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Smoking increases insulin resistance via multiple mechanisms but is a poorly understood risk factor for onset of type-2 diabetes. It is also associated with impaired beta-cell function in humans, but again the mechanisms are poorly understood. Mechanistic studies of the impact of smoking on carbohydrate metabolism mainly evaluated nicotine as the causal agent, and more rarely other tobacco constituents, making it impossible to conclude that the risk of diabetes is linked to the effects of nicotine alone. Active smoking also has negative impact on glycemic control in both type-1 and type-2 diabetic patients. It increases the risk of all-cause mortality and worsens the chronic complications of diabetes. Impact on microangiopathic complications in type-2 diabetic patients, however, is more controversial. Data on pharmacological and behavioral strategies for smoking cessation used in the general population are more sparse in diabetic patients, despite opportunities with recent therapeutic trials involving varenicline and GLP-1 analogues. It is essential for diabetic patients to stop smoking, and diabetologists must get involved in smoking cessation as they have done for many years in therapeutic education, which can easily include measures to help patients stop smoking., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: Pathogenic variants in PLIN1 -encoding PLIN1 (perilipin-1) are responsible for an autosomal dominant form of familial partial lipodystrophy (FPL) associated with severe insulin resistance, hepatic steatosis, and important hypertriglyceridemia. This study aims to decipher the mechanisms of hypertriglyceridemia associated with PLIN1 -related FPL., Methods: We performed an in vivo lipoprotein kinetic study in 6 affected patients compared with 13 healthy controls and 8 patients with type 2 diabetes. Glucose and lipid parameters, including plasma LPL (lipoprotein lipase) mass, were measured. LPL mRNA and protein expression were evaluated in abdominal subcutaneous adipose tissue from patients with 5 PLIN1 -mutated FPL and 3 controls., Results: Patients with PLIN1 -mutated FPL presented with decreased fat mass, insulin resistance, and diabetes (glycated hemoglobin A1c, 6.68±0.70% versus 7.48±1.63% in patients with type 2 diabetes; mean±SD; P =0.27). Their plasma triglycerides were higher (5.96±3.08 mmol/L) than in controls (0.76±0.27 mmol/L; P <0.0001) and patients with type 2 diabetes (2.94±1.46 mmol/L, P =0.006). Compared with controls, patients with PLIN1 -related FPL had a significant reduction of the indirect fractional catabolic rate of VLDL (very-low-density lipoprotein)-apoB100 toward IDL (intermediate-density lipoprotein)/LDL (low-density lipoprotein; 1.79±1.38 versus 5.34±2.45 pool/d; P =0.003) and the indirect fractional catabolic rate of IDL-apoB100 toward LDL (2.14±1.44 versus 7.51±4.07 pool/d; P =0.005). VLDL-apoB100 production was not different between patients with PLIN1 -related FPL and controls. Compared with patients with type 2 diabetes, patients with PLIN1 -related FPL also showed a significant reduction of the catabolism of both VLDL-apoB100 ( P =0.031) and IDL-apoB100 ( P =0.031). Plasma LPL mass was significantly lower in patients with PLIN1 -related FPL than in controls (21.03±10.08 versus 55.76±13.10 ng/mL; P <0.0001), although the LPL protein expression in adipose tissue was similar. VLDL-apoB100 and IDL-apoB100 indirect fractional catabolic rates were negatively correlated with plasma triglycerides and positively correlated with LPL mass., Conclusions: We show that hypertriglyceridemia associated with PLIN1 -related FPL results from a marked decrease in the catabolism of triglyceride-rich lipoproteins (VLDL and IDL). This could be due to a pronounced reduction in LPL availability, related to the decreased adipose tissue mass., Competing Interests: None.

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 β ± 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 [β = 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

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- 13 C]leucine followed by a 16-hour constant infusion., Results: Liraglutide reduced BMI (34.9 ± 4.7 vs 36.6 ± 4.9 kg/m 2 , 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Aims: Because tobacco smoking is a major risk factor of mortality in diabetes and guidelines suggest evaluating smoking behavior among individuals with diabetes and helping smokers quit, we aimed to assess knowledge about the tobacco smoking - diabetes relationship among diabetologists and smoking cessation specialists (SCS)., Methods: An online cross sectional survey was conceived by the Working Group on Smoking and Diabetes, France. The questionnaire was tested by the members of the Working Group and deemed to be completed in less than 5 min. Only questions receiving the highest number of approval ratings were kept for the survey. The questionnaire was sent to all members of the French Language Society of Diabetes (Société Francophone du Diabète, SFD), N = 969 and the French Language Society on Tobacco (Société Francophone de Tabacologie, SFT), N = 307. The mailing lists of members were obtained with the previous agreement of the societies' board., Results: 225 diabetologists and 97 SCS (response rate 23.2% and 31.5%, respectively) completed the questionnaire. Over 90% of the diabetologists reported recording smoking status of their patients. Although diabetologists were aware that smoking increases all-cause mortality of individuals with diabetes, only 29.3% were aware that smoking is a risk factor for type 2 diabetes (76.3% among SCS), for poor glycemic control: 32.9% (86.6% among SCS). Significantly less diabetologists (64%) than SCS (76.3%) were aware of smoking being a risk factor for microangiopathy. More diabetologists considered that smoking cessation is more important than optimizing glycemic control among individuals with type 2 (69.3%) than among those with type 1 diabetes (47.1%). Few diabetologists (11.1%) and SCS (14.4%) reported to be trained for smoking cessation among persons with diabetes., Conclusion: Specific knowledge about the negative tobacco smoking - diabetes association seems to be insufficient among French diabetologists. Diabetologists but also other health care professionals should be trained to help individuals with diabetes who smoke to quit smoking., Competing Interests: Declaration of Competing Interest None of the authors declares conflict of interest with respect of this work., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (© 2023. The Author(s).)

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., (© 2023. The Author(s).)

