Lean individuals with NAFLD have more severe liver disease and poorer clinical outcomes (NASH-CO Study).

BACKGROUND AND AIMS: The severity of liver injury and clinical outcomes in lean individuals with NAFLD is a subject of debate and very few studies have been performed in the general population. The aim of this study was to compare subject characteristics and mortality between lean and nonlean NAFLD in a community setting. APPROACH AND RESULTS: The study population included 169,303 participants from the nationwide Constances cohort. Subjects with excessive alcohol consumption, viral hepatitis, or other liver diseases were excluded and 137,206 subjects were analyzed. The diagnosis of NAFLD and fibrosis was performed using the Fatty Liver Index and the Forns Index. The median follow-up was 3.58 years. The prevalence of NAFLD was 5.3% (95% CI: 5.2-5.4) in lean subjects, while 16.3% (95% CI: 15.7-16.8) of NAFLD subjects were lean. Despite their better metabolic profile, the prevalence of advanced fibrosis was significantly higher in lean than in nonlean NAFLD (3.7% vs. 1.7%, respectively, p < 0.01). Among NAFLD subjects and after adjustment for demographics, metabolic risk factors and lifestyle, lean status was associated with advanced fibrosis (OR=1.26, 95% CI: 1.20-1.65, p = 0.005), an increased risk of liver-related events (adjusted HR=5.84, 95% CI: 4.03-8.46), chronic kidney disease (adjusted HR=2.49, 95% CI: 1.49-4.16), and overall mortality (adjusted HR=3.01, 95% CI: 2.21-4.11). Liver-related events and overall mortality were related to the severity of fibrosis, both in lean and nonlean NAFLD subjects, whatever the usual risk factors. CONCLUSION: This study in a large community-based cohort confirms that NAFLD in lean subjects is more severe for fibrosis, the progression of liver disease, chronic kidney disease, and overall mortality.

Plasma ceramides are associated with MRI-based liver fat content but not with noninvasive scores of liver fibrosis in patients with type 2 diabetes.

BACKGROUND: There is growing evidence that ceramides play a significant role in the onset and progression of non-alcoholic fatty liver disease (NAFLD), a highly prevalent condition in patients with type 2 diabetes associated with hepatic and cardiovascular events. However, the relationship between plasma ceramide levels and NAFLD severity in type 2 diabetes remains unclear. The main purpose of the present study was to investigate whether circulating levels of ceramides in patients with type 2 diabetes are associated with liver steatosis assessed by the highly accurate magnetic resonance imaging proton density fat fraction (MRI-PDFF). The secondary objective was to assess the relationship between plasma ceramides and noninvasive scores of liver fibrosis. METHODS: In this cross-sectional single-center study, plasma concentrations of 7 ceramides were measured by liquid chromatography-mass spectrometry in 255 patients with type 2 diabetes (GEPSAD cohort). Liver fat content was assessed by MRI-PDFF, and noninvasive scores of liver fibrosis (i.e. Fibrosis-4 index, NAFLD Fibrosis Score, FibroTest® and Fibrotic NASH Index) were calculated. A validation cohort of 80 patients with type 2 diabetes was also studied (LIRA-NAFLD cohort). RESULTS: Liver steatosis, defined as a liver fat content > 5.56%, was found in 62.4 and 82.5% of individuals with type 2 diabetes in the GEPSAD and LIRA-NAFLD cohorts, respectively. In GEPSAD, MRI-PDFF-measured liver fat content was positively associated with plasma levels of total ceramides (r = 0.232, p = 0.0002), and 18:0, 20:0, 22:0 and 24:0 ceramides in univariate analysis (p ≤ 0.0003 for all). In multivariate analysis, liver fat content remained significantly associated with total ceramides (p = 0.001), 18:0 (p = 0.006), 22:0 (p = 0.0009) and 24:0 ceramides (p = 0.0001) in GEPSAD, independently of age, diabetes duration, body mass index and dyslipidemia. Overall, similar relationship between plasma ceramides and liver fat content was observed in the LIRA-NAFLD validation cohort. No significant association was found between plasma ceramides and noninvasive scores of fibrosis after adjustment for age in both cohorts. CONCLUSIONS: Plasma ceramide levels are associated with liver steatosis in patients with type 2 diabetes, independently of traditional risk factors for NAFLD. The independent association between plasma ceramides and liver steatosis adds new insights regarding the relationship between ceramides and NAFLD in type 2 diabetes.

