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The parenchymal cells of the mammalian pineal gland are the hormone-producing pinealocytes and the interstitial cells. In addition, perivascular phagocytes are present. The phagocytes share antigenic properties with microglial and antigen-presenting cells. In certain species, the pineal gland also contains neurons and/or neuron-like peptidergic cells. The peptidergic cells might influence the pinealocyte by a paracrine secretion of the peptide. Nerve fibers innervating the mammalian pineal gland originate from perikarya located in the sympathetic superior cervical ganglion and the parasympathetic sphenopalatine and otic ganglia. The sympathetic nerve fibers contain norepinephrine and neuropeptide Y as neurotransmitters. The parasympathetic nerve fibers contain vasoactive intestinal peptide and peptide histidine isoleucine. Recently, neurons in the trigeminal ganglion, containing substance P, calcitonin gene-related peptide, and pituitary adenylate cyclase-activating peptide, have been shown to project to the mammalian pineal gland. Finally, nerve fibers originating from perikarya located in the brain containing, for example, GABA, orexin, serotonin, histamine, oxytocin, and vasopressin innervate the pineal gland directly via the pineal stalk. Biochemical studies have demonstrated numerous receptors on the pinealocyte cell membrane, which are able to bind the neurotransmitters located in the pinealopetal nerve fibers. These findings indicate that the mammalian pinealocyte can be influenced by a plethora of neurotransmitters.

BACKGROUND More data regarding effects of glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes (T2D) and heart failure (HF) are required.OBJECTIVES The purpose of this study was to investigate the effects of liraglutide on cardiovascular events and mortality in LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) participants, by HF history. METHODS In the multinational, double-blind, randomized LEADER trial, 9,340 patients with T2D and high cardiovascular risk were assigned 1:1 to liraglutide (1.8 mg daily or maximum tolerated dose up to 1.8 mg daily) or placebo plus standard care, and followed for 3.5 to 5 years. New York Heart Association (NYHA) functional class IV HF was an exclusion criterion. The primary composite major adverse cardiovascular events outcome was time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Post hoc Cox regression analyses of outcomes by baseline HF history were conducted.RESULTS At baseline, 18% of patients had a history of NYHA functional class I to III HF (liraglutide: n ¼ 835 of 4,668; placebo: n ¼ 832 of 4,672). Effects of liraglutide versus placebo on major adverse cardiovascular events were consistent in patients with (hazard ratio [HR]: 0.81 [95% confidence interval (CI): 0.65 to 1.02]) and without (HR: 0.88 [95% CI: 0.78 to 1.00]) a history of HF (p interaction ¼ 0.53). In both subgroups, fewer deaths were observed with liraglutide (HR:

Background Chronic kidney disease (CKD) is a common complication of type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycaemic control and lower body weight in people with T2D, and some reduce risk of cardiovascular (CV) events in those with high CV risk. GLP-1RAs might also have kidney-protective effects. We report the design and baseline data for FLOW, a trial investigating the effects of once-weekly (OW) GLP-1RA semaglutide on kidney outcomes in participants with CKD and T2D. Methods FLOW is a randomised, double-blind, parallel-group, multinational, phase 3b trial. Participants with T2D, estimated glomerular filtration rate (eGFR) ≥50‒≤75 mL/min/1.73 m2 and urine albumin-to-creatinine ratio (UACR) >300‒<5,000 mg/g or eGFR ≥ 25‒<50 mL/min/1.73 m2 and UACR > 100‒<5,000 mg/g, were randomised 1:1 to OW semaglutide 1.0 mg or matched placebo, with renin-angiotensin-aldosterone system blockade (unless not tolerated/contraindicated). The composite primary endpoint is time to first: kidney failure (persistent eGFR <15 mL/min/1.73 m² or initiation of chronic kidney replacement therapy); persistent ≥ 50% reduction in eGFR; or death from kidney or CV causes. Results Enrolled participants (N = 3 534) had a baseline mean (SD) age of 66.6 (9.0) years, HbA1c of 7.8 (1.3) %, diabetes duration of 17.4 (9.3) years, eGFR of 47.0 (15.2) mL/min/1.73 m2 and median UACR of 568 (range: 2‒11 852) mg/g. According to Kidney Disease: Improving Global Outcomes guideline categorisation, 68.2% were at very high risk for CKD progression. Conclusion FLOW will evaluate the effect of semaglutide on kidney outcomes in participants with CKD and T2D, and is expected to complete in late 2024.

BackgroundEpidemiological data on obesity are needed, particularly in patients with type 2 diabetes mellitus (T2DM) and high cardiovascular (CV) risk. We used the baseline data of liraglutide effect and action in diabetes: evaluation of CV outcome results—A long term Evaluation (LEADER) (a clinical trial to assess the CV safety of liraglutide) to investigate: (i) prevalence of overweight and obesity; (ii) relationship of the major cardiometabolic risk factors with anthropometric measures of adiposity [body mass index (BMI) and waist circumference (WC)]; and (iii) cardiometabolic treatment intensity in relation to BMI and WC.MethodsLEADER enrolled two distinct populations of high-risk patients with T2DM in 32 countries: (1) aged ≥50 years with prior CV disease; (2) aged ≥60 years with one or more CV risk factors. Associations of metabolic variables, demographic variables and treatment intensity with anthropometric measurements (BMI and WC) were explored using regression models (ClinicalTrials.gov identifier: NCT01179048).ResultsMean BMI was 32.5 ± 6.3 kg/m2 and only 9.1 % had BMI <25 kg/m2. The prevalence of healthy WC was also extremely low (6.4 % according to International Joint Interim Statement for the Harmonization of the Metabolic Syndrome criteria). Obesity was associated with being younger, female, previous smoker, Caucasian, American, with shorter diabetes duration, uncontrolled blood pressure (BP), antihypertensive agents, insulin plus oral antihyperglycaemic treatment, higher levels of triglycerides and lower levels of high-density lipoprotein cholesterol.ConclusionsOverweight and obesity are prevalent in high CV risk patients with T2DM. BMI and WC are related to the major cardiometabolic risk factors. Furthermore, treatment intensity, such as insulin, statins or oral antihypertensive drugs, is higher in those who are overweight or obese; while BP and lipid control in these patients are remarkably suboptimal. LEADER confers a unique opportunity to explore the longitudinal effect of weight on CV risk factors and hard endpoints.