Diabetologia最新文献

Progress in developing therapies for the maintenance of endogenous insulin secretion in, or the prevention of, type 1 diabetes has been hindered by limited animal models, the length and cost of clinical trials, difficulties in identifying individuals who will progress faster to a clinical diagnosis of type 1 diabetes, and heterogeneous clinical responses in intervention trials. Classic placebo-controlled intervention trials often include monotherapies, broad participant populations and extended follow-up periods focused on clinical endpoints. While this approach remains the ‘gold standard’ of clinical research, efforts are underway to implement new approaches harnessing the power of artificial intelligence and machine learning to accelerate drug discovery and efficacy testing. Here, we review emerging approaches for repurposing agents used to treat diseases that share pathogenic pathways with type 1 diabetes and selecting synergistic combinations of drugs to maximise therapeutic efficacy. We discuss how emerging multi-omics technologies, including analysis of antigen processing and presentation to adaptive immune cells, may lead to the discovery of novel biomarkers and subsequent translation into antigen-specific immunotherapies. We also discuss the potential for using artificial intelligence to create ‘digital twin’ models that enable rapid in silico testing of personalised agents as well as dose determination. To conclude, we discuss some limitations of artificial intelligence and machine learning, including issues pertaining to model interpretability and bias, as well as the continued need for validation studies via confirmatory intervention trials.

Graphical Abstract

Aims/hypothesis

The potential impact of childhood bereavement—a severe psychological stressor—on childhood type 1 diabetes development remains unclear. Here, we aimed to bridge this knowledge gap and assess whether bereavement characteristics influenced any impact.

Methods

We conducted a register-based cohort study encompassing 3,598,159 children born in Sweden between 1987 and 2020. Childhood bereavement was defined as the death of a biological mother, father or sibling. Diagnosis of type 1 diabetes in childhood (<18 years) was ascertained through the National Patient Register. We applied a Cox proportional hazards regression model to investigate the impact of childhood bereavement on type 1 diabetes, while adjusting for potential confounders (including parental type 1 diabetes status, country of birth and demographic characteristics).

Results

During follow-up, 86,226 children (2.4%) lost a family member, and 18,817 children (0.52%) were diagnosed with type 1 diabetes (median age at onset 9.1 years). We did not detect any overall association between childhood bereavement and type 1 diabetes (adjusted HR 1.04; 95% CI 0.93, 1.17). We found no influence of age at loss, cause of death, familial relationship to the deceased, and time since loss.

Conclusions/interpretation

In this large population-based Swedish study, we observed no evidence supporting a link between childhood bereavement and type 1 diabetes.

Graphical Abstract

Aims/hypothesis

The key pancreatic beta cell transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene homologue A (MafA) is critical for the maintenance of mature beta cell function and phenotype. The expression levels and/or activities of MafA are reduced when beta cells are chronically exposed to diabetogenic stress, such as hyperglycaemia (i.e. glucotoxicity). Interventional targets and adjuvant therapies to abate MafA loss in beta cells may provide evidence to support the effective treatment of diabetes. In this study, we aimed to investigate the function of stearoyl-CoA desaturase 1 (SCD1) in the stabilisation of MafA expression and activity in order to maintain functional beta cell mass, with a view to suppressing the development of type 2 diabetes.

Methods

SCD1 expression levels were analysed in islets obtained from humans with type 2 diabetes, hyperglycaemic db/db mice, and a high-fat diet (HFD)-induced mouse model of diabetes. Pancreatic beta cell-specific Scd1 knockin (βSCD1KI) mice were generated to study the role of SCD1 in beta cell function and identity. The protein-to-protein interactions between SCD1 and MafA were detected in MIN6 and HEK293A cells. We used experiments including chromatin immunoprecipitation, cell-based ubiquitination assay and fatty acid composition analysis to investigate the specific molecular mechanism underlying the effect of SCD1 on the restoration of MafA and beta cell function under glucotoxic conditions.

Results

SCD1 expression was reduced in beta cells of humans with type 2 diabetes and in HFD-fed and db/db mice compared with healthy controls, which was attributed to glucotoxicity-induced Scd1 promoter histone deacetylation. Gain-of-function of SCD1 in beta cells improved insulin deficiency, glucose intolerance and beta cell dedifferentiation/transdifferentiation in the HFD-induced mouse model of diabetes. Mechanistically, SCD1 directly bound to the E3 ubiquitin ligase HMG-CoA reductase degradation 1 (HRD1) and stabilised nuclear MafA through interrupting MafA–HRD1 interactions in mouse islets and MIN6 cells, which inhibited the ubiquitination-mediated degradation of MafA. Moreover, the products of SCD enzyme reactions (mainly oleic acid) also alleviated glucotoxicity-mediated oxidative stress in MIN6 cells.

