Characterization of the gut bacterial and viral microbiota in latent autoimmune diabetes in adults.

Latent autoimmune diabetes in adults (LADA) is a heterogeneous disease characterized by autoantibodies against insulin producing pancreatic beta cells and initial lack of need for insulin treatment. The aim of the present study was to investigate if individuals with LADA have an altered gut microbiota relative to non-diabetic control subjects, individuals with type 1 diabetes (T1D), and individuals with type 2 diabetes (T2D). Bacterial community profiling was performed with primers targeting the variable region 4 of the 16S rRNA gene and sequenced. Amplicon sequence variants (ASVs) were generated with DADA2 and annotated to the SILVA database. The gut virome was sequenced, using a viral particle enrichment and metagenomics approach, assembled, and quantified to describe the composition of the viral community. Comparison of the bacterial alpha- and beta-diversity measures revealed that the gut bacteriome of individuals with LADA resembled that of individuals with T2D. Yet, specific genera were found to differ in abundance in individuals with LADA compared with T1D and T2D, indicating that LADA has unique taxonomical features. The virome composition reflected the stability of the most dominant order Caudovirales and the families Siphoviridae, Podoviridae, and Inoviridae, and the dominant family Microviridae. Further studies are needed to confirm these findings.

Ceramides are decreased after liraglutide treatment in people with type 2 diabetes: a post hoc analysis of two randomized clinical trials.

BACKGROUND: Specific ceramides have been identified as risk markers for cardiovascular disease (CVD) years before onset of disease. Treatment with the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide has been shown to induce beneficial changes in the lipid profile and reduce the risk of CVD. Reducing lipotoxic lipids with an antidiabetic drug therapy could be a path towards precision medicine approaches for the treatment of complications to diabetes. In this post-hoc study, an investigation was carried out on the effect of liraglutide on CVD-risk associated ceramides in two randomized clinical trials including participants with type 2 diabetes (T2D). METHODS: This study analyzed plasma samples from two independent randomized placebo-controlled clinical trials. The first trial, Antiproteinuric Effects of Liraglutide Treatment (LirAlbu12) followed a crossover design where 27 participants were treated for 12 weeks with either liraglutide (1.8 mg/d) or placebo, followed by a four-week washout period, and then another 12 weeks of the other treatment. The second clinical trial, Effect of Liraglutide on Vascular Inflammation in Type-2 Diabetes (LiraFlame26), lasted for 26 weeks and followed a parallel design, where 102 participants were randomized 1:1 to either liraglutide or placebo. Heresix prespecified plasma ceramides were measured using liquid chromatography mass spectrometry and assessed their changes using linear mixed models. Possible confounders were assessed with mediation analyses. RESULTS: In the LiraFlame26 trial, 26-week treatment with liraglutide resulted in a significant reduction of two ceramides associated with CVD risk, C16 Cer and C24:1 Cer (p < 0.05) compared to placebo. None of the remaining ceramides showed statistically significant changes in response to liraglutide treatment compared to placebo. Significant changes in ceramides were not found after 12-weeks of liraglutide treatment in the LirAlbu12 trial. Mediation analyses showed that weight loss did not affect ceramide reduction. CONCLUSIONS: It was demonstrated that treatment with liraglutide resulted in a reduction in C16 Cer and C24:1 Cer after 26 weeks of treatment. These findings suggest the GLP-1RA can be used to modulate ceramides in addition to its other properties. TRIAL REGISTRATION: Clinicaltrial.gov identifier: NCT02545738 and NCT03449654.

Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide.

The host-microbiota co-metabolite trimethylamine N-oxide (TMAO) is linked to increased cardiovascular risk but how its circulating levels are regulated remains unclear. We applied "explainable" machine learning, univariate, multivariate and mediation analyses of fasting plasma TMAO concentration and a multitude of phenotypes in 1,741 adult Europeans of the MetaCardis study. Here we show that next to age, kidney function is the primary variable predicting circulating TMAO, with microbiota composition and diet playing minor, albeit significant, roles. Mediation analysis suggests a causal relationship between TMAO and kidney function that we corroborate in preclinical models where TMAO exposure increases kidney scarring. Consistent with our findings, patients receiving glucose-lowering drugs with reno-protective properties have significantly lower circulating TMAO when compared to propensity-score matched control individuals. Our analyses uncover a bidirectional relationship between kidney function and TMAO that can potentially be modified by reno-protective anti-diabetic drugs and suggest a clinically actionable intervention for decreasing TMAO-associated excess cardiovascular risk.

Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits.

We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue.

Ceramides as Risk Markers for Future Cardiovascular Events and All-Cause Mortality in Long-standing Type 1 Diabetes.

Ceramides are lipid molecules involved in inflammation-related signaling. Recent studies have shown that higher amounts of specific circulating ceramides and their ratios are associated with future development of cardiovascular (CV) disease (CVD). We examined the associations between serum ceramide levels with CVD, kidney failure, and all-cause mortality in individuals with long-standing type 1 diabetes (T1D). We included 662 participants with T1D and 6-year follow-up, with a mean age of 55 years and mean diabetes duration of 33 years. Baseline serum samples were analyzed using liquid chromatography-mass spectrometry. Six predefined ceramide levels were measured, and predefined ratios were calculated. Adjusted Cox regression analyses on ceramide levels in relation to future CV events (CVE), kidney failure, and all-cause mortality were performed, with and without adjustment for age, sex, BMI, LDL, triglycerides, systolic blood pressure, HbA1c, history of CVD, smoking status, statin use, estimated glomerular filtration rate (eGFR), and urinary albumin excretion rate (UAER). The ceramide ratio cer(d18:1/18:0)/cer(d18:1/24:0) was significantly associated with risk of CVE (hazard ratio [HR] = 1.33, P = 0.01) and all-cause mortality (HR = 1.48, P = 0.01) before and after adjustments. All five investigated ceramide ratios were associated with kidney failure, before adjusting for the kidney markers eGFR and UAER. In this study, we demonstrate specific ceramides and ratios associated with 6-year cardiovascular risk and all-cause mortality in a T1D cohort. This highlights the strength of ceramide association with vascular complications and presents a new potential tool for early risk assessment if validated in other cohorts. ARTICLE HIGHLIGHTS: Improved tools for assessing risk for diabetes complication before onset will help in complication prevention. We investigated a set of six predefined ceramides and their ratios versus 6-year outcomes of cardiovascular events, kidney failure, and all-cause mortality in people with long-standing type 1 diabetes, using Cox regression with and without adjustment for potential confounders. We found that several ceramides and ceramide ratios associated with cardiovascular events and all-cause mortality. The ratio of cer(d18:1/18:0)/cer(d18:1/24:0) was an especially robust marker. These finding show that ceramides can be biomarkers of cardiovascular disease and all-cause mortality in individuals with long-standing type 1 diabetes.

Alteration of Gut Microbiome in Patients With Schizophrenia Indicates Links Between Bacterial Tyrosine Biosynthesis and Cognitive Dysfunction.

Background: Schizophrenia (SCZ) is a heterogeneous neuropsychiatric disorder for which current treatment has insufficient efficacy and severe adverse effects. The modifiable gut microbiome might be a potential target for intervention to improve neurobiological functions through the gut-microbiome-brain axis. Methods: In this case-control study, gut microbiota of 132 patients with SCZ and increased waist circumference were compared with gut microbiota of two age- and sex-matched control groups, composed of 132 healthy individuals and 132 individuals with metabolic syndrome. Shotgun sequencing was used to characterize fecal samples at the taxonomic and functional levels. Cognition of the patients with SCZ was evaluated using the Brief Assessment of Cognition instrument. Results: SCZ gut microbiota differed significantly from those of healthy control subjects and individuals with metabolic syndrome in terms of richness and global composition. SCZ gut microbiota were notably enriched in Flavonifractor plautii, Collinsella aerofaciens, Bilophila wadsworthia, and Sellimonas intestinalis, while depleted in Faecalibacterium prausnitzii, Ruminococcus lactaris, Ruminococcus bicirculans, and Veillonella rogosae. Functional potential of the gut microbiota accounted for 11% of cognition variability. In particular, the bacterial functional module for synthesizing tyrosine, a precursor for dopamine, was in SCZ cases positively associated with cognitive score (ρ = 0.34, q ≤ .1). Conclusions: Overall, this study shows that the gut microbiome of patients with SCZ differs greatly from that of healthy control subjects or individuals with metabolic syndrome. Cognitive function of patients with SCZ is associated with the potential for gut bacterial biosynthesis of tyrosine, a precursor for dopamine, suggesting that gut microbiota might be an intervention target for alleviation of cognitive dysfunction in SCZ.