Smoking and diabetes mellitus (DM) have been identified as 2 major cardiovascular risk factors for many years. In the field of cardiovascular diseases, considering sex differences, or gender differences, or both has become an essential element in moving toward equitable and quality health care. We reviewed the effect of sex or gender on the link between smoking and DM. The risk of type 2 DM due to smoking has been established in both sexes at the same level. As is the case in the general population, the prevalence of smoking in those with DM is higher in men than in women, although the decrease in smoking observed in recent years is more pronounced in men than in women. Regarding chronic DM complications, smoking is an independent risk factor for all-cause mortality, as well as macrovascular and microvascular complications, in both sexes. Nevertheless, in type 2 DM, the burden of smoking appears to be greater in women than in men for coronary heart disease morbidity, with women having a 50% greater risk of fatal coronary event. Women are more dependent to nicotine, cumulate psychosocial barriers to quitting smoking, and are more likely to gain weight, which might make it more difficult for them to quit smoking. Smoking cessation advice and treatments should take into account gender differences to improve the success and long-term maintenance of abstinence in people with and without DM. This might include interventions that address emotions and stress in women or designed to reach specific populations of men., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Several randomized controlled trials have demonstrated the benefits of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on ischemic stroke in patients with diabetes. In this review, we summarize and discuss the potential mechanisms of stroke protection by GLP-1RAs. GLP-1RAs exert multiple anti-atherosclerotic effects contributing to stroke prevention such as enhanced plaque stability, reduced vascular smooth muscle proliferation, increased nitric oxide, and improved endothelial function. GLP-1RAs also lower the risk of stroke by reducing traditional stroke risk factors including hyperglycemia, hypertension, and dyslipidemia. Independently of these peripheral actions, GLP-1RAs show direct cerebral effects in animal stroke models, such as reduction of infarct volume, apoptosis, oxidative stress, neuroinflammation, excitotoxicity, blood-brain barrier permeability, and increased neurogenesis, neuroplasticity, angiogenesis, and brain perfusion. Despite these encouraging findings, further research is still needed to understand more thoroughly the mechanisms by which GLP-1RAs may mediate stroke protection specifically in the human diabetic brain., (© 2022. The Author(s).)

Postprandial hyperlipidaemia is an important feature of diabetic dyslipidaemia and plays an important role in the development of cardiovascular disease in individuals with type 2 diabetes. Postprandial hyperlipidaemia in type 2 diabetes is secondary to increased chylomicron production by the enterocytes and delayed catabolism of chylomicrons and chylomicron remnants. Insulin and some intestinal hormones (e.g. glucagon-like peptide-1 [GLP-1]) influence intestinal lipid metabolism. In individuals with type 2 diabetes, insulin resistance and possibly reduced GLP-1 secretion are involved in the pathophysiology of postprandial hyperlipidaemia. Several factors are involved in the overproduction of chylomicrons: (1) increased expression of microsomal triglyceride transfer protein, which is a key enzyme in chylomicron synthesis; (2) higher stability and availability of apolipoprotein B-48; and (3) increased de novo lipogenesis. Individuals with type 2 diabetes present with disorders of cholesterol metabolism in the enterocytes with reduced absorption and increased synthesis. The increased production of chylomicrons in type 2 diabetes is also associated with a reduction in their catabolism, mostly because of a reduction in activity of lipoprotein lipase. Modification of the microbiota, which is observed in type 2 diabetes, may also generate disorders of intestinal lipid metabolism, but human data remain limited. Some glucose-lowering treatments significantly influence intestinal lipid absorption and transport. Postprandial hyperlipidaemia is reduced by metformin, pioglitazone, alpha-glucosidase inhibitors, dipeptidyl peptidase 4 inhibitors and GLP-1 agonists. The most pronounced effect is observed with GLP-1 agonists, which reduce chylomicron production significantly in individuals with type 2 diabetes and have a direct effect on the intestine by reducing the expression of genes involved in intestinal lipoprotein metabolism. The effect of sodium-glucose cotransporter 2 inhibitors on intestinal lipid metabolism needs to be clarified., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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 ± 4.3 vs 35.5 ± 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 ± 16.5 vs -63.5 ± 18.7%, P = 0.14; and -62.1 ± 13.2 vs -54.7 ± 17.7%, P = 0.16, respectively)., Conclusion: Despite lipidomic abnormalities, the cholesterol efflux and anti-inflammatory capacities of HDL are preserved in T2D patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Mean amplitude of glucose excursion (MAGE) is considered as the "gold standard" for assessing the short-term within-day glycemic variability (GV), which is an important component of overall glycemic control. A 14-day continuous glucose monitoring system is now widely used and allows easier assessment of GV. However, it is still unknown whether MAGE, usually calculated on a 48-hour period is identical whatever the time during the 14-day lifespan of the sensor and whether a longer time period might give additional information. We evaluated in 68 patients with type 1 diabetes, MAGE during three 2-day periods (day1-day3; day6-day8; day11-day13) and during periods of 3 days and 4 days. MAGE calculated at the three 2-day periods were identical and not different from MAGE of the 3-day or 4-day periods.

Objective: This study assessed the impact of a history of metabolic and bariatric surgery (MBS) on the clinical outcomes in patients with type 2 diabetes (T2D) and severe obesity hospitalized for COVID-19., Methods: In this post hoc analysis from the nationwide observational CORONADO (Coronavirus SARS-CoV2 and Diabetes Outcomes) study, patients with T2D and a history of MBS were matched with patients without MBS for age, sex, and BMI either at the time of MBS or on admission for COVID-19. The composite primary outcome (CPO) combined invasive mechanical ventilation and/or death within 7 and 28 days following admission., Results: Out of 2,398 CORONADO participants, 20 had a history of MBS. When matching for BMI at the time of MBS and after adjustment for diabetes duration, the CPO occurred less frequently within 7 days (3 vs. 17 events, OR: 0.15 [0.01 to 0.94], p = 0.03) and 28 days (3 vs. 19 events, OR: 0.11 [0.01 to 0.71], p = 0.02) in patients with MBS (n = 16) vs. controls (n = 44). There was no difference in CPO rate between patients with MBS and controls when matching for BMI on admission., Conclusions: These data are reassuring regarding COVID-19 prognosis in patients with diabetes and a history of MBS compared with those without MBS., (© 2021 The Obesity Society.)

