Deep immunophenotyping reveals that autoimmune and autoinflammatory disorders are spread along two immunological axes capturing disease inflammation levels and types.

OBJECTIVES: Based on genetic associations, McGonagle and McDermott suggested a classification of autoimmune and autoinflammatory diseases as a continuum ranging from purely autoimmune to purely autoinflammatory diseases and comprising diseases with both components. We used deep immunophenotyping to identify immune cell populations and molecular targets characterising this continuum. METHODS: We collected blood from 443 patients with one of 15 autoimmune or autoinflammatory diseases and 71 healthy volunteers. Deep phenotyping was performed using 13 flow cytometry panels characterising over 600 innate and adaptive cell populations. Unsupervised and supervised analyses were conducted to identify disease clusters with their common and specific cell parameters. RESULTS: Unsupervised clustering categorised these diseases into five clusters. Principal component analysis deconvoluted this clustering into two immunological axes. The first axis was driven by the ratio of LAG3+ to ICOS+ in regulatory T lymphocytes (Tregs), and segregated diseases based on their inflammation levels. The second axis was driven by activated Tregs and type 3 innate lymphoid cells (ILC3s), and segregated diseases based on their types of affected tissues. We identified a signature of 23 cell populations that accurately characterised the five disease clusters. CONCLUSIONS: We have refined the monodimensional continuum of autoimmune and autoinflammatory diseases as a continuum characterised by both disease inflammation levels and targeted tissues. Such classification should be helpful for defining therapies. Our results call for further investigations into the role of the LAG3+/ICOS+ balance in Tregs and the contribution of ILC3s in autoimmune and autoinflammatory diseases. TRIAL REGISTRATION NUMBER: NCT02466217.

Clinical correlates of lifetime and current comorbidity patterns in autoimmune and inflammatory diseases.

BACKGROUND: Autoimmune and inflammatory diseases (AIDs) are a heterogeneous group of disorders with diverse etiopathogenic mechanisms. This study explores the potential utility of family history, together with present and past comorbidities, in identifying distinct etiopathogenic subgroups. This approach may facilitate more accurate diagnosis, prognosis and personalized therapy. METHODS: We performed a multiple correspondence analysis on patients' comorbidities, followed by hierarchical principal component clustering of clinical data from 48 healthy volunteers and 327 patients with at least one of 19 selected AIDs included in the TRANSIMMUNOM cross-sectional study. RESULTS: We identified three distinct clusters characterized by: 1) the absence of comorbidities, 2) polyautoimmunity, and 3) polyinflammation. These clusters were further distinguished by specific comorbidities and biological parameters. Autoantibodies, allergies, and viral infections characterized the polyautoimmunity cluster, while older age, BMI, depression, cancer, hypertension, periodontal disease, and dyslipidemia characterized the polyinflammation cluster. Rheumatoid arthritis patients were distributed across all three clusters. They had higher DAS28 and prevalence of extra-articular manifestations when belonging to the polyinflammation and polyautoimmunity clusters, and also lower ACPA and RF seropositivity and higher pain scores within the polyinflammation cluster. We developed a model allowing to classify AID patients into comorbidity clusters. CONCLUSIONS: In this study, we have uncovered three distinct comorbidity profiles among AID patients. These profiles suggest the presence of distinct etiopathogenic mechanisms underlying these subgroups. Validation, longitudinal stability assessment, and exploration of their impact on therapy efficacy are needed for a comprehensive understanding of their potential role in personalized medicine.

The short-term prognosis of diabetic foot ulceration is independent of nutritional status at admission.

Diabetic foot ulcers are one of the complications of diabetes. Malnutrition is one of the risk factors for wounds but, on the other hand, diabetic foot ulceration may promote malnutrition. In this single-centre retrospective study we evaluated the frequency of malnutrition at first admission and the severity of foot ulceration. We demonstrated that malnutrition at admission correlated with duration of hospitalisation and with death rate rather than with the risk of amputation. Our data challenged the concept that protein-energy deficiency may worsen the prognosis of diabetic foot ulcers. Nevertheless, it is still important to screen nutritional status at baseline and during the follow-up in order to start specific nutritional support therapy as soon as possible in order to reduce morbidity/mortality related to malnutrition.

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.

Intestinal alteration of α-gustducin and sweet taste signaling pathway in metabolic diseases is partly rescued after weight loss and diabetes remission.

