Inactive matrix gla protein plasma levels are associated with peripheral neuropathy in Type 2 diabetes.

AIMS/HYPOTHESIS Diabetic peripheral neuropathy is a frequent and severe complication of diabetes. As Matrix-gla-protein (MGP) is expressed in several components of the nervous system and is involved in some neurological disease, MGP could play a role in peripheral nervous system homeostasis. The aim of this study was to evaluate factors associated with sensitive diabetic neuropathy in Type 2 Diabetes, and, in particular, dephospho-uncarboxylated MGP (dp-ucMGP), the inactive form of MGP. METHODS 198 patients with Type 2 Diabetes were included. Presence of sensitive diabetic neuropathy was defined by a neuropathy disability score (NDS) ≥6. Plasma levels of dp-ucMGP were measured by ELISA. RESULTS In this cohort, the mean age was 64+/-8.4 years old, and 80% of patients were men. Peripheral neuropathy was present in 15.7% of the patients and was significantly associated (r = 0.51, p<0.0001) with dp-ucMGP levels (β = -0.26, p = 0.045) after integrating effects of height (β = -0.38, p = 0.01), insulin treatment (β = 0.42, p = 0.002), retinopathy treated by laser (β = 0.26, p = 0.02), and total cholesterol levels (β = 0.3, p = 0.03) by multivariable analysis. CONCLUSIONS The association between diabetic neuropathy and the inactive form of MGP suggests the existence of new pathophysiological pathways to explore. Further studies are needed to determine if dp-ucMGP may be used as a biomarker of sensitive neuropathy. Since dp-ucMGP is a marker of poor vitamin K status, clinical studies are warranted to explore the potential protective effect of high vitamin K intake on diabetic peripheral neuropathy

Association between metformin use and below-the-knee arterial calcification score in type 2 diabetic patients.

BACKGROUND Vascular calcification (VC) is common in type 2 diabetes, and is associated with cardiovascular complications. Recent preclinical data suggest that metformin inhibits VC both in vitro and in animal models. However, metformin's effects in patients with diabetic VC have not previously been characterized. The present study investigated the association between metformin use and lower-limb arterial calcification in patients with type 2 diabetes and high cardiovascular risk. METHODS The DIACART cross-sectional cohort study included 198 patients with type 2 diabetes but without severe chronic kidney disease. Below-the-knee calcification scores were assessed by computed tomography and supplemented by colour duplex ultrasonography. Data on anti-diabetic drugs were carefully collected from the patients' medical records and during patient interviews. Biochemical and clinical data were studied as potential confounding factors. RESULTS Metformin-treated patients had a significantly lower calcification score than metformin-free patients (mean ± standard deviation: 2033 ± 4514 and 4684 ± 9291, respectively; p = 0.01). A univariate analysis showed that metformin was associated with a significantly lower prevalence of severe below-the-knee arterial calcification (p = 0.02). VC was not significantly associated with the use of other antidiabetic drugs, including sulfonylureas, insulin, gliptin, and glucagon like peptide-1 analogues. A multivariate logistic regression analysis indicated that the association between metformin use and calcification score (odds ratio [95% confidence interval] = 0.33 [0.11-0.98]; p = 0.045) was independent of age, gender, tobacco use, renal function, previous cardiovascular disease, diabetes duration, neuropathy, retinopathy, HbA1c levels, and inflammation. CONCLUSIONS In patients with type 2 diabetes, metformin use was independently associated with a lower below-the-knee arterial calcification score. This association may contribute to metformin's well-known vascular protective effect. Further prospective investigations of metformin's potential ability to inhibit VC in patients with and without type 2 diabetes are now needed to confirm these results

Characterising the inhibitory actions of ceramide upon insulin signaling in different skeletal muscle cell models:a mechanistic insight

International audienceCeramides are known to promote insulin resistance in a number of metabolically important tissues including skeletal muscle, the predominant site of insulin-stimulated glucose disposal. Depending on cell type, these lipid intermediates have been shown to inhibit protein kinase B (PKB/Akt), a key mediator of the metabolic actions of insulin, via two distinct pathways: one involving the action of atypical protein kinase C (aPKC) isoforms, and the second dependent on protein phosphatase-2A (PP2A). The main aim of this study was to explore the mechanisms by which ceramide inhibits PKB/Akt in three different skeletal muscle-derived cell culture models; rat L6 myotubes, mouse C2C12 myotubes and primary human skeletal muscle cells. Our findings indicate that the mechanism by which ceramide acts to repress PKB/Akt is related to the myocellular abundance of caveolin-enriched domains (CEM) present at the plasma membrane. Here, we show that ceramide-enriched-CEMs are markedly more abundant in L6 myotubes compared to C2C12 myotubes, consistent with their previously reported role in coordinating aPKC-directed repression of PKB/Akt in L6 muscle cells. In contrast, a PP2A-dependent pathway predominantly mediates ceramide-induced inhibition of PKB/Akt in C2C12 myotubes. In addition, we demonstrate for the first time that ceramide engages an aPKC-dependent pathway to suppress insulin-induced PKB/Akt activation in palmitate-treated cultured human muscle cells as well as in muscle cells from diabetic patients. Collectively, this work identifies key mechanistic differences, which may be linked to variations in plasma membrane composition, underlying the insulin-desensitising effects of ceramide in different skeletal muscle cell models that are extensively used in signal transduction and metabolic studies