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., Competing Interests: Declaration of Competing Interest The authors’ employer (University Hospital, Dijon, France) received funding from NovoNordisk for this study. Otherwise, no potential conflicts of interest relevant to this article are reported., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Type 2 diabetes mellitus (T2DM) is a frequent comorbidity in patients with cirrhosis that is projected to rise in prevalence due to the worldwide burden of obesity, insulin-resistance and non-alcoholic fatty liver disease. The management of T2DM in patients with cirrhosis is complex given the requirement for accurate adaptation according to the level of liver function impairment, with lack of summary of the little evidence available in the literature. Here, we summarise the data available with respect to the epidemiology and the impact of T2DM in patients with cirrhosis, as well as those on the management of T2DM in these patients. We provide guidance for the diagnosis of T2DM and the monitoring of glycaemic control in patients with cirrhosis, and for the management of nutrition and pharmacological treatments in relation to the level of liver dysfunction., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Objective: Dyslipidemia observed in type 2 diabetes (T2D) is atherogenic. Important features of diabetic dyslipidemia are increased levels of triglyceride-rich lipoproteins and small dense LDL particles, which all have apolipoprotein B100 (apoB100) as a major apolipoprotein. This prompted us to study the effect of the GLP-1 agonist liraglutide on the metabolism of apoB100-containing lipoproteins., Research Design and Methods: We performed an in vivo kinetic study with stable isotopes (L-[1- 13 C]leucine) in 10 patients with T2D before and after 6 months of treatment with liraglutide (1.2 mg/day). We also evaluated in mice the effect of liraglutide on the expression of genes involved in apoB100-containing lipoprotein clearance., Results: In patients with T2D, liraglutide treatment significantly reduced plasma apoB100 (0.93 ± 0.13 vs. 1.09 ± 0.11 g/L, P = 0.011) and fasting triglycerides (1.76 ± 0.37 vs. 2.48 ± 0.69 mmol/L, P = 0.005). The kinetic study showed a significant increase in indirect catabolism of VLDL 1 -apoB100 (4.11 ± 1.91 vs. 2.96 ± 1.61 pools/day, P = 0.005), VLDL 2 -apoB100 (5.17 ± 2.53 vs. 2.84 ± 1.65 pools/day, P = 0.008), and IDL-apoB100 (5.27 ± 2.77 vs. 3.74 ± 1.85 pools/day, P = 0.017) and in catabolism of LDL-apoB100 (0.72 ± 0.22 vs. 0.56 ± 0.22 pools/day, P = 0.005). In mice, liraglutide increased lipoprotein lipase (LPL) gene expression and reduced proprotein convertase subtilisin/kexin type 9 (PCSK9), retinol-binding protein 4 (RBP4), and tumor necrosis factor-α (TNF-α) gene expression in adipose tissue and decreased PCSK9 mRNA and increased LDL receptor protein expression in liver. In vitro, liraglutide directly reduced the expression of PCSK9 in the liver., Conclusions: Treatment with liraglutide induces a significant acceleration of the catabolism of triglyceride-rich lipoproteins (VLDL 1 , VLDL 2 , IDL) and LDL. Liraglutide modifies the expression of genes involved in apoB100-containing lipoprotein catabolism. These positive effects on lipoprotein metabolism may reduce cardiovascular risk in T2D., (© 2021 by the American Diabetes Association.)

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/m 2 ), 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., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aim: To assess the relationship between body mass index (BMI) classes and early COVID-19 prognosis in inpatients with type 2 diabetes (T2D)., Methods: From the CORONAvirus-SARS-CoV-2 and Diabetes Outcomes (CORONADO) study, we conducted an analysis in patients with T2D categorized by four BMI subgroups according to the World Health Organization classification. Clinical characteristics and COVID-19-related outcomes (i.e. intubation for mechanical ventilation [IMV], death and discharge by day 7 [D7]) were analysed according to BMI status., Results: Among 1965 patients with T2D, 434 (22.1%) normal weight (18.5-24.9 kg/m 2 , reference group), 726 (36.9%) overweight (25-29.9 kg/m 2 ) and 805 (41.0%) obese subjects were analysed, including 491 (25.0%) with class I obesity (30-34.9 kg/m 2 ) and 314 (16.0%) with class II/III obesity (≥35 kg/m 2 ). In a multivariable-adjusted model, the primary outcome (i.e. IMV and/or death by D7) was significantly associated with overweight (OR 1.65 [1.05-2.59]), class I (OR 1.93 [1.19-3.14]) and class II/III obesity (OR 1.98 [1.11-3.52]). After multivariable adjustment, primary outcome by D7 was significantly associated with obesity in patients aged younger than 75 years, while such an association was no longer found in those aged older than 75 years., Conclusions: Overweight and obesity are associated with poor early prognosis in patients with T2D hospitalized for COVID-19. Importantly, the deleterious impact of obesity on COVID-19 prognosis was no longer observed in the elderly, highlighting the need for specific management in this population., (© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: The aim of the present study was to identify the affected gene in a French family with maturity-onset diabetes of the young (MODY) using whole-exome sequencing (WES)., Methods: WES was performed in one patient with MODY, and candidate variants were confirmed in members of the immediate family by Sanger sequencing., Results: In the proband, a new heterozygous missense mutation (c.340A>C) was identified in the NEUROD1 gene by WES analysis and confirmed by Sanger sequencing. Additional Sanger sequencing of the proband's sister and mother revealed the same heterozygous mutation. The proband and his sister displayed typical clinical characteristics of MODY, while their mother had the same typical MODY features except for later onset. When clinical and biological profiles were established for all three patients, the severity of diabetes-related complications varied substantially from one family member to another., Conclusion: A novel missense mutation found in NEUROD1 was associated with MODY 6 features in a single French family., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

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., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: SUSTAIN 10 compared the efficacy and safety of the anticipated most frequent semaglutide dose (1.0mg) with the current most frequently prescribed liraglutide dose in Europe (1.2mg), reflecting clinical practice., Methods: In this phase 3b, open-label trial, 577 adults with type 2 diabetes (HbA 1c 7.0-11.0%) on 1-3 oral antidiabetic drugs were randomized 1:1 to subcutaneous once-weekly semaglutide 1.0mg or subcutaneous once-daily liraglutide 1.2mg. Primary and confirmatory secondary endpoints were changes in HbA 1c and body weight from baseline to week 30, respectively., Results: Mean HbA 1c (baseline 8.2%) decreased by 1.7% with semaglutide and 1.0% with liraglutide (estimated treatment difference [ETD] -0.69%; 95% confidence interval [CI] -0.82 to -0.56, P<0.0001). Mean body weight (baseline 96.9kg) decreased by 5.8kg with semaglutide and 1.9kg with liraglutide (ETD -3.83kg; 95% CI -4.57 to -3.09, P<0.0001). The proportions of subjects achieving glycaemic targets of<7.0% and=6.5%, weight loss of=5% and=10%, and a composite endpoint of HbA 1c <7.0% without severe or blood glucose-confirmed symptomatic hypoglycaemia and no weight gain were greater with semaglutide vs liraglutide (all P<0.0001). Both treatments had similar safety profiles, except for more frequent gastrointestinal disorders (the most common adverse events [AEs]) and AEs leading to premature treatment discontinuation with semaglutide vs liraglutide (43.9% vs 38.3% and 11.4% vs 6.6%, respectively)., Conclusion: Semaglutide was superior to liraglutide in reducing HbA 1c and body weight. Safety profiles were generally similar, except for higher rates of gastrointestinal AEs with semaglutide vs liraglutide., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Despite the availability of a large number of therapeutic options throughout the world, rates of optimal glycaemic control in adult patients with type 2 diabetes mellitus remain low. Delays in treatment intensification to insulin and low adherence to insulin regimes, which are well-documented contributors to poor glycaemic control, are in many cases driven by fear of hypoglycaemic events, weight gain and injections. Over the last 10 years, injectable glucagon-like peptide-1 receptor agonists (GLP1-RAs) have emerged as alternatives to basal insulin for treatment intensification in patients inadequately controlled with oral antidiabetic drugs. As a class, GLP1-RAs are associated with weight loss and fewer hypoglycaemic events than insulin. In addition, some of them are available in once-a-week formulations and therefore require fewer injections. However, as randomized controlled trials are not representative of everyday practice, physicians should consider the results of real-life studies to guide their treatment decisions. In this review, while significant variations in efficacy, tolerability and adherence data were noted from one study to another, rates of glycaemic control overall were low. Indeed, our present analysis has suggested that regular re-evaluations of treatment, including response, tolerability, adherence, cost and quality of life, are necessary., (Copyright © 2019. Published by Elsevier Masson SAS.)