Carbohydrates and sweeteners are detected by the sweet taste receptor in enteroendocrine cells (EECs). This receptor is coupled to the gustducin G-protein, which α-subunit is encoded by GNAT3 gene. In intestine, the activation of sweet taste receptor triggers a signaling pathway leading to GLP-1 secretion, an incretin hormone. In metabolic diseases, GLP-1 concentration and incretin effect are reduced while partly restored after Roux-en-Y gastric bypass (RYGB). We wondered if the decreased GLP-1 secretion in metabolic diseases is caused by an intestinal defect in sweet taste transduction pathway. In our RNA-sequencing of EECs, GNAT3 expression is decreased in patients with obesity and type 2 diabetes compared with normoglycemic obese patients. This prompted us to explore sweet taste signaling pathway in mice with metabolic deteriorations. During obesity onset in mice, Gnat3 expression was downregulated in EECs. After metabolic improvement with enterogastro anastomosis surgery in mice (a surrogate of the RYGB in humans), the expression of Gnat3 increased in the new alimentary tract and glucose-induced GLP-1 secretion was improved. To evaluate if high-fat diet-induced dysbiotic intestinal microbiota could explain the changes in the expression of sweet taste α-subunit G-protein, we performed a fecal microbiota transfer in mice. However, we could not conclude if dysbiotic microbiota impacted or not intestinal Gnat3 expression. Our data highlight that metabolic disorders were associated with altered gene expression of sweet taste signaling in intestine. This could contribute to impaired GLP-1 secretion that is partly rescued after metabolic improvement.NEW & NOTEWORTHY Our data highlighted 1) the sweet taste transduction pathway in EECs plays pivotal role for glucose homeostasis at least at gene expression level; 2) metabolic disorders lead to altered gene expression of sweet taste signaling pathway in intestine contributing to impaired GLP-1 secretion; and 3) after surgical intestinal modifications, increased expression of GNAT3, encoding α-gustducin contributed to metabolic improvement.

Diabetic foot ulcer management in a multidisciplinary foot centre: one-year healing, amputation and mortality rate.

OBJECTIVE: To describe the rates of healing, major amputation and mortality after 12 months in patients with a new diabetic foot ulcer (DFU) and their care in a French diabetic foot service (DFS). METHOD: A prospective single-centre study including patients from March 2009 to December 2010. The length of time to healing, minor amputation, major amputation and mortality rate after inclusion were analysed using the Kaplan-Meier method. RESULTS: Some 347 patients were included (3% lost to follow-up), with a median follow-up (IQR) of 19 (12-24) months. The mean (SD) age was 65±12 years, 68% were male, and the median duration of the ulcer was 49 (19-120) days. Complications of the DFU were ischaemia (70%), infection (55%) and osteomyelitis (47%). Of the patients, 50% were inpatients in the DFS at inclusion (median duration of hospitalisation 26 (15-41) days). The rate of healing at one year was 67% (95% confidence interval (CI): 61-72); of major amputation 10% (95% CI: 7-17); of minor amputation 19% (95% CI: 14-25), and the death rate was 9% (95% CI: 7-13). Using an adjusted hazard ratio, the predictive factors of healing were perfusion and the area of the wound. The risk factors for a major amputation were active smoking and osteomyelitis. The risk factors for mortality were perfusion and age. CONCLUSION: This study confirms the need to treat DFUs rapidly, in a multidisciplinary DFS.

Low-dose IL-2 in children with recently diagnosed type 1 diabetes: a Phase I/II randomised, double-blind, placebo-controlled, dose-finding study.

