Diabetes, Obesity & Metabolism最新文献

Despite the recognition by key guidelines that achieving early glycaemic control has important benefits in individuals with type 2 diabetes (T2D) and that addressing excess adiposity is one of the central components of comprehensive person-centred T2D care, a substantial proportion of individuals with T2D do not meet their metabolic treatment goals. Prior treatment paradigms were limited by important treatment-associated risks such as hypoglycaemia and body weight gain. Therefore, a more conservative, sequential approach to treatment was typically utilized. One potential consequence of this approach has been a missed opportunity to achieve a 'legacy effect', where early treatment to reach glycaemic targets is associated with enduring long-term benefits in T2D. Additionally, while previous treatment approaches have addressed core defects in T2D, including insulin resistance and β-cell function decline, they have been unable to address one of the underlying causal abnormalities-excess adiposity. Here, we review currently available evidence for the beneficial long-term effects of early glycaemic control and management of body weight in people with T2D and discuss potential next steps.

Aims: The aim of this study was to assess postprandial glycaemic outcomes using automated insulin delivery with faster acting insulin aspart (FIA) or standard insulin aspart (SIA) over 4 weeks in youth (aged 10-18 years) with type 1 diabetes.

Materials and methods: We undertook a secondary analysis of postprandial glycaemic outcomes from a double-blind, randomised, crossover study comparing FIA to SIA using an investigational version of MiniMed™ 780G. Endpoints included postprandial time in tight range (70-140 mg/dL; TITR), postprandial glucose excursions and peak glucose, and incremental area under curve (iAUC).

Results: The mean ± SD age of 30 included participants was 15.0 ± 1.7 years, 47% were male, mean HbA1c was 7.5% ± 0.9% (58 ± 9.8 mmol/mol) and the number of meals per day per participant was 3.2 ± 1.2 meals. Overall, the postprandial outcomes were improved with FIA compared with SIA. Mean glucose at the start of the meal was 151 mg/dL in the FIA group and reached a peak glucose of 194 mg/dL, compared with starting level of 151 mg/dL in the SIA group and a peak of 198 mg/dL (difference in excursion: -3.8 mg/dL; 95% confidence interval -5.8 to -1.7; p <0.001). FIA group also had a 1.9% increase in mean TITR (p = 0.02) and a 2.0-mg/dL decrease in mean iAUC (p = 0.003). Differences in outcomes were the most noticeable for breakfast, meals with a larger amount of carbohydrates (>45 g) and participants with lower insulin-to-carbohydrate ratios.

Conclusions: Faster insulin formulation with AID improved postprandial glycaemic outcomes and could be a useful therapeutical option in youth with type 1 diabetes that have challenges achieving glycaemic targets.

Aims: Currently, there is a lack of evidence regarding time in tight range (TITR) and long-term adverse outcomes. We aimed to investigate the association between TITR and the risk of all-cause and cardiovascular mortality among patients with type 2 diabetes.

Materials and methods: A total of 6061 patients with type 2 diabetes were prospectively recruited in a single centre. TITR was measured with continuous glucose monitoring (CGM) at baseline and was defined as the percentage of time in the target glucose range of 3.9-7.8 mmol/L (70-140 mg/dL) during a 24-h period. Cox proportion hazard regression models were used to examine the association between TITR and the risk of all-cause and cardiovascular mortality.

Results: During a median follow-up period of 10.9 years, 1898 (31.3%) death events were confirmed, with 689 (11.4%) due to cardiovascular mortality. The restricted cubic spline revealed significant linear relationships between lower TITR and higher risks of all-cause and cardiovascular mortality (p for linearity <0.01). In the fully adjusted model including glycated haemoglobin A1c, each 10% decrease in TITR was associated with 4% (95% confidence interval, 1.01-1.06) increased risk of all-cause mortality and 4% (95% confidence interval, 1.00-1.08) increased risk of cardiovascular mortality. Subgroup analyses showed that the linear relationship between TITR and all-cause mortality risk was sustained in patients with haemoglobin A1c <7.0% and patients with fasting plasma glucose <7.0 mmol/L.

