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.

Use of the SINBAD score as a predicting tool for major adverse foot events in patients with diabetic foot ulcer: A French multicentre study.

OBJECTIVE: To assess the relationship between the site, ischaemia, neuropathy, bacterial infection, area, depth (SINBAD) score and major adverse foot events in patients with diabetes and foot ulcers. METHODS: For this retrospective ancillary study, patients (n = 537) followed for a diabetic foot ulcer (DFU) in six French hospitals were included between 1 February 2019 and 17 March 2019, and between 1 February 2020 and 17 March 2020. The SINBAD score was assessed at inclusion. The frequency of a composite outcome consisting of eight major adverse foot events (MAFE) was assessed after 5-6 months of follow-up: hospitalisation for DFU, septic surgery, revascularisation, minor amputation, major amputation, death, secondary infection and ulcer recurrence. A logistical regression explored the link between the SINBAD score and MAFE and each of its component. RESULTS: A low SINBAD score (from 0 to 3) was observed in 61% of patients and a high (from 4 to 6) in 39%. MAFE occurred in, respectively, 24% and 28% of these patients. Multivariate analyses showed a significant relationship between the SINBAD score and MAFE, with the continuous SINBAD score: odds ratio (OR) 1.72 [95% CI (1.51-1.97)] or dichotomic SINBAD score (values: 0-3 and 4-6): OR 3.71 [95% CI (2.54-5.42)]. The SINBAD score (continuous or dichotomic) at inclusion was also significantly associated with six out of the eight components of the MAFE. CONCLUSIONS: The SINBAD score is a useful tool for predicting major adverse foot events.

HDL functionality in type 1 diabetes: enhancement of cholesterol efflux capacity in relationship with decreased HDL carbamylation after improvement of glycemic control.

BACKGROUND: Reduced cholesterol efflux capacity (CEC) of HDLs is likely to increase cardiovascular risk in type 1 diabetes (T1D). We aimed to assess whether improvement of glycemic control in T1D patients is associated with changes in CEC in relation with changes in carbamylation of HDLs. METHODS: In this open-label trial, 27 uncontrolled T1D patients were given a three-month standard medical intervention to improve glycemic control. HDL fraction was isolated from plasma, and CEC was measured on THP-1 macrophages. Carbamylation of HDLs was evaluated by an immunoassay. Control HDLs from healthy subjects were carbamylated in vitro with potassium cyanate. RESULTS: HbA1c decreased from 11.4% [10.2-12.9] (median [1st-3rd quartiles]) at baseline to 8.1% [6.6-9.0] after the three-month intervention (P < 0.00001). The CEC of HDLs increased after intervention in 19 (70%) patients (P = 0.038). At the same time, the carbamylation of HDLs decreased in 22 (82%) patients after intervention (P = 0.014). The increase in CEC significantly correlated with the decrease in carbamylated HDLs (r = -0.411, P = 0.034), even after adjustment for the change in HbA1c (ß = -0.527, P = 0.003). In vitro carbamylation of control HDLs decreased CEC by 13% (P = 0.041) and 23% (P = 0.021) using 1 and 10 mmol/L of potassium cyanate, respectively. CONCLUSIONS: The improvement of CEC in relation to a decrease in the carbamylation of HDLs may likely contribute to the beneficial cardiovascular effect of glycemic control in T1D patients. TRIAL REGISTRATION: NCT02816099 ClinicalTrials.gov.

Role of apolipoprotein C1 in lipoprotein metabolism, atherosclerosis and diabetes: a systematic review.

Apolipoprotein C1 (apoC1) is a small size apolipoprotein whose exact role is not totally clarified but which seems to modulate significantly the metabolism of lipoproteins. ApoC1 is involved in the metabolism of triglyceride-rich lipoproteins by inhibiting the binding of very low density lipoproteins (VLDL) to VLDL-receptor (VLDL-R), to low density lipoprotein receptor (LDL-R) and to LDL receptor related protein (LRP), by reducing the activity of lipoprotein lipase (LPL) and by stimulating VLDL production, all these effects leading to increase plasma triglycerides. ApoC1 takes also part in the metabolism of high density lipoproteins (HDL) by inhibiting Cholesterol Ester Transfer Protein (CETP). The functionality of apoC1 on CETP activity is impaired in diabetes that might account, at least in part, for the increased plasma CETP activity observed in patients with diabetes. Its different effects on lipoprotein metabolism with a possible role in the modulation of inflammation makes the net impact of apoC1 on cardiometabolic risk difficult to figure out and apoC1 might be considered as pro-atherogenic or anti-atherogenic depending on the overall metabolic context. Making the link between total plasma apoC1 levels and the risk of cardio-metabolic diseases is difficult due to the high exchangeability of this small protein whose biological effects might depend essentially on its association with VLDL or HDL. The role of apoC1 in humans is not entirely elucidated and further studies are needed to determine its precise role in lipid metabolism and its possible pleiotropic effects on inflammation and vascular wall biology. In this review, we will present data on apoC1 structure and distribution among lipoproteins, on the effects of apoC1 on VLDL metabolism and HDL metabolism and we will discuss the possible links between apoC1, atherosclerosis and diabetes.

Intact Fish Skin Graft vs. Standard of Care in Patients with Neuroischaemic Diabetic Foot Ulcers (KereFish Study): An International, Multicentre, Double-Blind, Randomised, Controlled Trial Study Design and Rationale.