AIMS/HYPOTHESIS: Low-dose IL-2 (ld-IL2) selectively activates and expands regulatory T cells (Tregs) and thus has the potential to skew the regulatory/effector T (Treg/Teff) cell balance towards improved regulation. We investigated which low doses of IL-2 would more effectively and safely activate Tregs during a 1 year treatment in children with recently diagnosed type 1 diabetes. METHODS: Dose Finding Study of IL-2 at Ultra-low Dose in Children With Recently Diagnosed Type 1 Diabetes (DF-IL2-Child) was a multicentre, double-blinded, placebo-controlled, dose-finding Phase I/II clinical trial conducted in four centres at university hospitals in France: 24 children (7-14 years old) with type 1 diabetes diagnosed within the previous 3 months were randomly assigned 1:1:1:1 to treatment by a centralised randomisation system, leading to a 7/5/6/6 patient distribution of placebo or IL-2 at doses of 0.125, 0.250 or 0.500 million international units (MIU)/m2, given daily for a 5 day course and then fortnightly for 1 year. A study number was attributed to patients by an investigator unaware of the randomisation list and all participants as well as investigators and staff involved in the study conduct and analyses were blinded to treatments. The primary outcome was change in Tregs, expressed as a percentage of CD4+ T cells at day 5. It pre-specified that a ≥60% increase in Tregs from baseline would identify Treg high responders. RESULTS: There were no serious adverse events. Non-serious adverse events (NSAEs) were transient and mild to moderate. In treated patients vs placebo, the commonest NSAE was injection site reaction (37.9% vs 3.4%), whereas other NSAEs were at the same level (23.3% vs 19.2%). ld-IL2 induced a dose-dependent increase in the mean proportion of Tregs, from 23.9% (95% CI -11.8, 59.6) at the lowest to 77.2% (44.7, 109.8) at the highest dose, which was significantly different from placebo for all dose groups. However, the individual Treg responses to IL-2 were variable and fluctuated over time. Seven patients, all among those treated with the 0.250 and 0.500 MIU m-2 day-1 doses, were Treg high responders. At baseline, they had lower Treg proportions in CD4+ cells than Treg low responders, and serum soluble IL-2 receptor α (sIL-2RA) and vascular endothelial growth factor receptor 2 (VEGFR2) levels predicted the Treg response after the 5 day course. There was no significant change in glycaemic control in any of the dose groups compared with placebo. However, there was an improved maintenance of induced C-peptide production at 1 year in the seven Treg high responders as compared with low responders. CONCLUSIONS/INTERPRETATION: The safety profile at all doses, the dose-dependent effects on Tregs and the observed variability of the Treg response to ld-IL2 in children with newly diagnosed type 1 diabetes call for use of the highest dose in future developments. The better preservation of insulin production in Treg high responders supports the potential of Tregs in regulating autoimmunity in type 1 diabetes, and warrants pursuing the investigation of ld-IL2 for its treatment and prevention. TRIAL REGISTRATION: ClinicalTrials.gov NCT01862120. FUNDING: Assistance Publique-Hôpitaux de Paris, Investissements d'Avenir programme (ANR-11-IDEX-0004-02, LabEx Transimmunom and ANR-16-RHUS-0001, RHU iMAP) and European Research Council Advanced Grant (FP7-IDEAS-ERC-322856, TRiPoD).

Circulating Receptor Activator of Nuclear Factor kB Ligand and triglycerides are associated with progression of lower limb arterial calcification in type 2 diabetes: a prospective, observational cohort study.

BACKGROUND: Lower limb arterial calcification is a frequent, underestimated but serious complication of diabetes. The DIACART study is a prospective cohort study designed to evaluate the determinants of the progression of lower limb arterial calcification in 198 patients with type 2 diabetes. METHODS: Lower limb arterial calcification scores were determined by computed tomography at baseline and after a mean follow up of 31.20 ± 3.86 months. Serum RANKL (Receptor Activator of Nuclear factor kB Ligand) and bone remodeling, inflammatory and metabolic parameters were measured at baseline. The predictive effect of these markers on calcification progression was analyzed by a multivariate linear regression model. RESULTS: At baseline, mean ± SD and median lower limb arterial calcification scores were, 2364 ± 5613 and 527 respectively and at the end of the study, 3739 ± 6886 and 1355 respectively. Using multivariate analysis, the progression of lower limb arterial log calcification score was found to be associated with (ß coefficient [slope], 95% CI, p-value) baseline log(calcification score) (1.02, 1.00-1.04, p < 0.001), triglycerides (0.11, 0.03-0.20, p = 0.007), log(RANKL) (0.07, 0.02-0.11, p = 0.016), previous ischemic cardiomyopathy (0.36, 0.15-0.57, p = 0.001), statin use (0.39, 0.06-0.72, p = 0.023) and duration of follow up (0.04, 0.01-0.06, p = 0.004). CONCLUSION: In patients with type 2 diabetes, lower limb arterial calcification is frequent and can progress rapidly. Circulating RANKL and triglycerides are independently associated with this progression. These results open new therapeutic perspectives in peripheral diabetic calcifying arteriopathy. Trial registration NCT02431234.

Diabetic foot ulcer management in a multidisciplinary foot centre: one-year healing, amputation and mortality rate.