Quality of life, patient satisfaction, and cardiovascular outcomes of the randomised 2 x 3 factorial Copenhagen insulin and Metformin therapy (CIMT) trial - A detailed statistical analysis plan.

Background: The evidence on the effects of metformin and insulin in type 2 diabetes patients on quality of life, patient satisfaction, and cardiovascular outcomes is unclear. Methods: The Copenhagen Insulin and Metformin Therapy (CIMT) trial is an investigator-initiated multicentre, randomised, placebo-controlled trial with a 2 × 3 factorial design conducted at eight hospitals in Denmark. Participants with type 2 diabetes were randomised to metformin (n = 206) versus placebo (n = 206); in combination with open-label biphasic insulin aspart one to three times daily (n = 137) versus insulin aspart three times daily in combination with insulin detemir once daily (n = 138) versus insulin detemir once daily (n = 137).We present a detailed description of the methodology and statistical analysis of the clinical CIMT outcomes including a detailed description of tests of the assumptions behind the statistical analyses. The outcomes are quality of life (Short Form Health Survey (SF-36)), Diabetes Medication Satisfaction Questionnaire, and Insulin Treatment Satisfaction Questionnaire (assessed at entry and 18 months after randomisation) and cardiovascular outcomes including time to a composite of either myocardial infarction, stroke, peripheral amputation, coronary revascularisation, peripheral revascularisation, or death. Discussions: This statistical analysis plan ensure the highest possible quality of the subsequent post-hoc analyses. Trial registration: The protocol was approved by the Regional Committee on Biomedical Research Ethics (H-D-2007-112), the Danish Medicines Agency (EudraCT: 2007-006665-33 CIMT), and registered within ClinicalTrials.gov (NCT00657943, 8th of April 2008).

The gut microbiota in multiple sclerosis varies with disease activity.

BACKGROUND: Multiple sclerosis is a chronic immune-mediated disease of the brain and spinal cord resulting in physical and cognitive impairment in young adults. It is hypothesized that a disrupted bacterial and viral gut microbiota is a part of the pathogenesis mediating disease impact through an altered gut microbiota-brain axis. The aim of this study is to explore the characteristics of gut microbiota in multiple sclerosis and to associate it with disease variables, as the etiology of the disease remains only partially known. METHODS: Here, in a case-control setting involving 148 Danish cases with multiple sclerosis and 148 matched healthy control subjects, we performed shotgun sequencing of fecal microbial DNA and associated bacterial and viral microbiota findings with plasma cytokines, blood cell gene expression profiles, and disease activity. RESULTS: We found 61 bacterial species that were differentially abundant when comparing all multiple sclerosis cases with healthy controls, among which 31 species were enriched in cases. A cluster of inflammation markers composed of blood leukocytes, CRP, and blood cell gene expression of IL17A and IL6 was positively associated with a cluster of multiple sclerosis-related species. Bacterial species that were more abundant in cases with disease-active treatment-naïve multiple sclerosis were positively linked to a group of plasma cytokines including IL-22, IL-17A, IFN-ß, IL-33, and TNF-α. The bacterial species richness of treatment-naïve multiple sclerosis cases was associated with number of relapses over a follow-up period of 2 years. However, in non-disease-active cases, we identified two bacterial species, Faecalibacterium prausnitzii and Gordonibacter urolithinfaciens, whose absolute abundance was enriched. These bacteria are known to produce anti-inflammatory metabolites including butyrate and urolithin. In addition, cases with multiple sclerosis had a higher viral species diversity and a higher abundance of Caudovirales bacteriophages. CONCLUSIONS: Considerable aberrations are present in the gut microbiota of patients with multiple sclerosis that are directly associated with blood biomarkers of inflammation, and in treatment-naïve cases bacterial richness is positively associated with disease activity. Yet, the finding of two symbiotic bacterial species in non-disease-active cases that produce favorable immune-modulating compounds provides a rationale for testing these bacteria as adjunct therapeutics in future clinical trials.

Discovery of drug-omics associations in type 2 diabetes with generative deep-learning models.

The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug-omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug-drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.

Four groups of type 2 diabetes contribute to the etiological and clinical heterogeneity in newly diagnosed individuals: An IMI DIRECT study.

The presentation and underlying pathophysiology of type 2 diabetes (T2D) is complex and heterogeneous. Recent studies attempted to stratify T2D into distinct subgroups using data-driven approaches, but their clinical utility may be limited if categorical representations of complex phenotypes are suboptimal. We apply a soft-clustering (archetype) method to characterize newly diagnosed T2D based on 32 clinical variables. We assign quantitative clustering scores for individuals and investigate the associations with glycemic deterioration, genetic risk scores, circulating omics biomarkers, and phenotypic stability over 36 months. Four archetype profiles represent dysfunction patterns across combinations of T2D etiological processes and correlate with multiple circulating biomarkers. One archetype associated with obesity, insulin resistance, dyslipidemia, and impaired ß cell glucose sensitivity corresponds with the fastest disease progression and highest demand for anti-diabetic treatment. We demonstrate that clinical heterogeneity in T2D can be mapped to heterogeneity in individual etiological processes, providing a potential route to personalized treatments.

Microbiome and metabolome features of the cardiometabolic disease spectrum.

Previous microbiome and metabolome analyses exploring non-communicable diseases have paid scant attention to major confounders of study outcomes, such as common, pre-morbid and co-morbid conditions, or polypharmacy. Here, in the context of ischemic heart disease (IHD), we used a study design that recapitulates disease initiation, escalation and response to treatment over time, mirroring a longitudinal study that would otherwise be difficult to perform given the protracted nature of IHD pathogenesis. We recruited 1,241 middle-aged Europeans, including healthy individuals, individuals with dysmetabolic morbidities (obesity and type 2 diabetes) but lacking overt IHD diagnosis and individuals with IHD at three distinct clinical stages-acute coronary syndrome, chronic IHD and IHD with heart failure-and characterized their phenome, gut metagenome and serum and urine metabolome. We found that about 75% of microbiome and metabolome features that distinguish individuals with IHD from healthy individuals after adjustment for effects of medication and lifestyle are present in individuals exhibiting dysmetabolism, suggesting that major alterations of the gut microbiome and metabolome might begin long before clinical onset of IHD. We further categorized microbiome and metabolome signatures related to prodromal dysmetabolism, specific to IHD in general or to each of its three subtypes or related to escalation or de-escalation of IHD. Discriminant analysis based on specific IHD microbiome and metabolome features could better differentiate individuals with IHD from healthy individuals or metabolically matched individuals as compared to the conventional risk markers, pointing to a pathophysiological relevance of these features.

Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism.

OBJECTIVES: Gut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome's functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation. DESIGN: We performed metagenomic analyses in 1545 subjects from the MetaCardis cohorts and different murine experiments, including germ-free and antibiotic treated animals, faecal microbiota transfer, bariatric surgery and supplementation with biotin and prebiotics in mice. RESULTS: Severe obesity is associated with an absolute deficiency in bacterial biotin producers and transporters, whose abundances correlate with host metabolic and inflammatory phenotypes. We found suboptimal circulating biotin levels in severe obesity and altered expression of biotin-associated genes in human adipose tissue. In mice, the absence or depletion of gut microbiota by antibiotics confirmed the microbial contribution to host biotin levels. Bariatric surgery, which improves metabolism and inflammation, associates with increased bacterial biotin producers and improved host systemic biotin in humans and mice. Finally, supplementing high-fat diet-fed mice with fructo-oligosaccharides and biotin improves not only the microbiome diversity, but also the potential of bacterial production of biotin and B vitamins, while limiting weight gain and glycaemic deterioration. CONCLUSION: Strategies combining biotin and prebiotic supplementation could help prevent the deterioration of metabolic states in severe obesity. TRIAL REGISTRATION NUMBER: NCT02059538.