BACKGROUND: Cell and/or tissue-based wound care products have slowly advanced in the treatment of non-healing ulcers, however, few studies have evaluated the effectiveness of these devices in the management of severe diabetic foot ulcers. METHOD: This study (KereFish) is part of a multi-national, multi-centre, randomised, controlled clinical investigation (Odin) with patients suffering from deep diabetic wounds, allowing peripheral artery disease as evaluated by an ankle brachial index equal or higher than 0.6. The study has parallel treatment groups: Group 1 treatment with Kerecis® Omega3 Wound™ versus Group 2 treatment with standard of care. The primary objective is to test the hypothesis that a larger number of severe diabetic ulcers and amputation wounds, including those with moderate arterial disease, will heal in 16 weeks when treated with Kerecis® Omega3 Wound™ than with standard of care. CONCLUSION: This study has received the ethics committee approval of each participating country. Inclusion of participants began in March 2020 and ended in July 2022. The first results will be presented in March 2023. The study is registered in ClinicalTrials.gov as Identifier: NCT04537520.

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.

Referral of patients with diabetic foot ulcers in four European countries: patient follow-up after first GP visit.

OBJECTIVE: This study aimed to analyse the characteristics of patients, including demographics, medical history and treatment, with a diabetic foot ulcer (DFU) during their first follow-up visit to a general practitioner (GP). METHODS: A two-part quantitative online questionnaire was distributed among GPs in France, UK, Germany and Spain. Part one entailed a survey of GPs' perceptions of referrals for DFU. Part two collected data on recently managed DFU cases. The percentage of responses was compared for each question and across the four countries for significant differences. RESULTS: In part one of the study, 600 questionnaires were collected (150 per country) and 1188 patients managed for a DFU were included in the second part. About 88% of patients had type 2 diabetes, with a significant proportion of suboptimal control (average HbA1c: 10.64mmol/l). A patient complaint led to diagnosis in 60% of the cases. Wounds were found to be more frequently located in the toes and midfoot, and were superficial (according to the Texas Wound Classification system) in 80% of the cases. More than two-thirds of patients developed small wounds (<5cm2); more than half of them had infected wounds. Approximately 50% of wounds were ischaemic, which triggered the onset of a DFU. Follow-up wound examinations before and after hospitalisation were performed by nurses, except in Germany where GPs undertook this role, including prescribing offloading devices and in the UK where follow-up was managed by podiatrists. Ischaemia, wound necrosis, suspected osteomyelitis and absence of wound healing were the primary reasons for hospital admission during the first month after diagnosis. CONCLUSION: Delay in specialised foot care is a recurring topic in the treatment of DFUs, even with different health-care structures across Europe. Knowledge and education on DFUs should be reinforced among GPs and nurses to establish a global DFU care network between primary and specialised care, avoid hospitalisation and adequately manage high-risk patients.

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.

Delayed referral of patients with diabetic foot ulcers across Europe: patterns between primary care and specialised units.

OBJECTIVE: Diabetic foot ulceration (DFU) has the potential to deteriorate rapidly without prompt assessment and treatment. The aim of this study was to assess the referral patterns for DFU, from primary care to specialised diabetes foot care units. METHOD: A two-part, quantitative, online questionnaire was administered to GPs across four countries in Europe: France, the UK, Germany and Spain. The first part entailed a survey of GPs' perceptions of referrals for DFU. The second part of the questionnaire collected data on recently managed DFU cases. RESULTS: There were 600 questionnaires collected in the first part of the study (150 per country), and 1188 patient cases of DFU management were included in the second part. Up to 95% of patients had type 2 diabetes. Patients' complaints led to diagnosis, on average, 60% of the time, and the diagnosis was an incidental finding during a consultation 13-28% of the time. On average, only 40% of GPs completely agreed that they have clearly identified DFU clinical practitioners working in a hospital facility. In 55-66% of cases, the duration of DFU was unknown or DFU diagnosis was delayed more than three weeks from the onset of the wound. On average, 48% of patients were referred after an unknown duration or more than one month from the onset of DFU. CONCLUSION: Despite differences in health-care structures across Europe, delays in referral to specialist foot care teams seems to be a common theme. There is an ongoing need to educate GPs, nurses and patients to be more aware of the risk of DFU, and the need for prompt referral to specialist diabetic foot teams.

Perception of diabetic foot ulcers among general practitioners in four European countries: knowledge, skills and urgency.

OBJECTIVE: Diabetic foot ulcers (DFU) have the potential to deteriorate rapidly, in the absence of prompt assessment and treatment. The aim of this study was to analyse the awareness and perception of DFU among general practitioners (GPs) from four European countries, and to find possible differences between these countries in terms of management. METHOD: A two-part, quantitative, online questionnaire was distributed to GPs across four countries in Europe-the UK, France, Germany and Spain. The first part entailed a survey on the perception and knowledge of the pathogenesis and management of DFU, among GPs. The second part of the questionnaire was used for the collection of data on recently-managed DFU cases. RESULTS: For the first part of the study, 600 questionnaires were collected (150 per country) and 1188 patient cases of DFU management were included in the second part. In France, only 49% of GPs mentioned neuropathy as the main causative process in DFU development. However, in Germany and the UK, 82% and 83% of GPs, respectively, considered neuropathy as an important causative factor. DFU care in Spain and the UK is thought to be organised by multidisciplinary teams (MDT) (83% and 84% of GPs, respectively, completely agreed with this statement). In France and Germany, GPs are responsible for follow-up and management. Only UK physicians have clearly identified specialised podiatrists to refer patients to, if needed. Approximately 29-40% of GPs in all countries did not feel they were sufficiently trained in the DFU treatment protocol. Almost 30% of GPs in France and Germany thought that DFU treatment was not well-established due to the absence of clinical guidelines and protocols. CONCLUSION: The intra-country and inter-country management of the complex aspects of DFU is quite heterogeneous. The cause of this finding is multifactorial. Although there are international guidelines, it would be beneficial to establish clear and specific competencies for the different health professionals involved in DFU management. As a minimum, intra-country heterogeneity should improve with their development.

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.