Plasma 16:0 ceramide as a marker of cardiovascular risk estimated by carotid intima-media thickness in people with type 2 diabetes.

AIM: New tools are required to better assess cardiovascular risk in individuals with type 2 diabetes mellitus (T2DM). Plasma ceramides emerge as promising candidates, given their substantial influence on the pathogenesis of both T2DM and atherosclerosis. The current study aimed to investigate whether plasma ceramides in patients with T2DM are a predictive factor for carotid intima-media thickness (CIMT), a well-established noninvasive marker for atherosclerosis that predicts adverse cardiovascular outcomes. METHODS: A lipidomic analysis was carried out on the circulating ceramides of a large cohort consisting of 246 patients with T2DM who underwent a high-resolution real-time B ultrasonography to measure CIMT. RESULTS: Both plasma 16:0 ceramide and the 16:0/24:0 ceramide ratio were positively associated with CIMT, even after adjustment for traditional cardiovascular risk factors [standardized ß ± standard error: 0.168 ± 0.072 (P = 0.020) and 0.180 ± 0.068 (P = 0.009), respectively]. Similar independent associations were found with respect to the prediction of CIMT ≥ 0.80 mm [ß = 8.07 ± 3.90 (P = 0.038) and 16.5 ± 7.0 (P = 0.019), respectively]. The goodness-of-fit for multivariate models in predicting CIMT was 5.7 and 7.6 times higher when plasma 16:0 ceramide or the 16:0/24:0 ceramide ratio were included in combination with traditional cardiovascular risk factors (P = 0.020 and 0.015, respectively). This reached a 3.1 and 10.0-fold increase regarding the ability to predict CIMT ≥ 0.80 mm (P = 0.039 and 0.008, respectively). CONCLUSIONS: Our findings suggest that 16:0 ceramide and the 16:0/24:0 ceramide ratio may serve as plasma biomarkers to improve cardiovascular risk assessment in individuals with T2DM.

No effect of liraglutide on high density lipoprotein apolipoprotein AI kinetics in patients with type 2 diabetes.

AIM: The catabolism of high density lipoprotein (HDL) apolipoprotein AI (apoAI) is accelerated in patients with type 2 diabetes (T2D), related to hypertriglyceridemia, insulin resistance and low plasma adiponectin levels. Since liraglutide is likely to partly correct these abnormalities, we hypothesized that it might have a beneficial effect on HDL apoAI kinetics in patients with T2D. METHODS: An in vivo kinetic study of HDL apoAI was performed in 10 patients with T2D before and after 6 months of treatment with 1.2 mg/day of liraglutide, using a bolus of l-[1-13C]leucine followed by a 16-hour constant infusion. RESULTS: Liraglutide reduced BMI (34.9 ± 4.7 vs 36.6 ± 4.9 kg/m2, P = 0.012), HbA1c (7.1 ± 1.1 vs 9.6 ± 2.6%, P = 0.003), HOMA-IR (5.5 ± 1.9 vs 11.6 ± 11.2, P = 0.003), fasting triglycerides (1.76 ± 0.37 vs 2.48 ± 0.69 mmol/l, P < 0.001) and triglycerides during kinetics (2.34 ± 0.81 vs 2.66 ± 0.65 mmol/l, P = 0.053). Plasma HDL cholesterol and adiponectin concentrations were unchanged (respectively 0.97 ± 0.26 vs 0.97 ± 0.19 mmol/l, P = 1; 3169 ± 1561 vs 2618 ± 1651 µg/l, P = 0.160), similar to triglyceride content in HDL (5.13 ± 1.73 vs 5.39 ± 1.07%, P = 0.386). Liraglutide modified neither HDL apoAI fractional catabolic rate (0.35 ± 0.11 vs 0.38 ± 0.11 pool/day, P = 0.375), nor its production rate (0.44 ± 0.13 vs 0.49 ± 0.15 g/l/day, P = 0.375), nor its plasma concentration (1.26 ± 0.19 vs 1.29 ± 0.14 g/l, P = 0.386). CONCLUSION: Six months of treatment with 1.2 mg/day of liraglutide had no effect on the kinetics of HDL apoAI in patients with T2D. The lack of decrease in triglyceride content in HDL related to an only moderate decrease in triglyceridemia, probably greatly explains these results. Insufficient improvement of insulin sensitivity and adiponectinemia may also be implied.

Development and Implementation of Workshops to Optimize the Delivery of Vaccination Services in Community Pharmacies: Thinking beyond COVID-19.

