Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Differential Regulation of Plasma Obestatin and Ghrelin by Meal Intake and the Cholinergic System in Lean, But Not Obese Individuals

Context: Obestatin is cosecreted with and stemming from the same precursor as ghrelin and is apparently involved in energy metabolism. Relatively little is known about the regulation of obestatin release. Objective: The regulation of obestatin release and obestatin-to-ghrelin ratios by meal intake and the cholinergic system were studied in lean and obese subjects. Design, Participants, and Setting: We conducted a randomized, double-blind, placebo-controlled, crossover study with 4 study days in eight obese (body mass index Ͼ30 kg/m 2 ) and eight matched lean (body mass index Ͻ25 kg/m 2 ) healthy subjects (two males and six females per group) at a University Clinical Research Unit. Interventions: Atropine (1 mg iv) was administered alone and in combination with breakfast (550 kcal) intake, or placebo (isotonic saline) alone and in combination with breakfast. Main Outcome Measures: We measured plasma obestatin and obestatin/ghrelin ratios. Results: Both obestatin and ghrelin/obestatin ratios decreased significantly from baseline by either atropine or meal intake in lean individuals, with the two effects adding up on the combined atropine/breakfast day. In contrast, there were no statistically significant differences in obese subjects, who also showed significantly greater association between ghrelin and obestatin values than their lean counterparts. Conclusions: Obestatin and ghrelin release is differentially regulated by meal intake and the cholinergic system in lean individuals. This regulation is impaired in obesity. (J Clin Endocrinol Metab 95: 0000 -0000, 2010) G hrelin, the octanoylated peptide produced mainly by the stomach and natural ligand to the GH secretagogue-receptor, is now well established as an orexigenic hormone mediating increased food intake resulting in a positive energy balance (1). Obestatin, an amidated cleavage product of the preproghrelin gene, was initially described as opposing the functions of ghrelin on appetite, resulting in decreased gastric food intake and weight gain in rodents, by binding to its cognate receptor, an (until then) orphan receptor termed g protein coupled receptor 39 (2). These results have been partially confirmed, but also called into question (see Ref. 3 and the references therein). Obestatin does bind to membranes of pancreatic cells and cell lines with high affinity and promotes survival o

Effects of general receptor for phosphoinositides 1 on insulin and insulin-like growth factor I-induced cytoskeletal rearrangement, glucose transporter-4 translocation, and deoxyribonucleic acid synthesis

We investigated the effects of general receptor for phosphoinositides-1 (GRP1), a recently cloned protein that binds 3,4,5-phosphatidylinositol [PtdIns(3,4,5)P3] with high affinity, but not PtdIns(3,4)P2 nor PtdIns(3)P, on insulin and insulin-like growth factor I (IGF-I)-induced cytoskeletal rearrangement, glucose transporter-4 (GLUT4) translocation, and DNA synthesis. GRP1 consists of an NH2-terminally located coiled coil domain followed by a Sec7 domain and a COOH-terminal pleckstrin homology (PH) domain that is required for PtdIns binding. We used microinjection of glutathione-S-transferase fusion proteins containing residues 239-399 (PH domain), residues 52-260 (Sec7 domain), residues 5-71 (N-terminal domain), full-length GRP1, and an antibody (AB) raised against full-length GRP1 coupled with immunofluorescent detection of actin filament rearrangement, GLUT4 translocation, and 3'-bromo-5'-deoxyuridine incorporation. Microinjection of these constructs and the AB had no effect on insulin-induced GLUT4 translocation or DNA synthesis. However, microinjection of the GRP1-PH and the GRP1-Sec7 domain as well as the alpha-GRP1-AB significantly inhibited insulin- and IGF-I-stimulated actin rearrangement in an insulin receptor-overexpressing cell line (HIRcB) compared with that in control experiments. Coinjection of GRP1-Sec7 along with constitutively active Rac (Q67L) did not inhibit Rac-induced actin rearrangement. Furthermore, GRP1 is not able to bind and act as a nucleotide exchange factor for the small GTP-binding proteins of the Rho family. As GRP1 acts as a guanine nucleotide exchange factor for ARF6 proteins, we propose a signaling pathway distinct from the small GTP-binding protein Rac, connecting PtdIns(3,4,5)P3 via GRP1 to ARF6, leading to insulin- and IGF-I-induced actin rearrangement

G Alpha-q/11 Protein Plays a Key Role in Insulin-Induced Glucose Transport in 3T3-L1 Adipocytes

We evaluated the role of the G alpha-q (Gαq) subunit of heterotrimeric G proteins in the insulin signaling pathway leading to GLUT4 translocation. We inhibited endogenous Gαq function by single cell microinjection of anti-Gαq/11 antibody or RGS2 protein (a GAP protein for Gαq), followed by immunostaining to assess GLUT4 translocation in 3T3-L1 adipocytes. Gαq/11 antibody and RGS2 inhibited insulin-induced GLUT4 translocation by 60 or 75%, respectively, indicating that activated Gαq is important for insulin-induced glucose transport. We then assessed the effect of overexpressing wild-type Gαq (WT-Gαq) or a constitutively active Gαq mutant (Q209L-Gαq) by using an adenovirus expression vector. In the basal state, Q209L-Gαq expression stimulated 2-deoxy-d-glucose uptake and GLUT4 translocation to 70% of the maximal insulin effect. This effect of Q209L-Gαq was inhibited by wortmannin, suggesting that it is phosphatidylinositol 3-kinase (PI3-kinase) dependent. We further show that Q209L-Gαq stimulates PI3-kinase activity in p110α and p110γ immunoprecipitates by 3- and 8-fold, respectively, whereas insulin stimulates this activity mostly in p110α by 10-fold. Nevertheless, only microinjection of anti-p110α (and not p110γ) antibody inhibited both insulin- and Q209L-Gαq-induced GLUT4 translocation, suggesting that the metabolic effects induced by Q209L-Gαq are dependent on the p110α subunit of PI3-kinase. In summary, (i) Gαq appears to play a necessary role in insulin-stimulated glucose transport, (ii) Gαq action in the insulin signaling pathway is upstream of and dependent upon PI3-kinase, and (iii) Gαq can transmit signals from the insulin receptor to the p110α subunit of PI3-kinase, which leads to GLUT4 translocation