Diagnostic criteria should be considered when reviewing the effect of diabetes prevention studies

Correction to: Short-term progression of cardiometabolic risk factors in relation to age at type 2 diabetes diagnosis: a longitudinal observational study of 100,606 individuals from the Swedish National Diabetes Register Unfortunately, the symbols in Fig. 1 were incorrectly described in the legend.

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CD40-targeting KGYY 15 peptides do not efficiently block the CD40–CD40L interaction

Diabetes prevention and cardiovascular complications

A carbohydrate-reduced high-protein diet improves HbA 1c and liver fat content in weight stable participants with type 2 diabetes: a randomised controlled trial Abstract Aims/hypothesis Dietary recommendations for treating type 2 diabetes are unclear but a trend towards recommending a diet reduced in carbohydrate content is acknowledged. We compared a carbohydrate-reduced high-protein (CRHP) diet with an iso-energetic conventional diabetes (CD) diet to elucidate the effects on glycaemic control and selected cardiovascular risk markers during 6 weeks of full food provision of each diet. Methods The primary outcome of the study was change in HbA1c. Secondary outcomes reported in the present paper include glycaemic variables, ectopic fat content and 24 h blood pressure. Eligibility criteria were: men and women with type 2 diabetes, HbA1c 48–97 mmol/mol (6.5–11%), age >18 years, haemoglobin >6/>7 mmol/l (women/men) and eGFR >30 ml min−1 (1.73 m)−2. Participants were randomised by drawing blinded ballots to 6 + 6 weeks of an iso-energetic CRHP vs CD diet in an open label, crossover design aiming at body weight stability. The CRHP/CD diets contained carbohydrate 30/50 energy per cent (E%), protein 30/17E% and fat 40/33E%, respectively. Participants underwent a meal test at the end of each diet period and glycaemic variables, lipid profiles, 24 h blood pressure and ectopic fat including liver and pancreatic fat content were assessed at baseline and at the end of each diet period. Data were collected at Copenhagen University Hospital, Bispebjerg and Copenhagen University Hospital, Herlev. Results Twenty-eight participants completed the study. Fourteen participants carried out 6 weeks of the CRHP intervention followed by 6 weeks of the CD intervention, and 14 participants received the dietary interventions in the reverse order. Compared with a CD diet, a CRHP diet reduced the primary outcome of HbA1c (mean ± SEM: −6.2 ± 0.8 mmol/mol (−0.6 ± 0.1%) vs −0.75 ± 1.0 mmol/mol (−0.1 ± 0.1%); p < 0.001). Nine (out of 37) pre-specified secondary outcomes are reported in the present paper, of which five were significantly different between the diets, (p < 0.05); compared with a CD diet, a CRHP diet reduced the secondary outcomes (mean ± SEM or medians [interquartile range]) of fasting plasma glucose (−0.71 ± 0.20 mmol/l vs 0.03 ± 0.23 mmol/l; p < 0.05), postprandial plasma glucose AUC (9.58 ± 0.29 mmol/l × 240 min vs 11.89 ± 0.43 mmol/l × 240 min; p < 0.001) and net AUC (1.25 ± 0.20 mmol/l × 240 min vs 3.10 ± 0.25 mmol/l × 240 min; p < 0.001), hepatic fat content (−2.4% [−7.8% to −1.0%] vs 0.2% [−2.3% to 0.9%]; p < 0.01) and pancreatic fat content (−1.7% [−3.5% to 0.6%] vs 0.5% [−1.0% to 2.0%]; p < 0.05). Changes in other secondary outcomes, i.e. 24 h blood pressure and muscle-, visceral- or subcutaneous adipose tissue, did not differ between diets. Conclusions/interpretation A moderate macronutrient shift by substituting carbohydrates with protein and fat for 6 weeks reduced HbA1c and hepatic fat content in weight stable individuals with type 2 diabetes. Trial registration ClinicalTrials.gov NCT02764021. Funding The study was funded by grants from Arla Food for Health; the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen; the Department of Clinical Medicine, Aarhus University; the Department of Nutrition, Exercise and Sports, University of Copenhagen; and Copenhagen University Hospital, Bispebjerg.