Background: Self-monitoring of blood glucose supported by the diabetes-app OneTouch Reveal® has demonstrated to improve HbA1c. We aimed at analyzing costs savings related the integration of telemedical features into diabetes management., Methods: Data from a randomized controlled trial were used to assess the 10-year risk of patients for fatal myocardial infarction (MI). On the basis of this risk assessments-also related to a 5% or 10% reduction of hypoglycemic episodes-cost savings for the health care systems of five European countries-France, Germany, Italy, Spain, and the United Kingdom-were modeled., Results: HbA1c reduction of 0.92% in insulin-treated type 2 diabetes patients (T2DM) was associated with a 2.3% decreased 10-year risk for fatal MI. In combination with a 10% reduction of hypoglycemic events this risk reduction led to cost savings of €16.1 million (France), €57.8 million (Germany), €30.9 million (Italy), €23.8 million (Spain), and €5.8 million (UK), considering all insulin-treated T2DM patients in the respective countries., Conclusion: Improving metabolic control and thus risk for comorbidities like MI by combining the glucose meter with CRI with telemedical features has the potential to reduce costs for European health care systems.

Background: In patients with type 2 diabetes (T2D), glycaemic variability (GV), another component of glycaemic abnormalities, is a novel potentially aggravating factor for coronary artery disease (CAD)., Objectives: The aim of our study was to identify interactions between GV and severity of CAD in diabetes patients admitted for acute myocardial infarction (AMI)., Methods: All patients with T2D admitted to our university hospital for AMI from March 2015 to February 2017 who received intravenous (IV) insulin therapy and underwent coronary angiography were included. GV was assessed by mean amplitude of blood glucose excursion (MAGE) values taken within 2 days of admission. Patients with higher GV (highest MAGE tertile) were compared with those with lower GV (first and second MAGE tertiles)., Results: A total of 204 patients were included: median age was 72 (61-81) years; 32% were female; HbA 1c was 7.3% (6.4-8.2%); diabetes duration was 10 (2-17.5) years; and MAGE value was 0.65 (0.43-0.92) g/L. Compared with those with lower GV, patients with the highest GV were more often women, treated with previous insulin, and had higher blood glucose and HbA 1c levels. In addition, patients with elevated GV had significantly higher SYNTAX scores: 17 (10-28) vs. 12 (6-22) (P = 0.009). Indeed, SYNTAX scores (OR: 1.05, 95% CI: 1.02-1.08; P = 0.001) remained independently associated with high GV beyond HbA 1c levels (OR: 1.51, 95% CI: 1.2-1.89; P <  0.001)., Conclusion: In AMI patients with poorly controlled diabetes, GV is associated with CAD severity beyond chronic hyperglycaemia. Although no causality can be determined from our observational study, the results suggest that, in AMI, early evaluation of GV might contribute to the identification of those diabetes patients at high risk, and serve as a therapeutic target for both primary and secondary prevention., (Copyright © 2019. Published by Elsevier Masson SAS.)

Aims: GLP-1 analogues decrease food intake and have great promise for the fight against obesity. Little is known about their effects on food hedonic sensations and taste perception in poor controlled patients with type 2 diabetes (T2D)., Materials and Methods: Eighteen T2D patients with BMI ≥25 kg/m 2 and poor controlled glycemia were studied before and after 3 months of treatment with Liraglutide. Detection thresholds for salty, sweet and bitter tastes, optimal preferences, olfactory liking, wanting and recalled liking for several food items were assessed. Subjects also answered questionnaires to measure their attitudes to food., Results: T2D patients had a significant decrease in bodyweight and HbA1c after treatment with Liraglutide. Liraglutide improved gustative detection threshold of sweet flavors, and decreased wanting for sweet foods and recalled liking for fatty foods. It also led to a decrease in feelings of hunger., Conclusions: Liraglutide increases sensitivity to sweet tastes and decreases pleasure responses for fatty foods in poor controlled T2D patients, and is of particular interest in the understanding of the mechanisms of weight loss., Clinical Trial: NCT02674893., (Copyright © 2019 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

Introduction: Low-quality communication between patients and care providers and limited patient knowledge of the disease and the therapy are important factors associated with poor glycemic control in patients with type 2 diabetes. We conducted a multicenter study to determine whether structured and tailored information delivered by pharmacists to type 2 diabetic patients could improve patient treatment adherence, hemoglobin A1c (HbA1c) levels and knowledge about diabetes., Methods: One hundred seventy-four pharmacies were randomized to deliver an educational program on diet, drug treatment, disease and complications during three 30-min interviews over a 6-month period, or to provide no intervention, to type 2 diabetic patients treated with oral antidiabetic agents. Medication adherence was assessed by measuring the medication possession ratio and diabetes control by collecting HbA1c values. Levels of patient treatment self-management and disease knowledge were assessed using self-questionnaires., Results: Three hundred seventy-seven patients were analyzed. The medication possession ratio, already very high at baseline in the intervention (94.8%) and control (92.3%) groups, did not vary significantly after 6 months with no difference between the two groups. Significant decreases in HbA1c were observed in both groups at 6 months (p < 0.001) and 12 months (p < 0.01), with significantly greater changes from baseline in the intervention group than in the control group at 6 months (- 0.5% vs. - 0.2%, p = 0.0047) and 12 months (- 0.6% vs. - 0.2%, p = 0.0057). Patients in the intervention group showed greater improvement in their ability to self-manage treatment (+ 4.86 vs. + 1.58, p = 0.0014) and in the extent of their knowledge about diabetes (+ 0.6 vs. + 0.2, p < 0.01) at 6 months versus baseline compared with the control group., Conclusion: Tailored information provided by the pharmacist to patients with type 2 diabetes did not significantly improve the already high adherence rates, but was associated with a significant decrease in HbA1c and an improvement of patient knowledge about diabetes., Trial Registration: ISRCTN33776525., Funding: MSD France.

