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Science, Technology and Medicine open access publisher.Publish, read and share novel research. Beta-Cell Function and Failure in Type 2 DiabetesSimona Popa1 and Maria Mota1[1] Department of Diabetes, Nutrition and Metabolic Diseases; University of Medicine and Pharmacy, Craiova, Romania1. A better understanding of the body’s response to indulgent eating could lead to new approaches for treating diabetes and metabolic syndrome. High fat foods can contribute to obesity, which increases the risk for developing type 2 diabetes. The researchers learned a key protein called Bcl10 is needed for the free fatty acids, which are found in high-fat food and stored in body fat, to impair insulin action and lead to abnormally high blood sugar. In the laboratory study, mice deficient in Bcl10 were protected from developing insulin resistance when fed a high-fat diet. Insulin helps control blood sugar, but insulin resistance can lead to the abnormally high blood sugar levels that are the hallmark of diabetes. As millions of Americans become overweight and obese, type 2 diabetes and metabolic syndrome are on the rise. In the liver, free fatty acids undergo metabolism to produce diacylglycerols prior to inducing the inflammatory response. Diacylglycerols also activate NF-kB signaling which has been linked with cancer, metabolic and vascular diseases. The team of researchers concluded that Bcl10 is required for fatty acids to induce inflammation in the liver and insulin resistance. We will be provided with an authorization token (please note: passwords are not shared with us) and will sync your accounts for you. The prevalence of obesity and its associated disorders, such as type 2 diabetes mellitus (TDM2), has increased substantially worldwide over the last decades. Microorganisms colonize all surfaces of the human body that are exposed to the environment, with most residing in the intestinal tract. Much evidence now exists concerning an important change in our microbiota over recent decades, with some species increasing and others decreasing, though one of the most striking findings is that in developed countries there is a loss in the diversity of our microbiota. Recent decades have seen an increase in the prevalence of metabolic diseases in developed countries.
A second step toward the comprehension of the origin of metabolic diseases involves epigenetic and environmental factors. Studies during the last decade have associated the gut microbiota with the development of metabolic disorders, especially diabetes and obesity. The first discovery was related to the fact that mice with a mutation in the leptin gene (metabolically obese mice) have different microbiota as compared with other mice without the mutation (Ley et al., 2005). The shift in the relative abundance observed in these phyla is associated with the increased capacity to harvest energy from food and with increased low-grade inflammation.
The most relevant experiment dealing with the causality between microbiota and obesity was done by Turnbaugh et al. Surprisingly, the phenotype with increase capacity for energy harvest is simply transmitted by transplantation of the obesity-associated gut microbiota in to healthy and lean donors (Turnbaugh et al., 2006, 2008).
Schematic diagram representing the metabolism of selected amino acids, highlighting related metabolic stimulus-secretion coupling factors involved in insulin release. The malate–aspartate shuttle is the principal mechanism for the movement of reducing equivalents in the form of NADH from the cytoplasm to the mitochondrion in ?-cells. IntroductionType 1 diabetes mellitus (T1DM) is a chronically progressive autoimmune disease that affects approximately 1% of the population in the developed world. Perspective: emerging evidence for signaling roles of mitochondrial anaplerotic products in insulin secretion. Glucokinase as glucose sensor and metabolic signal generator in pancreatic betacells and hepatocytes. Evidence that glucose can control insulin release independently from its action on ATP-sensitive K+ channels in mouse B cells. Beta-cell deterioration determines the onset and rate of progression of secondary dietary failure in type 2 diabetes mellitus: the 10-year followup of the Belfast Diet Study. An overview of pancreatic beta-cell defects in human type 2 diabetes: Implications for treatment. Kir6.2 variant E23K increases ATP-sensitive K+ channel activity and is associated with impaired insulin release and enhanced insulin sensitivity in adults with normal glucose tolerance. A candidate type 2 diabetes polymorphism near the HHEX locus affects acute glucose-stimulated insulin release in European populations: results from the EUGENE2 study. The common SLC30A8 Arg325Trp variant is associated with reduced first-phase insulin release in 846 non-diabetic offspring of type 2 diabetes patients – the EUGENE2 study. Single-nucleotide polymorphism rs7754840 of CDKAL1 is associated with impaired insulin secretion in nondiabetic offspring of type 2 diabetic subjects and in a large sample of men with normal glucose tolerance.
Variants of CDKAL1 and IGF2BP2 affect first-phase insulin secretion during hyperglycaemic clamps.
