Diabetologia最新文献

Aims/hypothesis: We aimed to analyse TrialNet Anti-CD3 Prevention (TN10) data using oral minimal model (OMM)-derived indices to characterise the natural history of stage 2 type 1 diabetes in placebo-treated individuals, to describe early metabolic responses to teplizumab and to explore the predictive capacity of OMM measures for disease-free survival rate.

Methods: OMM-estimated insulin secretion, sensitivity and clearance and the disposition index were evaluated at baseline and at 3, 6 and 12 months post randomisation in placebo- and teplizumab-treated groups, and, within each group, in slow- and rapid-progressors (time to stage 3 disease >2 or $\le$ 2 years). OMM metrics were also compared with the standard AUC C-peptide. Percentage changes in CD8⁺ T memory cell and programmed death-1 (PD-1) expression were evaluated in each group.

Results: Baseline metabolic characteristics were similar between 28 placebo- and 39 teplizumab-treated participants. Over 12 months, insulin secretion declined in placebo-treated and rose in teplizumab-treated participants. Within groups, placebo slow-progressors (n=14) maintained insulin secretion and sensitivity, while both declined in placebo rapid-progressors (n=14). Teplizumab slow-progressors (n=28) maintained elevated insulin secretion, while teplizumab rapid-progressors (n=11) experienced mild metabolic decline. Compared with rapid-progressor groups, insulin clearance significantly decreased between baseline and 3, 6 and 12 months in the slow-progressor groups in both treatment arms. In aggregate, both higher baseline insulin secretion (p=0.027) and reduced 12 month insulin clearance (p=0.045) predicted slower progression. A >25% loss of insulin secretion at 3 months had specificity of 0.95 (95% CI 0.86, 1.00) to identify rapid-progressors and correctly classified the 2 year risk for progression in 92% of participants, with a sensitivity of 0.19 (95% CI 0.08, 0.30). OMM-estimated insulin secretion outperformed AUC C-peptide to differentiate groups by treatment or to predict progression. Metabolic changes were paralleled by relative frequency of change in PD-1⁺ CD8⁺ T effector memory cells.

Conclusions/interpretation: OMM measures characterise the metabolic heterogeneity in stage 2 diabetes, identifying differences between rapid- and slow-progressors, and heterogeneous impacts of immunotherapy, suggesting the need to account for these differences when designing and interpreting clinical trials.

Aims/hypothesis: Microvascular dysfunction contributes to insulin resistance. CD36, a fatty acid transporter and modulator of insulin signalling, is abundant in microvascular endothelial cells. Humans carrying the minor allele (G) of CD36 coding variant rs3211938 have 50% reduced CD36 expression and show endothelial dysfunction. We aimed to determine whether G allele carriers have microvascular resistance to insulin and, if so, how this affects glucose disposal.

Methods: Our multi-disciplinary approach included hyperinsulinaemic-euglycaemic clamps in Cd36^-/- and wild-type mice, and in individuals with 50% CD36 deficiency, together with control counterparts, in addition to primary human-derived microvascular endothelial cells with/without CD36 depletion.

Results: Insulin clamps showed that Cd36^-/- mice have enhanced insulin-stimulated glucose disposal but reduced vascular compliance and capillary perfusion. Intravital microscopy of the gastrocnemius showed unaltered transcapillary insulin flux. CD36-deficient humans had better insulin-stimulated glucose disposal but insulin-unresponsive microvascular blood volume (MBV). Human microvascular cells depleted of CD36 showed impaired insulin activation of Akt, endothelial NO synthase and NO generation. Thus, in CD36 deficiency, microvascular insulin resistance paradoxically associated with enhanced insulin sensitivity of glucose disposal.

Conclusions/interpretation: CD36 deficiency was previously shown to reduce muscle/heart fatty acid uptake, whereas here we showed that it reduced vascular compliance and the ability of insulin to increase MBV for optimising glucose and oxygen delivery. The muscle and heart respond to these energy challenges by transcriptional remodelling priming the tissue for insulin-stimulated glycolytic flux. Reduced oxygen delivery activating hypoxia-induced factors, endothelial release of growth factors or small intracellular vesicles might mediate this adaptation. Targeting NO bioavailability in CD36 deficiency could benefit the microvasculature and muscle/heart metabolism.

Trial registration: Clinicaltrials.gov NCT03012386 DATA AVAILABILITY: The RNAseq data generated in this study have been deposited in the NCBI Gene Expression Omnibus ( www.ncbi.nlm.nih.gov/geo/ ) under accession code GSE235988 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE235988 ).

Aims/hypothesis

We aimed to examine arrhythmias and hypoglycaemia among individuals with and without diabetes who are receiving haemodialysis and to investigate the association between arrhythmias and hypoglycaemia, hyperglycaemia and glycaemic variability.

Methods

This prospective multicentre cohort study included 70 participants on maintenance haemodialysis (35 with diabetes and 35 without diabetes). We employed implantable cardiac monitors for continuous heart rhythm monitoring in combination with periodic use of continuous glucose monitoring. Logistic-regression-type linear mixed models were used to examine associations between arrhythmias and glycaemic measures.