Effects of 18-months metformin versus placebo in combination with three insulin regimens on RNA and DNA oxidation in individuals with type 2 diabetes: A post-hoc analysis of a randomized clinical trial.

Formation of reactive oxygen species has been linked to the development of diabetes complications. Treatment with metformin has been associated with a lower risk of developing diabetes complications, including when used in combination with insulin. Metformin inhibits Complex 1 in isolated mitochondria and thereby decreases the formation of reactive oxygen species. Thus, we post-hoc investigated the effect of metformin in combination with different insulin regimens on RNA and DNA oxidation in individuals with type 2 diabetes. Four hundred and fifteen individuals with type 2 diabetes were randomized (1:1) to blinded treatment with metformin (1,000 mg twice daily) versus placebo and to (1:1:1) open-label biphasic insulin, basal-bolus insulin, or basal insulin therapy in a 2 × 3 factorial design. RNA and DNA oxidation were determined at baseline and after 18 months measured as urinary excretions of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), respectively. Urinary excretion of 8-oxoGuo changed by +7.1% (95% CI: 0.5% to 14.0%, P = 0.03) following metformin versus placebo, whereas changes in 8-oxodG were comparable between intervention groups. Biphasic insulin decreased urinary excretion of 8-oxoGuo (within-group: -9.6% (95% CI: -14.4% to -4.4%)) more than basal-bolus insulin (within-group: 5.2% (95% CI: -0.5% to 11.2%)), P = 0.0002 between groups, and basal insulin (within-group: 3.7% (95% CI: -2.0% to 9.7%)), P = 0.0007 between groups. Urinary excretion of 8-oxodG decreased more in the biphasic insulin group (within-group: -9.9% (95% CI: -14.4% to -5.2%)) than basal-bolus insulin (within group effect: -1.2% (95% CI: -6.1% to 3.9%)), P = 0.01 between groups, whereas no difference was observed compared with basal insulin. In conclusion, eighteen months of metformin treatment in addition to different insulin regimens increased RNA oxidation, but not DNA oxidation. Biphasic insulin decreased both RNA and DNA oxidation compared with other insulin regimens.

Liraglutide Lowers Palmitoleate Levels in Type 2 Diabetes. A Post Hoc Analysis of the LIRAFLAME Randomized Placebo-Controlled Trial.

Background: Liraglutide is a glucose-lowering medication used to treat type 2 diabetes and obesity. It is a GLP-1 receptor agonist with downstream metabolic changes beyond the incretin system, such as reducing the risk of cardiovascular complications. The understanding of these changes is critical for improving treatment outcomes. Herein, we present a post hoc experimental analysis using metabolomic phenotyping to discover molecular mecphanisms in response to liraglutide. Method: Plasma samples were obtained from The LiraFlame Study (ClinicalTrials.gov identifier: NCT03449654), a randomized double-blinded placebo-controlled clinical trial, including 102 participants with type 2 diabetes randomized to either liraglutide or placebo treatment for 26 weeks. Mass spectrometry-based metabolomics analyses were carried out on samples from baseline and the end of the trial. Metabolites (n=114) were categorized into pathways and linear mixed models were constructed to evaluate the association between changes in metabolites and liraglutide treatment. Results: We found the free fatty acid palmitoleate was significantly reduced in the liraglutide group compared to placebo (adjusted for multiple testing p-value = 0.04). The activity of stearoyl-CoA desaturase-1 (SCD1), the rate limiting enzyme for converting palmitate into palmitoleate, was found significantly downregulated by liraglutide treatment compared to placebo (p-value = 0.01). These metabolic changes have demonstrated to be linked to insulin sensitivity and cardiovascular health.

Combinatorial, additive and dose-dependent drug-microbiome associations.

