Rôle du système kallicréine-kinines dans le diabète et ses complications

Le système kallicréine-kinines (SKK) est un système peptidique vasodilatateur. Les métabolites actifs du système, les kinines, sont produites par la kallicréine tissulaire (TK), et agissent via leurs deux récepteurs, B2 et B1. Le SKK a été impliqué dans les processus physiopathologiques conduisant au diabète de type 2. Son rôle est bien établi dans la protection des complications cardiovasculaires et rénales du diabète. Nous avons étudié le rôle du SKK dans le développement des anomalies métaboliques liées à l'obésité en utilisant des souris déficientes en TK dans deux modèles d'obésité (mutation ob/ob et régime gras). Nous n'avons pas mis en évidence d'effet de la déficience en TK sur les anomalies glucidiques dans ces deux modèles. Chez l'homme, nous avons étudié l'effet d'un polymorphisme génétique de la TK dans une cohorte de 4843 sujets de la population générale suivi pendant 9 ans. Nous n'avons pas observé d'effet d'un déficit partiel en activité TK sur l'apparition des troubles glucidiques.Ensuite, nous avons étudié l'effet de la stimulation du SKK par des agonistes spécifiques de chaque récepteur lors d'une ischémie reperfusion cardiaque. Chez les souris non diabétiques, l'agoniste B2 réduit la taille de l'infarctus. L'agoniste B1 n'a pas d'effet. Chez les souris diabétiques, l'agoniste B2 n'a pas d'effet. En revanche, l'agoniste B1 diminue la taille de l'infarctus. On observe une induction de la synthèse du B1R dans le c¿ur diabétique.Nos travaux clarifient le rôle du SKK dans le développement du diabète et de ses complications cardiaques. L'effet des agonistes ouvre une nouvelle piste thérapeutique dans la prise en charge des du syndrome coronarien aigu.Kallikrein-kinin system (KKS) is a vasodilator peptide system. Kinins, the active peptides, are produced by tissue kallikrein (TK), and act via their two receptors, B1 and B2. KKS was involved in the pathophysiological process leading to type 2 diabetes. Its role is well established in the protection of cardiovascular and renal complications of diabetes. We studied the role of SKK in the development of metabolic abnormalities associated with obesity using TK deficient mice in two models of obesity (Ob/Ob and high fat diet). We did not observed any effect of TK deficiency on metabolic parameters in these two models. In humans, we studied the effect of a polymorphism of TK in a population-based cohort of 4843 subjects followed for 9 years. We did not observe any effect of a partial deficiency in TK on the occurrence of metabolic disorders. Next, we studied the effect of specific agonists of B1 and B2 receptors in cardiac ischemia reperfusion injury. In non-diabetic mice, the B2 agonist reduces infarct size. Agonist B1 has no effect. In diabetic mice, B2 agonist had no effect. In contrast, B1 agonist reduces infarct size. Overexpression of B1R is observed in the diabetic heart. Our work clarifies the role of SKK in the development of diabetes and its cardiac complications. Agonists of kinins receptors could be a new therapeutic approach in the management of acute coronary syndrome.PARIS-JUSSIEU-Bib.électronique (751059901) / SudocSudocFranceF

0052: Role of kinins in diabetic wound healing

The diabetic foot is associated with pain, decrease in patient's quality of life, considerable costs, and amputation. In this study, we determined the role of KKS, via activation of bradykinin receptors (B1R or B2R), in a mouse model of diabetic wound healing. Diabetic or nondiabetic mice are wounded with an 8-mm punch biopsy and then are treated or not with specific B1R or B2R agonists (720nmol/kg.d-1) and/or B2R antagonist (Icatibant, 500μg/kg.dg/d-1). The wound-healing surface was daily followed up. At 11 days, the scar were analysed by histology (Masson's trichrome staining) and B1R and B2R expression were assessed (RT-qPCR). Effects of the agonists on cells (fibroblasts and keratinocytes) migration and proliferation were also analysed. In diabetic condition, mRNA of B1R and B2R was increased in skin (p<0.01). B1R activation had no effect on wound closure in our model. In contrast, B2R activation dramatically delayed wound healing in diabetic (p<0.001) or nondiabetic (p<0.01) mice. Histological analysis of scar showed significant skin disorganization and epidermis thickening with B2R agonist (p<0.05). In vitro, B2R agonist induced an increase of keratinocyte proliferation (+46% after 48h, p<0.01) and a stimulation of keratinocyte migration (+30% after 24h, p<0.05). These effects was associated with ERK phosphorylation which occurs downstream of EGFR activation (p<0.05). B2R agonist had no effect on fibroblast migration but decreased fibroblast proliferation (–33% after 48h, p<0.05). Co-treatment with Icatibant abrogated in vivo and in vitro effects observed with B2R agonist. Moreover, Icatibant alone hastened wound healing and decrease the epidermis thickening induced by diabetes. In conclusion, KKS, through the B2R but not the B1R, plays a critical role in proliferation and remodelling phases of skin wound healing in mice. While more studies are needed, Icatibant could be used to correct the diabetic wound healing defect