Liraglutide reduces plasma dihydroceramide levels in patients with type 2 diabetes.

BACKGROUND: Emerging evidence supports that dihydroceramides (DhCer) and ceramides (Cer) contribute to the pathophysiology of insulin resistance and liver steatosis, and that their circulating concentrations are independently associated with cardiovascular outcomes. Circulating DhCer levels are increased in patients with type 2 diabetes (T2D). On the other hand, the GLP-1 receptor agonist liraglutide reduces major adverse cardiac events, insulin resistance and liver steatosis in T2D patients. The main purpose of the present study was therefore to investigate whether liraglutide decreases circulating levels of DhCer and Cer in T2D patients, which could be a mechanism involved in its cardiometabolic benefits. The secondary purpose was to assess the relationship between liraglutide-induced changes in DhCer/Cer levels and insulin resistance and liver steatosis. METHODS: Plasma concentrations of 11 DhCer and 15 Cer species were measured by a highly-sensitive mass spectrometry system in 35 controls and 86 T2D patients before and after 6 months of liraglutide (1.2 mg/day). Insulin resistance was estimated by the triglyceride-glucose (TyG) index. Liver fat content (LFC) was assessed in 53 patients by proton magnetic resonance spectroscopy. RESULTS: Plasma levels of total DhCer, 7 DhCer and 7 Cer species were increased in T2D patients compared to controls. Liraglutide decreased total DhCer by 15.1% (p = 0.005), affecting 16:0 (p = 0.037), 18:0 (p < 0.0001), 18:1 (p = 0.0005), 20:0 (p = 0.0003), 23:0 (p = 0.005) and 24:1 (p = 0.04) species. Total plasma Cer did not significantly change after liraglutide (p = 0.18), but 5 Cer species decreased significantly, i.e. 18:0 and 18:1 (both p < 0.0001), 19:0 and 24:1 (both p < 0.01) and 26:1 (p = 0.04). In multivariate analysis, the reduction in DhCer after liraglutide was independently associated with the reduction in LFC (p = 0.0005) and in TyG index (p = 0.05). CONCLUSIONS: Liraglutide reduces plasma levels of numerous DhCer and Cer species in T2D patients, which may contribute to the cardiovascular benefit observed in the LEADER trial. The independent association between the decrease in plasma DhCer level with the reduction in LFC and TyG index adds new insights regarding the relationship between DhCer, liver steatosis and insulin resistance. Trial registration ClinicalTrials.gov identifier: NCT02721888.

Inflammation and oxidative stress markers in type 2 diabetes patients with Advanced Carotid atherosclerosis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a major global health issue and a significant risk factor for atherosclerosis. Atherosclerosis in T2DM patients has been associated with inflammation, insulin resistance, hyperglycemia, dyslipidemia, and oxidative stress. Identifying molecular features of atherosclerotic plaques in T2DM patients could provide valuable insights into the pathogenesis of the disease. METHODS: The MASCADI (Arachidonic Acid Metabolism in Carotid Stenosis Plaque in Diabetic Patients) study aimed to investigate the increase of 2-arachidonoyl-lysophatidylcholine (2-AA-LPC) in carotid plaques from T2DM and control patients and to explore its association with plaque vulnerability as well as with blood and intra-plaque biomarkers altered during diabetes. RESULTS: In a population of elderly, polymedicated patients with advanced stage of atherosclerosis, we found that T2DM patients had higher systemic inflammation markers, such as high-sensitivity C-reactive protein (hsCRP) and IL-1ß, higher levels of oxysterols, increased triglyceride levels, and decreased HDL levels as compared to control patients. Furthermore, 2-AA-LPC was significantly enriched in plaques from diabetic patients, suggesting its potential role in diabetic atherosclerosis. Interestingly, 2-AA-LPC was not associated with systemic markers related to diabetes, such as hsCRP, triglycerides, or HDL cholesterol. However, it was significantly correlated with the levels of inflammatory markers within the plaques such as lysophospholipids and 25-hydroxycholesterol, strengthening the link between local inflammation, arachidonic acid metabolism and diabetes. CONCLUSION: Our study is in line with a key role for inflammation in the pathogenesis of diabetic atherosclerosis and highlights the involvement of 2-AA-LPC. Further research is needed to better understand the local processes involved in the alteration of plaque composition in T2DM and to identify potential therapeutic targets. TRIAL REGISTRATION: The MASCADI was registered on ClinicalTrials.gov (clinical registration number: NCT03202823).