Quantitative trait analysis of type 2 diabetes susceptibility loci identified from whole genome association studies in the Insulin Resistance Atherosclerosis Family Study. Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Association of 18 confirmed susceptibility loci for type 2 diabetes with indices of insulin release, proinsulin conversion, and insulin sensitivity in 5,327 nondiabetic Finnishmen.
Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIPand GLP-1 receptors and impaired beta- cell function. Impact of polymorphisms in WFS1 on prediabetic phenotypes in a population-based sample of middle-aged people with normal and abnormal glucose regulation. Association of type 2 diabetes candidate polymorphisms in KCNQ1 with incretin and insulin secretion. A variant in the KCNQ1 gene predicts future type 2 diabetes and mediates impaired insulin secretion. Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion.
TCF7L2 polymorphisms modulate proinsulin levels and beta-cell function in a British Europid population. TCF7L2 controls insulin gene expression and insulin secretion in mature pancreatic beta-cells. TCF-4 mediates cell type-specific regulation of proglucagon gene expression by beta-catenin and glycogen synthase kinase-3beta.
Hex homeobox gene-dependent tissue positioning is required for organogenesis of the ventral pancreas.
In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion.
Increased glucose sensitivity of both triggering and amplifying pathways of insulin secretion in rat islets cultured for 1 wk in high glucose. Role of ATP production and uncoupling protein-2 in the insulin secretory defect induced by chronic exposure to high glucose or free fatty acids and effects of peroxisome proliferator-activated receptor-gamma inhibition. Role of beta-cell dysfunction, ectopic fat accumulation and insulin resistance in the pathogenesis of type 2 diabetes mellitus. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol.
Palmitate activates AMPactivated protein kinase and regulates insulin secretion from beta cells. Chronic activation of liver X receptor induces beta-cell apoptosis through hyperactivation of lipogenesis: liver X receptor-mediated lipotoxicity in pancreatic beta-cells. Inhibition of PKCepsilon improves glucose-stimulated insulin secretion and reduces insulin clearance. Palmitate inhibits insulin gene expression by altering PDX-1 nuclear localization and reducing MafA expression in isolated rat islets of Langerhans. Palmitate inhibition of insulin gene expression is mediated at the transcriptional level via ceramide synthesis. Evidence against the involvement of oxidative stress in fatty acid inhibition of insulin secretion. Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates. Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. Monounsaturated fatty acids prevent the deleterious effects of palmitate and high glucose on human pancreatic beta-cell turnover and function. Free fatty acid-induced beta-cell defects are dependent on uncoupling protein 2 expression. Insulin resistance can occur as part of metabolic syndrome, a cluster of conditions that increase the risk for type 2 diabetes and heart disease. In the study, Bcl10 deficient mice showed significant improvement in regulation of blood sugar. You are free to copy, distribute, adapt, transmit, or make commercial use of this work as long as you attribute the University of Michigan Health System as the original creator and include a link to this article. This means that you will not need to remember your user name and password in the future and you will be able to login with the account you choose to sync, with the click of a button. This page doesn't support Internet Explorer 6, 7 and 8.Please upgrade your browser or activate Google Chrome Frame to improve your experience. Although obesity has been mainly related with perturbations of the balance between food intake and energy expenditure, other factors must nevertheless be considered. Recent insight suggests that an altered composition and diversity of gut microbiota could play an important role in the development of metabolic disorders. The fetal intestinal tract is sterile until birth, after which the newborn tract begins to be colonized.
To understand the stability of microbiota within an individual over time is an important step to predict diseases and develop therapies to correct dysbiosis (microbial community mismatches). One of the most important factors that can disturb microbiota composition is the increased use of antibiotic treatment.
Environmental factors, such as the increase in energy intake and the decrease in physical activity, have been considered causes of this spectacular increase in the prevalence of metabolic diseases. A drastic change in feeding habits in which dietary fiber has been replaced by a high fat diet contributes to the origin of metabolic diseases.
In this obese animal model, the proportion of the dominant gut phyla, Bacteroidetes and Firmicutes, is modified with a significant reduction in Bacteroidetes and a corresponding increase in Firmicutes (Ley, 2010). The increase in Firmicutes and the decrease in the proportion of Bacteroidetes observed in obese mice could be related with the presence of genes encoding enzymes that break down polysaccharides that cannot be digested by the host, increasing the production of monosaccharides and short-chain fatty acids (SCFA) and the conversion of these SCFA to triglycerides in the liver (Figure 1).
