Diabetes, Obesity & Metabolism最新文献

Aims: To compare the associations of HbA1c and continuous glucose monitoring (CGM)-derived average glucose with microvascular complications in adults with type 1 diabetes, and to assess the clinical utility and stability of metrics capturing glycation discordance.

Materials and methods: Observational assessment of 9023 paired measurements of CGM data (14 days) and HbA1c in 2721 adults with type 1 diabetes. CGM metrics, HbA1c, and markers of discordance between HbA1c and CGM average glucose were associated with prevalent retinopathy (any and proliferative) and microalbuminuria.

Results: HbA1c was higher than expected in older individuals (62 mmol/mol [54-71] age >45 vs. 61 mmol/mol [52-71], p = 0.004) and in women (62 mmol/mol [54-71] vs. 61 mmol/mol [53-71], p < 0.001) despite lower or similar average glucose levels. Fewer than one-third of individuals remain within the same HbA1c-average glucose discordance category over time. HbA1c (p < 0.001), average glucose (p < 0.001), CV glucose (p < 0.001), and socioeconomic deprivation (p = 0.003) were all independently associated with retinopathy risk (with similar results for proliferative retinopathy). Higher glycation was associated with a lower likelihood of prevalent retinopathy (p < 0.001).

Conclusions: CGM-derived average glucose appears superior to HbA1c as a marker of prevalent microvascular complications. These data challenge the high-glycator hypothesis and also suggest glucose variability may be an independent risk marker for microvascular disease.

Objective: High-altitude environments are characterized by hypobaric hypoxia and pose a significant physiological challenge. While obesity-related hypoxia is known to impair brown adipose tissue (BAT) function by suppressing lipolysis and thermogenesis, whether hypobaric hypoxia similarly compromises BAT function remains unclear. We hypothesize that, unlike obesity-associated hypoxia, hypobaric hypoxia perturbs BAT thermogenesis via a distinct mechanism involving the upregulation of Plin2.

Methods: Mice were exposed to either normoxia or hypobaric hypoxia (simulating 6000 m, 9.2% O₂) for 30 days. BAT function was assessed by analyzing lipid droplet size, lipid and triglyceride content, and expression of thermogenic protein. Thermogenic capacity was further evaluated in mice subjected to 30 days of normoxia or hypobaric hypoxia, followed by a 2-day cold exposure or 3-day treatment with the β3-adrenergic agonist CL316243. Differential proteomics and in vitro experiments were performed to explore underlying molecular mechanisms.

Results: After 30 days of hypobaric hypoxia, mice exhibited reduced body weight (normoxia: 26.64 ± 0.91 vs. hypoxia: 21.94 ± 0.79 g, p = 0.002), yet exhibited enlarged lipid droplets in BAT (142.7 ± 15.52 vs. 387.4 ± 31.91 μm², p < 0.001) and increased lipid accumulation. Compared with normoxia, hypoxic mice displayed impaired thermogenic responses to both cold exposure and β3-adrenergic stimulation, as indicated by suppressed thermogenic gene expression. Mechanistically, hypobaric hypoxia elevated lactate levels and upregulated PPARγ, which subsequently enhanced Plin2 expression, ultimately leading to defective lipolysis and impaired thermogenesis.

Conclusions: We identify a novel hypoxia-lactate/PPARγ-Plin2 axis that uncouples body weight loss from BAT thermogenesis under hypobaric hypoxia. This pathway represents a previously unrecognized therapeutic target for counteracting metabolic dysfunction induced by high-altitude exposure.

Aims: Pharmacotherapy for metabolic associated steatotic liver disease (MASLD) is reserved for steatohepatitis (MASH) with moderate Fibrosis Grades 2-3. Randomised controlled trials (RCT) of clinically available medications with biopsy data were evaluated for treatment benefits in steatohepatitis.