Aim: Protein-energy malnutrition is known to be involved in wound healing. While wound healing in patients with diabetic foot ulcers (DFU) is a complex and multifactorial process, the role of malnutrition in this case has rarely been explored. The objective of this study was to determine whether the nutritional status of diabetic patients influences the healing of DFU., Methods: 48 patients were included in this prospective, single-center study. All patients with comorbidities or factors involving malnutrition or influencing biological measurements were excluded. Patients were followed up for 24 weeks., Results: The malnutrition rate was 29.2% at baseline and 25.6% at the end of the study. The difference was not significant. Of the 35 patients with wound healing, 29% were undernourished at inclusion and 17% at the end of the study. Of the 12 patients without wound healing, 50% were undernourished at inclusion, and 42% at the end of the study. These differences were not significant. Rate and speed of wound healing were not associated with malnutrition at inclusion. 15% of patients without malnutrition at baseline had final malnutrition., Conclusion: We demonstrated that wound healing was not affected by the initial presence of malnutrition. In our study, there is no evidence to support nutritional intervention to improve wound healing in diabetic patients. Nevertheless, malnutrition is responsible for an increase in morbidity and mortality and it is essential to identify malnutrition systematically for all patients with DFU, initially and during follow-up to treat it quickly and efficiently.

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 (D 8 -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.

Aims: To evaluate the application of the recently proposed recommendations by the European Association for the Study of the Liver, European Association for the Study of Diabetes and European Association for the Study of Obesity for the diagnosis, treatment and follow-up of non-alcoholic fatty liver disease in people with Type 2 diabetes., Methods: A total of 179 people with Type 2 diabetes were included in this study. Liver fat content (assessed using proton magnetic resonance spectroscopy), fatty liver index score, non-alcoholic fatty liver disease fibrosis score, and SteatoTest and FibroTest scores were determined., Results: According to proton magnetic resonance spectroscopy, 68.7% of participants had steatosis (liver fat content >5.5%). The application of the guidelines using several combinations (fatty liver index + non-alcoholic fatty liver disease fibrosis scores, Steatotest + FibroTest scores, proton magnetic resonance spectroscopy + non-alcoholic fatty liver disease fibrosis score, proton magnetic resonance spectroscopy + FibroTest) resulted in a referral to a liver clinic for 33.5-84.9% people with Type 2 diabetes., Conclusions: The application of these new algorithms for the diagnosis, and follow-up of non-alcoholic fatty liver disease would lead to an excessive number of people with Type 2 diabetes being referred to a liver clinic. We suggest that new clinical and/or biological biomarkers of steatosis and fibrosis be specifically validated in people with Type 2 diabetes., (© 2017 Diabetes UK.)

The mammalian targets of rapamycin (mTOR) inhibitors are potent immunosuppressors used for prevention of acute rejection after transplantation and have been more recently used as anticancer drugs. mTOR inhibitors have a significant impact on glucose metabolism and frequently induce diabetes. mTOR inhibitors, when used as immunosuppressive agents (sirolimus, everolimus), can induce diabetes with an incidence which is low when used without calcineurin inhibitors but high when used in combination with calcineurin inhibitors (from 11.0% to 38.1%). mTOR inhibitors used as anticancer agents (everolimus, temsirolimus) increase significantly the risk for new-onset diabetes and induce a 5-fold increase in the risk for severe hyperglycemia. The deleterious effect of mTOR inhibitors on glucose metabolism is due to an increased insulin resistance secondary to a reduction of the insulin signaling pathway within the cell and a reduction of insulin secretion via a direct effect on the pancreatic beta cells. Because of the risk for diabetes, it is recommended, when starting a treatment with an mTOR inhibitor, to check fasting blood glucose every 2 weeks during the first month of treatment then every month and HbA1c every 3 months and to intensify self-monitoring of blood glucose in patients with known diabetes. When fasting blood glucose is more than 126 mg/dL (7.0 mmol/L), when plasma glucose is more than 200 mg/dL at any time, or when HbA1c is more than 6.5%, it is recommended to start antidiabetic treatment.

Non-alcoholic fatty liver disease (NAFLD) is very common in patients with type 2 diabetes (T2D), with approximately two-thirds having a diagnosis of the disease. Currently, the only validated treatment for NAFLD is weight loss. A number of studies of animal models and human trials have evaluated the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on liver fat content and suggest that the treatment could represent a new alternative for NAFLD management. In this review, our focus is on the main studies regarding the effects of GLP-1RAs on NAFLD. Also, the mechanisms that might explain their beneficial effects on liver diseases are analyzed., (© 2017 Elsevier Masson SAS. All rights reserved.)

Background: Nonalcoholic fatty liver disease is very frequent in type 2 diabetes, with increased risk of further development of liver fibrosis. Animal studies have shown that GLP-1 receptor agonists may reduce liver lipogenesis. However, data in humans are scarce., Objective: To study the effect of liraglutide 1.2 mg/d on liver fat content (LFC) in patients with uncontrolled type 2 diabetes and to evaluate the factors potentially associated with liraglutide-induced modification of LFC., Design, Setting, Participants: LFC was measured by proton magnetic resonance spectroscopy before and after 6 months of liraglutide treatment in 68 patients with uncontrolled type 2 diabetes mellitus., Intervention: Liraglutide 1.2 mg/d., Outcome Measure: Change in LFC., Results: Treatment with liraglutide was associated with a significant decrease in body weight, HbA1C, and a marked relative reduction in LFC of 31% (P < 0.0001). No significant modification of LFC was observed in a parallel group of patients 6 months after intensification of the antidiabetic treatment with insulin. The reduction in LFC and body weight were highly correlated (r = 0.490; P < 0.0001). In multivariate analysis, the reduction in LFC was independently associated with baseline LFC (P < 0.0001), age (P = 0.010), and reduction in body weight (P < 0.0001), triglycerides (P = 0.019), and HbA1c (P = 0.034). In the patients who had no significant decrease in body weight, no significant reduction in LFC was observed., Conclusions: Six months of treatment with liraglutide 1.2 mg/d significantly reduced LFC in patients with inadequately controlled type 2 diabetes and this effect was mainly driven by body weight reduction. Further studies are needed to confirm that this reduction in LFC may significantly reduce fibrosis progression., (Copyright © 2017 by the Endocrine Society)

Objectives: To describe the management of glucose-lowering agents in people with type 2 diabetes initially on oral monotherapy, cared for by French general practitioners, and to identify reasons underlying treatment non-intensification., Methods: People with type 2 diabetes on oral monotherapy were recruited by general practitioners and followed-up over 12 months. Patient characteristics, HbA1c, and glucose-lowering treatments were recorded electronically. Management objectives and reasons for treatment non-intensification were solicited from the general practitioners., Results: A total of 1212 patients were enrolled by 198 general practitioners; 937 patients (mean age 68 years) were treated with oral monotherapy, and 916 patients had at least two successive HbA1c values recorded. Of these, 390 patients (43%) had HbA1c≥6.5% on both occasions, and 164/390 (42%) had their treatment intensified. The 226 patients whose treatment was not intensified were older (69±11 years vs. 66±12 years, P=0.02) and had better glycaemic control at study inclusion (6.9%±0.6 vs. 7.3%±0.8, P<0.0001) than treatment intensified patients. Among uncontrolled patients, there were no differences in general practitioner treatment objectives at inclusion for treatment intensified and non-intensified patients; the main reason given by general practitioners for non-intensification was that the patient had an adequate HbA1c (66%). HbA1c did exceed the 6.5% target, but was less than 7.0% in 69% of cases., Conclusions: General practitioners showed a patient-centred approach to treatment, but clinical inertia was apparent for 31% of the uncontrolled patients., (Copyright © 2016. Published by Elsevier Masson SAS.)

