. In a subcohort of 14,766 patients observed for 0.1 million person-years, the respective incidence rates of lactic acidosis and HR in metformin users and non-users were 42.5 versus 226.4 events/100,000 person-years (p = 0.03) for eGFR-G1/G2 (HR = 0.57, 0.25–1.30) and 54.5 versus 300.6 events/100,000 person-years (p = 0.01) for eGFR-G3/G4 (HR = 0.49, 0.19–1.30). These real-world data underscore the major benefits and low risk of lactic acidosis with metformin use down to an eGFR of 30 mL/min/1.73 m2 and possibly even 15 mL/min/1.73 m2, while reinforcing the importance of dose adjustment and frequent monitoring of eGFR.
Hydroxylated PCBs (OH-PCBs) are a class of organic contaminants that have been found recently in the plasma of Great Lakes fish, the source of which is either bioformation from PCBs or accumulation ...from the environment. To address the potential for fish to biotransform PCBs and bioform OH-PCBs juvenile rainbow trout (
Oncorhynchus mykiss; ∼80
g) were exposed to dietary concentrations of an environmentally relevant mixture of PCBs. Eight OH-PCBs were found in the plasma of rainbow trout after 30 days of exposure to the PCBs, the relative pattern of which was similar to those observed in wild lake trout (
Salvelinus namaycush) from Lake Ontario. Hydroxylated-PCBs were not found (detection limit 0.02
pg/g) in the food or control (not PCB-exposed) fish. A curvilinear log
t
1/2–log
K
ow relationship for recalcitrant PCBs was found, similar to previously reported relationships, although
t
1/2 values were longer and shorter than studies using smaller fish or cooler temperatures, respectively. A number of PCB congeners fell below the log
t
1/2–log
K
ow relationship providing the first estimates of non-chiral PCB biotransformation rates in fish. Enantioselective degradation of the chiral congeners PCBs 91 and 136, also indicated biotransformation. Biotransformation of PCBs was structure-dependent with greater biotransformation of PCBs with vicinal hydrogen atoms in the
meta/
para positions, suggesting CYP 2B-like biotransformation. Other chiral congeners with a
meta/
para substitution pattern showed no enantioselective degradation but were biotransformed based on the log
t
1/2–log
K
ow relationship. The results of this study demonstrate that laboratory held rainbow trout can biotransform a number of PCB congeners and that bioformation is likely an important source of OH-PCBs in wild salmonids of the Great Lakes.
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.
IntroductionWe designed and implemented a patient-centered, data-driven, holistic care model with evaluation of its impacts on clinical outcomes in patients with young-onset type 2 diabetes (T2D) for ...which there is a lack of evidence-based practice guidelines.Research design and methodsIn this 3-year Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes-Randomized Controlled Trial, we evaluate the effects of a multicomponent care model integrating use of information and communication technology (Joint Asia Diabetes Evaluation (JADE) platform), biogenetic markers and patient-reported outcome measures in patients with T2D diagnosed at ≤40 years of age and aged ≤50 years. The JADE-PRISM group received 1 year of specialist-led team-based management using treatment algorithms guided by biogenetic markers (genome-wide single-nucleotide polymorphism arrays, exome-sequencing of 34 monogenic diabetes genes, C-peptide, autoantibodies) to achieve multiple treatment goals (glycated hemoglobin (HbA1c) <6.2%, blood pressure <120/75 mm Hg, low-density lipoprotein-cholesterol <1.2 mmol/L, waist circumference <80 cm (women) or <85 cm (men)) in a diabetes center setting versus usual care (JADE-only). The primary outcome is incidence of all diabetes-related complications.ResultsIn 2020–2021, 884 patients (56.6% men, median (IQR) diabetes duration: 7 (3–12) years, current/ex-smokers: 32.5%, body mass index: 28.40±5.77 kg/m2, HbA1c: 7.52%±1.66%, insulin-treated: 27.7%) were assigned to JADE-only (n=443) or JADE-PRISM group (n=441). The profiles of the whole group included positive family history (74.7%), general obesity (51.4%), central obesity (79.2%), hypertension (66.7%), dyslipidemia (76.4%), albuminuria (35.4%), estimated glomerular filtration rate <60 mL/min/1.73 m2 (4.0%), retinopathy (13.8%), atherosclerotic cardiovascular disease (5.2%), cancer (3.1%), emotional distress (26%–38%) and suboptimal adherence (54%) with 5-item EuroQol for Quality of Life index of 0.88 (0.87–0.96). Overall, 13.7% attained ≥3 metabolic targets defined in secondary outcomes. In the JADE-PRISM group, 4.5% had pathogenic/likely pathogenic variants of monogenic diabetes genes; 5% had autoantibodies and 8.4% had fasting C-peptide <0.2 nmol/L. Other significant events included low/large birth weight (33.4%), childhood obesity (50.7%), mental illness (10.3%) and previous suicide attempts (3.6%). Among the women, 17.3% had polycystic ovary syndrome, 44.8% required insulin treatment during pregnancy and 17.3% experienced adverse pregnancy outcomes.ConclusionsYoung-onset diabetes is characterized by complex etiologies with comorbidities including mental illness and lifecourse events.Trial registration numberNCT04049149.