Materials and methods: PUBMED, Cochrane, and Scopus databases were searched for 'MASH/NASH/NAFLD/randomised-controlled trials/liver biopsy' (N = 848 publications) which provided 14 publications with biopsy data. Outcomes were changes in biopsy MASLD Activity Scores (MAS), Fibrosis Grades, resolution of MASH with no worsening of liver fibrosis (RSw/oF) or reduction ≥1 fibrosis stage with no worsening of steatohepatitis (RFw/oS). Meta-analyses and meta-regression analyses were performed.

Results: There were 3173 subjects (age 53.1 ± 5.8 SD years). Steatohepatitis scores (MAS) improved with treatment versus placebo by mean difference (md) = -1.27 ± 0.16 SD Units, p < 0.001. MAS sub scores improved for steatosis, lobar inflammation, and ballooning for dapagliflozin, semaglutide, and pioglitazone (all p < 0.002). Fibrosis Grades improved compared to placebo (md = -0.352 ± 0.03 Units, p < 0.001). Relative rates (rr) of RSw/oF and RFw/oS were found with resmetirom, semaglutide, tirzepatide, and dapagliflozin (all p < 0.015). Changes in RSw/oF and RFw/oS inversely correlated with the baseline levels of Fibrosis Grades (p = 0.025, and p = 0.076 respectively), with greater improvements of both at lower Fibrosis Grades.

Conclusions: Clinically available medications are beneficial in reversing MASH. Improvements in RSw/oF and RFw/oS were greater at earlier stages of fibrosis. Future analyses of drug effects should include assessments adjusted for baseline study characteristics of Fibrosis Grades and may evaluate whether preventive therapy will have long term benefits if started at earlier stages of MASLD.

Aims: To evaluate the immunogenicity, efficacy, and safety of a biosimilar insulin glulisine candidate (T-Glu) compared to the reference product (R-Glu) in patients with type 1 diabetes mellitus (T1DM).

Materials and methods: In this phase III, randomised, open-label trial, adult patients with T1DM received either T-Glu or R-Glu by prefilled pens as their bolus insulin for 26 weeks. The primary outcome was the proportion of patients with an immune response at Week 26. Secondary endpoints included changes in glycaemia control parameters, insulin dose stability, treatment satisfaction, and other immunogenicity and safety outcomes.

Results: By Week 26, the immune response persisted in 16% of patients in the T-Glu group and 24% in the R-Glu group (p > 0.05), confirming similar immunogenicity. HbA1c reduction at Week 26 compared to baseline was similar between groups, with a mean change of 0.53% ± 1.19% in the T-Glu group and 0.38% ± 1.46% in the R-Glu group (mean difference: -0.15%, 95% CI: -0.50 to 0.20), demonstrating non-inferiority (according to a predefined margin of 0.4%). Fasting plasma glucose levels and the seven-point glucose profile showed no significant differences between groups (p > 0.05). Insulin dose remained stable throughout the study, and treatment satisfaction scores improved comparably in both groups (p > 0.05). The total number of AEs was similar, and hypoglycaemia was more frequent in the R-Glu group (p < 0.001), with no new safety concerns identified.

Conclusions: T-Glu demonstrated similar immunogenicity, efficacy, and safety to R-Glu in adults with T1DM, supporting its use as a biosimilar insulin glulisine.

Clinicaltrials: gov: NCT07070752.

Aims: Previous studies suggest that individuals from low-income households are at a higher risk of developing type 2 diabetes (T2D), but it remains unclear whether lower socioeconomic status affects the risk of postpartum T2D in women with gestational diabetes mellitus (GDM). This study aimed to explore whether the risk of T2D differs among women with a history of GDM across income levels.

Materials and methods: Using data from the Taiwan Maternal and Child Health Database, we identified 154 631 mothers with GDM between 1 January 2009 and 31 December 2017. We applied crude and multivariable-adjusted logistic regression models to assess the risk of postpartum T2D across different income levels.