But within a phylum, not all the genera have the same role, so that bacterial genera have been related with either beneficial or harmful characteristics associated within the same phylum. The pathway of glutamine metabolism via glutaminase, GDH, and entry into the TCA cycle (glutaminolysis) is shown along with key points of amino acid interaction with glutamine and glucose metabolism.
Cytoplasmic malate dehydrogenase (MDH) reduces oxaloacetate (OAA) to malate while oxidizing NADH to NAD+. The fluxes through the biochemical pathways shown here were calculated by using Michaelis-Menten function, intracellular metabolite concentrations estimated from different works. Islet inflammation is characterised by the presence of leukocyte infiltrates that mediate the destruction of ?-cells by release of cytokines, generation of ROS (NO, cytokine-NF?B-dependent]) and by activating the granzyme b- and death-receptor-mediated death pathways. This adverse immune response is induced and promoted by the interaction of both genetic and environmental factors.
Normal beta-cell functionThe main role of beta-cell is to synthesize and secrete insulin in order to maintain circulating glucose levels within physiological range. Sites of pretranslational regulation by glucose of glucose-induced insulin release in pancreatic islets. Most of the gut microorganisms reside in the large intestine, which contains an estimated 1011-12 bacterial concentrations per gram of content (Leser and Molbak, 2009). Data from longitudinal studies show the microbiota composition is relatively stable in healthy adults over time and is only transiently altered by external disturbances such as diet, disease, and environment (Delgado et al., 2006). However, even when the energy intake does not increase and physical activity does not decrease, the prevalence continues growing exponentially, so other environmental factors must be taken into account, including changes in gut microbiota. However, this simple concept cannot explain why some people are sensitive and others are resistant to the development of these metabolic diseases. These SCFAs are able to bind and activate two G-protein-coupled receptors (GPR41 and GPR43) of the gut epithelial cells.
Gut microbiota converts polysaccharides into monosac-charides and short-chain fatty acids (SCFA).
Other studies have suggested that obese subjects might be able to extract more energy from nutrients due to hydrogen transfer between taxa.
In this study, they demonstrated that microbiota transplantation from genetically obese mice to axenic mice provokes a very significant weight increase compared with the axenic mice transplanted with the microbiota from lean mice.
The mechanisms by which amino acids enhance insulin secretion are understood to primarily rely on (a) direct depolarization of the plasma membrane (e.g. Malate then enters the mitochondrion where the reverse reaction is performed by mitochondrial malate dehydrogenase. Percentages in parentheses refer to the proportional amount of the metabolite consumed through that step.
Also shown is the effect of excess glucose on ROS production and ER stress that ultimately activates caspase enzymes via mitochondrial- and ER-mediated death pathways. In contrast, in type 2 diabetes mellitus (T2DM), insulin-resistance coupled with reduced insulin output appears to be the major cause of hyperglycaemia (affecting approximately 6% of the population). Although there exist several triggers of insulin secretion like nutrients (amino acids such as leucine, glutamine in combination with leucine, nonesterified fatty acid), hormones, neurotransmitters and drugs (sulfonylurea, glinides), glucose represents the main physiological insulin secretagogue [1].According to the most widely accepted hypothesis, insulin secretion is a multistep process initiated with glucose transport into beta-cell through specific transporters (GLUT1 and GLUT2 in particular) and phosphorylation by glucokinase, which directs metabolic flux through glycolysis, producing pyruvate as the terminal product of the pathway [2]. This review discusses research aimed at understanding the role of gut microbiota in the pathogenesis of obesity and type 2 diabetes mellitus (TDM2). Infants born vaginally have similar communities to those found in the vaginal microbiota of their mothers. Particularly, changes in diet have shown important effects on the composition of the intestinal microbiota. One of the challenges is to elucidate the molecular origin of metabolic diseases, though the great diversity and social differences among humans make this difficult. Thus, with the environmental vulnerabilities, gut microbiota could provoke the development of impairment in energy homeostasis, causing metabolic diseases. The activation of these receptors induces peptide YY secretion, which suppresses gut motility and retards intestinal transit. In fact, a simultaneous increase in both hydrogen-producing Prevotellaceae and hydrogen-utilizing methanogenic Archaea has been previously associated with obesity by Zhang et al.
