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Over the recent past, the importance of aberrant immune cell activation as one of the contributing mechanisms to the development of insulin-resistance and type 2 diabetes (T2D) has been recognized. T2D is clearly associated with obesity, and clinical progression of this disease has been linked to chronic low-grade inflammation due to activation of immune cells. Given the recent developments in understanding inflammation as a mediator of disease progression, an understanding of factors related to IL-1β regulation is in order. The accumulation of DAMPs during chronic inflammatory diseases is hypothesized to contribute to systemic inflammation and disease pathogenesis.
Mitochondrial damage may be the common pathway between these stimuli because reactive oxygen species appear to be necessary for NLRP3 inflammasome activation, and changes in the redox state of the cell may be a common mediator between danger signals and inflammasome activation (Jin and Flavell, 2010).
Activated caspase-1 proceeds to cleave pro-IL-1β, pro-IL-18, and other undefined substrates. The NLRP3 inflammasome, as described in Figure 1, has emerged as a key regulator of glucose and insulin homeostasis.
Adipose is a complex tissue consisting of adipocytes, immune cells, vasculature, and stromal cells. Inflammation plays a causal role in insulin resistance, and in rodent models targeting inflammatory cytokine production through genetic and pharmacological approaches results in improvements in insulin signaling (Olefsky and Glass, 2010; Kanneganti and Dixit, 2012). Not only does caspase-1 activation influence whole adipose tissue insulin sensitivity, but it may have direct effects on adipocyte growth, differentiation and metabolism (Stienstra et al., 2010). Caspase-1 activates multiple protein substrates other than IL-1β and IL-18, so the exact contribution of downstream mediators of NLRP3 inflammasome activation remains unclear. Skeletal muscle is a large metabolically active tissue and accounts for the majority of insulin stimulated glucose disposal.
The liver is also a major contributor to glucose homeostasis by generating glucose through gluconeogenesis. Pancreatic islets, macrophages and dendritic cells may all be sources of IL-1β in the pancreas. Science, Technology and Medicine open access publisher.Publish, read and share novel research. Oxidative stress and the use of antioxidants in diabetes: linking basic science to clinical practice. Determination of the production of superoxide radicals and hydrogen peroxide in mitochondria. High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. High blood sugar levels increase the chances of a dangerous infection in those with diabetes, experts have long known. Now, scientists say they may have discovered the mechanism that sets this into motion on the molecular level. When blood sugar is out of control, ''you have the production of these bad molecules that can attach to certain proteins, and at least in the laboratory we have shown there is a significant effect on immune function," says Wesley Williams, PhD, a research scientist who conducted the study while at Case Western Reserve University School of Dental Medicine. Eventually, he says, the discovery may lead to the development of better antimicrobials to fight infection. In the study, Williams and his team took a close look at the harmful molecules, known as dicarbonyls.
The destructive molecule, when exposed to the infection-fighting molecules, also reduced their ability to be ''on the lookout,'' so to speak, for destructive microbes, an important task of the immune system. The research was entirely lab-based, so studies in animal models and human tissues must be done next to verify the findings, Williams says. As the bad molecules accumulate, the infection-fighting peptides could be overwhelmed, Williams says.
For better blood sugar control, the American Diabetes Association suggests paying attention to diet and exercise, measuring your blood sugar more frequently and perhaps changing your insulin dose and schedule. Sign Up for the FREE EndocrineWeb eNewsletter and receive treatment and research updates, news, and helpful tips on managing your condition. Abstract Type 2 diabetes (T2D) is a complex disease that is caused by a complex interplay between genetic, epigenetic and environmental factors.
This is an open access article distributed under the Creative Commons Attribution License (CC BY 4.0). All stock photos are provided by Dreamstime and are copyrighted by their respective owners. At Sanofi Diabetes, our priorities are focussed on the needs of people with diabetes around the world.
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However, up until recently, the identity of specific immunological sensors that are triggered in response to metabolic dysfunction to produce a state of inflammation was not fully understood. IL-1β is a proinflammatory cytokine that is implicated in the pathogenesis of many inflammatory diseases including diabetes, rheumatoid arthritis and genetic auto-inflammatory disorders (Dinarello, 2011). As demonstrated, these key proteins are identified as NLRP3 (for nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) ASC (apoptosis associated speck-like protein containing a CARD), and procaspase-1 (Figure 1). Treatment of macrophages with LPS and ATP leads to increased reactive oxygen species, mitochondrial damage, and release of mtDNA, a DAMP, into the cytosol (Nakahira et al., 2011).
The consequences of NLRP3 inflammasome activation during type II diabetes and possible benefits of NLRP3 and IL-1 targeted therapies. Macrophages are recruited to adipose tissue during obesity and represent the largest population of NLRP3 expressing cells in fat (Weisberg et al., 2003).