The burden of NAFLD in type 2 diabetic subjects from the general population: A Nationwide population-based follow-up study (NASHCO).

BACKGROUND: The epidemiology and natural history of non-alcoholic fatty liver disease (NAFLD) in diabetes have been mainly investigated in the hospital setting. The goal of this study was to evaluate the characteristics of NAFLD and its impact on morbidity and mortality in type 2 diabetic subjects in a community setting. METHOD: This study included 199 341 participants in the nationwide Constances cohort. After patients with excessive alcohol consumption, viral hepatitis or other causes of liver disease were excluded, 164 285 were analysed and 8386 (5.3%) were considered to have type 2 diabetes. The non-invasive diagnosis of NAFLD and advanced fibrosis was made using a combination of the fatty liver index and Forns index. Median follow-up was 2.5 years. RESULTS: Diabetes increased the risk of NAFLD by sixfold (adjusted OR 6.05, 95% CI 5.68-6.45) and the risk of advanced fibrosis by 3.76-fold (aOR 3.76, 95% CI 2.87-4.91) in NAFLD subjects. After controlling for confounders, the presence of NAFLD in diabetic subjects was associated with an increased risk of severe liver-related events (aHR 2.53, 95% CI 1.36-4.69), cardiovascular disease (CVD, aHR 2.71, 95% CI 1.72-4.26) and overall mortality (aHR 2.91, 95% CI 1.53-5.53). The risk of hepatic and extrahepatic complications in diabetic subjects with NAFLD significantly increased with the severity of fibrosis (P < .05). CONCLUSION: This prospective, longitudinal study in a large community-based cohort provides real-world evidence of the risk for NAFLD and advanced fibrosis in diabetes, and its impact on liver disease progression, diabetes-related complications such as CVD, and overall mortality. These data could be used to estimate real clinical and economic burden of NAFLD in diabetic subjects.

Impact of the COVID-19 Epidemic on hospitalization for diabetic foot ulcers during lockdown: A French nationwide population-based study.

AIMS/HYPOTHESIS: The aim of this study was to examine the impact of the COVID-19 epidemic on the hospitalization rates for diabetic foot ulcer (DFU), osteomyelitis and lower limb revascularization procedure in people with DFU. METHODS: This nationwide retrospective cohort study included hospital data on all people hospitalized in France for diabetes in weeks 2-43 in 2020, including the COVID-19 lockdown period, compared to same period in 2019. RESULTS: The number of hospitalizations for DFU decreased significantly in weeks 12-19 (during the lockdown) (p < 10-4 ). Hospitalization for foot osteomyelitis also decreased significantly in weeks 12-19 (p < 10-4 ). The trend was the same for lower limb amputations and revascularizations associated with DFU or amputation. CONCLUSIONS/INTERPRETATION: The marked drop in hospitalization rates for DFU, osteomyelitis and lower limb revascularization procedures in people with DFU observed in France during the lockdown period suggests that COVID-19 was a barrier to DFU care, and may illustrate the combined deleterious effects of hospital overload and changes in health-related behaviour.

Frequent and severe hypoglycaemia detected with continuous glucose monitoring in older institutionalised patients with diabetes.