OBJECTIVE: To describe the rates of healing, major amputation and mortality after 12 months in patients with a new diabetic foot ulcer (DFU) and their care in a French diabetic foot service (DFS). METHOD: A prospective single-centre study including patients from March 2009 to December 2010. The length of time to healing, minor amputation, major amputation and mortality rate after inclusion were analysed using the Kaplan-Meier method. RESULTS: Some 347 patients were included (3% lost to follow-up), with a median follow-up (IQR) of 19 (12-24) months. The mean (SD) age was 65±12 years, 68% were male, and the median duration of the ulcer was 49 (19-120) days. Complications of the DFU were ischaemia (70%), infection (55%) and osteomyelitis (47%). Of the patients, 50% were inpatients in the DFS at inclusion (median duration of hospitalisation 26 (15-41) days). The rate of healing at one year was 67% (95% confidence interval (CI): 61-72); of major amputation 10% (95% CI: 7-17); of minor amputation 19% (95% CI: 14-25), and the death rate was 9% (95% CI: 7-13). Using an adjusted hazard ratio, the predictive factors of healing were perfusion and the area of the wound. The risk factors for a major amputation were active smoking and osteomyelitis. The risk factors for mortality were perfusion and age. CONCLUSION: This study confirms the need to treat DFUs rapidly, in a multidisciplinary DFS.

Relationship between cardiac microvascular dysfunction measured with 82Rubidium-PET and albuminuria in patients with diabetes mellitus.

BACKGROUND: Albuminuria is of one the strongest predictors of cardiovascular disease (CVD) in diabetes. Diabetes is associated with cardiac microvascular dysfunction (CMD), a powerful, independent prognostic factor for cardiac mortality. The aim of this study was to evaluate the relationship between CMD and microvascular complications in patients without known CVD. METHODS: In this monocentric study, myocardial flow reserve (MFR) was measured with cardiac 82Rubidium positron emission tomography (Rb-PET) in 311 patients referred to nuclear medicine department of Bichat University Hospital for screening of coronary artery disease from 2012 to 2014. Patients with hemodynamically relevant stenosis on coronary angiography or myocardial ischemia on Rb-PET were excluded. Among patients with diabetes, MFR values were compared according to the presence of retinopathy and albuminuria. RESULTS: Overall, 175 patients (118 with type 2 diabetes) were included. MFR was significantly lower in patients with diabetes compared with those without diabetes (2.6 ± 1.1 vs. 3.3 ± 1.7; p < 0.005). In patients with diabetes, MFR decreased progressively in relation to albumin urinary excretion (normoalbuminuria: 2.9 ± 1.1, microalbuminuria: 2.3 ± 1.0, macroalbuminuria: 1.8 ± 0.7; p < 0.0001). MFR was not significantly different in patients with vs. without retinopathy (2.4 ± 1.0 vs. 2.7 ± 1.1, p = 0.07). Microalbuminuria and macroalbuminuria remained strongly associated with impaired MFR after multiple adjustments [odds ratio 2.6 (95% CI 1.1-8.4) and 5.3 (95% CI 1.2-44.7), respectively]. This association was confirmed when analyses were restricted to patients with low levels of coronary calcifications on computed tomography. CONCLUSIONS: Impaired MFR was more frequent in patients with diabetes and was strongly associated with the degree of albuminuria suggesting that CMD and albuminuria might share common mechanisms.

Hepatic deletion of serine palmitoyl transferase 2 impairs ceramide/sphingomyelin balance, bile acids homeostasis and leads to liver damage in mice.