Movement of mitochondrial oxaloacetate to the cytoplasm to maintain this cycle is achieved by transamination to aspartate with the amino group being donated by glutamate. Although the aetiology of diabetes may differ from T1DM to T2DM, a common feature associated with both types is the failure of pancreatic ?-cells in the islets of Langerhans, thus causing a reduction in insulin secretion, cell mass and ultimately apoptotic death.
Pyruvate then enters the mitochondria and is decarboxylated to acetyl-CoA, which enters the tricarboxylic acid cycle. In addition to an increased energy harvest from the diet, several mechanisms, including chronic low-grade endotoxemia, regulation of biologically active fatty acid tissue composition, and the modulation of gut-derived peptide secretion, have been proposed as links between gut microbiota and obesity (Musso et al., 2010). In contrast, those born by Caesarian section have the characteristic microbiota of the skin, with taxons like Staphylococcus and Propionibacterium spp. Indeed, dietary changes could explain 57% of the total structural variation in gut microbiota whereas changes in genetics accounted for no more than 12% (Zhang et al., 2010). A correlation has recently been proposed between the increasing global use of antibiotics and weight gain or obesity in humans (Thuny et al., 2010). During the last half century, with the advances in molecular biology, researchers have been investigating the genetics of metabolic diseases. Genetically identical mice in the same box and with a fat-rich diet for 6–9 months can develop both obesity and diabetes, or only one of the diseases. By this mechanism of SCFA-linked G-protein-coupled receptor activation, the gut microbiota may contribute markedly to increased nutrient uptake and deposition, contributing to the development of metabolic disorders (Erejuwa et al., 2014). Stool was collected at 6 and 12 months of life and it was found that the children who were 7 years old with a normal weight had a higher number of Bifidobacterium spp.
However, the impact and time-course of pancreatic ?-cell death, which may appear very different in T1 and T2DM, may be related through common molecular mechanisms.
The tricarboxylic acid cycle proper begins with a condensation of acetyl-CoA and oxaloacetate, to form citrate, a reaction catalysed by citrate synthase.
Teitelbaum of the U-M; and Jurgen Ruland, of Munich, Germany and the Laboratory of Signaling in the Immune System, Helmholtz Zentrum Munchen-Germany Research Center for Environmental Health, of Neuherberg, Germany. With effect from this point, gut microbiota remain quite stable, although changes take place between birth and adulthood due to external influences, such as diet, disease and environment. These studies have shown the great variability in microbiota composition among healthy subjects, even between twins sharing less than 50% of their bacterial taxons at the species level (Turnbaugh et al., 2010).
In spite of the great efforts and the identification of some mutations in the genome, no global view has yet been established.
There is a need to find a new paradigm that takes into account the genetic diversity, the environmental factor impact, the rapid development of metabolic diseases, and the individual behavior to develop diabetes and obesity. Starch digestion is an example of this process: H2is produced, and its increase inhibits starch digestion, moment at which other bacterial groups work and transform the H2 into methane.
For instance, intestinal starch digestion produces hydrogen, the increase of which inhibits digestion and methanogenic Archaea are able to transform this hydrogen into methane (Figure 1). Glucose-stimulated insulin secretion (GSIS) is central to the physiological control of metabolic fuel homeostasis, and its impairment is a hallmark of pancreatic ?-cell failure in T2DM.
This is probably for various reasons, such as the fact that the heterogeneous etiology of obesity and diabetes can be associated with different microbes, studies have involved participants of diverse ethnic origin and food habits, the large inter-individual variation in the composition of gut microbiota, and in particular the different methods that have been used to profile the microbiota in these studies (Tremaroli et al., 2012). Changes in the composition of the gut microbiota in response to dietary intake take place because different bacterial species are better equipped genetically to utilize different substrates (Scott et al., 2008). It has been suggested that antibiotics, such as avoparcin (a glycopeptide structurally related to vancomycin), exert selective pressure on Gram-positive bacteria and that gut colonization by Lactobacillus spp., which are known to be resistant to glycopeptides, used as a growth promoter in animals and found at a high concentration in the feces of obese patients, could be responsible for the weight gain observed in patients who had been treated with vancomycin. The conclusion reached concerns the concept of personalized medicine in which the individual characteristics should be identified in order to adapt a suitable therapeutic strategy for small patient groups. Thus, there is a specific microbiota that obtains more energy from the same energy intake (Turnbaugh et al., 2009a). The authors concluded that the alteration in the microbiota precedes the alteration in weight, an explanation that is relevant for obesity prevention.