Vaccines are widely recognized as the most economically efficient strategy to combat infectious diseases. Community pharmacists, being highly accessible healthcare professionals, have the potential to significantly contribute to the promotion and facilitation of vaccination uptake. In Canada, the jurisdiction of healthcare falls under provincial legislation, leading to variations in the extent of pharmacist practice throughout the country. While some pharmacists in Canada already functioned as immunizers, Québec pharmacists gained the authority to prescribe and administer vaccines in March 2020 amidst the COVID-19 pandemic. Our workshop aimed to equip pharmacists in Québec with the necessary guidance to optimize vaccinations, emphasizing the importance of maintaining and expanding immunization services beyond influenza and COVID-19 vaccines in the future. During the workshop, pharmacists had the opportunity to exchange valuable insights and best practices regarding workflow optimization, identifying areas for improvement in competency, effectively reaching vulnerable population groups, and integrating allied team members into their practice. Participants were also asked to develop a plan of action to help implement practice change beyond the workshop. Interactive workshops centered around discussions like these serve as catalysts for advancing the pharmacy profession, uniting professionals with a collective aim of enhancing patient care.

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.

Glycemic control in people with diabetes treated with cancer chemotherapy: contribution of continuous glucose monitoring.

AIMS: The aim of our study was to assess, with Continuous Glucose Monitoring (CGM), exhaustive information on the glucose profile in people with diabetes starting chemotherapy. We also evaluated the adaptation of glucose-lowering drugs following analysis of CGM recordings. METHODS: Eighty-five people with diabetes starting chemotherapy were included in the ONCODIAB study. A CGM was worn for up to fourteen days in blinded mode before and after the diabetologist's intervention to evaluate the impact of modifying the glucose-lowering drugs. RESULTS: Time spent in range was 67.2 ± 24.2%. Time below the target glucose range (TBR) (< 70 mg/dl) was 8.9% in all the study population. TBR was significantly higher in patients treated with at least one drug due to the risk of hypoglycemia compared to the others (11.5% vs. 4.4%, p = 0.009). Sixty-five patients had available sensor data for the two recordings. Forty-one patients (51.9%) saw a decrease in their antidiabetic treatment after the diabetologist's intervention guided by the first CGM recording. We observed a significant reduction in the time spent below the target glucose range (70-55 mg/dl) between the two CGM recordings (10.3 ± 14.6% vs. 6.3 ± 9.4%, p = 0.016 and 3.8 ± 8.4% vs. 1.2 ± 2.9%, p = 0.012, respectively). CONCLUSIONS: CGM use in blinded mode could be an interesting tool to reduce the risk of hypoglycemia in people with diabetes starting chemotherapy. Our findings fully support the recommendation that assessing hypoglycemia risk should be mandatory in patients with diabetes before starting chemotherapy.

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.

Normal HDL Cholesterol Efflux and Anti-Inflammatory Capacities in Type 2 Diabetes Despite Lipidomic Abnormalities.

OBJECTIVE: To assess whether, in type 2 diabetes (T2D) patients, lipidomic abnormalities in high-density lipoprotein (HDL) are associated with impaired cholesterol efflux capacity and anti-inflammatory effect, 2 pro-atherogenic abnormalities. DESIGN AND METHODS: This is a secondary analysis of the Lira-NAFLD study, including 20 T2D patients at T0 and 25 control subjects. Using liquid chromatography/tandem mass spectrometry, we quantified 110 species of the main HDL phospholipids and sphingolipids. Cholesterol efflux capacity was measured on THP-1 macrophages. The anti-inflammatory effect of HDL was measured as their ability to inhibit the tumor necrosis factor α (TNFα)-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) on human vascular endothelial cells (HUVECs). RESULTS: The cholesterol-to-triglyceride ratio was decreased in HDL from T2D patients compared with controls (-46%, P = 0.00008). As expressed relative to apolipoprotein AI, the amounts of phosphatidylcholines, sphingomyelins, and sphingosine-1-phosphate were similar in HDL from T2D patients and controls. Phosphatidylethanolamine-based plasmalogens and ceramides (Cer) were, respectively, 27% (P = 0.038) and 24% (P = 0.053) lower in HDL from T2D patients than in HDL from controls, whereas phosphatidylethanolamines were 41% higher (P = 0.026). Cholesterol efflux capacity of apoB-depleted plasma was similar in T2D patients and controls (36.2 ±â€…4.3 vs 35.5 ±â€…2.8%, P = 0.59). The ability of HDL to inhibit the TNFα-induced expression of both VCAM-1 and ICAM-1 at the surface of HUVECs was similar in T2D patients and controls (-70.6 ±â€…16.5 vs -63.5 ±â€…18.7%, P = 0.14; and -62.1 ±â€…13.2 vs -54.7 ±â€…17.7%, P = 0.16, respectively). CONCLUSION: Despite lipidomic abnormalities, the cholesterol efflux and anti-inflammatory capacities of HDL are preserved in T2D patients.