Ceramides (Cer) have been shown as lipotoxic inducers, which disturb numerous cell-signaling pathways, leading to metabolic disorders such as type 2 diabetes. In this study, we aimed to determine the role of de novo hepatic ceramide synthesis in energy and liver homeostasis in mice. We generated mice lacking serine palmitoyltransferase 2 (Sptlc2), the rate limiting enzyme of ceramide de novo synthesis, in liver under albumin promoter. Liver function, glucose homeostasis, bile acid (BA) metabolism and hepatic sphingolipids content were assessed using metabolic tests and LC-MS. Despite lower expression of hepatic Sptlc2, we observed an increased concentration of hepatic Cer, associated with a 10-fold increase in neutral sphingomyelinase 2 (nSMase2) expression, and a decreased sphingomyelin content in the liver. Sptlc2ΔLiv mice were protected against obesity induced by high fat diet and displayed a defect in lipid absorption. In addition, an important increase in tauro-muricholic acid was associated with a downregulation of the nuclear BA receptor FXR target genes. Sptlc2 deficiency also enhanced glucose tolerance and attenuated hepatic glucose production, while the latter effect was dampened in presence of nSMase2 inhibitor. Finally, Sptlc2 disruption promoted apoptosis, inflammation and progressive development of hepatic fibrosis, worsening with age. Our data suggest a compensatory mechanism to regulate hepatic ceramides content from sphingomyelin hydrolysis, with deleterious impact on liver homeostasis. In addition, our results show the involvement of hepatic sphingolipid modulation in BA metabolism and hepatic glucose production in an insulin-independent manner, which highlight the still under-researched role of ceramides in many metabolic functions.

Weight Loss After Sleeve Gastrectomy: Does Type 2 Diabetes Status Impact Weight and Body Composition Trajectories?

INTRODUCTION/ PURPOSE: Sleeve gastrectomy (SG), the most frequently performed bariatric procedure, induces marked weight-loss, but with high inter-individual variability. Since type 2 diabetes (T2D) negatively impacts weight-loss outcomes after Roux-en-Y gastric bypass (RYGB), we herein aimed to evaluate whether and how T2D status may influence weight-loss and body composition changes in individuals with or without T2D after SG. MATERIAL AND METHODS: We retrospectively included individuals with obesity operated from SG and prospectively followed at our center: 373 patients including 152 with T2D (40%). All subjects' clinical characteristics were collected before and during 4 years of follow-up post-SG. Linear mixed models were applied to analyze weight-loss trajectories post-surgery. RESULTS: Compared to individuals with obesity but no T2D, those with T2D before SG displayed lower weight-loss at 1 year (21 vs. 27% from baseline, p < 10-3). This difference was accentuated in patients with poorer glucose control (HbA1c > 7%) at baseline. Furthermore, patients with T2D underwent less favorable body composition changes at 1-year post-SG compared to individuals without T2D (% fat mass reduction: 28 vs. 37%, p < 10-3 respectively). CONCLUSION: When undergoing SG, subjects with obesity and T2D who have poor pre-operative glycemic control display reduced weight-loss and less improvement in body composition compared to patients with obesity but without T2D. This result suggests that glycemic control prior to surgery is important to take into account for the outcome of bariatric surgery.

Correction: Inactive matrix gla protein plasma levels are associated with peripheral neuropathy in Type 2 diabetes.

[This corrects the article DOI: 10.1371/journal.pone.0229145.].

Inactive matrix gla protein plasma levels are associated with peripheral neuropathy in Type 2 diabetes.

AIMS/HYPOTHESIS: Diabetic peripheral neuropathy is a frequent and severe complication of diabetes. As Matrix-gla-protein (MGP) is expressed in several components of the nervous system and is involved in some neurological disease, MGP could play a role in peripheral nervous system homeostasis. The aim of this study was to evaluate factors associated with sensitive diabetic neuropathy in Type 2 Diabetes, and, in particular, dephospho-uncarboxylated MGP (dp-ucMGP), the inactive form of MGP. METHODS: 198 patients with Type 2 Diabetes were included. Presence of sensitive diabetic neuropathy was defined by a neuropathy disability score (NDS) ≥6. Plasma levels of dp-ucMGP were measured by ELISA. RESULTS: In this cohort, the mean age was 64+/-8.4 years old, and 80% of patients were men. Peripheral neuropathy was present in 15.7% of the patients and was significantly associated (r = 0.51, p<0.0001) with dp-ucMGP levels (ß = -0.26, p = 0.045) after integrating effects of height (ß = -0.38, p = 0.01), insulin treatment (ß = 0.42, p = 0.002), retinopathy treated by laser (ß = 0.26, p = 0.02), and total cholesterol levels (ß = 0.3, p = 0.03) by multivariable analysis. CONCLUSIONS: The association between diabetic neuropathy and the inactive form of MGP suggests the existence of new pathophysiological pathways to explore. Further studies are needed to determine if dp-ucMGP may be used as a biomarker of sensitive neuropathy. Since dp-ucMGP is a marker of poor vitamin K status, clinical studies are warranted to explore the potential protective effect of high vitamin K intake on diabetic peripheral neuropathy.