Notably, rapid partial oxidation may also initially increase both the cellular content of ATP (impacting on K+ATP channel closure prompting membrane depolarization) and other stimulus secretion coupling factors.
?-Cells are often referred to as "fuel sensors" as they continually monitor and respond to dietary nutrients, under the modulation of additional neuro-hormonal and immunological signals, in order to secrete insulin to best meet the needs of the organism.
NAD-linked isocitrate dehydrogenase then oxidatively decarboxylates isocitrate to form ?-ketoglutarate. A new theory suggests that gut microbiota contribute to the regulation of energy homeostasis, provoking the development of an impairment in energy homeostasis and causing metabolic diseases, such as insulin resistance or TDM2.
On the other hand, the differences between gut microbiota in lean and obese individuals as well as the impact of diet in the composition of the gut microbiome are still not wholly understood. These data suggest that nutritional programs and follow-up of weight should be undertaken in patients under such treatment (Thuny et al., 2010).
These findings agree with the observation in which GF mice fed with a fat-rich diet gained less weight than conventional mice (Backhed et al., 2004). In the absence of glucose, fatty acids may be metabolised to generate ATP and maintain basal levels of insulin secretion. Therefore, ?-cell dysfunction and death in diabetes leads to hyperglycaemia and its complications. The ?-ketoglutarate is oxidised to succinyl-CoA in a reaction catalysed by ?-ketoglutarate dehydrogenase. The metabolic endotoxemia, modifications in the secretion of incretins and butyrate production might explain the influence of the microbiota in these diseases. Thus, manipulation of the gut microbiome represents a novel approach to treating obesity although it is in no way a substitute for diet and exercise.
The main bacterial phyla are: Firmicutes (Gram-positive), Bacteroidetes (Gram-negative), and Actinobacteria (Gram-positive).
Recent studies have found that mice [humanized germ-free (GF)] changed from a diet low in fat and rich in vegetable polysaccharides to a diet rich in fat and sugar and low in plant polysaccharides (western diet) changed their microbiota in just 1 day. Other recent studies have also demonstrated the beneficial effects of antibiotics on metabolic abnormalities in obese mice, giving rise to reduced glucose intolerance, body weight gain, metabolic endotoxemia, and markers of inflammation and oxidative stress (Bech-Nielsen et al., 2012). Succinyl-CoA synthase then catalyses the conversion of succinyl-CoA to succinate, with the concomitant phosphorylation of GDP to GTP. This review discusses the research conducted in understanding the role of gut microbiota in the pathogenesis of obesity and TDM2.
Moreover, these effects were associated with a reduced diversity of gut microbiota (Murphy et al., 2013). However and in contrast to professional immunoinflammatory cells, such as macrophages or neutrophils, the ?-cell is fragile when subjected to immune attack and is highly vulnerable to oxidative stress. The microbiota of formula-fed infants is more complex and includes enterobacterial genera, Streptococcus, Bacteroides, and Clostridium, as well as Bifidobacterium and Atopobium (Bezirtzoglou et al., 2011). Antibiotic treatment combined with a protective hydrolyzed casein diet has been found to decrease the incidence and delay the onset of diabetes in a rat model (Brugman et al., 2006).
Fumarase catalyses the conversion of fumarate to malate and after that malate dehydrogenase catalyses the ?nal step of the tricarboxylic acid cycle, oxidising malate to oxaloacetate and producing NADH.Three pathways enable the recycling of the tricarboxylic acid cycle intermediates into and out of mitochondrion, allowing a continuous production of intracellular messengers [3-5]. A recent study also reported that antibiotic-treated humans showed greater and less balanced sugar anabolic capabilities than non-treated individuals (Hernandez et al., 2013).
During adulthood the microbiota is relatively stable until old age, when this stability is reduced (McCartney et al., 1996). Moreover, murine studies have shown that carbohydrate-reduced diets result in enriched populations of bacteria from the Bacteroidetes phyla (Walker et al., 2011) while calorie-restricted diets prevent the growth of C. However, the majority of clinical studies are focused primarily on the characterization of the composition and diversity of gut microbes, it remaining uncertain whether antibiotic-induced gut microbiota alteration in human subjects with metabolic disorders is associated with improvements in metabolic derangements as observed in animal studies.