Reduced size at birth and persisting reductions in adiposity in recent, compared with earlier, cohorts of infants born to mothers with gestational diabetes mellitus Abstract Aims/hypothesis This study aimed to explore the infancy growth trajectories of ‘recent’ and ‘earlier’ offspring of mothers with gestational diabetes mellitus (OGDM), each compared with the same control infants, and investigate whether ‘recent’ OGDM still exhibit a classical phenotype, with macrosomia and increased adiposity. Methods Within a prospective observational birth cohort, 98 ‘earlier’ OGDM born between 2001 and 2009 were identified using 75 g oral glucose tolerance testing at 28 weeks gestation, 122 recent OGDM born between 2011 and 2013 were recruited postnatally through antenatal diabetes clinics, and 876 normal birthweight infants of mothers with no history of diabetes were recruited across the full study period as the control group. All infants followed the same study protocol (measurements at birth, 3, 12 and 24 months, including weight, length and skinfold thickness indicating adiposity, and detailed demographic data). In all cases, GDM was defined using the International Association of Diabetes and Pregnancy Study Group criteria. Results Earlier OGDM had higher birthweight SD scores (SDS) than control infants. Conversely, recent OGDM had similar birthweight- and length SDS to control infants (mean ± SD, 0.1 ± 1.0 and− 0.1 ± 0.9, respectively), but lower mean skinfold thickness SDS (−0.4 ± 0.6 vs 0.0 ± 0.9; p < 0.001). After birth, earlier OGDM showed reduced gains in weight and length between 3 and 12 months. In contrast, recent OGDM had increased weight and skinfold thickness gains until 3 months, followed by reduced gains in those variables from 3 to 12 months, compared with control infants. At 24 months, recent OGDM had lower adiposity than control infants (mean skinfold thickness SDS −0.3 ± 0.7 vs 0.0 ± 0.8; p < 0.001). At all time points recent OGDM had lower growth measurements than earlier OGDM. Conclusions/interpretation Recent OGDM showed different growth trajectories to the earlier group, namely normalisation of birthweight and reduced adiposity at birth, followed by initial rapid weight gain but subsequent reduced adiposity postnatally. While avoidance of macrosomia at birth may be advantageous, the longer-term health implications of these changing growth trajectories are uncertain.

The proposed systemic thermogenic metabolites succinate and 12,13-diHOME are inversely associated with adiposity and related metabolic traits: evidence from a large human cross-sectional study Abstract Aims/hypothesis Circulating succinate and 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) were recently shown to promote brown adipocyte thermogenesis and protect against metabolic disorders in rodents. This study aimed to evaluate the associations between plasma levels of these metabolites and adiposity and metabolic profile in humans. Methods Fasting plasma succinate and 12,13-diHOME levels were quantified using ultra HPLC-tandem MS in 2248 individuals (50% female, mean age 41.3 ± 5.9 years, mean BMI 26.1 ± 4.6 kg/m2) in addition to fasting plasma biochemistry. Total and regional adiposity were assessed with dual-energy x-ray absorptiometry. An age- and sex-adjusted linear regression model was used to determine the associations between succinate and 12,13-diHOME levels and body composition and metabolic profile. Two-sample Mendelian randomisation was used to assess the associations between genetically determined BMI and metabolic traits with circulating plasma succinate and 12,13-diHOME. Results A one-SD higher plasma succinate and 12,13-diHOME concentration was associated with a 0.15 SD (95% CI 0.28, 0.03) and 0.08 SD (0.15, 0.01) lower total fat mass respectively. Additionally, a one-SD higher plasma 12,13-diHOME level was associated with a 0.09 SD (0.16, 0.02) lower fasting plasma insulin and 0.10 SD (0.17, 0.04) lower plasma triacylglycerol. In Mendelian randomisation analyses, genetically determined higher BMI, fasting hyperinsulinaemia and elevated lipid levels were not associated with changes in either plasma succinate or plasma 12,13-diHOME concentrations. No indications of bias due to directional pleiotropy were detected in the Mendelian randomisation analyses. Conclusions/interpretation Our findings tentatively suggest that plasma succinate and 12,13-diHOME may play a role in the regulation of energy metabolism and brown adipose tissue activation in humans. Further studies encompassing direct assessment of brown adipose tissue activity and dietary supplementation are necessary to investigate the potential beneficial effects of these metabolites on systemic metabolism.

