Diabetes, Obesity & Metabolism最新文献

Background: The Stress Hyperglycemia Ratio (SHR), a new biomarker calculated from glucose and HbA1c levels, has been linked to significant clinical outcomes in diabetes. This study investigates the potential of the SHR to predict End-Stage Renal Disease (ESRD) among patients with Diabetic Kidney Disease (DKD).

Methods: We included 316 participants from the West China Hospital T2DM-DKD cohort (January 2008-September 2020), divided into three SHR tertiles: T1 (SHR <0.7), T2 (SHR ≥0.7 to <0.94) and T3 (SHR ≥0.94). A second retrospective cohort of 625 DKD patients was recruited from Sichuan University Hospital (January 2019-May 2022), with similar inclusion criteria. SHR was analysed using Restricted Cubic Spline, Kaplan-Meier curves and Cox proportional hazards models. Key confounders such as eGFR, proteinuria, hypoalbuminemia and glucose-lowering medications were adjusted for in the analysis.

Results: In Cohort 1 (median follow-up 42 months), 38.6% developed ESRD. Kaplan-Meier curves showed a higher incidence of ESRD in the lowest and highest SHR tertiles compared to the middle group (p < 0.01). Multivariate analysis confirmed that SHR <0.7 (HR 1.71, 95% CI: 1.01-2.90) and SHR ≥0.94 (HR 1.93, 95% CI: 1.16-3.20) were significantly associated with ESRD. In Cohort 2 (median follow-up 18.6 months), patients with SHR <0.7 and ≥0.94 had significantly higher risks of ≥30% eGFR decline or ESRD, with adjusted HRs of 2.18 (95% CI: 1.15-4.11) and 2.68 (95% CI: 1.38-5.23), respectively.

Conclusion: This study observed a U-shaped relationship between SHR and ESRD in patients with DKD. Both very high and very low SHR values correlate with increased risks, highlighting the critical importance of glucose management in chronic diabetes care.

Aims: The molecular mechanisms underlying the association between type 2 diabetes (T2D) and gastrointestinal (GI) disease are unclear. To identify protein pathways, we conducted a two-stage network Mendelian randomisation (MR) study.

Materials and methods: Genetic instruments for T2D were obtained from a large-scale summary-level genome-wide meta-analysis. Genetic associations with blood protein levels were obtained from three genome-wide association studies on plasma proteins (i.e. the deCODE study as the discovery and the UKB-PPP and Fenland studies as the replication). Summary-level data on 10 GI diseases were derived from genome-wide meta-analysis of the UK Biobank and FinnGen. MR and colocalisation analyses were performed. Pathways were constructed according to the directionality of total and indirect effects, and corresponding proportional mediation was estimated. Druggability assessments were conducted across four databases to prioritise protein mediators.

Results: Genetic liability to T2D was associated with 69 proteins in the discovery protein dataset after multiple testing corrections. All associations were replicated at the nominal significance level. Among T2D-associated proteins, genetically predicted levels of nine proteins were associated with at least one of the GI diseases. Genetically predicted levels of SULT2A1 (odds ratio = 1.98, 95% CI 1.80-2.18), and ADH1B (odds ratio = 2.05, 95% CI 1.43-2.94) were associated with cholelithiasis and cirrhosis respectively. SULT2A1 and cholelithiasis (PH4 = 0.996) and ADH1B and cirrhosis (PH4 = 0.931) have strong colocalisation support, accounting for the mediation proportion of 72.8% (95% CI 45.7-99.9) and 42.9% (95% CI 15.5-70.4) respectively.

Conclusions: The study identified some proteins mediating T2D-GI disease associations, which provided biological insights into the underlying pathways.

Aims: To investigate the effect of sodium-glucose co-transporter 2 inhibitor [SGLT-2i] therapy on renal haemodynamics in T2D patients with glomerular hyperfiltration.