Conclusions: Lower TITR is associated with an increased risk of all-cause and cardiovascular mortality in patients with type 2 diabetes, indicating that tight glycaemic control within the physiological range may be crucial for reducing long-term mortality risk, especially in those with seemingly well-controlled diabetes.

Aims: Physiological changes during pregnancy can infuence the performance of blood glucose meters. This study aimed to evaluate the analytical and clinical accuracy of glucose meters in pregnant women with hyperglycaemia.

Materials and methods: Glucose was measured by four commonly used meters among consecutive women with diabetes in pregnancy. Capillary and venous samples were collected concurrently and compared with i-STAT (amperometry) and laboratory (hexokinase) glucose as reference methods. Bland-Altman plot, International Organization for Standardization criteria, surveillance error grid (SEG) and haematocrit influence were assessed.

Results: In total, 824 paired samples from 103 women were analysed (GDM 57%, mean i-STAT capillary glucose 6.7 ± 2.3 mmol/L [121 ± 41 mg/dL], laboratory glucose 6.6 ± 2.4 mmol/L [119 ± 43 mg/dL], median haematocrit 0.36 L/L). Mean capillary glucose measured on all meters was significantly different from that measured on i-STAT (all p < 0.001), whereas venous glucose measured on Contour Next, Accu-Chek Guide and the laboratory (plasma) was similar. Contour Next had the lowest bias when using both reference methods (mean bias [95% limits of agreement] meter vs. i-STAT: Contour Next 1.3% [-8% to 10.6%], Accu-Chek Guide -3.2% [-11.4% to 5%], FreeStyle Optium Neo -11.9% [-24.7% to 0.8%] and LifeSmart 6.8% [-5.8% to 19.4%]; meter versus laboratory: -0.2% [-8.1% to 7.7%], -0.2% [-10.2% to 9.8%], -3.8% [-17.6% to 10%] and 6.1% [-5.9% to 18.2%]), respectively. Only Contour Next and Accu-Chek Guide had ≥97% of pairs within the SEG no-risk zone during both comparisons. Meters did not show haematocrit-related bias.

Conclusions: Accuracy of meters was higher when using venous samples than when using capillary samples. Contour Next and Accu-Chek Guide meters met accuracy standards in all analyses.

Aims: Glucagon-like peptide 1 receptor agonists (GLP1RA), used to treat type 2 diabetes and obesity, have been associated with off-target behavioural effects. We systematically assessed genetic variation in the GLP1R locus for impact on mental ill-health (MIH) and cardiometabolic phenotypes across diverse populations within UK Biobank.

Materials and methods: All genetic variants with minor allele frequency >1% in the GLP1R locus were investigated for associations with MIH phenotypes and cardiometabolic phenotypes. Linear or Logistic regression analyses (adjusted for age, sex, population structure and genotyping chip) were conducted separately in unrelated individuals of self-reported white British (N = 408 774), white European (N = 50 314), South Asian (N = 7667), multiple-ancestry groups (N = 10 437) or African-Caribbean (N = 7641) subsets. All ancestries were subsequently combined in an inverse variance-weighted fixed effects meta-analysis. Bonferroni correction for multiple testing was applied (for number of independent genetic variants).

Results: Associations were identified between GLP1R variants and body mass index (BMI), blood pressure and type 2 diabetes in all ancestries. All ancestries except South Asian had significant MIH associations (mood instability: rs111265626-G, odds ratio [OR] 0.851 [confidence interval, CI 0.79-0.92], risk-taking behaviour: rs75408972-T, OR 1.05 [CI 1.03-1.08] or chronic pain: rs9296280-C, OR 0.645 [CI 0.54-0.78]). The trans-ancestry meta-analysis showed mainly consistent effect sizes and directions for metabolic traits, but discordant directions MIH associations. Only signals for chronic pain, stroke and BMI influenced expression of GLP1R.

Conclusions: GLP1R variants have consistent cardiometabolic effects across ancestries, but effects on MIH phenotypes are more varied. Any observed behavioural changes with GLP1RA are likely not acting directly through GLP1R.