Conclusions/interpretation

Our findings indicate that SCD1 stabilises beta cell MafA both in desaturase-dependent and -independent manners, thus improving glucose homeostasis under metabolic stress. This provides a potential novel target for precision medicine for the treatment of diabetes.

Graphical Abstract

Aims/hypothesis

Quinine, when administered intraduodenally to activate bitter-taste receptors, in a dose of 600 mg, stimulates glucagon-like peptide-1 (GLP-1) and insulin, slows gastric emptying and lowers postprandial glucose in healthy people, with consequent implications for the management of type 2 diabetes; the effect of quinine on energy intake is uncertain. We have investigated the dose-related effects of quinine on postprandial blood glucose levels and energy intake in people with type 2 diabetes.

Methods

Male participants with type 2 diabetes (age: 68±5 years; HbA_1c: 49.0±5.0 mmol/mol [6.7±0.4%], BMI: 30±1 kg/m²) received in two study parts (A and B, n=12 each), on three separate occasions each, in randomised, crossover fashion, control, or 300 mg (QHCl-300) or 600 mg (QHCl-600) quinine hydrochloride, intraduodenally 30 min before a nutrient drink (2092 kJ, 74 g carbohydrate) (part A) or a standardised buffet-lunch (part B). Both the participants and investigators performing the study procedures were blinded to the treatments. In part A, plasma glucose, GLP-1, C-peptide and glucagon were measured at baseline, for 30 min after quinine alone and for 3 h post drink. Gastric emptying of the drink was measured with a ¹³C-acetate breath test. In part B, energy intake from the buffet-lunch was quantified.

Results

Quinine alone had no effect. Post drink, both quinine doses reduced peak plasma glucose markedly (QHCl-600 by 2.8±0.6 mmol/l) and slowed gastric emptying (all p<0.05; n=12, except for gastric emptying, n=11). QHCl-600, but not QHCl-300, stimulated plasma GLP-1 and C-peptide modestly (both p<0.05). Quinine did not affect energy intake.

Conclusions/interpretation

In type 2 diabetes, acute intraduodenal administration of quinine markedly reduces the plasma glucose response to oral carbohydrate, but does not affect energy intake. These findings support the potential use of quinine to reduce postprandial blood glucose levels in type 2 diabetes.

Trial registration

anzctr.org.au ACTRN12620000972921/ACTRN12621000218897

Funding

The study was funded by a Diabetes Australia Research Project Grant.

Graphical Abstract

Aims/hypothesis

Many studies of type 1 diabetes pathogenesis focus on individuals with high-risk HLA haplotypes. We tested the hypothesis that, among islet autoantibody-positive individuals, lacking HLA-DRB1*04-DQA1*03-DQB1*0302 (HLA-DR4-DQ8) and/or HLA-DRB1*0301-DQA1*0501-DQB1*0201 (HLA-DR3-DQ2) is associated with phenotypic differences, compared with those who have these high-risk HLA haplotypes.

Methods

We classified autoantibody-positive relatives of individuals with type 1 diabetes into four groups based on having both HLA-DR4-DQ8 and HLA-DR3-DQ2 (DR3/DR4; n=1263), HLA-DR4-DQ8 but not HLA-DR3-DQ2 (DR4/non-DR3; n=2340), HLA-DR3-DQ2 but not HLA-DR4-DQ8 (DR3/non-DR4; n=1607) and neither HLA-DR3-DQ2 nor HLA-DR4-DQ8 (DRX/DRX; n=1294). Group comparisons included demographics, metabolic markers and the prevalence of autoantibodies against GAD65 (GADA%), IA-2 (IA-2A%) or insulin (IAA%) at enrolment. A p value <0.01 was considered statistically significant.

Results

IA-2A% was lower in the DRX/DRX group (20.9%) than in the DR4/non-DR3 (38.5%, p<0.001) and DR3/DR4 (44.8%, p<0.001) groups, but similar to the DR3/non-DR4 group (20.0%). Conversely, IAA% was similar in the DRX/DRX (43.4%), DR4/non-DR3 (41.1%) and DR3/DR4 (41.0%) groups, but lower in the DR3/non-DR4 group (30.1%, p<0.001). Participants in the DRX/DRX group were older, with a lower prevalence of White participants and a higher prevalence of overweight/obesity, and higher preserved C-peptide (as measured by a lower Index60) than those in the DR3/DR4 group (all comparisons, p<0.005), a lower prevalence of White or non-Hispanic participants and a lower Index60 than those in the DR4/non-DR3 group, and younger age, a higher prevalence of Hispanic participants and a lower Index60 than those in the DR3/non-DR4 group (all comparisons, p<0.005). Among the 1292 participants who progressed to clinical type 1 diabetes, those in the DR3/non-DR4 group had higher GADA%, lower IA-2A% and lower IAA% than the other groups (all comparisons, p<0.01), and those in the DR3/DR4 group had the youngest age at diagnosis (all comparisons, p<0.001).