Two thirds of the patients hospitalized for an acute coronary syndrome (ACS) show disorders of glucose metabolism (diabetes, impaired fasting glucose, impaired glucose intolerance). Every patient hospitalized for an ACS whose HbA1c is equal or above 6.5% must be considered as diabetic. Each patient hospitalized for an ACS whose HbA1c is less than 6.5% should have measurement of plasma glucose fasting and after an oral glucose load between the 7th and the 28th day following the ACS in order to detect a disorder of glucose metabolism. During the hospitalization in cardiac intensive care unit, a treatment with insulin will be started when plasma glucose is≥1.80g/L (10.0mmol/L). In a patient with previously known diabetes, a treatment with insulin will also be started when preprandial plasma glucose is 1.40g/L (7.8mmol/L). Insulin treatment in cardiac intensive care unit will be performed by continuous IV infusion of insulin including bolus for meals. Insulin dosage will be determined according to the capillary glucose monitoring. After the hospitalization in cardiac intensive care unit, it is often possible to stop insulin treatment, which may be replaced by other antidiabetic treatments. The choice of the optimal antidiabetic treatment depends on the metabolic profile of the patient (insulin-resistance, insulin deficiency). This choice is not always easy and referral to an endocrinologist/diabetolgist may be needed. Because of the increased cardiovascular mortality associated with hypoglycemias, the long-term use of insulin or insulin-secretory agents (sulfonylureas, glinides) must be limited. During and in the immediate follow-up of an ACS, referral to an endocrinologist/diabetologist is recommended in case of diagnosis of diabetes, when HbA1c≥8%, when long-term treatment with insulin has been initiated and in case of frequent or severe hypoglycemias., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Introduction: Apolipoprotein C1 (apoC1) is likely to play an important role in triglyceride (TG) metabolism. Mice overexpressing human apoC1 present decreased adipose tissue stores. This study aimed to determine whether apoC1 concentration influences fat mass and distribution and liver fat content (LFC) in patients with type 2 diabetes (T2D)., Methods: ApoC1 concentrations were measured by ELISA in 113 T2D patients and 56 normolipidaemic-normoglycaemic subjects. Visceral and subcutaneous fat areas were determined by single-slice axial T1-weighted magnetic resonance imaging (MRI), while LFC was measured by hydrogen-1 ((1)H) MR spectroscopy., Results: ApoC1 concentrations were higher in T2D patients than in normolipidaemic-normoglycaemic subjects (P<0.0001), and did not correlate with visceral or subcutaneous fat areas, but significantly correlated with TG (P<0.0001) and LFC (P=0.02) in T2D patients. However, the correlation between apoC1 and LFC was lost after adjusting for TG. ApoC1 concentration was also significantly higher in T2D patients with TG<1.5mmol/L than in control subjects (P<0.0001), although both groups had similar TG levels. On multivariate analysis performed in T2D patients with TG<1.5mmol/L and control subjects, apoC1 concentration was independently and positively associated with type 2 diabetes (P<0.0001) and TG levels (P=0.03)., Conclusion: This study reports, for the first time, that apoC1 is increased in T2D patients and is significantly correlated with TG, whereas no association was found between apoC1 and adipose tissue. This indicates that, in T2D, apoC1 may play a role in TG metabolism, but is unlikely to modulate fat mass and distribution. This increased apoC1 concentration in T2D patients is not only explained by the increased TG level in T2D patients., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Aim: Type A personality, although classically known as a factor linked to increased vascular risk, has recently been associated with increased survival in patients with diabetes. As low-grade inflammation predicts a poor outcome, the present study explored the potential associations between Type A and plasma levels of C-reactive protein (CRP) in diabetes., Methods: Type A personality was assessed by the Bortner questionnaire in people with diabetes. The association between Type A and plasma CRP levels was examined by multivariable linear regression, and structural equation modelling (SEM) was performed to determine the impact of the major clinical, biological and psychological confounders., Results: The study included 626 participants with type 1 and type 2 diabetes from the Diabetes and Psychological Profile study. Multivariable analyses showed an independent inverse association between Type A score and CRP levels. The structural model adjusted for age, gender, diabetes type and duration, body mass index (BMI), smoking status, alcohol abuse, oral antidiabetic and statin treatments, HbA1c levels, lipids, perceived stress, anxiety and depression revealed significant associations between CRP and Type A (β=-0.135, 95% CI: -0.242, -0.028; P=0.014), BMI (β=0.194, 95% CI: 0.038, 0.350; P=0.015) and HDL cholesterol (β=-0.132, 95% CI: -0.245, -0.020; P=0.014)., Conclusion: Our present study data indicate that Type A personality is independently associated with lower CRP levels. This lower level of inflammation might explain the better clinical outcomes associated with Type A personality in patients with diabetes., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Cardiovascular risk events are frequent in patients with type 2 diabetes. The way to treat type 2 diabetes with history of cardiovascular disease is not really different from the one used in a patient without this history with a pathophysiologic approach designed according to the importance of each therapeutic target: insulin-resistance and insulin deficiency. However, it is recommended to use antidiabetic drugs without detrimental cardiovascular effects. Metformin can be used in patients with history of cardiovascular disease (in the exception of renal failure or severe heart failure) since its use has been shown to be associated with a reduction of cardiovascular events in several clinical trials. Among sulfonylureas, first generation sulfonylureas and glibenclamide are not recommended because they impair ischemic preconditioning. Glinides, acarbose, GLP-1 agonists and DPP-4 inhibitors can be used in type 2 diabetic patients with history of cardiovascular disease. DPP-4 inhibitors have been shown to he safe in recent cardiovascular outcome trials. In addition, data from the ORIGIN trial indicate that insulin itself is not likely to increase cardiovascular risk. Most importantly, the risk of hypoglycaemia must be an important concern in patients with history of cardiovascular disease and the use of antidiabetic agents that may induce hypoglycaemic events should he limited.

