Outcome of SARS-CoV-2 infection is linked to MAIT cell activation and cytotoxicity.

Immune system dysfunction is paramount in coronavirus disease 2019 (COVID-19) severity and fatality rate. Mucosal-associated invariant T (MAIT) cells are innate-like T cells involved in mucosal immunity and protection against viral infections. Here, we studied the immune cell landscape, with emphasis on MAIT cells, in cohorts totaling 208 patients with various stages of disease. MAIT cell frequency is strongly reduced in blood. They display a strong activated and cytotoxic phenotype that is more pronounced in lungs. Blood MAIT cell alterations positively correlate with the activation of other innate cells, proinflammatory cytokines, notably interleukin (IL)-18, and with the severity and mortality of severe acute respiratory syndrome coronavirus 2 infection. We also identified a monocyte/macrophage interferon (IFN)-α-IL-18 cytokine shift and the ability of infected macrophages to induce the cytotoxicity of MAIT cells in an MR1-dependent manner. Together, our results suggest that altered MAIT cell functions due to IFN-α-IL-18 imbalance contribute to disease severity, and their therapeutic manipulation may prevent deleterious inflammation in COVID-19 aggravation.

Blood Monocyte Phenotype Is A Marker of Cardiovascular Risk in Type 2 Diabetes.

BACKGROUND: Diabetes is a major risk factor for atherosclerotic cardiovascular diseases with a 2-fold higher risk of cardiovascular events in people with diabetes compared with those without. Circulating monocytes are inflammatory effector cells involved in both type 2 diabetes (T2D) and atherogenesis. METHODS: We investigated the relationship between circulating monocytes and cardiovascular risk progression in people with T2D, using phenotypic, transcriptomic, and metabolomic analyses. cardiovascular risk progression was estimated with coronary artery calcium score in a cohort of 672 people with T2D. RESULTS: Coronary artery calcium score was positively correlated with blood monocyte count and frequency of the classical monocyte subtype. Unsupervised k-means clustering based on monocyte subtype profiles revealed 3 main endotypes of people with T2D at varying risk of cardiovascular events. These observations were confirmed in a validation cohort of 279 T2D participants. The predictive association between monocyte count and major adverse cardiovascular events was validated through an independent prospective cohort of 757 patients with T2D. Integration of monocyte transcriptome analyses and plasma metabolomes showed a disruption of mitochondrial pathways (tricarboxylic acid cycle, oxidative phosphorylation pathway) that underlined a proatherogenic phenotype. CONCLUSIONS: In this study, we provide evidence that frequency and monocyte phenotypic profile are closely linked to cardiovascular risk in patients with T2D. The assessment of monocyte frequency and count is a valuable predictive marker for risk of cardiovascular events in patients with T2D. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04353869.

Heterogeneity of glycaemic phenotypes in type 1 diabetes.

AIMS/HYPOTHESIS: Our study aims to uncover glycaemic phenotype heterogeneity in type 1 diabetes. METHODS: In the Study of the French-speaking Society of Type 1 Diabetes (SFDT1), we characterised glycaemic heterogeneity thanks to a set of complementary metrics: HbA1c, time in range (TIR), time below range (TBR), CV, Gold score and glycaemia risk index (GRI). Applying the Discriminative Dimensionality Reduction with Trees (DDRTree) algorithm, we created a phenotypic tree, i.e. a 2D visual mapping. We also carried out a clustering analysis for comparison. RESULTS: We included 618 participants with type 1 diabetes (52.9% men, mean age 40.6 years [SD 14.1]). Our phenotypic tree identified seven glycaemic phenotypes. The 2D phenotypic tree comprised a main branch in the proximal region and glycaemic phenotypes in the distal areas. Dimension 1, the horizontal dimension, was positively associated with GRI (coefficient [95% CI]) (0.54 [0.52, 0.57]), HbA1c (0.39 [0.35, 0.42]), CV (0.24 [0.19, 0.28]) and TBR (0.11 [0.06, 0.15]), and negatively with TIR (-0.52 [-0.54, -0.49]). The vertical dimension was positively associated with TBR (0.41 [0.38, 0.44]), CV (0.40 [0.37, 0.43]), TIR (0.16 [0.12, 0.20]), Gold score (0.10 [0.06, 0.15]) and GRI (0.06 [0.02, 0.11]), and negatively with HbA1c (-0.21 [-0.25, -0.17]). Notably, socioeconomic factors, cardiovascular risk indicators, retinopathy and treatment strategy were significant determinants of glycaemic phenotype diversity. The phenotypic tree enabled more granularity than traditional clustering in revealing clinically relevant subgroups of people with type 1 diabetes. CONCLUSIONS/INTERPRETATION: Our study advances the current understanding of the complex glycaemic profile in people with type 1 diabetes and suggests that strategies based on isolated glycaemic metrics might not capture the complexity of the glycaemic phenotypes in real life. Relying on these phenotypes could improve patient stratification in type 1 diabetes care and personalise disease management.

