Glycaemic benefit of iGlarLixi in insulin-naive type 2 diabetes patients with high HbA1c or those with inadequate glycaemic control on two oral antihyperglycaemic drugs in the LixiLan-O randomized trial

In this post hoc analysis of the randomized controlled LixiLan‐O trial in insulin‐naive type 2 diabetes mellitus (T2DM) patients not controlled on metformin with or without a second oral antihyperglycaemic drug (OAD), the efficacy and safety of the fixed‐ratio combination, iGlarLixi (insulin glargine 100 U [iGlar] and lixisenatide [Lixi]), compared to its individual components was assessed in two patient subgroups: (1) a baseline HbA1c ≥9% (n = 134); (2) inadequate control (HbA1c ≥7.0% and ≤9.0%) despite administration of two OADs at screening (n = 725). Treatment with iGlarLixi resulted in a significantly greater reduction in least squares mean HbA1c compared with iGlar or Lixi alone in both subgroups (HbA1c ≥9% group: 2.9%, 2.5%, 1.7%; two OADs group: 1.5%, 1.2%, 0.7%, respectively). Target HbA1c 70% of patients on iGlarLixi in both subgroups, while mitigating the weight gain observed with iGlar alone. Rates of hypoglycaemic events were low overall. These results suggest that iGlarLixi achieves superior glycaemic control compared with iGlar or Lixi alone in T2DM patients with HbA1c ≥9% or those inadequately controlled on two OADs

Albuminuria is associated with too few glomeruli and too much testosterone

Normally, the glomerular filtration barrier almost completely excludes circulating albumin from entering the urine. Genetic variation and both pre- and postnatal environmental factors may affect albuminuria in humans. Here we determine whether glomerular gene expression in mouse strains with naturally occurring variations in albuminuria would allow identification of proteins deregulated in relatively 'leaky' glomeruli. Albuminuria increased in female B6 to male B6 to female FVB/N to male FVB/N mice, whereas the number of glomeruli/kidney was the exact opposite. Testosterone administration led to increased albuminuria in female B6 but not female FVB/N mice. A common set of 39 genes, many expressed in podocytes, were significantly differentially expressed in each of the four comparisons: male versus female B6 mice, male versus female FVB/N mice, male FVB/N versus male B6 mice, and female FVB/N versus female B6 mice. The transcripts encoded proteins involved in oxidation/reduction reactions, ion transport, and enzymes involved in detoxification. These proteins may represent novel biomarkers and even therapeutic targets for early kidney and cardiovascular disease

Complementary actions of dopamine D2 receptor 1 agonist and anti-Vegf therapy on tumoral vessel normalization in a transgenic mouse model

International audienceAngiogenesis contributes in multiple ways to disease progression in tumors and reduces treatment efficiency. Molecular therapies targeting Vegf signaling combined with chemotherapy or other drugs exhibit promising results to improve efficacy of treatment. Dopamine has been recently proposed to be a novel safe anti-angiogenic drug that stabilizes abnormal blood vessels and increases therapeutic efficacy. Here, we aimed to identify a treatment to normalize tumoral vessels and restore normal blood perfusion in tumor tissue with a Vegf receptor inhibitor and/or a ligand of dopamine G protein-coupled receptor D2 (D2R). Dopamine, via its action on D2R, is an endogenous effector of the pituitary gland, and we took advantage of this system to address this question. We have used a previously described Hmga2/T mouse model developing haemorrhagic prolactin-secreting adenomas. In mutant mice, blood vessels are profoundly altered in tumors, and an aberrant arterial vascularization develops leading to the loss of dopamine supply. D2R agonist treatment blocks tumor growth, induces regression of the aberrant blood supply and normalizes blood vessels. A chronic treatment is able to restore the altered balance between pro- and anti-angiogenic factors. Remarkably, an acute treatment induces an upregulation of the stabilizing factor Angiopoietin 1. An anti-Vegf therapy is also effective to restrain tumor growth and improves vascular remodeling. Importantly, only the combination treatment suppresses intratumoral hemorrhage and restores blood vessel perfusion, suggesting that it might represent an attractive therapy targeting tumor vasculature. Similar strategies targeting other ligands of GPCRs involved in angiogenesis may identify novel therapeutic opportunities for cancer

Loss of endogenous thymosin β4 accelerates glomerular disease

Glomerular disease is characterized by morphologic changes in podocyte cells accompanied by inflammation and fibrosis. Thymosin $\beta_4$ regulates cell morphology, inflammation, and fibrosis in several organs and administration of exogenous thymosin $\beta_4$ improves animal models of unilateral ureteral obstruction and diabetic nephropathy. However, the role of endogenous thymosin $\beta_4$ in the kidney is unknown. We demonstrate that thymosin β4 is expressed prominently in podocytes of developing and adult mouse glomeruli. Global loss of thymosin $\beta_4$ did not affect healthy glomeruli, but accelerated the severity of immune-mediated nephrotoxic nephritis with worse renal function, periglomerular inflammation, and fibrosis. Lack of thymosin $\beta_4$ in nephrotoxic nephritis led to the redistribution of podocytes from the glomerular tuft toward the Bowman capsule suggesting a role for thymosin $\beta_4$ in the migration of these cells. Thymosin $\beta_4$ knockdown in cultured podocytes also increased migration in a wound-healing assay, accompanied by F-actin rearrangement and increased RhoA activity. We propose that endogenous thymosin $\beta_4$ is a modifier of glomerular injury, likely having a protective role acting as a brake to slow disease progression

Mechanical forces and TGF{beta}1 reduce podocyte adhesion through {alpha}3{beta}1 integrin downregulation

BACKGROUND: Podocyturia is a marker of diabetic nephr- opathy, a possible determinant of its progression and a powerful risk factor for cardiovascular disease. A reduction in podocyte adhesion to the glomerular basement membrane (GBM) via downregulation of alpha3beta1 integrin expression, the main podocyte anchoring dimer to the GBM, may represent one of the mechanisms of podocyturia in glomerular disease. This study investigated the role of mechanical forces and transforming growth factor beta1 (TGFbeta1) in podocyte adhesion and integrin expression. METHODS: Conditionally immortalized murine podocytes were exposed to mechanical stretch and/or TGFbeta1 for 48 h. Podocyte adhesion, apoptosis and alpha3beta1 integrin expression were assessed. RESULTS: Stretch and TGFbeta1 significantly reduced podocyte adhesion and alpha3beta1 integrin expression, events paralleled by increased apoptosis. Blockade of beta1 integrin, with a specific antibody, demonstrated a reduced podocyte adhesion indicating that beta1 integrin downregulation was required for the loss of podocyte adhesion. This was linked to an increase in podocyte apoptosis. The role of apoptosis in podocyte adhesion was further investigated using caspase-3 inhibitors. Podocyte apoptosis inhibition did not affect stretch- and TGFbeta1-mediated integrin downregulation and the loss of podocyte adhesion, suggesting that alpha3beta1 integrin downregulation is sufficient to alter cell adhesion. Although stretch significantly increased podocyte TGFbeta type I, II and III receptors but not podocyte TGFbeta1 secretion, the combination of stretch and TGFbeta1 did not show any additive or synergistic effects on podocyte adhesion and alpha3beta1 integrin expression. CONCLUSIONS: These results suggest that downregulation of alpha3beta1 integrin expression, by mechanical forces or TGFbeta1, is per se sufficient to reduce podocyte adhesion. Apoptosis may represent a parallel important determinant of the podocyte loss from the GBM