Follow-up at 1 year and beyond of women with gestational diabetes treated with insulin and/or oral glucose-lowering agents: a core outcome set using a Delphi survey Abstract Aims/hypothesis Gestational diabetes mellitus (GDM) is linked with a higher lifetime risk for the development of impaired fasting glucose, impaired glucose tolerance, type 2 diabetes, the metabolic syndrome, cardiovascular disease, postpartum depression and tumours. Despite this, there is no consistency in the long-term follow-up of women with a previous diagnosis of GDM. Further, the outcomes selected and reported in the research involving this population are heterogeneous and lack standardisation. This amplifies the risk of reporting bias and diminishes the likelihood of significant comparisons between studies. The aim of this study is to develop a core outcome set (COS) for RCTs and other studies evaluating the long-term follow-up at 1 year and beyond of women with previous GDM treated with insulin and/oral glucose-lowering agents. Methods The study consisted of three work packages: (1) a systematic review of the outcomes reported in previous RCTs of the follow-up at 1 year and beyond of women with GDM treated with insulin and/or oral glucose-lowering agents; (2) a three-round online Delphi survey with key stakeholders to prioritise these outcomes; and (3) a consensus meeting where the final COS was decided. Results Of 3344 abstracts identified and evaluated, 62 papers were retrieved and 25/62 papers were included in this review. A total of 121 outcomes were identified and included in the Delphi survey. Delphi round 1 was emailed to 835 participants and 288 (34.5%) responded. In round 2, 190 of 288 (65.9%) participants responded and in round 3, 165 of 190 (86.8%) participants responded. In total, nine outcomes were selected and agreed for inclusion in the final COS: assessment of glycaemic status; diagnosis of type 2 diabetes since the index pregnancy; number of pregnancies since the index pregnancy; number of pregnancies with a diagnosis of GDM since the index pregnancy; diagnosis of prediabetes since the index pregnancy; BMI; post-pregnancy weight retention; resting blood pressure; and breastfeeding. Conclusions/interpretation This study identified a COS that will help bring consistency and uniformity to outcome selection and reporting in clinical trials and other studies involving the follow-up at 1 year and beyond of women diagnosed with GDM treated with insulin and/or oral glucose-lowering agents during pregnancy.

Phenotypically distinct anti-insulin B cells repopulate pancreatic islets after anti-CD20 treatment in NOD mice Abstract Aims/hypothesis Autoreactive B cells escape immune tolerance and contribute to the pathogenesis of type 1 diabetes. While global B cell depletion is a successful therapy for autoimmune disease, the fate of autoreactive cells during this treatment in autoimmune diabetes is unknown. We aimed to identify and track anti-insulin B cells in pancreatic islets and understand their repopulation after anti-CD20 treatment. Methods We generated a double transgenic system, the VH125.hCD20/NOD mouse. The VH125 transgenic mouse, expressing an increased frequency of anti-insulin B cells, was crossed with a human CD20 (hCD20) transgenic mouse, to facilitate B cell depletion using anti-CD20. B cells were analysed using multiparameter and ImageStream flow cytometry. Results We demonstrated that anti-insulin B cells were recruited to the pancreas during disease progression in VH125.hCD20/NOD mice. We identified two distinct populations of anti-insulin B cells in pancreatic islets, based on CD19 expression, with both populations enriched in the CD138int fraction. Anti-insulin B cells were not identified in the plasma-cell CD138hi fraction, which also expressed the transcription factor Blimp-1. After anti-CD20 treatment, anti-insulin B cells repopulated the pancreatic islets earlier than non-specific B cells. Importantly, we observed that a CD138intinsulin+CD19− population was particularly enriched after B cell depletion, possibly contributing to the persistence of disease still observed in some mice after anti-CD20 treatment. Conclusions/interpretation Our observations may indicate why the loss of C-peptide is only temporarily delayed following anti-CD20 treatment in human type 1 diabetes.