Prospective head-to-head comparison of non-invasive scores for diagnosis of fibrotic MASH in patients with type 2 diabetes.

BACKGROUND & AIMS: Non-invasive scores have been proposed to identify patients with fibrotic, metabolic dysfunction-associated steatohepatitis (MASH), who are at the highest risk of progression to complications of cirrhosis and may benefit from pharmacologic treatments. However, data in patients with type 2 diabetes (T2DM) are lacking. The aim of this multicenter prospective study was to perform a head-to-head comparison of FAST (FibroScan-aspartate aminotransferase [AST]), MAST (MRI-AST), MEFIB (magnetic resonance elastography [MRE] plus FIB-4), and FNI (fibrotic NASH index) for detecting fibrotic MASH in patients with T2DM. METHODS: A total of 330 outpatients with T2DM and biopsy-proven metabolic dysfunction-associated steatotic liver disease (MASLD) from the QUID-NASH study (NCT03634098), who underwent FibroScan, MRI-proton density fat fraction and MRE at the time of liver biopsy were studied. The main outcome was fibrotic MASH, defined as NAS ≥4 (with at least one point for each parameter) and fibrosis stage ≥2 (centrally reviewed). RESULTS: All data for score comparisons were available for 245 patients (median age 59 years, 65% male, median BMI 31 kg/m2; fibrotic MASH in 39%). FAST and MAST had similar accuracy (AUROCs 0.81 vs. 0.79, p = 0.41) but outperformed FNI (0.74; p = 0.01) and MEFIB (0.68; p <0.0001). When using original cut-offs, MAST outperformed FAST, MEFIB and FNI when comparing the percentage of correctly classified patients, in whom liver biopsy would be avoided (69% vs. 48%, 46%, 39%, respectively; p <0.001). When using cut-offs specific to our population, FAST outperformed FNI and MAST (56% vs. 40%, and 38%, respectively; p <0.001). CONCLUSION: Our findings show that FAST, MAST, MEFIB and FNI are accurate non-invasive tools to identify patients with T2DM and fibrotic MASH in secondary/tertiary diabetes clinics. Cut-offs adapted to the T2DM population should be considered. IMPACT AND IMPLICATIONS: Among patients with type 2 diabetes (T2DM), identifying those with metabolic dysfunction-associated steatohepatitis and significant fibrosis, who are the most at risk of developing clinical liver-related outcomes and who may benefit from pharmacologic treatments, is an unmet need. In this prospective multicenter study, we compared four non-invasive scores, three based on imaging (MRI or ultrasound technologies) and one on laboratory blood tests, for this purpose, using original and study-specific cut-offs. Our findings show that FAST, MAST, MEFIB and FNI are accurate non-invasive tools to identify patients with T2DM and fibrotic MASH in secondary/tertiary diabetes clinics. Cut-offs adapted to the T2DM population should be considered. TRIAL REGISTRATION NUMBER: NCT03634098.

Untargeted Multiomics Approach Coupling Lipidomics and Metabolomics Profiling Reveals New Insights in Diabetic Retinopathy.

Diabetic retinopathy (DR) is a microvascular complication of diabetes mellitus (DM) which is the main cause of vision loss in the working-age population. Currently known risk factors such as age, disease duration, and hemoglobin A1c lack sufficient efficiency to distinguish patients with early stages of DR. A total of 194 plasma samples were collected from patients with type 2 DM and DR (moderate to proliferative (PDR) or control (no or mild DR) matched for age, gender, diabetes duration, HbA1c, and hypertension. Untargeted lipidomic and metabolomic approaches were performed. Partial-least square methods were used to analyze the datasets. Levels of 69 metabolites and 85 lipid species were found to be significantly different in the plasma of DR patients versus controls. Metabolite set enrichment analysis indicated that pathways such as metabolism of branched-chain amino acids (methylglutaryl carnitine p = 0.004), the kynurenine pathway (tryptophan p < 0.001), and microbiota metabolism (p-Cresol sulfate p = 0.004) were among the most enriched deregulated pathways in the DR group. Moreover, Glucose-6-phosphate (p = 0.001) and N-methyl-glutamate (p < 0.001) were upregulated in DR. Subgroup analyses identified a specific signature associated with PDR, macular oedema, and DR associated with chronic kidney disease. Phosphatidylcholines (PCs) were dysregulated, with an increase of alkyl-PCs (PC O-42:5 p < 0.001) in DR, while non-ether PCs (PC 14:0-16:1, p < 0.001; PC 18:2-14:0, p < 0.001) were decreased in the DR group. Through an unbiased multiomics approach, we identified metabolites and lipid species that interestingly discriminate patients with or without DR. These features could be a research basis to identify new potential plasma biomarkers to promote 3P medicine.