Objective: Previous experiments have demonstrated that BGM0504, a GLP-1R/GIPR dual agonist drug by molecular dynamics-guided optimization, had enhanced agonistic activity compared to tirzepatide. This study aims to investigate its safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) in Chinese healthy volunteers.

Methods: A randomized, double-blind, placebo-controlled and dose-escalation Phase I study was conducted as follows: a single dose (2.5 mg) and once-weekly administration for 2 weeks to reach target doses (5, 10 and 15 mg) by titration.

Results: A total of 40 volunteers received at least one dose of BGM0504 or placebo. The PK profile of BGM0504 was investigated over a wide dose range and supported once-weekly administration. It was observed that C_max and AUC of BGM0504 were linearly proportional to the dose from 2.5-15 mg. The change in body weight (%) from baseline in BGM0504 groups was greater than that in the placebo group, with -3.24%, -6.26%, -7.09% and - 8.30% in 2.5, 5, 10 and 15 mg groups, respectively, indicating a certain dose correlation. Meanwhile, the potential roles of BGM0504 in glycaemic control were also observed. The most frequent adverse events reported were gastrointestinal (vomiting, nausea, decreased appetite, diarrhoea and abdominal distension).

Conclusion: BGM0504 was generally safe and well tolerated with favourable PK profile and potential role in weight loss was also confirmed. These findings support subsequent development of BGM0504 for type 2 diabetes mellitus (T2DM) and obesity.

Aims: Evaluate glycated haemoglobin (HbA1c) and weight changes after 6 months of once-weekly (QW) injectable glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy in UK primary care.

Materials and methods: Retrospective, non-interventional study, using the Clinical Practice Research Datalink Aurum primary care database, identified adults with type 2 diabetes (T2D) newly initiating a QW injectable GLP-1 RA between January 2020 and November 2021. Dual primary outcomes were proportion of patients with (1) HbA1c < 7% (<53 mmol/mol) and (2) weight loss categories (from 0% to 15+%) after 6 months of continuous GLP-1 RA therapy.

Results: The study cohort comprised 10 816 adults: mean ± standard deviation age 58.8 ± 11.4 years, baseline HbA1c 9.3% ± 1.7% (78.1 ± 18.6 mmol/mol) and body mass index 36.6 ± 7.2 kg/m². Of 5236 patients with data, 32.8% achieved HbA1c < 7% after 6 months; this proportion was higher for time since T2D diagnosis <5 years (34.1%) versus longer disease duration: ≥5-<10 years (28.0%), ≥10-<15 years (18.7%) and ≥15 years (19.3%). Of 3963 patients with weight data, 22.0% did not lose weight; 34.0%, 27.0%, 11.4% and 5.6% achieved weight reductions of >0%-<5%, ≥5%-<10%, ≥10%-<15% and ≥15%, respectively. No major differences in weight loss were observed by diabetes duration.

Conclusions: Two thirds of T2D patients receiving QW injectable GLP-1 RA for 6 months did not attain target HbA1c < 7%, and less than half and one-quarter of patients achieved ≥5% and ≥10% weight loss, respectively. Results suggest an unmet need for better clinical management of T2D in UK primary care.

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is mainly secreted by the liver, and plays a crucial role in lipid metabolism disorder. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) can regulate lipid metabolism through various pathways, including reducing visceral fat accumulation, modulating serum lipoprotein levels and alleviating hepatic steatosis. However, the specific regulatory mechanisms remain unclear.

Methods: We built a model of glucose and lipid metabolism disorder in vivo and in vitro, and explored the regulatory mechanism of dapagliflozin in regulating liver lipid metabolism.

Results: We found that the SGLT2i dapagliflozin significantly reduced serum levels of PCSK9, total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) in high-fat diet (HFD)-fed mice, while also improving hepatic steatosis. In vitro studies confirmed that dapagliflozin increased LDL receptor (LDLR) expression in HepG2 cells, enhancing their ability to uptake LDL-C.

Conclusions: Further mechanistic studies revealed that the hepatocyte nuclear factor-1-alpha (HNF1α)/PCSK9/LDLR signalling pathway may be involved in dapagliflozin's regulation of lipid metabolism homeostasis.