Background: Gain in VO2 peak after cardiac rehabilitation (CR) following an acute coronary syndrome (ACS), is associated with reduced mortality and morbidity. We have previously shown in CR, that gain in VO2 peak is reduced in Type 2 diabetic patients and that response to CR is impaired by hyperglycemia., Methods: We set up a prospective multicenter study (DARE) whose primary objective was to determine whether good glycemic control during CR may improve the gain in VO2 peak. Sixty four type 2 diabetic patients, referred to CR after a recent ACS, were randomized to insulin intensive therapy or a control group with continuation of the pre-CR antidiabetic treatment. The primary objective was to study the effect of glycemic control during CR on the improvement of peak VO2 by comparing first the 2 treatment groups (insulin intensive vs. control) and second, 2 pre-specified glycemic control groups according to the final fructosamine level (below and above the median)., Results: At the end of the CR program, the gain in VO2 peak and the final fructosamine level (assessing glycemic level during CR) were not different between the 2 treatment groups. However, patients who had final fructosamine level below the median value, assessing good glycemic control during CR, showed significantly higher gain in VO2 peak (3.5 ± 2.4 vs. 1.7 ± 2.4 ml/kg/min,p = 0.014) and ventilatory threshold (2.7 ± 2.5 vs. 1.2 ± 1.9 ml/kg/min,p = 0.04) and a higher proportion of good CR-responders (relative gain in VO2 peak ≥ 16 %): 66 % vs. 36 %, p = 0.011. In multivariate analysis, gain in VO2 peak was associated with final fructosamine level (p = 0.010) but not with age, gender, duration of diabetes, type of ACS, insulin treatment or basal fructosamine., Conclusions: The DARE study shows that, in type 2 diabetes, good glycemic control during CR is an independent factor associated with gain in VO2 peak. This emphasizes the need for good glycemic control in CR for type 2 diabetic patients., Trial Registration: Trial registered as NCT00354237 (19 July 2006).

Cardiovascular disease is a major cause of morbidity and mortality in patients with type 2 diabetes mellitus, with a two- to fourfold increase in cardiovascular disease risk compared with non-diabetic individuals. Abnormalities in lipid metabolism that are observed in the context of type 2 diabetes are among the major factors contributing to an increased cardiovascular risk. Diabetic dyslipidaemia includes not only quantitative lipoprotein abnormalities, but also qualitative and kinetic abnormalities that, together, result in a shift towards a more atherogenic lipid profile. The primary quantitative lipoprotein abnormalities are increased triacylglycerol (triglyceride) levels and decreased HDL-cholesterol levels. Qualitative lipoprotein abnormalities include an increase in large, very low-density lipoprotein subfraction 1 (VLDL1) and small, dense LDLs, as well as increased triacylglycerol content of LDL and HDL, glycation of apolipoproteins and increased susceptibility of LDL to oxidation. The main kinetic abnormalities are increased VLDL1 production, decreased VLDL catabolism and increased HDL catabolism. In addition, even though LDL-cholesterol levels are typically normal in patients with type 2 diabetes, LDL particles show reduced turnover, which is potentially atherogenic. Although the pathophysiology of diabetic dyslipidaemia is not fully understood, the insulin resistance and relative insulin deficiency observed in patients with type 2 diabetes are likely to contribute to these lipid changes, as insulin plays an important role in regulating lipid metabolism. In addition, some adipocytokines, such as adiponectin or retinol-binding protein 4, may also contribute to the development of dyslipidaemia in patients with type 2 diabetes.

In type 2 diabetes (T2DM), glycaemic control delays the development and slows the progression of complications. Although there are numerous glucose-lowering agents in clinical use, only approximately half of T2DM patients achieve glycaemic control, while undesirable side-effects, such as hypoglycaemia and body weight gain, often impede treatment in those taking these medications. Thus, there is a need for novel agents and treatment options. Sodium-glucose cotransporter-2 inhibitors (SGLT-2-i) have recently been developed for the treatment of T2DM. The available data suggest a good tolerability profile for the three available drugs - canagliflozin, dapagliflozin and empagliflozin - approved by the US Food and Drug Administration (FDA) for the American market as well as in other countries. The most frequently reported adverse events with SGLT-2-i are female genital mycotic infections, urinary tract infections and increased urination. The pharmacodynamic response to SGLT-2-i declines with increasing severity of renal impairment, requiring dosage adjustments or restrictions with moderate-to-severe renal dysfunction. Most patients treated with SGLT-2-i also have a modest reduction in blood pressure and modest effects on serum lipid profiles, some of which are beneficial (increased high-density lipoprotein cholesterol and decreased triglycerides) and others which are not (increased low-density lipoprotein cholesterol, LDL-C). A number of large-scale and longer-term cardiovascular trials are now ongoing. In patients treated with dapagliflozin, a non-significant excess number of breast and bladder cancers has been reported; considered as due to a bias, this is nevertheless being followed in the ongoing trials. No other significant safety issues have been reported so far. Although there is some benefit for several cardiovascular risk factors such as HbA1c, high blood pressure, obesity and increases in LDL-C, adequately powered trials are still required to determine the effects of SGLT-2-i on macrovascular outcomes., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Context: High-density lipoproteins (HDLs) from type 2 diabetic patients are unable to counteract the inhibitory effect of oxidized low-density lipoproteins (ox-LDLs) on vasorelaxation. We hypothesized that glitazones, which improve glycemic control and dyslipidemia, could correct this abnormality., Objectives and Design: We compared the ability of HDL from controls (n = 12) and from type 2 diabetic patients before and after 6 months of treatment with either rosiglitazone (n = 11) or pioglitazone (n = 8) to counteract the inhibitory effect of ox-LDL on vasodilatation of rabbit aorta rings., Results: Rosiglitazone induced a decrease in hemoglobin A1c (7.7% ± 1.1% vs 9.8% ± 1.0%, P = .003) and an increase in HDL cholesterol (1.14 ± 0.32 vs 0.98 ± 0.24 mmol/L, P = .033). Pioglitazone induced a decrease in hemoglobin A1c (8.3% ± 2.5% vs 9.5% ± 3.2%, P = .068) and serum triglycerides (1.58 ± 0.89 vs 2.03 ± 0.70 mmol/L, P = .069) and an increase in HDL cholesterol (1.39 ± 0.22 vs 1.14 ± 0.22 mmol/L, P = .018). The triglyceride content of HDL was unchanged by rosiglitazone and was decreased by 25% (P = .068) by pioglitazone. HDL from controls counteracted the inhibitory effect of ox-LDL on vasodilatation (maximal relaxation [Emax] = 74.4% ± 3.5% vs 51.9% ± 3.3%, P = .0029), whereas HDL from type 2 diabetic patients did not (Emax = 51.7% ± 5.8% vs 52.3% ± 4.6% [P = .66] and 52.7% ± 5.5% vs 51.9% ± 4.5% [P = .78] for the rosiglitazone and pioglitazone group, respectively). Rosiglitazone or pioglitazone did not improve Emax (58.6% ± 5.9% vs 52.3% ± 4.6% [P = .15] and 49.3% ± 6.5% vs 51.9% ± 4.5% [P = .48], respectively)., Conclusion: Glitazones increased the concentration of HDL cholesterol without restoring the ability of HDL particles to protect the endothelium from oxidative stress-induced dysfunction, meaning that HDL remained dysfunctional with impaired antiatherogenic properties.