Leukocyte telomere length, allelic variations in related genes and risk of coronary heart disease in people with long-standing type 1 diabetes.

BACKGROUND: Type 1 diabetes is associated with accelerated vascular aging and advanced atherosclerosis resulting in increased rates of cardiovascular disease and premature death. We evaluated associations between Leukocyte telomere length (LTL), allelic variations (SNPs) in LTL-related genes and the incidence of coronary heart disease (CHD) in adults with long-standing type 1 diabetes. METHODS: We assessed associations of LTL, measured at baseline by RT-PCR, and of SNPs in 11 LTL-related genes with the risk of coronary heart disease (CHD: myocardial infarction or coronary revascularization) and all-cause death during follow-up in two multicenter French-Belgian prospective cohorts of people with long-standing type 1 diabetes. RESULTS: In logistic and Cox analyses, the lowest tertile of LTL distribution (short telomeres) at baseline was associated with the prevalence of myocardial infarction at baseline and with increased risk of CHD (Hazard ratio 3.14 (1.39-7.70), p = 0.005, for shorter vs longer tertile of LTL) and all-cause death (Hazard ratio 1.63 (95% CI 1.04-2.55), p = 0.03, for shorter vs combined intermediate and longer tertiles of LTL) during follow-up. Allelic variations in six genes related to telomere biology (TERC, NAF1, TERT, TNKS, MEN1 and BICD1) were also associated with the incidence of CHD during follow-up. The associations were independent of sex, age, duration of diabetes, and a range of relevant confounding factors at baseline. CONCLUSIONS: Our results suggest that short LTL is an independent risk factor for CHD in people with type 1 diabetes.

Therapeutic indications and metabolic effects of metreleptin in patients with lipodystrophy syndromes: Real-life experience from a national reference network.

AIM: To describe baseline characteristics and follow-up data in patients with lipodystrophy syndromes treated with metreleptin in a national reference network, in a real-life setting. PATIENTS AND METHODS: Clinical and metabolic data from patients receiving metreleptin in France were retrospectively collected, at baseline, at 1 year and at the latest follow-up during treatment. RESULTS: Forty-seven patients with lipodystrophy including generalized lipodystrophy (GLD; n = 28) and partial lipodystrophy (PLD; n = 19) received metreleptin over the last decade. At baseline, the median (interquartile range [IQR]) patient age was 29.3 (16.6-47.6) years, body mass index was 23.8 (21.2-25.7) kg/m2 and serum leptin was 3.2 (1.0-4.9) ng/mL, 94% of patients had diabetes (66% insulin-treated), 53% had hypertension and 87% had dyslipidaemia. Metreleptin therapy, administered for a median (IQR) of 31.7 (14.2-76.0) months, was ongoing in 77% of patients at the latest follow-up. In patients with GLD, glycated haemoglobin (HbA1c) and fasting triglyceride levels significantly decreased from baseline to 1 year of metreleptin treatment, from 8.4 (6.5-9.9)% [68 (48-85) mmol/mol] to 6.8 (5.6-7.4)% [51(38-57) mmol/mol], and 3.6 (1.7-8.5) mmol/L to 2.2 (1.1-3.7) mmol/L, respectively (P < 0.001), with sustained efficacy thereafter. In patients with PLD, HbA1c was not significantly modified (7.7 [7.1-9.1]% [61 (54-76) mmol/mol] at baseline vs. 7.7 [7.4-9.5]% [61(57-80) mmol/mol] at 1 year), and the decrease in fasting triglycerides (from 3.3 [1.9-9.9] mmol/L to 2.5 [1.6-5.3] mmol/L; P < 0.01) was not confirmed at the latest assessment (5.2 [2.2-11.3] mmol/L). However, among PLD patients, at 1 year, 61% were responders regarding glucose homeostasis, with lower baseline leptin levels compared to nonresponders, and 61% were responders regarding triglyceridaemia. Liver enzymes significantly decreased only in the GLD group. CONCLUSIONS: In this real-life setting study, metabolic outcomes are improved by metreleptin therapy in patients with GLD. The therapeutic indication for metreleptin needs to be clarified in patients with PLD.