BACKGROUND: Little is known about the prevalence of hypoglycaemia in older people with diabetes. However, the HbA1c goal is ≥8% for institutionalised patients with treatments that can cause hypoglycaemia. PURPOSE: We aimed to assess the prevalence of hypoglycaemia with continuous glucose monitoring and to evaluate the link with HbA1C in older institutionalised patients with diabetes taking potentially hypoglycaemia-inducing drugs. DESIGN: Prospective, multicentre study carried out in six geriatric care centres in the Côte d'Or region of France between January 2019 and July 2020. SETTINGS, SUBJECTS AND METHODS: A FreeStyle Libre Pro® (FSLP) was worn for up to 14 days in blinded mode in 42 patients taking at least one potentially hypoglycaemia-inducing antidiabetic drug. RESULTS: Two hundred and forty-two hypoglycaemic events were detected in 79% (n = 33) of patients wearing the FSLP. One or more hypoglycaemic event was detected in 100% of patients with HbA1C < 7% and in 79% of patients with HbA1C ≥ 8% (P = 0.02). The time spent in hypoglycaemia was higher in patients with HbA1C < 7% than those with HbA1C ≥ 8% (P = 0.015). Time spent <54 mg/dl was detected in 45% of patients. CONCLUSIONS: We report a very high prevalence of hypoglycaemia, with a significant proportion of severe hypoglycaemia, in older institutionalised patients with diabetes taking potentially hypoglycaemia-inducing drugs. Having HbA1C < 7% exposes patients to a higher risk of hypoglycaemia, but this risk remains also high in patients with HbA1C ≥ 8%. In this population, continuous glucose monitoring could be considered an effective tool to detect hypoglycemia, which is associated with increased risk of cardiovascular events, falling, fractures, cognitive impairment and mortality.

Characteristics of new patient referrals to specialised diabetic foot units across Europe and factors influencing delays.

OBJECTIVE: Foot ulcers are a common complication of diabetes and are associated with an increase in lower limb amputation and death. Early referral to a specialised unit is recommended. The aim of this study was to assess the characteristics of new-patient referrals to specialised diabetes foot care units across Europe and to determine the factors involved in delayed referral. METHOD: In this prospective observational study, consecutive patients with a new foot ulcer presenting to nine diabetic foot centres in five European countries (France, Germany, Italy, Spain and the UK) were included. RESULTS: Some 25% of the 332 patients included had presented with a foot ulcer >3 months before referral to the participating foot clinic. Compared with patients referred earlier, patients with a long time to referral (>3 months) were older (p=0.006) and had a less severe wound according to Infectious Diseases Society of America (IDSA) classification (p=0.003) and University of Texas classification (grade D=infection + peripheral artery disease, p=0.004). CONCLUSION: The proportion of patients with a diabetic foot ulcer (DFU) referred to a specialised unit >3 months after the beginning of the ulcer remained high throughout Europe. Patients with severe DFU were, however, referred more quickly by front line health professionals. Primary care professionals need to be made aware of the importance of early referral to a specialised unit in order to improve the management of foot disease in patients with diabetes. DECLARATION OF INTEREST: The authors have no conflicts of interest to declare.

Association between hospital admission for ketoacidosis and subsequent suicide attempt in young adults with type 1 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to examine the associations between hospitalisation for diabetic ketoacidosis and subsequent hospitalisation for suicide attempt in young adults with type 1 diabetes. METHODS: This nationwide historical cohort study included hospital data on all young people hospitalised in France for type 1 diabetes in 2008. Epidemiological follow-up focused on hospitalisations (medical and psychiatric hospital data) from the index hospitalisation to 2017. Survival analyses were done using a Cox proportional hazards regression model to explore the association between hospitalisation for ketoacidosis and subsequent hospitalisation for a suicide attempt. RESULTS: In 2008, 16,431 people aged 18-35 years had a hospitalisation mentioning type 1 diabetes. Among them, 1539 (9.4%) had at least one hospitalisation for ketoacidosis between 2008 and 2010. At 9 years, 7.2% of the group hospitalised for ketoacidosis had been hospitalised for a suicide attempt vs only 2.5% in the group not hospitalised for ketoacidosis. The association between hospitalisation for ketoacidosis and suicide attempt decreased over time and was no longer significant after 5 years. CONCLUSIONS/INTERPRETATION: We found that young adults admitted to hospital for diabetic ketoacidosis have an increased risk of being admitted to hospital for a subsequent suicide attempt. The risk of a suicide attempt was the highest in the 12 months following the ketoacidosis episode. Our findings support the recommendation that screening for depression and suicide risk should be part of the routine clinical assessment of individuals with type 1 diabetes and ketoacidosis.

