Targeting the NLRP3 inflammasome-IL-1β pathway in type 2 diabetes and obesity.

Increased activity of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome-IL-1β pathway is observed in obesity and contributes to the development of type 2 diabetes and its complications. In this review, we describe the pathological activation of IL-1β by metabolic stress, ageing and the microbiome and present data on the role of IL-1β in metabolism. We explore the physiological role of the IL-1β pathway in insulin secretion and the relationship between circulating levels of IL-1β and the development of diabetes and associated diseases.

Ablation of PC1/3 in POMC-Expressing Tissues but Not in Immune Cells Induces Sepsis Hypersensitivity.

Prohormone convertase 1/3 (PC1/3) is an endopeptidase required for the processing of neuropeptide and endocrine peptide precursors; it is expressed in neuroendocrine tissues as well as in immune cells. In response to endotoxemia, global PC1/3 knockout mice mount a cytokine storm and die rapidly. Further, immune cells isolated from these mice have a pro-inflammatory signature, suggesting that PC1/3 activates an unknown anti-inflammatory peptide precursor in immune cells.

CO Capture with Polyethylenimine Supported on 3D-Printed Porous SiO Structures.

Amines supported on porous solid materials have a high CO adsorption capacity and low regeneration temperature. However, the high amine load on such substrates and the substrate itself may lead to substantial pressure drop across the reactor. Herein, we compare the CO adsorption capacity and pressure drop of fumed silica powder to 3D-printed monolithic fumed silica structures, both functionalized by polyethylenimine (PEI), and find a drastically reduced pressure drop for 3D-printed substrates (0.

Similar metabolic pathways are affected in both Congenital Myasthenic Syndrome-22 and Prader-Willi Syndrome.

Loss of prolyl endopeptidase-like (PREPL) encoding a serine hydrolase with (thio)esterase activity leads to the recessive metabolic disorder Congenital Myasthenic Syndrome-22 (CMS22). It is characterized by severe neonatal hypotonia, feeding problems, growth retardation, and hyperphagia leading to rapid weight gain later in childhood. The phenotypic similarities with Prader-Willi syndrome (PWS) are striking, suggesting that similar pathways are affected.

Protocol for isolation and spectral flow cytometry analysis of immune cells from the murine exocrine and endocrine pancreas.

Diabetes mellitus is a disease of the hormone-secreting endocrine pancreas. However, increasing evidence suggests that the exocrine pancreas is also involved in the pathogenesis of diabetes. In this protocol, we describe how to harvest both isolated islets and exocrine tissue from one mouse pancreas, followed by a detailed explanation of how to isolate and analyze immune cells using full-spectrum flow cytometry.

Cystine/Glutamate antiporter system xc- deficiency impairs macrophage glutathione metabolism and cytokine production.

System xc-, encoded by Slc7a11, is an antiporter responsible for exporting glutamate while importing cystine, which is essential for protein synthesis and the formation of thiol peptides, such as glutathione. Glutathione acts as a co-factor for enzymes responsible for scavenging reactive oxygen species. Upon exposure to bacterial products, macrophages exhibit a rapid upregulation of system xc-.

CSF1R inhibition with PLX5622 affects multiple immune cell compartments and induces tissue-specific metabolic effects in lean mice.

Aims/hypothesis: Colony stimulating factor 1 (CSF1) promotes the proliferation, differentiation and survival of macrophages, which have been implicated in both beneficial and detrimental effects on glucose metabolism. However, the physiological role of CSF1 signalling in glucose homeostasis and the potential therapeutic implications of modulating this pathway are not known. We aimed to study the composition of tissue macrophages (and other immune cells) following CSF1 receptor (CSF1R) inhibition and elucidate the metabolic consequences of CSF1R inhibition.

Cystine/glutamate antiporter System x deficiency impairs insulin secretion in mice.

Aims/hypothesis: Glutamate-induced cytotoxicity (excitotoxicity) has been detected in pancreatic beta cells. The cystine/glutamate antiporter System x exports glutamate to the extracellular space and is therefore implicated as driving excitotoxicity. As of yet, it has not been investigated whether System x contributes to pancreatic islet function.

Diesel Exhaust Particle (DEP)-induced glucose intolerance is driven by an intestinal innate immune response and NLRP3 activation in mice.

Background: We previously found that air pollution particles reaching the gastrointestinal tract elicit gut inflammation as shown by up-regulated gene expression of pro-inflammatory cytokines and monocyte/macrophage markers. This inflammatory response was associated with beta-cell dysfunction and glucose intolerance. So far, it remains unclear whether gut inflammatory changes upon oral air pollution exposure are causally linked to the development of diabetes.

Lung versus gut exposure to air pollution particles differentially affect metabolic health in mice.

Background: Air pollution has emerged as an unexpected risk factor for diabetes. However, the mechanism behind remains ill-defined. So far, the lung has been considered as the main target organ of air pollution.

Review on CO Capture Using Amine-Functionalized Materials.

CO capture from industry sectors or directly from the atmosphere is drawing much attention on a global scale because of the drastic changes in the climate and ecosystem which pose a potential threat to human health and life on Earth. In the past decades, CO capture technology relied on classical liquid amine scrubbing. Due to its high energy consumption and corrosive property, CO capture using solid materials has recently come under the spotlight.

Prohormone convertase 1/3 deficiency causes obesity due to impaired proinsulin processing.

Defective insulin processing is associated with obesity and diabetes. Prohormone convertase 1/3 (PC1/3) is an endopeptidase required for the processing of neurotransmitters and hormones. PC1/3 deficiency and genome-wide association studies relate PC1/3 with early onset obesity.

The cephalic phase of insulin release is modulated by IL-1β.

The initial cephalic phase of insulin secretion is mediated through the vagus nerve and is not due to glycemic stimulation of pancreatic β cells. Recently, IL-1β was shown to stimulate postprandial insulin secretion. Here, we describe that this incretin-like effect of IL-1β involves neuronal transmission.

Targeting colonic macrophages improves glycemic control in high-fat diet-induced obesity.

The obesity epidemic continues to worsen worldwide. However, the mechanisms initiating glucose dysregulation in obesity remain poorly understood. We assessed the role that colonic macrophage subpopulations play in glucose homeostasis in mice fed a high-fat diet (HFD).

Inflammation in obesity, diabetes, and related disorders.

Obesity leads to chronic, systemic inflammation and can lead to insulin resistance (IR), β-cell dysfunction, and ultimately type 2 diabetes (T2D). This chronic inflammatory state contributes to long-term complications of diabetes, including non-alcoholic fatty liver disease (NAFLD), retinopathy, cardiovascular disease, and nephropathy, and may underlie the association of type 2 diabetes with other conditions such as Alzheimer's disease, polycystic ovarian syndrome, gout, and rheumatoid arthritis. Here, we review the current understanding of the mechanisms underlying inflammation in obesity, T2D, and related disorders.

Discordance between estimated and measured changes in plasma volume among patients with acute heart failure.

Aims: In acute heart failure (AHF), changes of venous haemoglobin (Hb) concentrations, haematocrit (Hct), and estimated plasma volume (ePV) have been proposed as surrogates of decongestion. These estimates are based on the theoretical assumptions that changes of Hb concentrations and Hct are driven by the intravascular volume status and that the intravascular Hb pool remains stable. The objective of this study was to assess the relationship of changes of measured plasma volume (mPV) with changes of Hb, Hct, and ePV in AHF.

IL-1beta promotes the age-associated decline of beta cell function.

Aging is the prime risk factor for the development of type 2 diabetes. We investigated the role of the interleukin-1 (IL-1) system on insulin secretion in aged mice. During aging, expression of the protective IL-1 receptor antagonist decreased in islets, whereas IL-1beta gene expression increased specifically in the CD45 + islet immune cell fraction.

Serum creatinine and cystatin C-based estimates of glomerular filtration rate are misleading in acute heart failure.

Aims: We aimed to test whether the endogenous filtration markers serum creatinine or cystatin C and equation-based estimates of glomerular filtration rate (GFR) based on these markers appropriately reflect changes of measured GFR in patients with acute heart failure.

Methods: In this prospective cohort study of 50 hospitalized acute heart failure patients undergoing decongestive therapy, we applied an intravenous visible fluorescent injectate (VFI), consisting of a low molecular weight component to measure GFR and a high molecular weight component to correct for measured plasma volume. Thirty-eight patients had two sequential GFR measurements 48 h apart.

Low concentration IL-1β promotes islet amyloid formation by increasing hIAPP release from humanised mouse islets in vitro.

Aims/hypothesis: Aggregation of the beta cell secretory product human islet amyloid polypeptide (hIAPP) results in islet amyloid deposition, a pathological feature of type 2 diabetes. Amyloid formation is associated with increased levels of islet IL-1β as well as beta cell dysfunction and death, but the mechanisms that promote amyloid deposition in situ remain unclear. We hypothesised that physiologically relevant concentrations of IL-1β stimulate beta cell islet amyloid polypeptide (IAPP) release and promote amyloid formation.

Inhibition of IL-1beta improves Glycaemia in a Mouse Model for Gestational Diabetes.

Gestational diabetes mellitus (GDM) is one of the most common diseases associated with pregnancy, however, the underlying mechanisms remain unclear. Based on the well documented role of inflammation in type 2 diabetes, the aim was to investigate the role of inflammation in GDM. We established a mouse model for GDM on the basis of its two major risk factors, obesity and aging.

Inflammation in the Pathophysiology and Therapy of Cardiometabolic Disease.

The role of chronic inflammation in the pathogenesis of type 2 diabetes mellitus and associated complications is now well established. Therapeutic interventions counteracting metabolic inflammation improve insulin secretion and action and glucose control and may prevent long-term complications. Thus, a number of anti-inflammatory drugs approved for the treatment of other inflammatory conditions are evaluated in patients with metabolic syndrome.

Islet inflammation in type 2 diabetes.

Metabolic diseases including type 2 diabetes are associated with meta-inflammation. β-Cell failure is a major component of the pathogenesis of type 2 diabetes. It is now well established that increased numbers of innate immune cells, cytokines, and chemokines have detrimental effects on islets in these chronic conditions.

A Novel Fluorescent Clinical Method to Rapidly Quantify Plasma Volume.

Objectives: To determine the performance of a rapid fluorescent indicator technique for measuring plasma volume (PV).

Methods: This was an open-label, observational evaluation of a two-component intravenous visible fluorescent dye technique to rapidly measure PV in 16 healthy subjects and 16 subjects with chronic kidney disease (8 stage 3 and 8 stage 4 CKD), at 2 clinical research sites. The method consisted of a single intravenous injection of 12 mg of a large 150-kDa carboxy-methyl dextran conjugated to a fluorescent rhodamine-derived dye as the PV marker (PVM), and 35 mg of a small 5-kDa carboxy-methyl dextran conjugated to fluorescein, the renal clearance marker.