Predictors of hospital discharge and mortality in patients with diabetes and COVID-19: updated results from the nationwide CORONADO study.

AIMS/HYPOTHESIS: This is an update of the results from the previous report of the CORONADO (Coronavirus SARS-CoV-2 and Diabetes Outcomes) study, which aims to describe the outcomes and prognostic factors in patients with diabetes hospitalised for coronavirus disease-2019 (COVID-19). METHODS: The CORONADO initiative is a French nationwide multicentre study of patients with diabetes hospitalised for COVID-19 with a 28-day follow-up. The patients were screened after hospital admission from 10 March to 10 April 2020. We mainly focused on hospital discharge and death within 28 days. RESULTS: We included 2796 participants: 63.7% men, mean age 69.7 ± 13.2 years, median BMI (25th-75th percentile) 28.4 (25.0-32.4) kg/m2. Microvascular and macrovascular diabetic complications were found in 44.2% and 38.6% of participants, respectively. Within 28 days, 1404 (50.2%; 95% CI 48.3%, 52.1%) were discharged from hospital with a median duration of hospital stay of 9 (5-14) days, while 577 participants died (20.6%; 95% CI 19.2%, 22.2%). In multivariable models, younger age, routine metformin therapy and longer symptom duration on admission were positively associated with discharge. History of microvascular complications, anticoagulant routine therapy, dyspnoea on admission, and higher aspartate aminotransferase, white cell count and C-reactive protein levels were associated with a reduced chance of discharge. Factors associated with death within 28 days mirrored those associated with discharge, and also included routine treatment by insulin and statin as deleterious factors. CONCLUSIONS/INTERPRETATION: In patients with diabetes hospitalised for COVID-19, we established prognostic factors for hospital discharge and death that could help clinicians in this pandemic period. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04324736.

Relationship between obesity and severe COVID-19 outcomes in patients with type 2 diabetes: Results from the CORONADO study.

AIM: To assess the relationship between body mass index (BMI) classes and early COVID-19 prognosis in inpatients with type 2 diabetes (T2D). METHODS: From the CORONAvirus-SARS-CoV-2 and Diabetes Outcomes (CORONADO) study, we conducted an analysis in patients with T2D categorized by four BMI subgroups according to the World Health Organization classification. Clinical characteristics and COVID-19-related outcomes (i.e. intubation for mechanical ventilation [IMV], death and discharge by day 7 [D7]) were analysed according to BMI status. RESULTS: Among 1965 patients with T2D, 434 (22.1%) normal weight (18.5-24.9 kg/m2 , reference group), 726 (36.9%) overweight (25-29.9 kg/m2 ) and 805 (41.0%) obese subjects were analysed, including 491 (25.0%) with class I obesity (30-34.9 kg/m2 ) and 314 (16.0%) with class II/III obesity (≥35 kg/m2 ). In a multivariable-adjusted model, the primary outcome (i.e. IMV and/or death by D7) was significantly associated with overweight (OR 1.65 [1.05-2.59]), class I (OR 1.93 [1.19-3.14]) and class II/III obesity (OR 1.98 [1.11-3.52]). After multivariable adjustment, primary outcome by D7 was significantly associated with obesity in patients aged younger than 75 years, while such an association was no longer found in those aged older than 75 years. CONCLUSIONS: Overweight and obesity are associated with poor early prognosis in patients with T2D hospitalized for COVID-19. Importantly, the deleterious impact of obesity on COVID-19 prognosis was no longer observed in the elderly, highlighting the need for specific management in this population.

The COVID-19 lockdown as an opportunity to change lifestyle and body weight in people with overweight/obesity and diabetes: Results from the national French COVIDIAB cohort.

BACKGROUND AND AIMS: To analyze lifestyle habits and weight evolution during the COVID-19 pandemic-associated lockdown, in diabetes and overweight/obesity patients (body mass index (BMI) [25-29.9] and ≥30 kg/m2, respectively). METHODS AND RESULTS: We collected information on participants' characteristics and behavior regarding lifestyle before and during the lockdown, through the CoviDIAB web application, which is available freely for people with diabetes in France. We stratified the cohort according to BMI (≥25 kg/m2vs < 25 kg/m2) and examined the determinants of weight loss (WL), WL > 1 kg vs no-WL) in participants with a BMI ≥25 kg/m2, in both univariate and multivariate analyses. Of the 5280 participants (mean age, 52.5 years; men, 49%; diabetes, 100% by design), 69.5% were overweight or obese (mean BMI, 28.6 kg/m2 (6.1)). During the lockdown, patients often quit or decreased smoking; overweight/obese participants increased alcohol consumption less frequently as compared with normal BMI patients. In addition, overweight/obese patients were more likely to improve other healthy behaviors on a larger scale than patients with normal BMI: increased intake of fruits and vegetables, reduction of snacks intake, and reduction of total dietary intake. WL was observed in 18.9% of people with a BMI ≥25 kg/m2, whereas 28.6% of them gained weight. Lifestyle favorable changes characterized patients with WL. CONCLUSIONS: A significant proportion of overweight/obese patients with diabetes seized the opportunity of lockdown to improve their lifestyle and to lose weight. Identifying those people may help clinicians to personalize practical advice in the case of a recurrent lockdown.

Prevalence, severity stages, and risk factors of diabetic retinopathy in 1464 adult patients with type 1 diabetes.

PURPOSE: To determine the prevalence of diabetic retinopathy (DR) and its risk factors in adult type 1 diabetes (T1D) patients METHODS: In this cross-sectional study, all T1D patients followed in the University Center for Diabetes and its Complications of Lariboisière Hospital (Paris, France) between January 2017 and February 2019 were included. Ophthalmologic and systemic data were collected from electronic records. The association between DR (and each grade) and associated factors were estimated by univariate and multivariate analyses using logistic regression models. RESULTS: A total of 1464 patients (46.2% of women, mean age: 42.2 ± 15.8 years) were included. The mean hemoglobin A1c (HbA1c) was 7.8 ± 1.7% and the mean diabetes duration was 20.5 ± 13.5 years. DR prevalence was 50.1% (47.4-52.6) and the prevalence of mild, moderate, and severe non-proliferative DR and proliferative DR was 19.1%, 9.4%, 3.9%, and 17.6%, respectively. DR was significantly associated with male gender, an older age, former and current smoking status, a higher BMI, the presence of nephropathy and neuropathy, higher HBA1c, and longer diabetes duration. Patients with HbA1c > 10% had an adjusted odds ratio (OR) of 3.25 (1.77-6.01) of having DR compared to patients with HbA1c < 6.5%. Patients with a diabetes duration > 30 years had an adjusted OR of 24.87 (14.82-42.67) higher of having DR compared to patients with a diabetes duration < 10 years. CONCLUSION: In this study, 50.1% of adult T1D patients had DR and 17.6% had proliferative DR. Diabetes duration and HbA1c were major risk factors.

Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study.

AIMS/HYPOTHESIS: Coronavirus disease-2019 (COVID-19) is a life-threatening infection caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus. Diabetes has rapidly emerged as a major comorbidity for COVID-19 severity. However, the phenotypic characteristics of diabetes in COVID-19 patients are unknown. METHODS: We conducted a nationwide multicentre observational study in people with diabetes hospitalised for COVID-19 in 53 French centres in the period 10-31 March 2020. The primary outcome combined tracheal intubation for mechanical ventilation and/or death within 7 days of admission. Age- and sex-adjusted multivariable logistic regressions were performed to assess the prognostic value of clinical and biological features with the endpoint. ORs are reported for a 1 SD increase after standardisation. RESULTS: The current analysis focused on 1317 participants: 64.9% men, mean age 69.8 ± 13.0 years, median BMI 28.4 (25th-75th percentile: 25.0-32.7) kg/m2; with a predominance of type 2 diabetes (88.5%). Microvascular and macrovascular diabetic complications were found in 46.8% and 40.8% of cases, respectively. The primary outcome was encountered in 29.0% (95% CI 26.6, 31.5) of participants, while 10.6% (9.0, 12.4) died and 18.0% (16.0, 20.2) were discharged on day 7. In univariate analysis, characteristics prior to admission significantly associated with the primary outcome were sex, BMI and previous treatment with renin-angiotensin-aldosterone system (RAAS) blockers, but not age, type of diabetes, HbA1c, diabetic complications or glucose-lowering therapies. In multivariable analyses with covariates prior to admission, only BMI remained positively associated with the primary outcome (OR 1.28 [1.10, 1.47]). On admission, dyspnoea (OR 2.10 [1.31, 3.35]), as well as lymphocyte count (OR 0.67 [0.50, 0.88]), C-reactive protein (OR 1.93 [1.43, 2.59]) and AST (OR 2.23 [1.70, 2.93]) levels were independent predictors of the primary outcome. Finally, age (OR 2.48 [1.74, 3.53]), treated obstructive sleep apnoea (OR 2.80 [1.46, 5.38]), and microvascular (OR 2.14 [1.16, 3.94]) and macrovascular complications (OR 2.54 [1.44, 4.50]) were independently associated with the risk of death on day 7. CONCLUSIONS/INTERPRETATIONS: In people with diabetes hospitalised for COVID-19, BMI, but not long-term glucose control, was positively and independently associated with tracheal intubation and/or death within 7 days. TRIAL REGISTRATION: clinicaltrials.gov NCT04324736.