These results demonstrate the pleiotropic effects of the NLRP3 inflammasome on activation and recruitment of adipose tissue leukocytes. After insulin binds to the insulin receptor, insulin initiates signaling cascades that activate downstream pathways, notably PI3K-AKT and the mitogenic MAP kinase-ERK pathways (Biddinger and Kahn, 2006). Interestingly, human and mouse adipocyte cell lines express the caspase-1 protein, and its expression is increased over the course of adipocyte differentiation (Stienstra et al., 2010). The liver also becomes insulin resistant during the development of T2D, and this is associated with increases in the levels of hepatic steatosis.


IntroductionDiabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects of insulin action, insulin secretion or both [1]. This causes closure of K+ATP channels, depolarization of the plasma membrane, increased cytoplasmic calcium concentrations through voltage-gated calcium channels, and exocytosis of insulin-containing secretory granules. Infections in the feet and hands of those with diabetes that can't be brought under control with antibiotics can result in amputation.
What appears to happen, say researchers, is that the high glucose levels associated with type 1 and type 2 diabetes unleash destructive molecules that hamper the body's natural immune defenses that fight infections.
They found that two types of dicarbonyls changed the structure of infection-fighting peptides known as human beta-defensin-2. When they exposed the infection-fighting peptides in the lab to the harmful molecule, it slashed the ability of the peptides to inhibit the bacteria by about half, Williams found. It's possible, the scientists say, that additional human peptides other than those they studied in the lab could be affected negatively by the harmful molecules. Guidance from your healthcare practitioner and diabetes support team is needed for all those measures. X axis shows the chromosomal location, Y shows the effect sizes and Z axis shows the year of discovery. The variants are represented by gene names here, which could indicate that the location is present either in the gene, or in the vicinity of the gene.
While the major environmental factors, diet and activity level, are well known, identification of the genetic factors has been a challenge.
Therefore, factors that control secretion of bioactive IL-1β have therapeutic implications. The underlying clinical rationale to identify the immunological triggers of metabolically driven inflammation has been to develop approaches to therapeutically target the immune sensors and break the feed-forward cycle of organ dysfunction and development of diabetes.
Although IL-1β is produced by many cell types, it is predominately produced by monocytes, macrophages, and neutrophils (Dinarello, 2011). NLRP3 is expressed predominantly in circulating monocytes and tissue macrophages (Guarda et al., 2011). The mechanism of inflammasome activation that links these events remains ambiguous, but it may be that these danger signals converge on similar signaling pathways resulting in inflammasome activation.
Although mitochondrial DNA is sensed by the AIM2 inflammasome, it also serves as a co-activator of caspase-1 in conjunction with NLRP3 activation by LPS and ATP (Nakahira et al., 2011). NLRP3 inflammasome activation during type II diabetes results in the production of IL-1β and IL-18, which go on to cause insulin resistance and organ dysfunction in the pancreas, adipose tissue, liver, skeletal muscle, and circulation. Recent studies in animal models demonstrate that obesity is associated with progressive caspase-1 activation in adipose tissue (Vandanmagsar et al., 2011). This reduction in T cells in response to reduced NLRP3 inflammasome activation is attributable to a decrease in effector-memory T cell subtype presence in the adipose tissue (Vandanmagsar et al., 2011). Surprisingly, IL-18 does not appear to have an effect on 3T3-L1 adipocyte differentiation or the expression of adipogenic genes in spite of its known pro-inflammatory properties (Stienstra et al., 2010). The effects on skeletal muscle are most likely driven through decreased adipose tissue and systemic inflammation because there are not high concentrations of Nlrp3 expressing cells within skeletal muscle, however, local macrophages could be influencing this process.
Macrophages and dendritic cells also reside in the pancreas, and macrophages are increased in rodent models of T2D and in patients with T2D (Ehses et al., 2007).
Diabetes has taken place as one of the most important diseases worldwide, reaching epidemic proportions.
In conditions in which insulin demand is increased, -cell glucose metabolism can be enhanced by increased glucokinase enzyme activity (a) and by replenishment of tricarboxylic acid cycle intermediates by anaplerosis (b).
In the process of changing that structure, the harmful molecules hampered the ability of the peptides to fight off bacteria and infection.
However, he adds that the finding ''doesn't prove anything." More research, he agrees, is needed. Only 1 risk variant was reported in 1998; there were 2 in 2002, and today, we have a total of ~153 T2D variants. The black circle represents T2D, and the gene names in black in this represent variants only associated with T2D. However, recent years have seen an explosion of genetic variants in risk and protection of T2D due to the technical development that has allowed genome-wide association studies and next-generation sequencing.
Among several sites of inflammation in metabolic diseases, adipose tissue is a large contributor to circulating proinflammatory cytokines during obesity. During type II diabetes there is increased accumulation of endogenous danger-associated molecular patterns (ceramides, free cholesterol, etc.) which are sensed by the NLRP3 inflammasome. Autophagy, a process by which cells remove damaged organelles, buffers inflammasome activation by removing damaged mitochondria, and limiting ROS production and mtDNA escape into the cytosol, and is activated by NLRP3 inflammasome activators (Shi et al., 2012). NLRP3 and IL-1β targeted therapy may have potential to reduce local tissue inflammation and systemic inflammation resulting in systemic improvement in insulin secretion, insulin sensitivity as well as organ function. Consistent with the causal role of NLRP3 inflammasome activation in the development of inflammation, deletion of Nlrp3 in mice, prevents obesity-induced caspase-1 activation. The reduction of IL-1 signaling also improves adipose tissue insulin sensitivity in a similar way. This study determined that both during basal and inflammasome activating conditions (stimulation with free fatty acids, ATP, or urate) blood monocytes from patients with T2D have greater caspase-1 activation and secretion of the caspase-1 activated proteins, IL-1β and IL-18. Global estimates predict that the proportion of adult population with diabetes will increase 69% for the year 2030 [2].Hyperglycemia in the course of diabetes usually leads to the development of microvascular complications, and diabetic patients are more prone to accelerated atherosclerotic macrovascular disease. Glucose-induced increases in citrate levels lead to increased amounts of malonyl CoA (c), which, through inhibition of carnitine palmitoyl transferase-1 (CPT1), leads to increased levels of long-chain acyl CoA, increased diacylglycerol (DAG) and signalling through protein kinase C (PKC).
Today, more than 120 variants have been convincingly replicated for association with T2D and many more with diabetes-related traits. After sensing of DAMPs, inflammasome assembly occurs by interactions in the protein domains of NLRP3 ASC and procaspase-1. Thus, the pyrin domain of NLRP3 interacts with the pyrin domain of ASC, and the CARD (caspase activation recruitment domain) of ASC interacts with the CARD domain of procaspase-1 (Figure 1).
IL-1 signaling is necessary for the inflammatory response, but is highly regulated due to the negative effects of chronic inflammation to body tissues and organs. Adipose tissue explants from high-fat-fed IL-1 receptor null mice exhibit improved insulin signaling compared to wild type animals, including increased glucose transport, AKT phosphorylation, and increased gene expression of proteins involved with insulin signaling and glucose uptake (Irs-1 and Glut4) (McGillicuddy et al., 2011). Inflammasome activation can occur in response to diverse cellular stresses including reactive oxygen species, the unfolded protein response and altered autophagy.
These complications account for premature mortality and most of the social and economical burden in the long term of diabetes [3].


Fatty acids influence insulin release by signalling through the G-protein-coupled receptor GPR40 (d) or through metabolism to fatty acyl CoA (e) and stimulation of insulin granule exocytosis, either directly or through PKC-dependent mechanisms. The NLRP3 inflammasome appears to be an important sensor of metabolic dysregulation and controls obesity-associated insulin resistance and pancreatic beta cell dysfunction.
Accordingly, Tnf mRNA expression was shown to be increased in adipose tissue of obese hyperinsulinemic human subjects (Hotamisligil et al., 1995).
Classically, the inflammasome driven caspase-1 activation and IL-1β secretion occurs as innate immune cells like macrophages engulf bacterial, fungal, and viral proteins. This leads to caspase-1 activation and the secretion of bioactive IL-1β and IL-18, which go on to cause insulin resistance and organ dysfunction. In this way, the NLRP3 inflammasome is formed leading to the cleavage of procaspase-1 to its enzymatically activated form (Figure 1). Thus, there is a complex interplay between autophagic maintenance of mitochondria and inflammasome proteins that controls inflammasome activation. Regulation of IL-1 signaling is maintained in healthy individuals, but appears to be elevated during chronic proinflammatory disease states, which makes this pathway a valuable therapeutic target in T2D.
These results demonstrate the strong immune and metabolic consequences of NLRP3 inflammasome activation and IL-1 signaling during obesity. Notably, recent studies also show that NLRP3 inflammasome is required for the maintenance of gut epithelial integrity. In the context of this experiment, hyperglycemia in these T2D patients resulted in elevated ROS production and greater inflammasome activation. Increasing evidence suggests that oxidative stress plays a role in the pathogenesis of diabetes mellitus and its complications [4]. The incretin GLP-1 potentiates glucose-stimulated insulin release through its G-protein-coupled receptor (f) by means of mechanisms that include stimulation of protein kinase A (PKA) and the guanine nucleotide exchange factor EPAC2. The data clearly illustrates the difficulty classifying diabetic patients at diagnosis with 19% unclassifiable.
Furthermore, weight loss-induced improvement in insulin-sensitivity was associated with reduction in TNF suggesting that this pro-inflammatory cytokine impairs insulin-action.
