Diabetologia最新文献

Aims/hypothesis: Fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, shows some promise in alleviating beta cell stress and preserving beta cell function in preclinical studies of type 1 diabetes. The aim of this phase 2, placebo-controlled, double-blinded, randomised clinical trial was to investigate the efficacy and safety of fenofibrate in adults and adolescents with newly diagnosed type 1 diabetes.

Methods: We enrolled 58 individuals (aged 16 to 40 years old) with newly diagnosed type 1 diabetes and randomised them to daily oral treatment with fenofibrate 160 mg or placebo for 52 weeks (in a block design with a block size of 4, assigned in a 1:1 ratio). Our primary outcome was change in beta cell function after 52 weeks of treatment, assessed by AUC for C-peptide levels following a 2 h mixed-meal tolerance test. Secondary outcomes included glycaemic control (assessed by HbA_1c and continuous glucose monitoring), daily insulin use, and proinsulin/C-peptide (PI/C) ratio as a marker of beta cell stress. We assessed outcome measures before and after 4, 12, 26 and 52 weeks of treatment. Blinding was maintained for participants, their healthcare providers and all staff involved in handling outcome samples and assessment.

Results: The statistical analyses for the primary outcome included 56 participants (n=27 in the fenofibrate group, after two withdrawals, and n=29 in the placebo group). We found no significant differences between the groups in either 2 h C-peptide levels (mean difference of 0.08 nmol/l [95% CI -0.05, 0.23]), insulin use or glycaemic control after 52 weeks of treatment. On the contrary, the fenofibrate group showed a higher PI/C ratio at week 52 compared with placebo (mean difference of 0.024 [95% CI 0.000, 0.048], p<0.05). Blood lipidome analysis revealed that fenofibrate repressed pathways involved in sphingolipid metabolism and signalling at week 52 compared with placebo. The 52 week intervention evoked few adverse events and no serious adverse events. Follow-up in vitro experiments in human pancreatic islets demonstrated a stress-inducing effect of fenofibrate.

Conclusions/interpretation: Contrary to the beneficial effects of fenofibrate found in preclinical studies, this longitudinal, randomised, placebo-controlled trial does not support the use of fenofibrate for preserving beta cell function in individuals with newly diagnosed type 1 diabetes.

Trial registration: EudraCT number: 2019-004434-41 FUNDING: This study was funded by the Sehested Hansens Foundation.

Aims/hypothesis: We aimed to: (1) externally validate the five-item Hypoglycaemia Awareness Questionnaire (HypoA-Q) impaired awareness subscale (HypoA-Q IA); (2) examine how impaired awareness of hypoglycaemia (IAH) relates to the risk of severe hypoglycaemia and level 2 hypoglycaemia; and (3) identify factors associated with IAH.

Methods: Nationwide survey of T1D Exchange registrants was conducted to collect data on demographics, 6 month severe-hypoglycaemia history, hypoglycaemia awareness status (via HypoA-Q IA, the Gold instrument and the Clarke instrument) and continuous glucose monitor (CGM) measures. The Clarke hypoglycaemia awareness factor (Clarke-HAF) was calculated to exclude severe-hypoglycaemia history items. Analyses included Cronbach's α, Spearman correlations and logistic regression.

Results: Valid survey responses were collected from N=1580 adults with type 1 diabetes (median age, 44 years; 52% female participants; median HbA_1c, 48 mmol/mol [6.5%]). Of these, 94% of participants were using CGMs and 69% were using hybrid closed-loop (HCL) systems; 30% had at least one severe-hypoglycaemia episode in the past 6 months. The HypoA-Q IA had satisfactory internal reliability (α=0.79) and construct validity. Higher HypoA-Q IA scores were independently associated with greater risk of severe hypoglycaemia (p<0.001), performing comparably to the Gold instrument and the Clarke-HAF instrument. HypoA-Q IA-determined IAH was independently associated with 88% higher odds of developing severe hypoglycaemia (p<0.001) and twofold higher odds for spending ≥1% of time in level 2 hypoglycaemia (p=0.011). Higher age and longer diabetes duration were associated with higher IAH risk (p<0.001). CGM and HCL use was associated with lower IAH risk (p<0.001).

Conclusions/interpretation: The HypoA-Q IA is a brief, valid and reliable tool for assessing IAH in today's technology-oriented era. IAH was independently associated with severe hypoglycaemia and level 2 hypoglycaemia in a cohort with high prevalence of advanced diabetes technology use and HbA_1c within the recommended range. CGM and HCL use was related to lower IAH risk.

Human molecular genetics has brought incredible insights into the variants that confer risk for the development of tissue-specific autoimmune diseases, including type 1 diabetes. The hallmark cell-mediated immune destruction that is characteristic of type 1 diabetes is closely linked with risk conferred by the HLA class II gene locus, in combination with a broad array of additional candidate genes influencing islet-resident beta cells within the pancreas, as well as function, phenotype and trafficking of immune cells to tissues. In addition to the well-studied germline SNP variants, there are critical contributions conferred by T cell receptor (TCR) and B cell receptor (BCR) genes that undergo somatic recombination to yield the Adaptive Immune Receptor Repertoire (AIRR) responsible for autoimmunity in type 1 diabetes. We therefore created the T1D TCR/BCR Repository (The Type 1 Diabetes T Cell Receptor and B Cell Receptor Repository) to study these highly variable and dynamic gene rearrangements. In addition to processed TCR and BCR sequences, the T1D TCR/BCR Repository includes detailed metadata (e.g. participant demographics, disease-associated parameters and tissue type). We introduce the Type 1 Diabetes AIRR Consortium goals and outline methods to use and deposit data to this comprehensive repository. Our ultimate goal is to facilitate research community access to rich, carefully annotated immune AIRR datasets to enable new scientific inquiry and insight into the natural history and pathogenesis of type 1 diabetes.

Aims/hypothesis: The aim of this study was to clarify the impact of autoimmune disease (AD) comorbidity on the risk and prognosis of latent autoimmune diabetes in adults (LADA).

Methods: We used data from a Swedish study comprising newly diagnosed cases of LADA (n=586, stratified into LADA^low and LADA^high by autoantibody levels), type 2 diabetes (n=2003) and matched control participants (n=2355). Information on 33 ADs and diabetic retinopathy was obtained by linkage to regional and national registers. We estimated the ORs for LADA and type 2 diabetes in relation to ADs before diabetes diagnosis, and the HRs for diabetic retinopathy after diabetes diagnosis. We performed functional pathway analyses to explore biological mechanisms driving the associations.

Results: Individuals with ADs exhibit an increased susceptibility to LADA (OR 1.70; 95% CI 1.36, 2.13), particularly those with thyroid dysfunction (OR 1.88; 95% CI 1.38, 2.56), inflammatory bowel disease (OR 1.78; 95% CI 1.00, 3.16) or vitiligo (OR 3.91; 95% CI 1.93, 7.94), with stronger associations being observed for the LADA^high phenotype. Only psoriasis was linked to type 2 diabetes (OR 1.47; 95% CI 1.08, 1.99). The biological pathways shared by LADA and ADs revolved around immune responses, including innate and adaptive immune pathways. The HRs for diabetic retinopathy in LADA patients with and without AD vs those with type 2 diabetes were 2.11 (95% CI 1.34, 3.32) and 1.68 (95% CI 1.15, 2.45), respectively.

Conclusions/interpretation: We confirm that several common ADs confer an excess risk of LADA, especially LADA with higher GADA levels, but having such a comorbidity does not appear to affect the risk of diabetic retinopathy.

Aims/hypothesis: Some studies find an increased risk of type 1 diabetes in children exposed to antibiotics. We investigated if exposure to antibiotics increases the risk of latent autoimmune diabetes in adults (LADA) and type 2 diabetes.

Methods: We used data from a Swedish case-control study (Epidemiological Study of Risk Factors for LADA and Type 2 Diabetes [ESTRID]: LADA, n=597; type 2 diabetes, n=2065; control participants matched on participation time, n=2386) and a case-control study nested within the Norwegian Trøndelag Health Study (HUNT) (n=82/1279/2050). Anatomical Therapeutic Chemical (ATC) codes indicating antibiotic dispensations were retrieved from the Swedish National Prescribed Drug Register and Norwegian Prescription Database. Multivariable adjusted ORs with 95% CIs were estimated by conditional logistic regression and pooled using fixed-effects inverse-variance weighting.

Results: We observed no increased risk of LADA with exposure to antibiotics up to 1 year (OR_pooled 1.15, 95% CI 0.93, 1.41) or 1-5 years (OR_pooled 0.98, 95% CI 0.80, 1.20) prior to diagnosis/matching for one or more vs no dispensation of any type of antibiotic. An increased risk was observed for one or more vs no dispensations of narrow-spectrum antibiotics, but not broad-spectrum antibiotics, 6-10 years prior to LADA diagnosis (OR_pooled 1.39, 95% CI 1.01, 1.91), which was driven by the Swedish data. There was little evidence of an increased risk of type 2 diabetes associated with antibiotic exposure 1-10 years prior to diagnosis.