Results

During 18 months of follow-up, clinically significant arrhythmias (bradyarrhythmia and ventricular tachycardia) were identified in 12 (34%) participants with diabetes and 11 (31%) without diabetes. Atrial fibrillation was detected in 13 (37%) participants with diabetes and 14 (40%) without, while other supraventricular tachycardia was detected in seven (20%) and 11 (31%) participants with and without diabetes, respectively. Hypoglycaemia (sensor glucose <3.9 mmol/l) was observed in 27 (77%) participants with diabetes and 32 (91%) without diabetes. Compared with euglycaemia, hypoglycaemia was associated with an increased rate of arrhythmias among participants without diabetes (incidence rate ratio [IRR] 3.13 [95% CI 1.49, 6.55]), while hyperglycaemia (sensor glucose >10.0 mmol/l) was associated with a decreased rate of arrhythmias among participants with diabetes (IRR 0.58 [95% CI 0.37, 0.92]). Glycaemic variability showed no association with arrhythmias regardless of the presence of diabetes.

Conclusions/interpretation

Arrhythmias and hypoglycaemia were common in those undergoing haemodialysis regardless of diabetes status. Our data suggest a temporal relationship between arrhythmias and glucose level in both individuals with and without diabetes.

Trial registration

Clinicaltrials.gov: NCT04841304.

Graphical Abstract

Aims/hypothesis

While investigating markers for declining beta cell function in type 1 diabetes, we previously demonstrated 11 statistically significant protein associations with fasting C-peptide/glucose ratios in longitudinal serum samples from newly diagnosed (ND) individuals (n=86; 228 samples in total) participating in the INNODIA (Innovative approaches to understanding and arresting type 1 diabetes) study. Furthermore, comparison with protein measurements from age- and sex-matched autoantibody-negative unaffected family members (UFMs, n=194) revealed differences in the serum levels of 13 target proteins. To further evaluate these findings, we analysed longitudinal serum drawn during the first year after diagnosis from a new group of ND individuals subsequently enrolled in the study, together with samples from additional UFMs.

Methods

To validate the previously reported statistically significant protein associations with type 1 diabetes progression, selected reaction monitoring (SRM) MS analyses were carried out. Sera from individuals diagnosed with type 1 diabetes under the age of 18 years (n=146) were collected within 6 weeks of diagnosis and at 3, 6 and 12 months after diagnosis (560 samples in total). The resulting SRM data were compared with fasting C-peptide/glucose measurements, which were used as a proxy for beta cell function. The protein data were further compared with cross-sectional SRM measurements from age- and sex-matched UFMs (n=272).

Results

Our results confirmed the presence of significant (p<0.05) inverse associations between fasting C-peptide/glucose ratios and peptides from apolipoprotein B-100, apolipoprotein M and glutathione peroxidase 3 (GPX3) in ND individuals. Additionally, we observed consistent differences in the levels of ten of the 13 targeted proteins between individuals with type 1 diabetes and UFMs. These proteins included GPX3, transthyretin, prothrombin, apolipoprotein C1 and afamin.

Conclusions/interpretation

The validated results reflect the landscape of biological changes accompanying type 1 diabetes. For example, the association of the targeted apolipoproteins with fasting C-peptide/glucose ratios in the first year after diagnosis is likely to relate to lipid abnormalities observed in individuals with type 1 diabetes, and reiterates the connection of apolipoproteins with the underlying changes accompanying the disease. Further research is needed to explore the clinical value and relevance of these targets.

Graphical Abstract

Aims/hypothesis

Accurate understanding of type 1 diabetes risk is critical for optimisation of counselling, monitoring and interventions, yet even within established staging classifications, individual time to clinical disease varies. Previous work has associated IA-2A positivity with increased type 1 diabetes progression but a comprehensive assessment of the impact of screening for IA-2A positivity across the natural history of autoantibody positivity has not been performed. We asked whether IA-2A would consistently be associated with higher risk of progression within and across established stages of type 1 diabetes in a large natural history study.

Methods

Genetic, autoantibody and metabolic data from adult and paediatric autoantibody-negative (n=192) and autoantibody-positive (n=4577) relatives of individuals with type 1 diabetes followed longitudinally in the Type 1 Diabetes TrialNet Pathway to Prevention Study were analysed. Cox regression was used to compare cumulative incidences of clinical diabetes by autoantibody profiles and disease stages.