Lower-extremity amputation as a marker for renal and cardiovascular events and mortality in patients with long standing type 1 diabetes

International audienceAbstractBackgroundWe evaluated the risks of renal and cardiovascular complications, and mortality associated with lower extremity amputation (LEA) in patients with type 1 diabetes.MethodsWe studied two cohorts of people with long standing type 1 diabetes: GENEDIAB (n = 456) and GENESIS (n = 611). Subsets of the cohorts (n = 260, n = 544) were followed for 9 and 5 years, respectively. Outcomes were the incidence of end stage renal disease (ESRD), myocardial infarction, stroke and mortality during follow-up. Analyses were performed in pooled cohorts.ResultsThe prevalence of LEA at baseline was 9.3 % (n = 99). A positive history of LEA was associated with the baseline prevalence of established (OR 4.50, 95 % CI 2.33–8.91, p < 0.0001) and advanced diabetic nephropathy (OR 5.50, 95 % CI 2.89–10.78, p < 0.0001), ESRD (OR 2.86, 95 % CI 1.43–5.50, p = 0.004), myocardial infarction (OR 3.25, 95 % CI 1.68–6.15, p = 0.0006) and stroke (OR 3.88, 95 % CI 1.67–8.72, p = 0.002, adjusted for sex, age, and cohort membership). A positive history of LEA at baseline was associated with the incidence during follow-up of ESRD (HR 2.69, 95 % CI 1.17–6.20, p = 0.02), and myocardial infarction (HR 3.53, 95 % CI 1.79–6.97, p = 0.0001). History of LEA was also associated with increased risk for all-cause (HR 3.55, 95 % CI 2.05–6.16, p < 0.0001), cardiovascular (HR 3.30, 95 % CI 1.36–8.02, p = 0.008), infectious disease (HR 5.18, 95 % CI 1.13–23.84, p = 0.03) and other-cause mortality (HR 2.81, 95 % CI 1.09–7.26, p = 0.03). History of LEA at baseline was associated with a 40 % reduction in the duration of survival in the subset of patients who died during follow-up. Population attributable risk of the history of LEA at baseline for total mortality during follow-up was 0.31.ConclusionsPatients with LEA have a higher risk of ESRD, myocardial infarction and cardiovascular and non-cardiovascular mortality. Our results highlight the importance of LEA as a key-predictor for major vascular events and premature death in type 1 diabetic patients

More Similarities Than Differences Testing Insulin Glargine 300 Units/mL Versus Insulin Degludec 100 Units/mL in Insulin-Naive Type 2 Diabetes: The Randomized Head-to-Head BRIGHT Trial