Liraglutide reduces plasma PCSK9 in patients with type 2 diabetes not treated with statins.

AIM: Dyslipidaemia in type 2 diabetes mellitus (T2DM), which increases cardiovascular risk, includes abnormal metabolism of low-density lipoproteins (LDL). Our group has recently shown that liraglutide increases LDL catabolism in patients with T2DM and that it reduces the expression of PCSK9 (a major inhibitor of LDL-receptor expression) in vitro and in mice. This prompted us to study the effect of liraglutide on plasma PCSK9 level in patients with T2DM. METHODS: We studied prospectively 82 patients with T2DM (51 without statins, 31 with statins). Plasma PCSK9 and plasma lipids were measured before and six months after the initiation of a treatment with liraglutide at a dose of 1.2 mg/day. RESULTS: Plasma PCSK9 was significantly reduced by liraglutide treatment (214.9 ± 56.4 vs 244.5 ± 99.2 ng/ml, P = 0.024) in patients not on statins, but not in patients treated with statins (301.1 ± 91.5 vs 281.2 ± 96.9 ng/ml, P = 0.41). In patients not on statins, a very significant 17% decrease in plasma PCSK9 was observed in patients with baseline haemoglobin A1c (HbA1c) < 10% (n = 33; mean = -45.0 ng/ml, P = 0.013), when it was not observed in patients with baseline HbA1c ≥ 10% (n = 18; mean = +5.2 ng/ml, P = 0.75). In multivariate analysis, baseline HbA1c was an independent factor associated with plasma PCSK9 reduction, in patients not on statins. CONCLUSION: Treatment with liraglutide induces a significant reduction of plasma PCSK9 in patients with T2DM not on statins. This is in line with the acceleration of LDL catabolism that has been observed with liraglutide. However, this decrease in plasma PCSK9 is significantly influenced by glycaemic control and is not observed in patients with poorly controlled T2DM.

Fewer Type A personality traits in type 2 diabetes patients with diabetic foot ulcer.

AIM: Type A personality-characterized by time urgency, strong drive, and a need for achievement and competitiveness-has been shown to be associated with reduced mortality in patients with diabetes. However, it is not known whether a Type A personality might protect against diabetic foot ulcer (DFU). This prompted our present analysis of the association between Type A personality and DFU. METHODS: The Bortner Scale questionnaire was used to assess Type A personality in 386 patients with type 2 diabetes (T2D), including 104 patients also presenting with, and 282 presenting without, DFU. Additional questionnaires were used to assess perceived stress and depression. RESULTS: Type A Bortner scores were significantly lower in T2D patients with vs without DFU (166.64 ± 38.76 vs 178.79 ± 36.61, respectively; P = 0.005). In patients with DFU, the prevalence of Type A personality traits was significantly lower than in those without DFU (48% vs 64.5%, respectively; P = 0.005) whereas, in contrast, Type B personality traits (the opposite of Type A) were more prevalent (52% vs 35.5%, respectively; P = 0.005). On multivariate analysis, Type A Bortner scores were negatively associated with DFU (P = 0.008) independently of age, gender, BMI, depression scores or perceived stress. CONCLUSION: The Type A personality, characterized by competitiveness and a need for achievement, is significantly less frequently seen in T2D patients with DFU. On the other hand, the Type B personality is much more prevalent in such patients. It may be that the Type B personality, which is characterized by fewer problem-focused coping strategies and a decreased adherence to care, might favour the development of DFU.

Successful Control of Hypoglycemia with Pasireotide LAR in a Patient with Inappropriate Insulin Secretion.

INTRODUCTION: Inappropriate insulin secretion could be due to several diseases. Nesidioblastosis is characterized by diffuse hyperplasia of pancreatic beta cells, causing organic hypoglycemia. No pancreatic lesions are found on the imaging of patients with this condition. Diazoxide is used as a first-line treatment but can be poorly tolerated because of its side effects, and therapeutic failure is possible. Somatostatin analogues have limited efficacy because of their poor affinity to somatostatin (SST) receptors. Pasireotide is a somatostatin analogue with a much higher affinity to SST receptors, especially SST5, and it could thus be more efficient for treating nesidioblastosis-related hypoglycemia. OBSERVATION: A 56 years-old diabetic woman had symptoms of hypoglycemia, persistent after treatment's withdrawal. A fasting test authentify an organic hypoglycemia, at 34mg/dL, a plasma insulin level at 6mUI/L above the 5 mU/L threshold, a C-peptide level at 1.9 ng/mL above the threshold of 0.6, and an insulin/C-peptide ratio 0.066, below the threshold of 1. No lesions were found on CT-scan or endoscopic ultrasound. Somatostatin receptor scintigraphy was also negative. Diazoxide and octreotide failed to improve the recurrence of hypoglycemia episodes. With pasireotide LAR, hypoglycemia disappeared and glycemia increased. Hyperglycemia was controlled with sitagliptin. The patient has now been treated with pasireotide LAR for two years, with no more episode of hypoglycemia until now. DISCUSSION: We present the first case of nesidioblastosis treatment with pasireotide LAR, with success. Patients diagnosed with nesidioblastosis and diazoxide-resistant hypoglycemia, or who experience difficulties with other treatments, could use pasireotide LAR in conjunction with glycemia monitoring, particularly if they are diabetic.

Increased body fat mass reduces the association between fructosamine and glycated hemoglobin in obese type 2 diabetes patients.

Obesity is increasing in patients with type 2 diabetes. A possible reduced association between fructosamine and glycated hemoglobin (HbA1c) in obese individuals has been previously discussed, but this has never been specifically evaluated in type 2 diabetes, and the potential influence of body fat mass and fat distribution has never been studied. We studied 112 type 2 diabetes patients with assessment of fat mass, liver fat and fat distribution. Patients with body mass index (BMI) above the median (34.9 kg/m2 ), versus BMI below the median, had a correlation coefficient between fructosamine and HbA1c significantly reduced (r = 0.358 vs r = 0.765). In the whole population, fructosamine was correlated negatively with BMI and fat mass. In multivariate analysis, fructosamine was associated with HbA1c (positively) and fat mass (negatively), but not with BMI, liver fat or fat distribution. The association between fructosamine and HbA1c is significantly reduced in the most obese type 2 diabetes patients, and this is mostly driven by increased fat mass.

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.

T2-weighted MRI signal predicts hormone and tumor responses to somatostatin analogs in acromegaly.

GH-secreting pituitary adenomas can be hypo-, iso- or hyper-intense on T2-weighted MRI sequences. We conducted the current multicenter study in a large population of patients with acromegaly to analyze the relationship between T2-weighted signal intensity on diagnostic MRI and hormonal and tumoral responses to somatostatin analogs (SSA) as primary monotherapy. Acromegaly patients receiving primary SSA for at least 3 months were included in the study. Hormonal, clinical and general MRI assessments were performed and assessed centrally. We included 120 patients with acromegaly. At diagnosis, 84, 17 and 19 tumors were T2-hypo-, iso- and hyper-intense, respectively. SSA treatment duration, cumulative and mean monthly doses were similar in the three groups. Patients with T2-hypo-intense adenomas had median SSA-induced decreases in GH and IGF-1 of 88% and 59% respectively, which were significantly greater than the decreases observed in the T2-iso- and hyper-intense groups (P < 0.001). Tumor shrinkage on SSA was also significantly greater in the T2-hypo-intense group (38%) compared with the T2-iso- and hyper-intense groups (8% and 3%, respectively; P < 0.0001). The response to SSA correlated with the calculated T2 intensity: the lower the T2-weighted intensity, the greater the decrease in random GH (P < 0.0001, r = 0.22), IGF-1 (P < 0.0001, r = 0.14) and adenoma volume (P < 0.0001, r = 0.33). The T2-weighted signal intensity of GH-secreting adenomas at diagnosis correlates with hormone reduction and tumor shrinkage in response to primary SSA treatment in acromegaly. This study supports its use as a generally available predictive tool at diagnosis that could help to guide subsequent treatment choices in acromegaly.

Monsters and the case of L. Joseph: André Feil's thesis on the origin of the Klippel-Feil syndrome and a social transformation of medicine.

André Feil (1884-1955) was a French physician best recognized for his description, coauthored with Maurice Klippel, of patients with congenital fusion of cervical vertebrae, a condition currently known as Klippel-Feil syndrome. However, little is known about his background aside from the fact that he was a student of Klippel and a physician who took a keen interest in describing congenital anomalies. Despite the relative lack of information on Feil, his contributions to the fields of spinal disease and teratology extended far beyond science to play an integral role in changing the misguided perception shrouding patients with disfigurements, defects, deformities, and so-called monstrous births. In particular, Feil's 1919 medical school thesis on cervical abnormalities was a critical publication in defying long-held theory and opinion that human "monstrosities," anomalies, developmental abnormalities, and altered congenital physicality were a consequence of sinful behavior or a reversion to a primitive state. Indeed, his thesis on a spinal deformity centering on his patient, L. Joseph, was at the vanguard for a new view of a patient as nothing less than fully human, no matter his or her physicality or appearance.