The inflammasome activation is therefore a vital immune response to protect the host against numerous pathogens (Schroder and Tschopp, 2010). In response to methionine-choline deficiency (a model of NASH in mice), NLRP3 inflammasome deficient animals develop exaggerated fatty liver disease due to microbial pathogen-associated molecular patterns leakage into the liver via the portal circulation and activation of the pro-inflammatory response via the Toll-like receptors 4 and 9 (Henao-Mejia et al., 2012). In support of this concept, mice that lack NLRP3 inflammasome components (Nlrp3, Asc) have increased pancreatic islet size in response to chronic high-fat diet, resulting in increased insulin response to glucose challenge despite improvements in peripheral insulin sensitivity (Youm et al., 2011). Knockdown of ASC or NLRP3 using RNA interference abrogated the response to DAMPs demonstrating specificity to this pathway in T2D patients (Lee et al., 2013).
Hyperglycemia increases oxidative stress, which contributes to the impairment of the main processes that fail during diabetes, insulin action and insulin secretion. Release of acetylcholine from parasympathetic nerve terminals activates the M2 muscarinic receptor (g), stimulating insulin release in a DAG- and PKC-dependent manner.
However, this potential therapeutic approach remains to be fully substantiated through phase-II clinical studies. Interestingly, new evidence suggest that inflammasome activation may be important in chronic diseases such as obesity and diabetes where low grade inflammation occurs without overt infection (Schroder and Tschopp, 2010). Additionally, reduction of Nlrp3 inflammasome activation in chronically obese mice protects the pancreatic beta cells against cell death (Youm et al., 2011).
This study provides evidence that the Nlrp3 inflammasome activation in T2D patients contributes toward the chronic pro-inflammatory state.
In addition, antioxidant mechanisms are diminished in diabetic patients, which may further augment oxidative stress [5, 6].
Dual actions on insulin secretion have been described for sympathetic nerves (h), with 2-adrenergic agonists inhibiting and -adrenergic agonists stimulating insulin secretion.
Here, we outline the new immunological mechanisms that link metabolic dysfunction to the emergence of chronic inflammation and discuss the opportunities and challenges of future therapeutic approaches to dampen NLRP3 inflammasome activation or IL-1β signaling for controlling type 2 diabetes.
These findings suggest that reduction in Nlrp3 inflamamsome activity may protect the pancreatic islet from caspase-1 mediated inflammatory death.
Both pathways act through adenylyl cyclase, resulting in a decrease or increase in cAMP levels, respectively.
T2D has been associated with increased circulating endotoxin concentration, but it is unclear whether this is cause or consequence in disease pathogenesis (Pussinen et al., 2011). TXNIP may be a crucial mediator connecting beta cell death and inflammasome activation by linking glucotoxicity and ER stress to NLRP3 inflammasome activation (Zhou et al., 2010).
Oxidative stress At the beginning of life, the organisms obtained their energy (ATP) by anoxygenic photosinthesis, for which oxygen was toxic. Further studies to enhance the delivery and tissue availability of TNF targeted treatments are being pursued to improve treatment outcomes.
Most of the metabolic pathways were developed during this anaerobic stage of life, in which oxygen came later.
Cyanobacteria started producing oxygen from photosynthesis, which raised the atmospheric oxygen, and favored those organisms which have evolved into eukaryotic cells with mitochondria, able to use oxygen for a more efficient energy production [9].Whenever a cell’s internal environment is perturbed by infections, disease, toxins or nutritional imbalance, mitochondria diverts electron flow away from itself, forming reactive oxygen species (ROS) and reactive nitrogen species (RNS), thus lowering oxygen consumption. TXNIP serves as a signaling node linking ER stress, IL-1B production and beta cell apoptosis. This “oxidative shielding” acts as a defense mechanism for either decreasing cellular uptake of toxic pathogens or chemicals from the environment, or to kill the cell by apoptosis and thus avoid the spreading to neighboring cells [9]. The consequences of pancreatic beta cell TXNIP and inflammasome activation in vivo are unclear because beta cell and myeloid cell specific knockouts have not been used to address this issue. The term “oxidative stress” has been used to define a state in which ROS and RNS reach excessive levels, either by excess production or insufficient removal. Thus, lowering Nlrp3 inflammasome activation may protect against the transition from insulin-resistance to an overt type 2 diabetic stage by mechanisms that involve protection from loss of insulin-producing beta cells. Being highly reactive molecules, the pathological consequence of ROS and RNS excess is damage to proteins, lipids and DNA [10]. It is presently unclear whether persistent Nlrp3 inflammasome activation causes the transition from insulin-resistance to islet decompensation and development of overt T2D. Consistent with the primary role of ROS and RNS formation, this oxidative stress damage may lead to physiological dysfunction, cell death, pathologies such as diabetes and cancer, and aging of the organism [11].



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