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

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

Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide

The host-microbiota co-metabolite trimethylamine N-oxide (TMAO) is linked to increased cardiovascular risk but how its circulating levels are regulated remains unclear. We applied "explainable" machine learning, univariate, multivariate and mediation analyses of fasting plasma TMAO concentration and a multitude of phenotypes in 1,741 adult Europeans of the MetaCardis study. Here we show that next to age, kidney function is the primary variable predicting circulating TMAO, with microbiota composition and diet playing minor, albeit significant, roles. Mediation analysis suggests a causal relationship between TMAO and kidney function that we corroborate in preclinical models where TMAO exposure increases kidney scarring. Consistent with our findings, patients receiving glucose-lowering drugs with reno-protective properties have significantly lower circulating TMAO when compared to propensity-score matched control individuals. Our analyses uncover a bidirectional relationship between kidney function and TMAO that can potentially be modified by reno-protective anti-diabetic drugs and suggest a clinically actionable intervention for decreasing TMAO-associated excess cardiovascular risk

Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology

Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism

Effet de l AMP activated protein kinase sur la lipolyse dans l adipocyte humain

L AMP-activated protein kinase (AMPK) joue un rôle majeur dans la régulation du métabolisme énergétique. L AMPK stimule les voies cataboliques et inhibe les voies anaboliques. Pour approfondir les mécanismes par lesquels l AMPK contrôle l homéostasie énergétique, nous avons exploré son rôle dans la régulation de la lipolyse adipocytaire humaine. Dans l adipocyte murin, l AMPK inhibe la lipolyse. Comme les biguanides et les thiazolidinediones activent cette enzyme, nous avons testé l hypothèse que ceux-ci pourraient avoir un effet anti-lipolytique dans l adipocyte humain. Pour répondre à cette question, les adipocytes, obtenus chez des patients bénéficiant d une plastie abdominale, ont été incubés avec différents agents lipolytiques (isoprénaline et peptide atrial natriuretique/ANP) en présence ou non de biguanides ou de thiazolidinediones. Dans l adipocyte humain, ces antidiabétiques activent l AMPK et inhibent la lipolyse induite par l isoprénaline et l ANP de 30 à 40%, probablement par l inhibition de la translocation de la lipase hormono-sensible à la gouttelette lipidique. La stimulation de la lipolyse induit par ailleurs l activation de l AMPK. Nous avons montré pour la première fois dans l adipocyte humain que les biguanides et les thiazolidinediones activent l AMPK, inhibant ainsi la lipolyse induite par l isoprénaline et l ANP. Par ailleurs, les agonistes adrénergiques ainsi que l ANP stimulent l activité AMPK via l augmentation du rapport AMP/ATP, lié à l activation des acides gras en acyl-CoA. L AMPK pourrait être utilisée pour restreindre de manière pharmacologique la libération d acides gras dans la circulation.AMP-activated protein kinase (AMPK) plays a key role in regulating energy metabolism. AMPK switches-on catabolic pathways and switches-off anabolic pathways. In order to understand further how AMPK controls energy homeostasis, we have investigated its role in the regulation of human adipose tissue lipolysis. In rodent adipocytes, activated AMPK reduces the lipolytic rate. As metformin and thiazolidinediones activate this enzyme, we tested the hypothesis that they could have an anti-lipolytic effect in human adipocytes. Adipocytes, obtained from individuals undergoing plastic surgery, were isolated and incubated with lipolytic agents (isoprenaline, atrial natriuretic peptide/ANP) and biguanides or thiazolidinediones. Biguanides and thiazolidinediones activated AMPK and inhibited lipolysis induced by isoprenaline and ANP by 30-40%, at least in part by inhibiting hormone-sensitive lipase translocation to the lipid droplet. Inhibition of AMPK by compound C precluded this inhibitory effect on lipolysis. Stimulation of lipolysis also induced an activation of AMP-activated protein kinase concomitant with a drop in ATP concentration. We show for the first time in human adipocytes that biguanides and thiazolidinediones activate AMP-activated protein kinase, thus counteracting lipolysis induced by lipolytic agents. In addition, induction of lipolysis increases AMPK activity, because of an increase in the AMP/ATP ratio, linked to activation of some of the released fatty acids into acyl-CoA. AMPK activation could represent a physiological means of avoiding a deleterious drain of energy during lipolysis but could be used to restrain pharmacological release of fatty acids.PARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Effets des lipides alimentaires sur la glycémie post-prandiale chez le patient diabétique de type 1 (implications en insulinothérapie fonctionnelle)

La glycémie post-prandiale comme la glycémie à jeun participe à l équilibre glycémique moyen et l on sait que c est cet équilibre glycémique qui déterminera en grande partie la survenue ou non de complications du diabète notamment micro-angiopathiques (rétinopathie, néphropathie et neuropathie). L insulinothérapie fonctionnelle dans le diabète de type 1 a apporté des progrès majeurs tant en terme de qualité de vie qu en terme de contrôle glycémique. Mais habituellement cette adaptation des doses d insuline prandiale ne se fait que par rapport aux apports glucidiques sans prendre en compte la composition lipidique des repas. Lors d une hospitalisation au sein de la structure d éducation thérapeutique du service de diabétologie de l Hôpital de la Pitié-Salpêtrière, 20 patients diabétiques de type 1 ont consommé un repas du midi normal en lipides appelé LF (composé de 30g de lipides) et le lendemain un repas riche en lipides appelé HF (composé de 60g de lipides). L apport glucidiques (80g) et l index glycémique des deux repas étaient identiques. Nos résultats montrent que les lipides alimentaires influent fortement sur la régulation de la glycémie post-prandiale, et suggèrent que certains patients diabétiques de type 1 seraient plus sensibles à cette influence. Le mécanisme physiopathologique pourrait intervenir tant au niveau de la régulation de la vidange gastro-intestinale qu au niveau de mécanismes mettant en jeu l insulino-résistance périphérique.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF