Diabetologia最新文献

Aims/hypothesis: Exercise elicits a spectrum of metabolic and inflammatory responses that are crucial for skeletal muscle adaptation and overall health, particularly in the context of metabolic diseases, yet the contribution of prostanoid signalling to these processes remains unclear. We hypothesised that exercise-induced thromboxane production enhances skeletal muscle glucose uptake and improves whole-body glucose control.

Methods: Plasma prostanoids were quantified in men and women with normal glucose tolerance or type 2 diabetes before, immediately after and 3 h after a single bout of exercise. Cyclooxygenase (COX-2) transcript levels were evaluated in human skeletal muscle, whole blood, peripheral blood mononuclear cells and skeletal muscle-resident immune cells. Metabolic and transcriptomic effects of thromboxane receptor activation were analysed in mouse C2C12, rat L6 and human primary skeletal muscle cells. Glucose tolerance in vivo was assessed following i.p. administration of the thromboxane receptor agonist I-BOP in male and female mice. Tissue-specific glucose uptake was quantified by measuring radiolabelled 2-deoxyglucose incorporation during an IVGTT.

Results: Acute exercise increased plasma thromboxane B₂ concentrations and skeletal muscle mRNA levels of PTGS2 (encoding COX-2) selectively in monocyte/macrophage populations. In skeletal muscle cells, the thromboxane receptor agonist I-BOP increased glucose uptake in a dose-dependent manner up to 2.5-fold within 4 h and enhanced glycogen synthesis by 430%. Transcriptomic and signalling analysis revealed activation of protein kinase A and cytoskeletal remodelling pathways linked to GLUT4 trafficking. In vivo, I-BOP improved glucose tolerance in male mice in a dose-dependent manner, without altering insulin levels. Thromboxane receptor stimulation increased glucose uptake in extensor digitorum longus muscle by 43%. Importantly, thromboxane receptor activation preserved its glucose-lowering efficacy in diet-induced obese male mice.

Conclusions/interpretation: Exercise induces skeletal muscle-derived thromboxane production through macrophage-specific COX-2 activation. Thromboxane receptor stimulation enhances glucose uptake and glycogen storage via cytoskeletal remodelling, partially mimicking the acute exercise transcriptomic response. In vivo, thromboxane receptor activation improves glucose tolerance and skeletal muscle glucose uptake, with preserved efficacy in obesity. These findings identify thromboxane signalling as a previously unrecognised immunometabolic axis linking inflammation to glucose regulation and highlight the thromboxane receptor as a potential therapeutic target for metabolic disease.

Aims/hypothesis: This large observational cohort real-world study explored the effects of three forms of exercise (walking [WALK], aerobic excluding walking [AER] and anaerobic [ANAER]) on glucose levels and hypoglycaemia risk in type 1 diabetes.

Methods: Data were collected from 3248 users of mySugr Logbook and Apple Health (mean ± SD age 41.23±12.25 years; glucose management index of 7.05±1.09%; 41.5% were female) over a total of 428,058 exercise sessions. Acute and 24 h glycaemic effects were examined across exercise types. Post-exercise glycaemia data over 24 h were compared with sedentary glycaemic data. Time of exercise was used to assess the probability of nocturnal hypoglycaemia.

Results: Independent of type, exercise decreased glucose by -1.06±0.89 mmol/l. For the individual types of exercise, WALK decreased levels by -1.24±0.81 mmol/l, AER by -1.43±1.02 mmol/l and ANAER by -0.52±0.81 mmol/l (all p<0.001). Comparing sedentary days vs active days, the time in range (3.9-10 mmol/l glucose) increased by +2.08±6.06% for WALK, +2.94±6.46% for AER and +3.93±7.16% for ANAER, and the time below range (<3.9 mmol/l) increased by 0.37±1.57% for WALK, 0.74±1.70% for AER and 0.68±1.79% for ANAER (all p<0.001). ANAER yielded a smaller chance of acute hypoglycaemia and WALK yielded a smaller chance of nocturnal hypoglycaemia (p<0.001). Activities done after 15:30 hours did not increase the risk of nocturnal hypoglycaemia when compared with earlier exercise sessions (+0.9±0.34%; p<0.01).