Correction to: Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study.

The authors regret a mistake in Table 1.

Lipid environment induces ER stress, TXNIP expression and inflammation in immune cells of individuals with type 2 diabetes.

AIMS/HYPOTHESIS: Obesity and type 2 diabetes are concomitant with low-grade inflammation affecting insulin sensitivity and insulin secretion. Recently, the thioredoxin interacting protein (TXNIP) has been implicated in the activation process of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome. In this study, we aim to determine whether the expression of TXNIP is altered in the circulating immune cells of individuals with type 2 vs type 1 diabetes and whether this can be related to specific causes and consequences of inflammation. METHODS: The expression of TXNIP, inflammatory markers, markers of the unfolded protein response (UPR) to endoplasmic reticulum (ER) stress and enzymes involved in sphingolipid metabolism was quantified by quantitative reverse transcription real-time PCR (qRT-PCR) in peripheral blood mononuclear cells (PBMCs) of 13 non-diabetic individuals, 23 individuals with type 1 diabetes and 81 with type 2 diabetes. A lipidomic analysis on the plasma of 13 non-diabetic individuals, 35 individuals with type 1 diabetes and 94 with type 2 diabetes was performed. The effects of ER stress or of specific lipids on TXNIP and inflammatory marker expression were analysed in human monocyte-derived macrophages (HMDMs) and THP-1 cells. RESULTS: The expression of TXNIP and inflammatory and UPR markers was increased in the PBMCs of individuals with type 2 diabetes when compared with non-diabetic individuals or individuals with type 1 diabetes. TXNIP expression was significantly correlated with plasma fasting glucose, plasma triacylglycerol concentrations and specific UPR markers. Induction of ER stress in THP-1 cells or cultured HMDMs led to increased expression of UPR markers, TXNIP, NLRP3 and IL-1ß. Conversely, a chemical chaperone reduced the expression of UPR markers and TXNIP in PBMCs of individuals with type 2 diabetes. The lipidomic plasma analysis revealed an increased concentration of saturated dihydroceramide and sphingomyelin in individuals with type 2 diabetes when compared with non-diabetic individuals and individuals with type 1 diabetes. In addition, the expression of specific enzymes of sphingolipid metabolism, dihydroceramide desaturase 1 and sphingomyelin synthase 1, was increased in the PBMCs of individuals with type 2 diabetes. Palmitate or C2 ceramide induced ER stress in macrophages as well as increased expression of TXNIP, NLRP3 and IL-1ß. CONCLUSIONS/INTERPRETATION: In individuals with type 2 diabetes, circulating immune cells display an inflammatory phenotype that can be linked to ER stress and TXNIP expression. Immune cell ER stress can in turn be linked to the specific exogenous and endogenous lipid environment found in type 2 diabetes.

Occurrence of type 1 and type 2 diabetes in patients treated with immunotherapy (anti-PD-1 and/or anti-CTLA-4) for metastatic melanoma: a retrospective study.