Conclusions/interpretation

Autoantibody-positive individuals who lack both high-risk HLA haplotypes (DRX/DRX) or have HLA-DR3-DQ2 but lack HLA-DR4-DQ8 (DR3/non-DR4) have phenotypic differences compared with DR3/DR4 and DR4/non-DR3 individuals, suggesting that there is aetiological heterogeneity in type 1 diabetes.

Graphical Abstract

Aims/hypothesis

Resistin, inducing insulin resistance, is elevated in the sera of individuals with the G-A haplotype at c.-420 C>G (rs1862513) and c.-358 G>A (rs3219175). This haplotype is associated with visceral obesity and low grip strength. To elucidate the hidden relationship between the G-A haplotype and insulin resistance, integration of specific phenotypes defined by body composition and 75 g OGTT would be a promising strategy.

Methods

The 803 Japanese participants (average age: 62 years), attending annual medical checkups, were evaluated every 5 years. Participants were categorised by skeletal muscle mass, visceral fat score and OGTT results. Hierarchical clustering was performed using body composition and glucose metabolism parameters. Whole blood cells from participants homozygous for the G-A or C-G haplotype (n=25 and 33, respectively), matched for age, sex and BMI, using propensity score matching, were used for RNA-seq, pathway analysis and RT-PCR.

Results

Multivariate analysis showed that individuals with the G-A haplotype, when accompanied by latent skeletal muscle loss and visceral obesity (latent sarcopenic obesity), presented a pronounced deterioration in insulin resistance over a 5 year period. Cluster 2, identified using hierarchical clustering, was characterised by low skeletal muscle mass, visceral obesity and insulin resistance. This cluster, with the G-A haplotype, demonstrated deterioration in insulin resistance. RNA-seq and RT-PCR revealed altered expression of mitophagy-related genes in whole blood cells of the G-A homozygotes.

Conclusions/interpretation

The G-A haplotype, accompanied by latent low skeletal muscle mass and visceral obesity, led to the deterioration of insulin resistance over a 5 year period in this cohort, possibly through the altered expression of mitophagy-related genes.

Graphical Abstract

Aims/hypothesis

A better understanding of the mechanisms underlying an elevated infection risk in individuals with type 2 diabetes is needed to guide risk stratification and prevention. We investigated the risk of infection in subgroups of individuals with type 2 diabetes according to indices of insulin sensitivity and beta cell function.

Methods

We classified 7265 individuals with recently diagnosed type 2 diabetes (median duration 1.4 years, IQR 0.5–2.9 years) into hyperinsulinaemic (high beta cell function [HOMA 2-beta-cell function, HOMA2-B], low insulin sensitivity [HOMA 2-insulin sensitivity, HOMA2-S]), classical (low HOMA2-B, low HOMA2-S) and insulinopenic (low HOMA2-B, high HOMA2-S) type 2 diabetes. Individuals were followed until first hospital-treated infection or first prescription for an anti-infective agent (community-treated infection). We used Cox regression analysis to estimate HRs adjusted for age, sex, index year, diabetes duration and treatment, lifestyle behaviours and comorbidities.

Results

Among study participants, 28% had hyperinsulinaemic, 63% had classical and 9% had insulinopenic type 2 diabetes. The 10 year risks of hospital-treated infections were 42.3%, 36.8% and 31.0% in the three subgroups, respectively. Compared with the insulinopenic subgroup, adjusted HRs for hospital-treated infections were elevated for hyperinsulinaemic (1.38 [95% CI 1.16, 1.65]) and classical type 2 diabetes (1.20 [95% CI 1.02, 1.42]). The 10 year risks of community-treated infections were high in all three subgroups at 91.6%, 90.1% and 88.3%, respectively, corresponding to adjusted HRs of 1.20 (95% CI 1.08, 1.33) for the hyperinsulinaemic and 1.10 (95% CI 1.00, 1.21) for the classical subgroup. Infection risk in the hyperinsulinaemic subgroup decreased substantially when further adjusted for abdominal obesity, metabolic derangements and low-grade inflammation.

Conclusions/interpretation

The risk of severe infections is clearly elevated in individuals with type 2 diabetes characterised by a higher degree of insulin resistance/hyperinsulinaemia.

Graphical Abstract

Aims/hypothesis

In the Study Of diabetic Nephropathy with AtRasentan (SONAR), the endothelin receptor antagonist (ERA) atrasentan slowed progression of chronic kidney disease (CKD) in individuals with type 2 diabetes. Pre-clinical research suggests sex-based differences in the endothelin system might influence the efficacy and safety of atrasentan. We therefore assessed the effects of atrasentan in men and women participating in SONAR.