Are older patients with diabetes still being overtreated in French long-term care homes?

BACKGROUND: Diabetes management has not been evaluated in French nursing homes (NHs) for 10 years. OBJECTIVES: The present study aimed to compare the management of diabetes with guidelines in older patients living in NHs. DESIGN: Observational, retrospective and multicentre study carried out in 13 NH in the Cote d'Or region of France. SETTINGS AND SUBJECTS: Between January and June 2018, all NH residents older than 65 years and known to have diabetes (n = 148) were included. METHODS: Epidemiological, clinical and biological data and diabetes characteristics were collected from the medical records. RESULTS: The average glycated haemoglobin (HbA1C) was 7.2 ± 1.2%. In total, 51% of patients had HbA1C < 7% (n = 70), of which 39 took one or more antidiabetic drugs. In total, 28 of those patients (40%) were at risk of developing hypoglycaemia as a result of their treatment. In all, 44.6% of patients were treated with insulin. Glinides were the most commonly prescribed oral antidiabetic drug (OAD) (27%). Capillary blood glucose monitoring (CBGM) was not carried out daily for 75% of patients taking a potentially hypoglycaemia-inducing OAD. CONCLUSIONS: We found that glycaemic control was too tight in at least 36.5% of the total population and that 40% of patients with HbA1C < 7% were potentially overtreated. The use of dipeptidyl peptidase 4 (DPP-4) inhibitors was still insufficient, as was CBGM. Avoiding hypoglycaemia is one of the priorities in the management of older patients with diabetes. Therefore, NHs should focus on improving the use of glycaemic targets and antidiabetic drugs that do not induce hypoglycaemia, as well as better monitoring of capillary blood glucose.

Liraglutide Reduces Postprandial Hyperlipidemia by Increasing ApoB48 (Apolipoprotein B48) Catabolism and by Reducing ApoB48 Production in Patients With Type 2 Diabetes Mellitus.

Objective- Treatment with liraglutide, a GLP-1 (glucagon-like peptide-1) agonist, has been shown to reduce postprandial lipidemia, an important feature of diabetic dyslipidemia. However, the underlying mechanisms for this effect remain unknown. This prompted us to study the effect of liraglutide on the metabolism of ApoB48 (apolipoprotein B48). Approach and Results- We performed an in vivo kinetic study with stable isotopes (D8-valine) in the fed state in 10 patients with type 2 diabetes mellitus before treatment and 6 months after the initiation of treatment with liraglutide (1.2 mg/d). We also evaluated, in mice, the effect of a 1-week liraglutide treatment on postload triglycerides and analysed in vitro on jejunum, the direct effect of liraglutide on the expression of genes involved in the biosynthesis of chylomicron. In diabetic patients, liraglutide treatment induced a dramatic reduction of ApoB48 pool (65±38 versus 162±87 mg; P=0.005) because of a significant decrease in ApoB48 production rate (3.02±1.33 versus 6.14±4.27 mg kg-1 d-1; P=0.009) and a significant increase in ApoB48 fractional catabolic rate (5.12±1.35 versus 3.69±0.75 pool d-1; P=0.005). One-week treatment with liraglutide significantly reduced postload plasma triglycerides in mice and liraglutide, in vitro, reduced the expression of ApoB48, DGAT1 (diacylglycerol O-acyltransferase 1), and MTP (microsomal transfer protein) genes. Conclusions- We show that treatment with liraglutide induces a significant reduction of the ApoB48 pool because of both a reduction of ApoB48 production and an increase in ApoB48 catabolism. In vitro, liraglutide reduces the expression of genes involved in chylomicron synthesis. These effects might benefit cardiovascular health. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02721888.

Liver Fat Content in People with Pituitary Diseases: Influence of Serum IGF1 Levels.

Non-alcoholic fatty liver disease (NAFLD) is commonly associated with obesity, metabolic syndrome, and type 2 diabetes. NAFLD is also seen in patients with endocrinopathies. However, the relationship between endocrine diseases and the development of NAFLD is not well known. In this study, we set out to determine whether liver fat content (LFC) was associated with IGF1 levels in people with pituitary diseases (PD). Eighty-nine patients with pituitary diseases and 74 healthy controls were included in this study. LFC was measured using MRI. Hepatic steatosis was defined as LFC>5.5%. Patients with PD were older, and had a higher BMI than healthy controls. LFC was significantly higher in people with PD than in controls (6.5% vs. 3.2%; p<0.001). LFC was negatively associated with the IGF1 level. The prevalence of steatosis was higher in PD patients than in controls (36.3% vs. 14.8%; p=0.002). In multivariate analysis, which included patients and controls, the predictive variables for steatosis were age, BMI and IGF1 levels, whereas the presence of pituitary diseases and gender were not associated with steatosis. Our data showed that LFC was strongly associated with IGF1 levels. These results suggest that steatosis associated with PD is probably a consequence of a low IGF1 level in these patients.

Impairment of the Ability of HDL From Patients With Metabolic Syndrome but Without Diabetes Mellitus to Activate eNOS: Correction by S1P Enrichment.

OBJECTIVE: High-density lipoprotein (HDL) from nondiabetic patients with metabolic syndrome (MetS) displays abnormalities in their lipidome, such as triglyceride enrichment and sphingosine-1-phosphate depletion. We hypothesized that these abnormalities could impair the ability of HDL to stimulate endothelial nitric oxide synthase (eNOS). APPROACH AND RESULTS: Compared with HDL from control subjects, HDL from normoglycemic patients with MetS was 39% richer in triglycerides (P<0.01) and 15% poorer in sphingosine-1-phosphate (P<0.05; n=23 in each group). eNOS activity, assessed by the conversion of L-[3H]arginine to L-[3H]citrulline, was 69% lower in human umbilical vein endothelial cells incubated with HDL from MetS patients than in cells incubated with HDL from controls (P<0.0001). In addition, the activating phosphorylation of eNOS at serine (Ser) 1177 and of Akt (protein kinase B) at Ser473 was 37% (P<0.001) and 39% (P<0.05) lower, respectively, with HDL from MetS patients. Sphingosine-1-phosphate enrichment of HDL from MetS patients restored their ability to stimulate eNOS activity (P<0.05), in relation with a significant increase in eNOS phosphorylation at Ser1177 (P<0.05) and in Akt phosphorylation at Ser473 (P=0.05). By contrast, triglyceride enrichment of HDL from control subjects did not modify eNOS activity (P=0.90) and phosphorylation at Ser1177 (P=0.87). CONCLUSIONS: We provide evidence that the activation of eNOS by HDL is decreased in MetS patients before the appearance of diabetes mellitus and that sphingosine-1-phosphate depletion of HDL is the main factor responsible for this defect. This has important consequences on the impairment of HDL functionality and antiatherogenic properties in these patients.

Heparan sulfates and the decrease of N-glycans promote early adipogenic differentiation rather than myogenesis of murine myogenic progenitor cells.

In vitro, extracted muscle satellite cells, called myogenic progenitor cells, can differentiate either in myotubes or preadipocytes, depending on environmental factors and the medium. Transcriptomic analyses on glycosylation genes during satellite cells differentiation into myotubes showed that 31 genes present a significant variation of expression at the early stages of murine myogenic progenitor cells (MPC) differentiation. In the present study, we analyzed the expression of 383 glycosylation related genes during murine MPC differentiation into preadipocytes and compared the data to those previously obtained during their differentiation into myotubes. Fifty-six glycosylation related genes are specifically modified in their expression during early adipogenesis. The variations correspond mainly to: a decrease of N-glycans, and of alpha (2,3) and (2,6) linked sialic acids, and to a high level of heparan sulfates. A high amount of TGF-ß1 in extracellular media during early adipogenesis was also observed. It seems that the increases of heparan sulfates and TGF-ß1 favor pre-adipogenic differentition of MPC and possibly prevent their myogenic differentiation.

Insulin response dysregulation explains abnormal fat storage and increased risk of diabetes mellitus type 2 in Cohen Syndrome.

Cohen Syndrome (CS) is a rare autosomal recessive disorder, with defective glycosylation secondary to mutations in the VPS13B gene, which encodes a protein of the Golgi apparatus. Besides congenital neutropenia, retinopathy and intellectual deficiency, CS patients are faced with truncal obesity. Metabolism investigations showed abnormal glucose tolerance tests and low HDL values in some patients, and these could be risk factors for the development of diabetes mellitus and/or cardiovascular complications. To understand the mechanisms involved in CS fat storage, we used two models of adipogenesis differentiation: (i) SGBS pre-adipocytes with VPS13B invalidation thanks to siRNA delivery and (ii) CS primary fibroblasts. In both models, VPS13B invalidation led to accelerated differentiation into fat cells, which was confirmed by the earlier and increased expression of specific adipogenic genes, consequent to the increased response of cells to insulin stimulation. At the end of the differentiation protocol, these fat cells exhibited decreased AKT2 phosphorylation after insulin stimulation, which suggests insulin resistance. This study, in association with the in-depth analysis of the metabolic status of the patients, thus allowed us to recommend appropriate nutritional education to prevent the occurrence of diabetes mellitus and to put forward recommendations for the follow-up of CS patients, in particular with regard to the development of metabolic syndrome. We also suggest replacing the term obesity by abnormal fat distribution in CS, which should reduce the number of inappropriate diagnoses in patients who are referred only on the basis of intellectual deficiency associated with obesity.

Glycaemic control influences the relationship between plasma PCSK9 and LDL cholesterol in type 1 diabetes.

Pro-protein convertase subtilisin/kexin type 9 (PCSK9) is a critical regulator of LDL cholesterol metabolism. Little is known, however, about the regulation of PCSK9 in patients with type 1 diabetes (T1D). In the present study, we aimed to determine the relationship between circulating PCSK9 and metabolic variables in T1D. Plasma PCSK9 levels were measured in 195 people with T1D (mean age 38.8 years, mean diabetes duration 17.2 years, mean glycated haemoglobin [HbA1c] 8.3%), who were free of any lipid-lowering agent. Plasma PCSK9 was positively correlated with LDL cholesterol (P = .0007), triglycerides (P = .004), apolipoprotein B (P = .005), HbA1c (P = .003), systolic (P = .003) and diastolic (P = .001) blood pressure and body mass index (0.02). In multivariate analysis, PCSK9 concentration was independently associated with HbA1c (P = .02) and LDL cholesterol (P = .03). After classifying patients according to HbA1c tertile, the correlation between PCSK9 and LDL cholesterol was only observed in the highest tertile (P = .0006; Rho = 0.43), whereas no correlation was found in the lowest and intermediate tertiles. This study suggests that good glycaemic control abolishes the positive relationship between PCSK9 and LDL cholesterol in patients with T1D; however, the underlying molecular mechanisms remain to be established.

PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy.

Short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay (SHORT) syndrome is a developmental disorder with an unknown genetic cause and hallmarks that include insulin resistance and lack of subcutaneous fat. We ascertained two unrelated individuals with SHORT syndrome, hypothesized that the observed phenotype was most likely due to de novo mutations in the same gene, and performed whole-exome sequencing in the two probands and their unaffected parents. We then confirmed our initial observations in four other subjects with SHORT syndrome from three families, as well as 14 unrelated subjects presenting with syndromic insulin resistance and/or generalized lipoatrophy associated with dysmorphic features and growth retardation. Overall, we identified in nine affected individuals from eight families de novo or inherited PIK3R1 mutations, including a mutational hotspot (c.1945C>T [p.Arg649Trp]) present in four families. PIK3R1 encodes the p85α, p55α, and p50α regulatory subunits of class IA phosphatidylinositol 3 kinases (PI3Ks), which are known to play a key role in insulin signaling. Functional data from fibroblasts derived from individuals with PIK3R1 mutations showed severe insulin resistance for both proximal and distal PI3K-dependent signaling. Our findings extend the genetic causes of severe insulin-resistance syndromes and provide important information with respect to the function of PIK3R1 in normal development and its role in human diseases, including growth delay, Rieger anomaly and other ocular affections, insulin resistance, diabetes, paucity of fat, and ovarian cysts.

Early cardiovascular events in women with a history of gestational diabetes mellitus.

BACKGROUND: The effect of gestational diabetes mellitus (GDM) on cardiovascular diseases (CVD) is not assessed within the first 10 years postpartum, regardless of subsequent diabetes. The aim of this study was to determine the risk of CVD events related to GDM within 7 years of postpartum. METHODS: This nationwide population-based study of deliveries in 2007 and 2008 with a follow-up of 7 years was based on data from the French medico-administrative database. Two groups were formed: women with a history of GDM and women without GDM or previous diabetes. CVD included angina pectoris, myocardial infarction, stroke, heart bypass surgery, coronary angioplasty, carotid endarterectomy and fibrinolysis. Hypertensive disease was assessed separately. Determinants studied included age, obesity, subsequent diabetes mellitus and hypertensive diseases during pregnancy. Adjusted odds ratios for outcomes were calculated using multiple logistic regressions. RESULTS: The hospital database recorded 1,518,990 deliveries in 2007 and 2008. Among these, 62,958 women had a history of GDM. After adjusting for age, DM, obesity and hypertensive disorders in pregnancy, GDM was significantly associated with a higher risk of CVD (adjusted Odds Ratio aOR = 1.25 [1.09-1.43]). Considering each variable in a separate model, GDM was associated with angina pectoris (aOR = 1.68 [1.29-2.20]), myocardial infarction (aOR = 1.92 [1.36-2.71]) and hypertension (aOR = 2.72 [2.58-2.88]) but not with stroke. CONCLUSIONS: A history of GDM was identified as a risk factor of CVD, especially coronary vascular diseases, within the 7 years postpartum. A lifestyle changes from postpartum onwards can be recommended and supported.

Associations between Thyroid Stimulating Hormone Levels and Both Severity and Early Outcome of Patients with Ischemic Stroke.

We aimed to investigate associations between serum thyroid stimulating hormone (TSH) levels and both severity and outcome after ischemic stroke (IS). A total of 731 patients consecutive IS patients were enrolled (mean age 69.4 ± 15.4, 61.6% men), and serum TSH levels were measured at admission and analyzed according to the tertiles of their distribution (<0.822 vs. 0.822-1.6 vs. >1.6 mUI/l). Associations between TSH and both severity at admission (National Institutes of Health Stroke Scale (NIHSS) scores <5 vs. ≥5) and functional outcome at discharge assessed by the modified Rankin Scale were analyzed using logistic regression and ordinal logistic regression models, respectively. High TSH levels were independently associated with both a decreased risk of NIHSS score ≥5 at admission (prevalence proportion ratio = 0.62; 95% CI 0.41-0.94, p = 0.024 for tertile 3 vs. tertile 1). In addition, patients with high TSH levels had a better functional outcome at discharge (OR 0.43; 95% CI 0.30-0.60, p < 0.001 for tertile 2 vs. tertile 1; OR 0.39; 95% CI 0.27-0.56, p < 0.001 for tertile 3 vs. tertile 1). The mechanisms underlying these associations and their potential exploitation in terms of therapeutic strategies need to be explored.