Anti-PD-1 and anti-CTLA-4 antibodies cause immune-related side effects such as autoimmune type 1 diabetes (T1D). It has also been suggested that by increasing TNF-α, IL-2 and IFN-γ production, anti-PD-1 and/or anti-CTLA-4 treatment could affect pancreatic beta cell function and insulin sensitivity. This study was based on a retrospective observational analysis from 2 July 2014 to 27 June 2016, which evaluated the occurrence of T1D and changes in glycemia and C-reactive protein (CRP) plasma concentrations in patients undergoing anti-PD-1 and/or anti-CTLA-4 treatment for melanoma at the Saint Louis Hospital. All cases of T1D that developed during immunotherapy registered in the French Pharmacovigilance Database (FPVD) were also considered. Among the 132 patients included, 3 cases of T1D occurred. For the remaining subjects, blood glucose was not significantly affected by anti-PD-1 treatment, but CRP levels (mg/l) significantly increased during anti-PD-1 treatment (p = 0.017). However, 1 case of type 2 diabetes (T2D) occurred (associated with a longer therapy duration). Moreover, glycemia of patients pretreated (n = 44) or concomitantly treated (n = 8) with anti-CTLA-4 tended to increase during anti-PD-1 therapy (p = 0.068). From the FPVD, we obtained 14 cases of T1D that occurred during immunotherapy and were primarily characterized by the rapidity and severity of onset. In conclusion, in addition to inducing this rare immune-related diabetes condition, anti-PD-1 treatment appears to increase CRP levels, a potential inflammatory trigger of insulin resistance, but without any short-term impact on blood glucose level.

Non-severe hypoglycaemia is associated with weight gain in patients with type 1 diabetes: Results from the Diabetes Control and Complication Trial.

It is unclear whether the frequent non-severe episodes of hypoglycaemia observed during intensive glucose control in individuals with type 1 diabetes (T1D) are associated with subsequent weight gain. We analysed the association between non-severe hypoglycaemia and weight gain in 1441 Diabetes Control and Complication Trial (DCCT) participants. Non-severe hypoglycaemia was assessed by hypo-score (ie, number of blood glucose values <70 mg/dL divided by the total number of measurements during the DCCT quarterly visits). Significant associations were observed between the hypo-score and annual and total weight gain. The annual weight gain by hypo-score tertiles was 0.8 ± 1.2 (T1), 1.3 ± 1.5 (T2) and 1.4 ± 1.3 kg/y (T3), P < .001 for T2 and T3 vs T1, and for T3 vs T2. The odds ratio for a weight gain of 1.8 kg/y was 2.14 (95% CI, 1.56-2.93) for T2, and 2.53 (95%CI, 1.85-3.45) for T3 vs T1. These differences in weight gain and in risk of weight gain remained significant after adjustment for sex, age, duration of diabetes, HbA1c at baseline and treatment arms. In conclusion, our analysis shows a significant association between non-severe hypoglycaemia and weight gain in individuals with T1D from the DCCT.

Autoimmune diabetes induced by PD-1 inhibitor-retrospective analysis and pathogenesis: a case report and literature review.

Anti-PD-1 antibody treatment is approved in advanced melanoma and provides median overall survival over 24 months. The main treatment-related side effects are immune-related adverse events, which include rash, pruritus, vitiligo, thyroiditis, diarrhoea, hepatitis and pneumonitis. We report a case of autoimmune diabetes related to nivolumab treatment. A 73-year-old man was treated in second line with nivolumab at 3 mg/kg every two weeks for metastatic melanoma. At 6 weeks of treatment, he displayed diabetic ketoacidosis. Nivolumab was withheld 3.5 weeks and insulin therapy was initiated, enabling a normalization of glycaemia and the disappearance of symptoms. Laboratory investigations demonstrated the presence of islet cell autoantibodies, while C-peptide was undetectable. Retrospective explorations on serum banked at week 0 and 3 months before the start of nivolumab, already showed the presence of autoantibodies, but normal insulin, C-peptide secretion and glycaemia. Partial response was obtained at month 3, and nivolumab was then resumed at the same dose. The clinical context and biological investigations before, at and after nivolumab initiation suggest the autoimmune origin of this diabetes, most likely induced by anti-PD-1 antibody in a predisposed patient. The role of PD-1/PD-L1 binding is well known in the pathogenesis of type 1 diabetes. Therefore, this rare side effect can be expected in a context of anti-PD-1 treatment. Glycaemia should be monitored during PD-1/PD-L1 blockade. The presence of autoantibodies before treatment could identify individuals at risk of developing diabetes, but systematic titration may not be relevant considering the rarity of this side effect.

Death, end-stage renal disease and renal function decline in patients with diabetic nephropathy in French cohorts of type 1 and type 2 diabetes.