Methods

SONAR was a double-blind, placebo-controlled trial that compared atrasentan 0.75 mg/day with placebo in individuals with type 2 diabetes and CKD (eGFR 25–75 ml/min per 1.73 m², urine albumin/creatinine ratio [UACR] 300–5000 mg/g). The primary endpoint was defined as the time from randomisation to the first occurrence of a doubling in serum creatinine or kidney failure (eGFR <15 ml/min per 1.73 m², chronic dialysis, kidney transplantation or death from kidney failure). Hospitalisation for heart failure was the secondary endpoint. We performed Cox proportional hazards regression analyses to compare the treatment effect of atrasentan between male and female participants on the risk of the composite kidney outcome as well as hospitalisation for heart failure. Additionally, differences between male and female participants in atrasentan plasma exposure and eGFR change were assessed using, respectively, a t test and linear mixed effect model.

Results

Among 3668 randomised participants, 946 (25.8%) were female. Atrasentan significantly reduced the risk of the composite kidney outcome in female participants (HR 0.46 [95% CI 0.28, 0.76]) but not in male participants (HR 0.83 [95% CI 0.65, 1.05]; p value for interaction 0.032). Atrasentan compared with placebo reduced eGFR decline to a greater extent in female than in male participants (treatment effect difference between male vs female participants −0.99 ml/min per 1.73 m², p value for interaction=0.020). The RR for hospitalisation for heart failure with atrasentan vs placebo was 1.14 (95% CI 0.74, 1.76) in male participants and 1.88 (95% CI 0.98, 3.63) in female participants (p value for interaction=0.217). Female participants also had significantly higher atrasentan plasma exposure than male participants (geometric mean AUC 54.5 vs 42.6 ng/ml×h; p<0.001).

Conclusions/interpretation

Atrasentan showed greater kidney protection in female than in male participants but also induced more heart failure events in the female participants. These data suggest that sex-specific dosing regimens may be considered to optimise ERA treatment.

Trial registration

ClinicalTrials.gov NCT01858532

Graphical Abstract

Regular physical activity and exercise (PA) are cornerstones of diabetes care for individuals with type 1 diabetes. In recent years, the availability of automated insulin delivery (AID) systems has improved the ability of people with type 1 diabetes to achieve the recommended glucose target ranges. PA provide additional health benefits but can cause glucose fluctuations, which challenges current AID systems. While an increasing number of clinical trials and reviews are being published on different AID systems and PA, it seems prudent at this time to collate this information and develop a position statement on the topic. This joint European Association for the Study of Diabetes (EASD)/International Society for Pediatric and Adolescent Diabetes (ISPAD) position statement reviews current evidence on AID systems and provides detailed clinical practice points for managing PA in children, adolescents and adults with type 1 diabetes using AID technology. It discusses each commercially available AID system individually and provides guidance on their use in PA. Additionally, it addresses different glucose responses to PA and provides stratified therapy options to maintain glucose levels within the target ranges for these age groups.

Graphical Abstract

Aims/hypothesis

Our aim was to assess sex differences in the efficacy of angiotensin receptor blockers (i.e. losartan and irbesartan) on kidney and cardiovascular outcomes in individuals with type 2 diabetes and diabetic kidney disease.

Methods

Data from the Angiotensin II Antagonist Losartan Study (RENAAL) and Irbesartan type II Diabetic Nephropathy Trial (IDNT) were used. The kidney outcome was time to first event of end-stage kidney disease or doubling of serum creatinine. The cardiovascular outcome was time to first event of a composite of stroke, myocardial infarction, cardiovascular death or hospitalisation for heart failure. Sex differences were assessed by a sex × treatment interaction term in Cox proportional hazards models.

Results

Included were 1737 male participants and 924 female participants. The beneficial effect of angiotensin receptor blockers on the kidney outcome was similar between male and female participants (HR in male participants 0.72 [95% CI 0.59, 0.86] vs HR in female participants 0.86 [95% CI 0.69, 1.06]; sex × treatment interaction HR 1.19 [95% CI 0.89, 1.59]). For the cardiovascular outcome, angiotensin receptor blockers lowered the risk in male but not in female participants (HR in male participants 0.81 [95% CI 0.69, 0.95] vs HR in female participants 1.11 [95% CI 0.88, 1.40]; sex × treatment interaction HR 1.37 [95% CI 1.03, 1.82]).

Conclusions/interpretation

This study in individuals with type 2 diabetes and diabetic kidney disease suggests that the beneficial effects of angiotensin receptor blockers are similar in male and female participants for the kidney outcome but not for the cardiovascular outcome. More attention to sex differences in angiotensin receptor blockers’ efficacy and underlying mechanisms of differences in response is needed.

Trial registration

ClinialTrials.gov NCT00308347

Graphical Abstract