OBJECTIVE To compare insulin glargine 300 units/mL (Gla-300) versus insulin degludec 100 units/mL (IDeg-100) in this first head-to-head randomized controlled trial. RESEARCH DESIGN AND METHODS BRIGHT (NCT02738151) was a multicenter, open-label, active-controlled, two-arm, parallel-group, 24-week, noninferiority study in insulin-naive patients with uncontrolled type 2 diabetes. Participants were randomized 1:1 to evening dosing with Gla-300 (N = 466) or IDeg-100 (N = 463), titrated to fasting self-monitored plasma glucose of 80–100 mg/dL. The primary end point was HbA1c change from baseline to week 24. Safety end points included incidence and event rates of hypoglycemia. RESULTS At week 24, HbA1c improved similarly from baseline values of 8.7% (72 mmol/mol) in the Gla-300 group and 8.6% (70 mmol/mol) in the IDeg-100 group to 7.0% (53 mmol/mol)—least squares mean difference −0.05% (95% CI −0.15 to 0.05) (−0.6 mmol/mol [−1.7 to 0.6])—demonstrating noninferiority of Gla-300 versus IDeg-100 (P &lt; 0.0001). Hypoglycemia incidence and event rates over 24 weeks were comparable with both insulins, whereas during the active titration period (0–12 weeks) the incidence and rate of anytime (24-h) confirmed hypoglycemia (≤70 and &lt;54 mg/dL) were lower with Gla-300. Both insulins were properly titrated and exhibited no specific safety concerns. CONCLUSIONS Gla-300 and IDeg-100 provided similar glycemic control improvements with relatively low hypoglycemia risk. Hypoglycemia incidence and rates were comparable with both insulins during the full study period but lower in favor of Gla-300 during the titration period. The choice between these longer-acting basal insulins may be determined by factors such as access and cost, alongside clinical considerations

Real-world outcomes of treatment with insulin glargine 300 U/mL versus standard-of-care in people with uncontrolled type 2 diabetes mellitus

Objective: To compare real-world outcomes with newer (insulin glargine 300 U/mL; Gla-300) versus standard of care (SoC) basal insulins (BIs) in the REACH (insulin-naive; NCT02967224) and REGAIN (basal insulin-treated; NCT02967211) studies in participants with uncontrolled type 2 diabetes (T2DM) in Europe and Brazil. Methods: In these open-label, parallel-group, pragmatic studies, patients (HbA(1c) > 7.0%) were randomized to Gla-300 or SoC BI for a 6-month treatment period (to demonstrate non-inferiority of Gla-300 vs SoC BIs for HbA(1c) change [non-inferiority margin 0.3%]) and a 6-month extension period (continuing with their assigned treatment). Insulin titration/other medication changes were at investigator/patient discretion post-randomization. Results: Overall, 703 patients were randomized to treatment in REACH (Gla-300, n = 352; SoC, n = 351) and 609 (Gla-300, n = 305, SoC, n = 304) in REGAIN. The primary outcome, non-inferiority of Gla-300 versus SoC for HbA(1c) change from baseline to month 6, was met in REACH (least squares [LS] mean difference 0.12% [95% CI -0.046 to 0.281]) but not REGAIN (LS mean difference 0.17% [0.015-0.329]); no between-treatment difference in HbA(1c) change was shown after 12 months in either study. BI dose increased minimally from baseline to 12 months in REACH (Gla-300, +0.17 U/kg; SoC, +0.15 U/kg) and REGAIN (Gla-300, +0.11 U/kg; SoC, +0.07 U/kg). Hypoglycemia incidence was low and similar between treatment arms in both studies. Conclusions: In both REACH and REGAIN, no differences in glycemic control or hypoglycemia outcomes with Gla-300 versus SoC BIs were seen over 12 months. However, the suboptimal insulin titration in REACH and REGAIN limits comparisons of outcomes between treatment arms and suggests that more titration instruction/support may be required for patients to fully derive the benefits from newer basal insulin formulations

The T-381C SNP in BNP gene may be modestly associated with type 2 diabetes: an updated meta-analysis in 49 279 subjects

A recent study reported an association between the brain natriuretic peptide (BNP) promoter T-381C polymorphism (rs198389) and protection against type 2 diabetes (T2D). As replication in several studies is mandatory to confirm genetic results, we analyzed the T-381C polymorphism in seven independent case-control cohorts and in 291 T2D-enriched pedigrees totalling 39 557 subjects of European origin. A meta-analysis of the seven case-control studies (n = 39 040) showed a nominal protective effect [odds ratio (OR) = 0.86 (0.79-0.94), P = 0.0006] of the CC genotype on T2D risk, consistent with the previous study. By combining all available data (n = 49 279), we further confirmed a modest contribution of the BNP T-381C polymorphism for protection against T2D [OR = 0.86 (0.80-0.92), P = 1.4 × 10−5]. Potential confounders such as gender, age, obesity status or family history were tested in 4335 T2D and 4179 normoglycemic subjects and they had no influence on T2D risk. This study provides further evidence of a modest contribution of the BNP T-381C polymorphism in protection against T2D and illustrates the difficulty of unambiguously proving modest-sized associations even with large sample size