A surrogate of Roux-en-Y gastric bypass (the enterogastro anastomosis surgery) regulates multiple beta-cell pathways during resolution of diabetes in ob/ob mice.

BACKGROUND: Bariatric surgery is an effective treatment for type 2 diabetes. Early post-surgical enhancement of insulin secretion is key for diabetes remission. The full complement of mechanisms responsible for improved pancreatic beta cell functionality after bariatric surgery is still unclear. Our aim was to identify pathways, evident in the islet transcriptome, that characterize the adaptive response to bariatric surgery independently of body weight changes. METHODS: We performed entero-gastro-anastomosis (EGA) with pyloric ligature in leptin-deficient ob/ob mice as a surrogate of Roux-en-Y gastric bypass (RYGB) in humans. Multiple approaches such as determination of glucose tolerance, GLP-1 and insulin secretion, whole body insulin sensitivity, ex vivo glucose-stimulated insulin secretion (GSIS) and functional multicellular Ca2+-imaging, profiling of mRNA and of miRNA expression were utilized to identify significant biological processes involved in pancreatic islet recovery. FINDINGS: EGA resolved diabetes, increased pancreatic insulin content and GSIS despite a persistent increase in fat mass, systemic and intra-islet inflammation, and lipotoxicity. Surgery differentially regulated 193 genes in the islet, most of which were involved in the regulation of glucose metabolism, insulin secretion, calcium signaling or beta cell viability, and these were normalized alongside changes in glucose metabolism, intracellular Ca2+ dynamics and the threshold for GSIS. Furthermore, 27 islet miRNAs were differentially regulated, four of them hubs in a miRNA-gene interaction network and four others part of a blood signature of diabetes resolution in ob/ob mice and in humans. INTERPRETATION: Taken together, our data highlight novel miRNA-gene interactions in the pancreatic islet during the resolution of diabetes after bariatric surgery that form part of a blood signature of diabetes reversal. FUNDING: European Union's Horizon 2020 research and innovation programme via the Innovative Medicines Initiative 2 Joint Undertaking (RHAPSODY), INSERM, Société Francophone du Diabète, Institut Benjamin Delessert, Wellcome Trust Investigator Award (212625/Z/18/Z), MRC Programme grants (MR/R022259/1, MR/J0003042/1, MR/L020149/1), Diabetes UK (BDA/11/0004210, BDA/15/0005275, BDA 16/0005485) project grants, National Science Foundation (310030-188447), Fondation de l'Avenir.

Impact of bariatric surgery on type 2 diabetes: contribution of inflammation and gut microbiome?

Obesity is a chronic low-grade inflammatory disease (both at the systemic and adipose tissue level) that continues to rise worldwide. It is associated with an abundance of comorbidities, including type 2 diabetes (T2D). Bariatric surgery, which induces modifications of the intestinal tract, is to date the most successful treatment for obesity. Its use has dramatically increased in number as it enables both weight reduction and metabolic improvements, with 60% of patients even achieving diabetes remission. Several mechanisms are actually demonstrated to be involved in those clinical improvements. Importantly, both obesity and T2D share many phenotypic characteristics, including increased systemic and adipose tissue inflammation, as well as gut microbiota dysbiosis. These characteristics are deeply modulated after bariatric surgery. This review will address the host metabolic changes observed after bariatric surgery, focusing on the induced gut architectural changes, as well as on the modifications of the inflammatory tone and the gut microbiota.

Insulin Pump Combined with Flash Glucose Monitoring: A Therapeutic Option to Improve Glycemic Control in Severely Nonadherent Patients with Type 1 Diabetes.

