Diabetologia最新文献

Automated insulin delivery (AID) systems have significantly advanced diabetes management, progressively reducing user interactions required for optimal glucose management. This review evaluates the current landscape and future potential of AID systems without meal announcement, particularly focusing on real-world insights from open-source AID (OS-AID) technologies. Although commercial AID systems operating in hybrid closed-loop (HCL) mode have improved glycaemic outcomes, they remain dependent on manual meal announcement and user-driven actions, limiting their real-world utility. Current versions of OS-AID systems, developed by the diabetes community, can allow operation without meal announcements, presenting an opportunity to move closer to truly automated diabetes management. Recent clinical trials suggest that OS-AID systems can effectively manage glucose levels without meal announcements, achieving glucose levels comparable with those obtained by AID systems in HCL mode, with the potential of reduced management burden for users. However, practical challenges persist, including the need for expert configuration and handling of rapid changes in insulin sensitivity, such as during exercise or rapid glucose fluctuations following predicted low-glucose. This review synthesises insights from user and healthcare professional experiences, and emerging clinical evidence. It highlights the fact that successful implementation of AID without meal announcement requires advanced algorithmic responsiveness, user personalisation and ongoing clinician engagement. Looking forward, integrating adjunctive therapies, artificial intelligence and enhanced physiological modelling will likely enhance system performance to drive the next generation of diabetes care towards wider adoption and true 'set-and-forget' functionality.

Three diseases primarily affecting the exocrine pancreas-chronic pancreatitis, cystic fibrosis and pancreatic ductal adenocarcinoma-are all associated with a high incidence of diabetes. Together, they may account for more cases of diabetes than autoimmune type 1 diabetes. All forms of pancreatogenic (type 3c) diabetes are characterised by impaired insulin secretion but maintenance of significant islet beta cell mass, even in the presence of virtually complete destruction of the exocrine component of the gland. Pancreatic ductal injury and associated fibrosis are common features in chronic pancreatitis, cystic fibrosis and ductal adenocarcinoma. Increased peri-ductal fibrosis is also seen in type 2 and type 1 diabetes. Here, we review the literature regarding a potential common aetiological role of pancreatic fibrosis in the pathogenesis of type 3c, type 2 and type 1 diabetes. A vicious profibrotic signalling cycle involving injured ducts, pancreatic stellate cells and macrophages with increased levels of pancreatic tissue TGF-β at the core has increasingly been recognised as an essential driver of pancreatic exocrine fibrosis. We propose a second diabetogenic perpetual cycle comprising paracrine signalling between activated pancreatic stellate cells, macrophages and the islets themselves, leading to potentially reversible beta cell failure. The antifibrotic agents pirfenidone and nintedanib, thought to work primarily through suppression of TGF-β function, are used routinely in clinical practice for non-pancreatic indications, with a first trial in pancreatitis underway. Trials evaluating these licensed therapeutics that include primary diabetes-related endpoints and measures aiming to elucidate the underlying mechanisms of action merit consideration in type 3c diabetes and ultimately in type 2 diabetes and in combinatorial regimens in type 1 diabetes.

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: The role of red meat in type 1 diabetes risk remains unclear. We examined whether maternal and early-life red meat intake is associated with the development of type 1 diabetes and whether such associations are modified by genetic susceptibility.

Methods: We analysed data from 15,717 children participating in the All Babies In Southeast Sweden (ABIS) cohort, followed for type 1 diabetes diagnosis via national registers until the age of 24-26 years. Dietary intake was assessed through food frequency questionnaires during pregnancy and at ages 1, 2.5 and 5 years. Cox models estimated adjusted HRs and 95% CIs for type 1 diabetes in relation to red meat, including beef, pork and sausage, analysed as high vs low intake frequency and per serving/week. Analyses were stratified by HLA risk genotype and family history of type 1 diabetes.

Results: Frequency of red meat intake during pregnancy or at age 1 was not associated with type 1 diabetes risk. The corresponding HRs per serving/week were 0.98 (95% CI 0.90, 1.07) and 0.98 (95% CI 0.88, 1.08), respectively. In type-specific analyses, higher frequency of beef intake at age 5 was associated with an increased risk of type 1 diabetes (HR 1.29 [95% CI 1.05, 1.58]), with a similar tendency for exposure at age 2.5 (HR 1.12 [95% CI 0.93, 1.36]). The association at age 5 was evident among children with high-risk HLA genotypes (HR 1.40 [95% CI 1.11, 1.78]) or a family history of type 1 diabetes (HR 1.56 [95% CI 1.08, 2.26]). In contrast, no statistically significant association was observed among children with low-risk HLA genotypes (HR 0.34 [95% CI 0.10, 1.19]) or without a family history of type 1 diabetes (HR 1.20 [95% CI 0.92, 1.56]). No associations were found for higher frequency of beef consumption during pregnancy or at age 1, nor for pork and sausage at any age.

Conclusions/interpretation: Childhood beef consumption may contribute to type 1 diabetes development in genetically at-risk individuals. Further research is needed to confirm this finding and clarify underlying mechanisms.

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.