During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1-5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug-host-microbiome interactions in cardiometabolic disease.

Profiles of Glucose Metabolism in Different Prediabetes Phenotypes, Classified by Fasting Glycemia, 2-Hour OGTT, Glycated Hemoglobin, and 1-Hour OGTT: An IMI DIRECT Study.

Differences in glucose metabolism among categories of prediabetes have not been systematically investigated. In this longitudinal study, participants (N = 2,111) underwent a 2-h 75-g oral glucose tolerance test (OGTT) at baseline and 48 months. HbA1c was also measured. We classified participants as having isolated prediabetes defect (impaired fasting glucose [IFG], impaired glucose tolerance [IGT], or HbA1c indicative of prediabetes [IA1c]), two defects (IFG+IGT, IFG+IA1c, or IGT+IA1c), or all defects (IFG+IGT+IA1c). ß-Cell function (BCF) and insulin sensitivity were assessed from OGTT. At baseline, in pooling of participants with isolated defects, they showed impairment in both BCF and insulin sensitivity compared with healthy control subjects. Pooled groups with two or three defects showed progressive further deterioration. Among groups with isolated defect, those with IGT showed lower insulin sensitivity, insulin secretion at reference glucose (ISRr), and insulin secretion potentiation (P < 0.002). Conversely, those with IA1c showed higher insulin sensitivity and ISRr (P < 0.0001). Among groups with two defects, we similarly found differences in both BCF and insulin sensitivity. At 48 months, we found higher type 2 diabetes incidence for progressively increasing number of prediabetes defects (odds ratio >2, P < 0.008). In conclusion, the prediabetes groups showed differences in type/degree of glucometabolic impairment. Compared with the pooled group with isolated defects, those with double or triple defect showed progressive differences in diabetes incidence.

Once-weekly subcutaneous semaglutide treatment for persons with type 2 diabetes: Real-world data from a diabetes out-patient clinic.

AIMS: The once-weekly administered glucagon-like peptide 1 (GLP-1) receptor agonist (GLP-1RA) semaglutide, has, in clinical trials, demonstrated significant reductions in glycated haemoglobin A1c (HbA1c ) and body weight in persons with type 2 diabetes. We evaluated the real-world clinical effects of semaglutide once weekly in a hospital-based diabetes out-patient clinic. METHODS: This retrospective observational cohort study included persons with type 2 diabetes (n = 119) on a broad range of antidiabetic medicine: GLP-1RA naïve persons (n = 37) and GLP-1RA-experienced persons (n = 82). Person characteristics at inclusion: age [median (quartiles)]: 65 (57, 72) years; body weight 99 (86, 118) kg; body mass index (BMI) 33 (29, 38) kg/m²; HbA1c 61 (54, 69) mmol/mol/(7.7 (7.1, 8.5) %). Data were collected at baseline and after 3, 6 and 12 months of semaglutide treatment. Data were analysed using a general linear mixed model for repeated measurements. RESULTS: After 12 months, the reductions in HbA1c were (mean [95% confidence interval]: GLP-1RA naïve: -12.8 [-17.0, -8.5] mmol/mol/ -1.2 [-1.6, -0.8]% (p < 0.01) and GLP-1RA experienced: -6.4 [-9.0, -3.8] mmol/mol/ -0.6 [-0.8, -0.4]% (p < 0.01), respectively. Body weight reductions in GLP-1RA naïve: -5 [-6.9, -3.1] kg (p < 0.01) and GLP-1RA experienced: -3.2 [-4.4, -2.0] kg (p < 0.01), respectively. Seventy-five percent received 1 mg QW semaglutide. CONCLUSION: We observed effects of semaglutide once weekly on HbA1c and body weight comparable with the effects observed in clinical studies with fewer persons in our cohort receiving maximum dose of semaglutide.

Genetic markers of abdominal obesity and weight loss after gastric bypass surgery.