Materials and methods: Sixty T2D patients with elevated [HYPER] and normal [NORMO] GFR were randomized to dapagliflozin 10 mg/day [DAPA/HYPER, n = 15; DAPA/NORMO, n = 15] or to metformin/glipizide [CONTROL/HYPER, n = 15; CONTROL/NORMO, n = 15] to reach similar glycaemic control after 4 months. GFR was measured with Iohexol and hyperfiltration was empirically defined as >125 mL/min/1.73 m². GFR, renal plasma flow [RPF], mean arterial pressure [MAP], filtration fraction [FF], and renal vascular resistance [RVR] were determined before/after therapy.

Results: HbA1c decreased similarly in all 4 groups. GFR declined by ~18% in DAPA/HYPER and by ~7% in DAPA/NORMO and did not change in CONTROLS (p < 0.05 vs. DAPA). RPF remained unchanged in all four groups. Thus, FF (%) declined from 0.23 ± 0.01 to 0.18 ± 0.01 in DAPA/HYPER and from 0.17 ± 0.01 to 0.15 ± 0.01 in DAPA/NORMO and remained unchanged in CONTROLS (p < 0.05 vs. DAPA). MAP (mmHg) decreased from 95.4 ± 1.4 to 88.1 ± 1.3 in DAPA/HYPER and from 95.6 ± 1.3 to 91.8 ± 0.8 in DAPA/NORMO and remained unchanged in CONTROLS (p < 0.05 vs. DAPA). RVR [mmHg/L/min] declined in DAPA/HYPER (92.7 ± 7.8 to 80.4 ± 6.1) and DAPA/NORMO (90.1 ± 3.0 to 81.4 ± 2.1) but not in CONTROLS (p < 0.05 vs. DAPA).

Conclusions: Despite comparable glycaemic control, dapagliflozin treatment, but not metformin and /or glipizide, reduced glomerular hyperfiltration in T2D patients and decreased both filtration fraction and renal vascular resistance. These findings suggest that a post-glomerular vasodilatory action of SGLT2 inhibitors contributes to their renal protective effect in T2D.

Aims: To provide an updated comprehensive evaluation of the quality and evidence association of existing studies on health outcomes related to intermittent fasting (IF).

Materials and methods: We conducted a systematic search of PubMed, Web of Science, Cochrane Library, and Embase databases, covering literature up to June 2024. Meta-analyses and systematic reviews that include adult populations and quantitatively analyse health outcomes related to IF interventional studies are included. For evidence with complete data, we reanalyzed health evidence effect sizes and 95% confidence intervals using random-effects models. Article quality and the certainty of the evidence were graded using A Measurement Tool to Assess Systematic Reviews (AMSTAR-2), Grading of Recommendations Assessment, Development and Evaluation (GRADE) system, and a standardized credibility grading system.

Results: Twelve meta-analysis studies and 122 health outcome associations with IF were identified. High-quality evidence indicated significant associations between time-restricted eating (TRE) and weight loss, fat mass reduction, decreased fasting insulin and glycosylated haemoglobin levels in overweight or obese adults, as well as between the 5:2 diet and reduced low-density lipoprotein cholesterol levels. Moderate-to-low-quality evidence suggested associations between modified alternate-day fasting and improvements in body weight, lipid profile and blood pressure. Additionally, high-to-low-quality evidence showed that IF regimens effectively improved liver health in non-alcoholic fatty liver disease.

Conclusions: This umbrella review highlights IF, especially TRE, as a promising intervention for weight and metabolic health, particularly beneficial for overweight or obese adults. We also highlight the need for further extensive research to understand the long-term effects, individualized IF plans and potential adverse effects of IF in different populations.

Objective: This study aimed to evaluate the cardiorenal effect of combining sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) when compared with monotherapy of either agent in patients with type 2 diabetes (T2D).