Conclusions/interpretation: We found no evidence that exposure to broad-spectrum antibiotics up to 10 years prior to diagnosis increases the risk of LADA. There was some indication of increased LADA risk with exposure to narrow-spectrum antibiotics, which warrants further investigation.

Aims/hypothesis

We assessed the impact of initiating intermittently scanned continuous glucose monitoring (isCGM) compared with capillary blood glucose monitoring (BGM) on HbA_1c levels and hospitalisations for diabetes-related complications in adults with insulin-treated type 2 diabetes in Sweden.

Methods

This retrospective comparative cohort study included adults with type 2 diabetes who had a National Diabetes Register initiation date for isCGM after 1 June 2017. Prescribed Drug Register records identified subgroups treated with multiple daily insulin injections (T2D-MDI) or basal insulin (T2D-B), with or without other glucose-lowering drugs. The National Patient Register provided data on hospitalisation rates.

Results

We identified 2876 adults in the T2D-MDI group and 2292 in the T2D-B group with an isCGM index date after 1 June 2017, matched with 33,584 and 43,424 BGM control participants, respectively. The baseline-adjusted difference in the change in mean HbA_1c for isCGM users vs BGM control participants in the T2D-MDI cohort was −3.7 mmol/mol (−0.34%) at 6 months, and this was maintained at 24 months. The baseline-adjusted difference in the change in HbA_1c for isCGM users vs BGM control participants in the T2D-B cohort was −3.5 mmol/mol (−0.32%) at 6 months, and this was also maintained at 24 months. Compared with BGM control participants, isCGM users in the T2D-MDI cohort had a significantly lower RR of admission for severe hypoglycaemia (0.51; 95% CI 0.27, 0.95), stroke (0.54; 95% CI 0.39, 0.73), acute non-fatal myocardial infarction (0.75; 95% CI 0.57, 0.99) or hospitalisation for any reason (0.84; 95% CI 0.77, 0.90). isCGM users in the T2D-B cohort had a lower RR of admission for heart failure (0.63; 95% CI 0.46, 0.87) or hospitalisation for any reason (0.76; 95% CI 0.69, 0.84).

Conclusions/interpretation

This study shows that Swedish adults with type 2 diabetes on insulin who are using isCGM have a significantly reduced HbA_1c and fewer hospital admissions for diabetes-related complications compared with BGM control participants.

Graphical Abstract

Aims/hypothesis

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone secreted by enteroendocrine K cells in the proximal small intestine. This study aimed to explore the function of human K cells at the molecular and cellular levels.

Methods

CRISPR-Cas9 homology-directed repair was used to insert transgenes encoding a yellow fluorescent protein (Venus) or an Epac-based cAMP sensor (Epac-S-H187) in the GIP locus in human duodenal-derived organoids. Fluorescently labelled K cells were purified by FACS for RNA-seq and peptidomic analysis. GIP reporter organoids were employed for GIP secretion assays, live-cell imaging of Ca²⁺ using Fura-2 and cAMP using Epac-S-H187, and basic electrophysiological characterisation. The G protein-coupled receptor genes GPR142 and CASR were knocked out to evaluate roles in amino acid sensing.

Results

RNA-seq of human duodenal K cells revealed enrichment of several G protein-coupled receptors involved in nutrient sensing, including FFAR1, GPBAR1, GPR119, CASR and GPR142. Glucose induced action potential firing and cytosolic Ca²⁺ elevation and caused a 1.8-fold increase in GIP secretion, which was inhibited by the sodium glucose co-transporter 1/2 (SGLT1/2) blocker sotagliflozin. Activation of the long-chain fatty acid receptor free fatty acid receptor 1 (FFAR1) induced a 2.7-fold increase in GIP secretion, while tryptophan and phenylalanine stimulated secretion by 2.8- and 2.1-fold, respectively. While CASR knockout blunted intracellular Ca²⁺ responses, a CASR/GPR142 double knockout was needed to reduce GIP secretory responses to aromatic amino acids.

Conclusions/interpretation

The newly generated human organoid K cell model enables transcriptomic and functional characterisation of nutrient-sensing pathways involved in human GIP secretion. Both calcium-sensing receptor (CASR) and G protein-coupled receptor 142 (GPR142) contribute to protein-stimulated GIP secretion. This model will be further used to identify potential targets for modulation of native GIP secretion in diabetes and obesity.

Graphical Abstract