Conclusions/interpretation: Aerobic activities decreased glucose more during exercise sessions than anaerobic exercise and yielded larger acute hypoglycaemia risk; anaerobic activities yielded the largest 24 h glycaemic improvements. More-intense exercise resulted in a larger nocturnal hypoglycaemia than walking; exercise timing was not a relevant contributor to nocturnal hypoglycaemia.

Aims/hypothesis: Corneal confocal microscopy is a valuable technique for assessing neuropathy; however, whether it can distinguish painful from painless neuropathy remains uncertain and existing evidence is based on the results of smaller studies. This study assessed the association of corneal nerve parameters with abnormalities identified by electromyography (EMG) and neuropathic pain in a large population with and without (pre)diabetes.

Methods: In this study we included cross-sectional data for 3425 participants from the Maastricht Study. Wide-field corneal confocal microscopy (WF-CCM) was performed using fully automated analysis of three corneal nerve parameters: corneal nerve branch density (CNBD), corneal nerve fibre density (CNFD) and corneal nerve fibre length (CNFL). An axonal degeneration composite score comprising compound muscle action potential amplitudes (peroneal and tibial) and the sensory nerve action potential amplitude of the sural nerve was created by categorising EMG amplitudes as normal or indicating minor (≤10th percentile), moderate (≤5th percentile) or severe (≤2.5th percentile) abnormalities. Neuropathic pain was determined as a modified Douleur Neuropathique en 4 Questions (DN4) interview score ≥3.

Results: The mean age of the participants was 59.2 years; 51.6% were female, 15% had prediabetes (defined as impaired fasting glucose, impaired glucose tolerance or both) and 19% had type 2 diabetes. The median diabetes duration was 3.0 years. Regression analyses revealed statistically significant associations between the axonal degeneration EMG score and WF-CCM parameters (CNFL: β=-0.51 [95% CI -0.78, -0.24]; CNFD: β=-1.56 [95% CI -3.04, -0.08]; CNBD: β=-3.08 [95% CI -5.51, -0.64]; all p<0.05) but no statistically significant associations between neuropathic pain and WF-CCM parameters (CNFL: β=-0.06; CNFD: β=-1.15; CNBD: β=-0.22; all p>0.1).

Conclusions/interpretation: The study found associations between the axonal degeneration EMG score and WF-CCM, but no associations were observed between neuropathic pain and WF-CCM parameters, suggesting that WF-CCM has limited value in assessing neuropathic pain.

Aims/hypothesis: Diabetic kidney disease (DKD), a prevalent complication of diabetes, is the leading cause of chronic kidney disease globally. The current standard of care cannot halt disease progression and thus new therapeutic targets are needed. We previously showed that the metalloprotease ADAM17 mediates the profibrotic response to high glucose in kidney mesangial cells. Its upregulation in high glucose conditions augments its profibrotic effects. Here we investigate regulation of the Adam17 promoter region -2304/-1567, previously shown to be glucose responsive, for which regulatory factors have not yet been identified.

Methods: Adam17 promoter regulation, cell surface translocation and activation were assessed in primary rat mesangial cells using standard molecular biology techniques. Type 1 diabetes was induced in mice using streptozocin and kidney function and development of fibrosis were assessed after 24 weeks. Human and mouse kidneys were immunostained for LASP1.

Results: In rat mesangial cells, the LIM and SH3 protein 1 (LASP1) was identified as a regulator of the Adam17 promoter in response to high glucose by mass spectrometry of nuclear lysate proteins binding to the -2304/-1567 promoter region. Knockdown of LASP1 prevented glucose-induced Adam17 promoter activation and transcript and protein upregulation. LASP1 nuclear localisation and regulation of Adam17 promoter activity in high glucose required phosphorylation of LASP1 on S146 by protein kinase A, but not protein kinase G, and Y171 phosphorylation by Src kinase. LASP1 also regulated glucose-induced ADAM17 cell surface localisation and activation, dependent on its phosphorylation by Src and interaction with focal adhesion kinase. Profibrotic responses to glucose were inhibited by LASP1 downregulation. In vivo, LASP1 expression was increased in the kidneys of type 1 diabetic mice and in kidneys of patients with DKD. Mice with Lasp1 knockout showed attenuated development of DKD.

Conclusions/interpretation: LASP1 regulates the synthesis and activation of ADAM17 in mesangial cells and is required for the profibrotic response to high glucose. Its deletion protects against DKD in mice. Targeting LASP1 may have therapeutic value as an indirect method of ADAM17 inhibition to inhibit fibrosis in DKD.