Some patients with type 1 diabetes (T1D) are severely noncompliant; they rarely perform self-blood glucose measures and miss insulin injections. Their HbA1c is far above the target rate. Current guidelines do not recommend starting treatment with an insulin pump (continuous subcutaneous insulin infusion [CSII]) for these persons. The aim of this study was to determine whether a CSII associated with a flash glucose monitoring (FGM) device could reduce HbA1c without increasing the risk of acute events, diabetic ketoacidosis (DKA) and severe hypoglycemia (SH), in these patients. We conducted a 6-month nonrandomized, pilot prospective study. Patients with T1D on multiple daily injections who performed less than two self-blood glucose tests/day and had an HbA1c >9% were equipped with CSII and an FGM device. The primary composite endpoint was defined by a change in HbA1c ≥1% without any episode of DKA or SH during 6 months. Change in mean HbA1c, weight, treatment satisfaction, frequency of minor hypoglycemia, and ketoacidosis were secondary endpoints. Nineteen adults were included. Median (Q1-Q3) HbA1c at baseline was 10.8 (10.3-13.0), 14 participants did not perform any self-monitoring and 5 performed maximum two tests daily. Twelve participants (63%) (95% confidence interval 41%-81%) met the primary composite endpoint. Seventeen patients completed the study. HbA1c decreased by 2% (1.0-3.3) (P < 0.001), and satisfaction with treatment significantly improved. Three participants experienced SH and one a DKA, versus, respectively, five and eight in the year preceding the study. Participants scanned the sensor 4 (3-6) times per day and injected 3 (2.7-4.1) boluses per day. Weight increased significantly. An association of an insulin pump with an FGM device can be an effective and safe therapeutic option in severely nonadherent and noncompliant patients with high HbA1c.

Serum concentration and vascular expression of adiponectin are differentially associated with the diabetic calcifying peripheral arteriopathy.

BACKGROUND: Medial calcification in diabetes contributes to the arterial occlusive process occurring below the knee level. Adiponectin is an adipokine with atheroprotective properties and possible protective role against arterial calcification. The aim of the study was to investigate, in type 2 diabetes, the link between vascular expression and serum concentration of adiponectin and (1) peripheral arterial calcification and (2) lower limb occlusive arterial disease. METHODS: Scoring of peripheral vascular calcification and peripheral arterial occlusive disease, using CT-scan and color-duplex ultrasonography respectively, were conducted and explored in relation to serum adiponectin level in a cross sectional study of 197 patients with type 2 diabetes. Vascular adiponectin expression in the arterial wall of diabetic patients with and without medial calcification was evaluated by immunohistochemistry. RESULTS: Peripheral arterial calcification score was higher in patients with the highest adiponectin concentration. In a multivariate logistic regression analysis, an increase of 1 µg/mL of adiponectin was associated with a 22% increase of arterial calcification (adjusted OR = 1.22; 95% CI 1.03-1.44; p = 0.02). Arterial occlusive score was also higher in patients with adiponectin concentration > median (2.8 ± 4.8 vs 4.2 ± 5.7, p = 0.034). Immunohistochemical analyses showed a strong and specific staining of adiponectin in smooth muscle cells in calcified arteries, with a more pronounced expression of adiponectin in early stages of medial calcification. CONCLUSIONS: Peripheral arterial calcification is positively associated with circulating adiponectin levels in patients with type 2 diabetes, but vascular adiponectin expression is already observed at early stages of calcification. Adiponectin secretion could be a compensatory mechanism against the calcification process.Trial registration DIACART NCT number: NCT02431234. Registered 30 April 2015.

Diabetes Mellitus, Extreme Insulin Resistance, and Hypothalamic-Pituitary Langerhans Cells Histiocytosis.

BACKGROUND: Langerhans Cell Histiocytosis (LCH) is a rare inflammatory neoplasm characterized by an infiltration of organs by Langerin + (CD207+) and CD1a+ histiocytes. Diabetes insipidus is a frequent manifestation of the disease, while diabetes mellitus is very rare. We report the first case of a 20-year-old man suffering from hypothalamopituitary histiocytosis and diabetes mellitus with serum anti-insulin receptor antibodies. CASE PRESENTATION: A 20-year-old patient was admitted for the evaluation of growth delay and hyperphagia. HbA1c level and fasting blood glucose were in the normal range. The diagnosis of hypothalamopituitary histiocytosis was based on histological features after biopsy of a large suprachiasmatic lesion identified on magnetic resonance imaging (MRI). Association of vinblastine and purinethol was started followed by a second-line therapy by cladribine. During the follow-up, the patient was admitted for recurrence of hyperglycemic states and extreme insulin resistance. The screening for serum anti-insulin receptor antibodies was positive. Each episode of hyperglycemia appeared to be correlated with tumoral activity and increase in serum anti-insulin receptor antibodies and appeared to be improved when the disease was controlled by chemotherapy. CONCLUSION: We report the first description of a hypothalamopituitary histiocytosis associated with serum anti-insulin receptor antibodies, extreme insulin resistance, and diabetes. Parallel evolution of glucose levels and serum anti-insulin receptor antibodies seemed to be the consequence of immune suppressive properties of cladribine.