Results: Among 154 631 mothers with GDM, 701 (0.45%) had very low income, 51 990 (33.62%) had low income, 81 575 (52.75%) had middle income, and 20 365 (13.17%) had high income. The mean maternal age was 31.95 years (SD = 4.73 years). Compared to the middle-income group, mothers with GDM and very low income had a higher risk of postpartum T2D (adjusted hazard ratio [aHR]: 1.86; 95% CI: 1.28-2.71), as did those with low income (aHR: 1.20; 95% CI: 1.12-1.29). Conversely, those with high income had a lower risk (aHR: 0.74; 95% CI: 0.66-0.83). Kaplan-Meier analysis showed a higher risk of postpartum T2D in lower-income groups (log-rank p < 0.0001).

Conclusions: This study demonstrates that women with GDM and low family income have a significantly increased risk of postpartum T2D. These findings highlight the need for targeted prevention and follow-up care for this high-risk group.

Aims: Hypoglycaemia remains a major barrier to optimal diabetes management. Current treatments based on simple sugars have limitations, including rapid glucose fluctuations and persistent neuroglycopenic symptoms. We investigated FLO23011, a novel multi-substrate energy formulation containing glucose and beta-hydroxybutyrate, as a superior hypoglycaemia treatment.

Methods: Two studies were conducted: Study A, a randomised, crossover pharmacokinetic investigation in six healthy adults comparing FLO23011 versus standard glucose treatment over 180 min; and Study B, a 12-week randomised, open-label, crossover clinical trial in 12 adults with type 1 diabetes comparing FLO23011 to standard of care. Study B evaluated glycaemic control using continuous glucose monitoring and assessed patient experience through structured questionnaires across 14 domains.

Results: Study A demonstrated a comparable glucose response between FLO23011 and standard of care (Cmax 7.4 ± 0.3 vs. 7.9 ± 0.2 mmol/L, p = 0.122), but FLO23011 resulted in sustained beta-hydroxybutyrate elevation (Cmax 0.6-1.2 mmol/L). Study B participants experienced 1032 hypoglycaemic episodes, as recorded by continuous glucose monitoring. FLO23011 significantly improved post-hypoglycaemia time in range (82.5% vs. 77.0%, p = 0.019) and reduced recurrent episodes by 27% (p = 0.031). Patient-reported outcomes favoured FLO23011 in 13 of 14 domains.

Conclusions: FLO23011 provides superior hypoglycaemia management through improved glycaemic stability, reduced recurrence, and enhanced patient experience compared to current glucose-only treatments.

Aims: To evaluate glycaemic control in adults enrolled in a rural cardiovascular disease prevention trial receiving Medical Nutrition Therapy (MNT) delivered via telehealth versus usual care.

Materials and methods: This secondary analysis used a subsample of participants (N = 81, n = 56 intervention, n = 25 control) with diagnosed or possible diabetes from the 'Healthy Rural Hearts' cluster randomised controlled trial (RCT), conducted in a large rural area in Australia. The general practitioner (GP) (primary care physician) reported 'diagnosed' diabetes, while 'possible diabetes' was a baseline fasting blood glucose level (FBG) ≥5.5 mmol/L or glycated haemoglobin (HbA1c) ≥6.0%. The intervention group received five telehealth-based MNT sessions over 6 months. Both control and intervention groups received usual care from their GP (n = 7 and n = 9 primary care practices, respectively) and up to four personalised nutrition reports. Within and between group changes in FBG and HbA1c were calculated from baseline to 12 months using Bayesian hierarchical regression models and reporting posterior mean differences and 95% credible intervals (CrI).

Results: Results suggested between group differences of -0.43 mmol/L in FBG (95% CrI -1.05, 0.19) and -0.26% in HbA1c (95% CrI -0.51, -0.00) at 12 months, when accounting for medication use. Evidence ratios of 10.64 and 39.45 indicate that the posterior probability of a positive intervention effect was approximately 10.6 and 39.5 times higher than that of a negative effect for FBG and HbA1c, respectively.

Conclusions: Current results indicate that MNT delivered via telehealth supports improvement in glucose control in individuals with diagnosed diabetes and possible diabetes. Larger studies are needed to confirm these findings in similar populations.