Aims/hypothesis: We aimed to investigate whether maternal and fetal genetic predispositions to insulin deficiency and resistance affect offspring fetal growth through distinct pathways in multi-ethnic populations.

Methods: In 5065 multi-ethnic mother-infant pairs, we examined the conditional associations of maternal and fetal partitioned polygenic risk scores (pPRSs) for type 2 diabetes-related pathways with fetal growth outcomes, including birthweight, sum of skinfold thicknesses (SSF), large-for-gestational-age (LGA) births and small-for-gestational-age (SGA) births. Two-sample Mendelian randomisation (2SMR) in Europeans was performed for triangulation. Exposures were eight type 2 diabetes-related pathways (n=1,812,017), eight beta cell function indices (n=26,356) and two insulin sensitivity indices (n=53,657). Outcomes were maternal and fetal genetically determined birthweight (n=406,063). Mediation analysis was used to assess the mediation effects of maternal glucose levels and BMI on maternal genetic effects and of cord blood C-peptide on fetal genetic effects. Co-localisation analyses were performed to test for shared causal variants.

Results: Fetal type 2 diabetes polygenic risk score (PRS) and pPRSs for lipodystrophy-related insulin resistance and impaired fasting glucose (IFG)-related insulin deficiency were associated with lower birthweight and SSF, while maternal type 2 diabetes PRS and pPRSs for IFG-related insulin deficiency and obesity-related insulin resistance were associated with higher offspring birthweight, SSF and LGA. These associations were consistent across five ethnic groups. Maternal post-load hyperglycaemia mediated 44.2% and 34.2% of the effects of type 2 diabetes PRS and IFG pPRS, respectively, while maternal BMI mediated 43.4% of the effect of Obesity pPRS. 2SMR found consistent results in Europeans and further revealed that fetal insulin sensitivity index and corrected insulin response were associated with higher birthweight. Some loci with shared causal variants acted through multiple pathways, including CDKAL1, TCF7L2, ADCY5 and MACF1.

Conclusions/interpretation: Reduced fetal growth may be driven by lipodystrophy-related insulin resistance and IFG-related insulin deficiency pathways. Targeting pregnant women with high type 2 diabetes PRS/pPRS and prescribing interventions to reduce their post-load hyperglycaemia and BMI may help reduce offspring risk of LGA.

Aims/hypothesis: Children with early-stage (pre-symptomatic) type 1 diabetes are currently identified primarily via research-based screening programmes in Australia. Once identified, families live with the knowledge that their child has an increased chance of developing symptomatic, lifelong, insulin-requiring type 1 diabetes but have no specific clinical pathway available to them in Western Australia (WA) for accessing tailored support or education. This project aimed to co-design a new clinical pathway to address this unmet need.

Methods: Experience-based co-design (EBCD) methodology was applied, comprising three phases undertaken consecutively over 12 months. Recruitment for each phase was via open invitation with voluntary participation. Phases 1 and 2 involved facilitated community conversations and focus groups conducted separately for type 1 diabetes community members and healthcare professionals (HCPs). Data from these phases were analysed using deductive and inductive content analysis to identify key categories of information and a prototype clinical pathway was developed incorporating these. For phase 3, a combined workshop was held with all stakeholders to obtain feedback on the prototype, and refine it accordingly.

Results: In phase 1, 16 community members (people living with type 1 diabetes, families whose child or children had been screened for type 1 diabetes) and 36 HCPs (doctors, nurse educators, social workers, dietitians, a mental health nurse and administrative staff from Perth Children's Hospital) participated in separate community conversations. The following three key categories were identified: (1) the need for education; (2) the need for support and strategies for managing uncertainty; and (3) the need for information on disease-modifying therapies and access to clinical trials. In phase 2, seven community members and 11 HCPs participated in separate focus groups. The following key priorities were identified: (1) the need for access to HCPs skilled in supporting patients to manage uncertainty; (2) the need for flexibility in delivery modes (telehealth/in-person); (3) the need for early referral to relevant clinical trials; and (4) the need for reliable and up-to-date resources. In phase 3, three community members and three HCPs attended a combined workshop to provide feedback on a prototype clinical pathway and their feedback was incorporated into a final version.

Conclusions/interpretation: Application of EBCD methodology enabled the development of a new clinical pathway tailored to the needs of WA families with a child living with early-stage type 1 diabetes.