Methods: PubMed, Web of Science, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrial.gov were systematically searched from inception to June 2024. Eligible studies included randomised controlled trials and observational studies assessing that compared with SGLT2i or GLP-1RA monotherapy, the risk of cardiorenal outcomes in patients with T2D who treated with combination therapy. Pooled relative risk (RR) and 95% confidence intervals (CIs) were computed in random-effects model.

Results: In all, five RCTs, 10 post hoc analyses and one observational study were included. The reduced risk of the composite cardiovascular outcome was observed in patients receiving combination therapy of SGLT2i and GLP-1RA when compared with SGLT2i monotherapy (RR = 0.57, 95% CI 0.38-0.86, p = 0.008) or GLP-1RA monotherapy (RR = 0.77, 95% CI 0.65-0.91, p = 0.002). Likewise, the composite renal adverse events were less frequent in patients receiving combination therapy of SGLT2i and GLP-1RA when compared with SGLT2i monotherapy (RR = 0.69, 95% CI 0.59-0.82, p < 0.001) or GLP-1RA monotherapy (RR = 0.66, 95% CI 0.53-0.83, p < 0.001). Compared with GLP-1RA monotherapy, the combination therapy of SGLT2i and GLP-1RA was associated with lower risks of heart failure-related outcomes (RR = 0.63, 95% CI 0.51-0.77, p < 0.001) and all-cause mortality (RR = 0.66, 95% CI 0.50-0.88, p = 0.004) in patients with T2D.

Conclusion: The cardiorenal benefits might be magnified with the combination therapy of SGLT2i and GLP-1RA when compared with monotherapy of either agent. Further investigations are needed to validate the findings.

Aims: GLP-1 receptor agonists (GLP-1 RAs) are proven therapies for type 2 diabetes mellitus (T2DM) and overweight or obesity. We performed non-clinical and first-in-human (FIH) evaluation of ECC5004/AZD5004, an oral small-molecule GLP-1 RA.

Materials and methods: ECC5004 was profiled in cell lines overexpressing human GLP-1R, in glucose-stimulated insulin secretion (GSIS) assays in a human β-cell line and non-human primates (NHPs). To evaluate safety, ECC5004 was orally administered to NHPs for 9 months and a phase I, double-blind, placebo-controlled FIH study was conducted. This study evaluated single doses of ECC5004 (1-300 mg) in healthy volunteers, and multiple daily doses (5, 10, 30 and 50 mg) in patients with T2DM for 28 days.

Results: ECC5004 bound to the hGLP-1R (IC₅₀ = 2.4 nM) augmented cAMP signalling without β-arrestin-2 recruitment or receptor internalization. ECC5004 potentiated GSIS in both EndoC-βH5 cells (EC₅₀ = 5.9 nM) and in vivo in NHPs (EC₅₀ = 0.022 nM). Dose-dependent body weight changes compared to control were seen in the 9-month NHP toxicity study. In the first-in-human study, ECC5004 was well tolerated with no serious adverse events. Dose-dependent reductions in glucose and body weight were observed with a dose-proportional exposure at doses ≥25 mg.

Conclusion: ECC5004 engaged the GLP-1R across the therapeutic dose range tested and had a safety and tolerability profile consistent with other GLP-1 RAs, along with a pharmacokinetic profile compatible with once-daily oral dosing. These data support continued development of ECC5004 as a potential therapy for T2DM and overweight or obesity.

Clinical trial registration: NCT05654831.

Aims: Psychosocial impacts of early continuous glucose monitoring (CGM) initiation in youth soon after type 1 diabetes diagnosis are underexplored. We report parent/guardian and youth patient-reported outcomes (PROs) that measure psychosocial states for families in 4T Study 1.

Materials and methods: Of the 133 families in the 4T Study 1, 132 parent/guardian and 66 youth (≥11 years) were eligible to complete PROs. PROs evaluated included diabetes distress, global health, diabetes technology attitudes and CGM benefits/burden scales. Temporal trends of PROs were assessed via generalised linear mixed effects regression. Sociodemographic and clinical characteristics associated with PROs were evaluated. Psychosocial associations were evaluated by regressing parental distress on youth distress.