Context: Lipopolysaccharides (LPSs) are inflammatory components of the outer membrane of Gram-negative bacteria and, in plasma, are mostly associated with lipoproteins. This association is thought to promote their catabolism while reducing their proinflammatory effects., Objectives: Our aim was to determine the impact of lipoprotein kinetics on plasma LPS distribution and how it may affect patients with type 2 diabetes mellitus (T2DM)., Design: We performed a kinetic study in 30 individuals (16 T2DM patients, 14 controls) and analyzed the impact of changes in lipoprotein kinetics on LPS distribution among lipoproteins., Results: Plasma LPS levels in T2DM patients were not different from those in controls, but LPS distribution in the two groups was different. Patients with T2DM had higher LPS-very low-density lipoprotein (VLDL; 31% ± 7% vs 22% ± 11%, P = .002), LPS-high-density lipoprotein (HDL; 29% ± 9% vs 19% ± 10%, P = .015), free (nonlipoprotein bound) LPS (10% ± 4% vs 7% ± 4%, P = .043) and lower LPS-low-density lipoprotein (LDL; 30% ± 13% vs 52% ± 16%, P = .001). In multivariable analysis, VLDL-LPS was associated with HDL-LPS (P < .0001); LDL-LPS was associated with VLDL-LPS (P = .004), and VLDL apolipoprotein (apo) B100 catabolism (P = .002); HDL-LPS was associated with free LPS (P < .0001) and VLDL-LPS (P = .033); free LPS was associated with HDL-LPS (P < .0001). In a patient featuring a dramatic decrease in VLDL catabolism due to apoA-V mutation, LDL-LPS was severely decreased (0.044 EU/mL vs 0.788 EU/mL in controls). The difference between T2DM patients and controls for LDL-LPS fraction was no longer significant after controlling for VLDL apoB100 total fractional catabolic rate., Conclusions: Our data suggest that in humans, free LPS transfers first to HDL and then to VLDL, whereas the LPS-bound LDL fraction is mainly derived from VLDL catabolism; the latter may hence represent a LPS catabolic pathway. T2DM patients show lower LDL-LPS secondary to reduced VLDL catabolism, which may represent an impaired catabolic pathway.

Reducing low-density lipoprotein cholesterol (LDL-C) levels using statins is associated with significant reductions in cardiovascular (CV) events in a wide range of patient populations. Although statins are generally considered to be safe, recent studies suggest they are associated with an increased risk of developing Type 2 diabetes (T2D). This led the US Food and Drug Administration (FDA) to change their labelling requirements for statins to include a warning about the possibility of increased blood sugar and HbA1c levels and the European Medicines Agency (EMA) to issue guidance on a small increased risk of T2D with the statin class. This review examines the evidence leading to these claims and provides practical guidance for primary care physicians on the use of statins in people with or at risk of developing T2D. Overall, evidence suggests that the benefits of statins for the reduction of CV risk far outweigh the risk of developing T2D, especially in individuals with higher CV risk. To reduce the risk of developing T2D, physicians should assess all patients for T2D risk prior to starting statin therapy, educate patients about their risks, and encourage risk-reduction through lifestyle changes. Whether some statins are more diabetogenic than others requires further study. Statin-treated patients at high risk of developing T2D should regularly be monitored for changes in blood glucose or HbA1c levels, and the risk of conversion from pre-diabetes to T2D should be reduced by intensifying lifestyle changes. Should a patient develop T2D during statin treatment, physicians should continue with statin therapy and manage T2D in accordance with relevant national guidelines., (Copyright © 2014. Published by Elsevier Ireland Ltd.)

OBJECTIVE Apolipoprotein (apo)C1 is a potent physiological inhibitor of cholesteryl ester transfer protein (CETP). ApoC1 operates through its ability to modify the electrostatic charge at the lipoprotein surface. We aimed to determine whether the inhibitory ability of apoC1 is still effective in vivo in patients with diabetes and whether in vitro glycation of apoC1 influences its electrostatic charge and its CETP inhibitory effect. RESEARCH DESIGN AND METHODS ApoC1 concentrations and CETP activity were measured in 70 type 1 diabetic (T1D) patients, 113 patients with type 2 diabetes, and 83 control subjects. The consequences of in vitro glycation by methylglyoxal on the electrostatic properties of apoC1 and on its inhibitory effect on CETP activity were studied. An isoelectric analysis of apoC1 was performed in patients with T1D and in normolipidemic-normoglycemic subjects. RESULTS An independent negative correlation was found between CETP activity and apoC1 in control subjects but not in patients with diabetes. HbA1c was independently associated with CETP activity in T1D patients. In vitro glycation of apoC1 modified its electrostatic charge and abrogated its ability to inhibit CETP activity in a concentration-dependent manner. The isoelectric point of apoC1 in T1D patients was significantly lower than that in control subjects. CONCLUSIONS The ability of apoC1 to inhibit CETP activity is impaired in patients with diabetes. Glycation of apoC1 leads to a change in its electrostatic properties that might account, at least in part, for a loss of constitutive CETP inhibition and an increase in plasma CETP activity in patients with diabetes.

The increasing role for structured and personalized self-monitoring of blood glucose (SMBG) in management of type 2 diabetes has been underlined by randomized and prospective clinical trials. These include Structured Testing Program (or STeP), St. Carlos, Role of Self-Monitoring of Blood Glucose and Intensive Education in Patients with Type 2 Diabetes Not Receiving Insulin, and Retrolective Study Self-Monitoring of Blood Glucose and Outcome in Patients with Type 2 Diabetes (or ROSSO)-in-praxi follow-up. The evidence for the benefit of SMBG both in insulin-treated and non-insulin-treated patients with diabetes is also supported by published reviews, meta-analyses, and guidelines. A Cochrane review reported an overall effect of SMBG on glycemic control up to 6 months after initiation, which was considered to subside after 12 months. Particularly, the 12-month analysis has been criticized for the inclusion of a small number of studies and the conclusions drawn. The aim of this article is to review key publications on SMBG and also to put them into perspective with regard to results of the Cochrane review and current aspects of diabetes management., (© 2013 Diabetes Technology Society.)