AIMS/HYPOTHESIS: Microvascular complications are a common feature of diabetes but additional research is needed regarding diabetic nephropathy endpoints in type 1 and type 2 diabetes. METHODS: We compared 277 type 1 diabetes patients with 942 type 2 diabetes patients, with clinical proteinuria and no endstage renal disease (ESRD) at baseline, prospectively followed for death, ESRD and decline in estimated glomerular filtration rate (eGFR, all available measures). RESULTS: The incidence rate of death was 67.0 (95% CI 59.2, 74.8) vs. 24.6 (95% CI, 19.0, 30.2) per 1,000 patient-years, in type 2 diabetes and type 1 diabetes, respectively. Unadjusted risk for death was greater for type 2 diabetes patients (HR 3.423; 95% CI, 2.501, 4.683; p<0.0001), but the difference did not persist after adjustment for age (HRage-adj 0.859; 95% CI 0.581, 1.269; p=0.445). The incidence rate of ESRD was 18.4 (95% CI 14.2, 22.5) vs. 47.1 (95%CI 38.4, 55.9) per 1,000 patient-years, in type 2 diabetes and type 1 diabetes, respectively. Unadjusted risk for ESRD was lower in type 2 diabetes (HR 0.399; 95% CI 0.287, 0.554; p<0.0001), but the difference did not persist after adjustment for sex, age and baseline serum creatinine (HRadj 0.989; 95% CI 0.597, 1.639; p=0.965). In a mixed linear model, eGFR decline was not significantly different in type 2 vs. type 1 diabetes (difference in slope −0.19 [0.28] ml min(−1) 1.73 m(−2) year(−1); p=0.512). CONCLUSIONS/INTERPRETATION: In diabetic nephropathy, once baseline risk factors were taken into account the risk for death, ESRD and renal function decline did not significantly differ between type 1 diabetes and type 2 diabetes.

Association of serum leptin and adiponectin with anthropomorphic indices of obesity, blood lipids and insulin resistance in a Sub-Saharan African population.

BACKGROUND: There is little data on the metabolic effects of adipokines in sub-Saharan African populations. This study aimed to explore the potential relationship of leptin and adiponectin, with obesity, plasma lipids and insulin resistance in a Cameroonian population. METHODS: We enrolled 167 men and 309 women aged ≥18 years from the general population in Cameroon. Data were collected on waist circumference (WC), body mass index (BMI), waist-to-hip ratio (WHR), body fat (BF%), fasting blood glucose, plasma lipids, adiponectin, leptin, insulin and homeostasis model for assessment of insulin resistance (HOMA-IR). Pearson's correlation and multiple stepwise linear regression analyses were used to determine correlates of leptin and adiponectin serum levels. RESULTS: The prevalence of obesity was higher in women compared to men (p < 0.0001), and Central obesity which is more prevalent particularly in women (WC = 42.4%, WHR = 42.3%), is almost for 90% comparable to %BF (42.7%). Adiponectin negatively with BMI (r = -0.294, p < 0.0001), WC (r = -0.294, p < 0.0001), %BF (r = -0.122, p = 0.028), WHR (r = -0.143, p = 0.009), triglycerides (r = -0.141, p = 0.011), HOMA-IR (r = -0.145, p = 0.027) and insulin (r = -0.130, p = 0.048). Leptin positively correlated with BMI (r = 0.628), WC (r = 0.530), BF% (r = 0.720), (all p < 0.0001); with DBP (r = 0.112, p = 0.043), total cholesterol (r = 0.324, p < 0.0001), LDL-cholesterol (r = 0.298, p < 0.0001), insulin (r = 0.320, p < 0.001 and HOMA-IR (r = 0.272, p < 0.0001). In multiple stepwise regression analysis, adiponectin was negatively associated with WC (ß = -0.38, p = 0.001) and BF% (ß = 0.33, p < 0.0001), while leptin was positively associated with BF% (ß = 0.60, p < 0.0001), total cholesterol (ß = 0.11, p = 0.02) and HOMA-IR (ß = 0.11, p = 0.02). When controlled for gender, HOMA-IR was found significantly associated to adiponectin (ß = 0.13, p = 0.046), but not BF%, while the association previously found between leptin and HOMA-IR disappeared; BMI and WC were significantly associated with leptin (ß = 0.18, p = 0.04 & ß = 0.19, p = 0.02 respectively). CONCLUSION: This study, which includes a population who was not receiving potentially confounding medications, confirms the associations previously observed of adiponectin with reduced adiposity especially central adiposity and improved insulin sensitivity. Confirmatory associations were also observed between leptin and obesity, blood lipids and insulin resistance for the first time in an African population. Gender was significant covariate interacting with insulin sensitivity/insulin resistance and obesity indexes associations in this population.