Results

Compared with IA-2A⁻ individuals, IA-2A⁺ individuals had higher genetic risk scores and clinical progression risk within single-autoantibody-positive (5.3-fold increased 5 year risk), stage 1 (2.2-fold increased 5 year risk) and stage 2 (1.3-fold increased 5 year risk) type 1 diabetes categories. Individuals with single-autoantibody positivity for IA-2A showed increased metabolic dysfunction and diabetes progression compared with people who were autoantibody negative, those positive for another single autoantibody, and IA-2A⁻ stage 1 individuals. Individuals at highest risk within the single-IA-2A⁺ category included children (HR 14.2 [95% CI 1.9, 103.1], p=0.009), individuals with IA-2A titres above the median (HR 3.5 [95% CI 1.9, 6.6], p<0.001), individuals with high genetic risk scores (HR 1.4 [95% CI 1.2,1.6], p<0.001) and individuals with HLA DR4-positive status (HR 3.7 [95% CI 1.6, 8.3], p=0.002). When considering all autoantibody-positive individuals, progression risk was similar for euglycaemic IA-2A⁺ individuals and dysglycaemic IA-2A⁻ individuals.

Conclusions/interpretation

IA-2A positivity is consistently associated with increased progression risk throughout the natural history of type 1 diabetes development. Individuals with single-autoantibody positivity for IA-2A have a greater risk of disease progression than those who meet stage 1 criteria but who are IA-2A⁻. Approaches to incorporate IA-2A⁺ status into monitoring strategies for autoantibody-positive individuals should be considered.

Graphical Abstract

Aims/hypothesis: Brown adipose tissue (BAT) consumes excess energy through heat production by uncoupling protein 1 (UCP1) to regulate the metabolic profile, but the UCP1-independent mechanisms of BAT, such as in endocrine function, are largely unknown. Our previous study showed that BAT-derived neuregulin 4 (NRG4) displays anti-atherosclerotic properties. Thus, we hypothesised that BAT could regulate diabetic nephropathy, a diabetic microvascular complication, via NRG4.

Methods: To investigate the influence of NRG4 from BAT on podocyte apoptosis, both loss- and gain-of-function approaches were used in in vivo experiments. Diabetic nephropathy models were created using BAT-specific Nrg4-knockout (BKO) mice, global Nrg4-knockout (KO) mice and wild-type (WT) mice. In in vitro studies, podocytes (MPC5) were exposed to glucose and recombinant NRG4 (rNrg4). Additionally, brown adipocytes were co-cultured with MPC5 podocytes using a transwell system. The expression levels of proteins associated with podocyte apoptosis and signalling pathways were measured.

Results: BAT-specific NRG4 deficiency aggravated podocyte apoptosis (increased by 47.46%) and increased the urinary albumin/creatinine ratio (increased by 41.71%), decreased nephrin expression and increased desmin expression. As expected, these changes were reversed by NRG4 replenishment using adeno-associated virus-NRG4 interscapular BAT injection and BAT transplantation assays in KO mice. Additionally, co-culture experiments demonstrated that brown adipocytes from WT mice could alleviate high-glucose-induced podocyte apoptosis. In in vitro experiments, recombinant NRG4 inhibited high-glucose-induced podocyte apoptosis. Mechanistically, the Akt-glycogen synthase kinase 3 β (GSK-3β) pathway is crucial for the protection that BAT-derived NRG4 provides to podocytes in diabetic nephropathy.

Conclusions/interpretation: Our data show that BAT had a protective effect on podocyte apoptosis in diabetic nephropathy through BAT-derived NRG4, and the Akt-GSK‑3β signalling pathway may mediate the inhibition of BAT-derived NRG4 on podocyte apoptosis in diabetic nephropathy.

Aims/hypothesis

Growing evidence suggests that timing may be an important aspect of physical activity that influences cardiometabolic health. However, the current literature is inconclusive regarding the time of day that physical activity offers the greatest metabolic advantages. We investigated associations between hourly physical activity levels and diabetes mellitus and glycaemic biomarkers in a cross-sectional and nationally representative sample of US adults.

Methods

We studied 7074 adults (mean age 48 years; 52% women) from the National Health and Nutrition Examination Survey (2011–2014). Physical activity was measured by actigraphy. A monitor-independent movement summary (MIMS) unit was used to derive the total activity level (divided into quintiles) for hourly windows that were defined relative to sleep timing and according to clock time. The primary outcome was prevalent diabetes, and secondary outcomes included fasting glucose, fasting insulin, HOMA-IR and 2 h OGTT results.

Results

Physical activity levels in late morning and late afternoon were associated with lower adjusted odds of diabetes. Specifically, in late morning (8:01–9:00 h after the sleep midpoint), the highest quintile of activity was associated with a 35% decrease (OR 0.65; 95% CI 0.44, 0.96) in the odds of diabetes when compared with the lowest quintile, while in late afternoon (11:01–17:00 h after the sleep midpoint), the highest quintiles were associated with 56% and 36% lower odds (OR 0.44; 95% CI 0.29, 0.69 and OR 0.64; 95% CI 0.43, 0.95). Higher night-time activity was associated with higher odds of diabetes. Similar patterns of results were observed with OGTT data and across subgroups of age, gender, race/ethnicity, chronotype and sleep duration.

Conclusions/interpretation

Our findings suggest that the timing of physical activity may modulate its metabolic effects.

Graphical Abstract