BACKGROUND: Weight loss after bariatric surgery varies widely between individuals, partly due to genetic differences. In addition, genetic determinants of abdominal obesity have been shown to attenuate weight loss after dietary intervention with special attention paid to the rs1358980-T risk allele in the VEGFA locus. Here we aimed to test if updated genetic risk scores (GRSs) for adiposity measures and the rs1358980-T risk allele are linked with weight loss following gastric bypass surgery. METHODS: Five hundred seventy six patients with morbid obesity underwent Roux-en-Y gastric bypass. A GRS for BMI and a GRS for waist-hip-ratio adjusted for BMI (proxy for abdominal obesity), respectively, were constructed. All patients were genotyped for the rs1358980-T risk allele. Associations between the genetic determinants and weight loss after bariatric surgery were evaluated. RESULTS: The GRS for BMI was not associated with weight loss (ß = -2.0 kg/100 risk alleles, 95% CI -7.5 to 3.3, p = 0.45). Even though the GRS for abdominal obesity was associated with an attenuated weight loss response adjusted for age, sex and center (ß = -14.6 kg/100 risk alleles, 95% CI -25.4 to -3.8, p = 0.008), it was not significantly associated with weight loss after adjustment for baseline BMI (ß = -7.9 kg/100 risk alleles, 95% CI -17.5 to 1.6, p = 0.11). Similarly, the rs1358980-T risk allele was not significantly associated with weight loss (ß = -0.8 kg/risk allele, 95% CI -2.2 to 0.6, p = 0.25). DISCUSSION: GRSs for adiposity derived from large meta-analyses and the rs1358980-T risk allele in the VEGFA locus did not predict weight loss after gastric bypass surgery. The association between a GRS for abdominal obesity and the response to bariatric surgery may be dependent on the association between the GRS and baseline BMI.

Trans-ethnic gut microbiota signatures of type 2 diabetes in Denmark and India.

BACKGROUND: Type 2 diabetes (T2D), a multifactorial disease influenced by host genetics and environmental factors, is the most common endocrine disease. Several studies have shown that the gut microbiota as a close-up environmental mediator influences host physiology including metabolism. The aim of the present study is to examine the compositional and functional potential of the gut microbiota across individuals from Denmark and South India with a focus on T2D. Many earlier studies have investigated the microbiome aspects of T2D, and it has also been anticipated that such microbial associations would be dependent on diet and ethnic origin. However, there has been no large scale trans-ethnic microbiome study earlier in this direction aimed at evaluating any "universal" microbiome signature of T2D. METHODS: 16S ribosomal RNA gene amplicon sequencing was performed on stool samples from 279 Danish and 294 Indian study participants. Any differences between the gut microbiota of both populations were explored using diversity measures and negative binomial Wald tests. Study samples were stratified to discover global and country-specific microbial signatures for T2D and treatment with the anti-hyperglycemic drug, metformin. To identify taxonomical and functional signatures of the gut microbiota for T2D and metformin treatment, we used alpha and beta diversity measures and differential abundances analysis, comparing metformin-naive T2D patients, metformin-treated T2D patients, and normoglycemic individuals. RESULTS: Overall, the gut microbial communities of Danes and Indians are compositionally very different. By analyzing the combined study materials, we identify microbial taxonomic and functional signatures for T2D and metformin treatment. T2D patients have an increased relative abundance of two operational taxonomic units (OTUs) from the Lachnospiraceae family, and a decreased abundance of Subdoligranulum and Butyricicoccus. Studying each population per se, we identified T2D-related microbial changes at the taxonomic level within the Danish population only. Alpha diversity indices show that there is no significant difference between normoglycemic individuals and metformin-naive T2D patients, whereas microbial richness is significantly decreased in metformin-treated T2D patients compared to metformin-naive T2D patients and normoglycemic individuals. Enrichment of two OTUs from Bacteroides and depletion of Faecalibacterium constitute a trans-ethnic signature of metformin treatment. CONCLUSIONS: We demonstrate major compositional differences of the gut microbiota between Danish and South Indian individuals, some of which may relate to differences in ethnicity, lifestyle, and demography. By comparing metformin-naive T2D patients and normoglycemic individuals, we identify T2D-related microbiota changes in the Danish and Indian study samples. In the present trans-ethnic study, we confirm that metformin changes the taxonomic profile and functional potential of the gut microbiota.