Results: PRO completion rates were 85.6% and varied between parent/guardian and youth. Throughout the study, parent/guardian and youth distress remained low and youth had increased technology acceptance (p = 0.046). Each additional month of CGM use was associated with a 14% decrease in the odds of experiencing diabetes distress (aOR = 0.86, 95% CI [0.76, 0.99], p = 0.029). Additionally, higher time-in-range was associated with decreased diabetes distress (p = 0.048). Age, diabetic ketoacidosis at diagnosis, gender, ethnicity, insurance status and language spoken were not associated with PROs.

Conclusions: Initiation of CGM shortly after type 1 diabetes diagnosis does not have unintended negative psychological consequences. Longer duration of CGM use was associated with decreased youth distress and technology acceptance increased throughout the study.

Aims: This study aimed to identify the distinct change trajectories of the Chinese visceral adiposity index (CVAI) over time and to investigate their associations with risk of type 2 diabetes mellitus (T2DM).

Materials and methods: This study included 52 394 participants from the prospective project, the Prediction for Atherosclerotic Cardiovascular Disease Risk in China (China-PAR). The CVAI was calculated using measures of age, body mass index, waist circumference, triglycerides and high-density lipoprotein cholesterol. Latent mixture modelling was conducted to fit distinct trajectory patterns. The logistic regression model was applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of T2DM with various CVAI trajectory patterns.

Results: Four distinct CVAI trajectory patterns were identified: low-increasing, moderate-increasing, moderate high-increasing and high-increasing. Compared with low-increasing CVAI, participants with moderate-increasing (OR 1.73, 95% CI 1.49-2.00), moderate high-increasing (3.48, 3.01-4.03) and high-increasing CVAI (5.50, 4.67-6.47) had a significantly increased risk of T2DM. Similar trajectory patterns were identified in both men and women. The ORs (95% CI) for moderate-increasing, moderate high-increasing and high-increasing groups were 3.28 (2.56-4.19), 7.85 (6.09-10.13) and 13.21 (9.98-17.49) in women respectively, and 1.20 (0.99-1.45), 2.18 (1.82-2.62) and 3.60 (2.93-4.43) in men respectively, when compared to the low-increasing CVAI group. Further, significant effect modifications for age, smoking and physical activity (all P_interaction <0.05) were observed in the relationship between CVAI trajectory patterns and T2DM.

Conclusions: Initially high and persistently elevated CVAI is significantly associated with an increased risk of T2DM, with a particular focus on women, younger people, nonsmokers and physically inactive individuals. Continuous monitoring of CVAI levels will benefit effective identification, early intervention and management of individuals at high risk of T2DM.

Aim: To investigate the effect of different physical activity patterns on obesity.

Materials and methods: Data from adults aged 17-79 years were extracted from the Hong Kong Territory-Wide Physical Fitness Survey conducted in 2011-2012 and 2021-2022. Moderate to vigorous physical activity (MVPA) patterns were collected through questionnaires and categorized as inactive (no MVPA ≥10 min), insufficiently active (<150 min MVPA/week), weekend warriors (≥150 min MVPA/week from 1 to 2 days) and regularly active (≥150 min MVPA/week from ≥3 days). The association between these activity patterns with obesity risk and body fat percentage was analysed.

Results: This study included 9863 obesity data (including valid waist circumference and body mass index) and 7496 body fat data. Compared with the inactive group, the weekend warriors and regularly active individuals had lower risks of general and abdominal obesity, as well as reduced body fat. Furthermore, individuals who were insufficiently active but engaged in ≥3 days of MVPA showed significantly lower body fat and obesity risk than their inactive counterparts.

Conclusion: Engaging in physical activity even once or twice a week can positively impact weight control.