There is increasing attention on association between eating patterns and diabetes control following global changes in eating patterns. There had been very limited research on the eating patterns of ...diabetic patients with employment, although working age population has seen the highest increase in diabetes incidence. This study aimed to identify workplace eating patterns in relation to glycaemic control among type 2 diabetic patients with employment.
This is a sequential mixed-methods study. The exploratory qualitative study involved focus group interviews with 31 type 2 diabetic patients with employment, which guided the design of a subsequent cross-sectional investigation involving 185 patients with employment. Thematic analysis was conducted on the qualitative data to identify workplace eating patterns most relevant to glycaemic control. Hierarchical multiple linear regression was performed to examine association between workplace eating pattern and glycaemic control, proxied by HbA1c.
The focus group interviews identified frequency in the consumption of home-prepared meals (HPM) and meal hours as the major workplace eating patterns that affected glycaemic control. The cross-sectional study confirmed that regular consumption of HPM at workplace could explain variance of HbA1c, independent of socio-demographic factors, lifestyle factors and disease condition, with R
= 0.146, F(14, 170) = 2.075, p = 0.015; adjusted R
= 0.076. Patients who were female, in non-skilled occupation, on shift, with fixed work location and had break during work were more likely to consume HPM.
Consumption of HPM at workplace should be promoted to facilitate better glycaemic control by type 2 diabetic patients with employment, possibly through more practical dietary advice, and workplace accommodation in terms of space and facilities. In the context of COVID-19 pandemic, consumption of HPM also meant additional protection for diabetic patients through reducing close contact exposures in restaurants.
Intensive lifestyle modification showed variable success in the prevention of major clinical events and mortality among people with prediabetes. We propose that age may partly explain the ...heterogeneity and that health hazards related to prediabetes are age-specific.
We conducted a retrospective analysis of a territory-wide diabetes surveillance dataset from the Hong Kong Hospital Authority between 2000 and 2019. Prediabetes was defined according to the American Diabetes Association criteria. Proportional Cox regression was performed, stratified by baseline age categories (20-39, 40-59, 60-79 and ≥80 years).
1,630,942 individuals were included in the analysis. Compared with normoglycaemia, prediabetes was associated with greater hazards for cardiovascular disease (CVD) and all-cause mortality in most age groups but the effect size attenuated with ascending age (p value for trend <0·05). In the youngest and in the oldest age categories, the respective hazard ratios (95% confidence interval) of prediabetes vs normoglycaemia were 1·79 (1·59, 2·01) and 1·00 (0·95, 1·05) for CVD, and 1·36 (1·20, 1·55) and 0·99 (0·97, 1·02) for all-cause mortality. Similar associations were found for chronic kidney disease, end-stage kidney disease, all-site cancer, all-site infection, subtypes of CVD, and cause-specific mortality. The associations became attenuated but remained after excluding people who later developed diabetes and adjusting for metabolic factors. Similar associations were observed in prediabetes defined by impaired fasting glucose, but not HbA1c.
Prediabetes is associated with higher risk of major clinical events, even excluding subsequent development of diabetes and adjusting for metabolic factors. The risk relationships are stronger in young than older people.
This study did not receive any specific funding.