Regulation of ?-cell function and insulin secretionControl of energy metabolism is essential in maintaining cellular homeostasis in all animals across the metazoan (all animals with differentiated tissues). Malate exits the mitochondria to the cytoplasm where it is subsequently oxidised to pyruvate concomitant with the production of NADPH by cytosolic malic enzyme. The ELDERMET consortium studied the microbiota of elderly Irish subjects, finding a different characteristic microbiota composition to that of young persons, particularly in the proportions of Bacteroides spp. Insulin and glucagon are hormones produced by vertebrate organisms to regulate glycaemic homeostasis.
In addition, insulin-like and glucagon-like peptide genes have been detected in invertebrate organisms including, insects, molluscs and nematodes, thus inferring a similar metabolic control that is conserved among most species [1,2].
Citrate then exits the mitochondrion to the cytoplasm where it is converted back to oxaloacetate and acetyl-CoA by ATP-citrate lyase. However, in the case of vertebrates, insulin and glucagon are produced by cells located in the islets of Langerhans of the animal pancreas. Oxaloacetate is converted by cytosolic malate dehydrogenase to malate before being converted to pyruvate by malic enzyme. Under normal physiological conditions, blood glucose concentration is maintained within narrow limits by an alternate release of these powerful proteins, regardless of nutrient intake or expenditure (e.g. These authors postulated that gut microbiota co-evolved with the plant-rich diet of the African children, allowing them to maximize energy extraction from dietary fiber while also protecting them from inflammation and non-infectious intestinal diseases (De Filippo et al., 2010). There are four main cell types that contribute to the regulation of this pancreatic function and they include, ?-cells, ?-cells, ?-cells and pancreatic peptide (PP)-cells [3].
The role of ?-cells is to synthesise and secrete glucagon in response to low extracellular glucose concentrations, thus replenishing the plasma carbohydrate level [3]. The NADPH oxidase complex in the plasma membrane is also activated through protein kinase C, which is activated by fatty acid derived signalling molecules. Conversely, the function of ?-cells has been extensively studied and they are responsible for the biosynthesis and release of insulin in response to elevated plasma glucose, amino acid and saturated fatty acid levels [3]. These events result in an enhanced ratio of ATP to ADP in the cytoplasm, which determines the closure of the ATP-sensitive K+ channels, depolarization of the plasma membrane, influx of extracellular Ca2+ and activation of exocytosis which takes place in several stages including recruitment, docking, priming, and fusion of insulin granules to the beta-cell plasma membrane [1,6,7].
A vegetarian diet has also been shown to decrease the amount and change the diversity of Clostridium cluster IV and Clostridium clusters XIV and XVII (Liszt et al., 2009).
These cells represent the most abundant cell type in pancreatic islets and are the primary source of dysfunction in DM.?-Cell responsiveness and subsequent insulin secretion is subject to a plethora of cellular regulatory mechanisms. Two independent studies, using diazoxide for maintaining the ATP-sensitive K+ channels in the open state or mice in which the ATP-sensitive K+ channels were disrupted, indicated that glucose –stimulated insulin secretion can also occur independently of ATP-sensitive K+ channels activity [8].Under physiological conditions, there is a hyperbolic relation between insulin secretion and insulin sensitivity.
However, large well-controlled trials are needed to elucidate the mechanisms that link dietary changes to alterations in microbial composition as well as the implications of key population changes for health and disease. Classically, glucose-stimulated insulin secretion is characterized by a first phase, which ends within a few minutes, and prevents or decreases glucose concentration and a more prolonged second phase in which insulin is released proportionally to the plasma glucose [9].In addition, it has been demonstrated that the release of insulin is oscillatory, with relatively stable rapid pulses occurring at every 8-10 minutes which are superimposed on low-frequency oscillations [10]. Furthermore, the fact that cellular insulin secretion is achieved by the physical release of vesicles or granules containing the protein, suggests that the process acquires a greater degree of complexity and control, and is subject to vesicle manufacture, recruitment and finally plasma membrane docking.Glucose-Stimulated Insulin Secretion (GSIS) is fundamental to insulin exocytosis as glucose is the most potent insulin secretagogue [4].
In an environment of excess extracellular glucose, ?-cell plasma membrane transporter proteins GLUT1 and GLUT2, actively transport free glucose molecules inside the cell where glycolysis can be initiated to create the nucleotide ATP (Fig. Place of beta-cell dysfunction in natural history of type 2 diabetesT2DM is a progressive condition caused by genetic and environmental factors that induce tissue insulin resistance and beta-cell dysfunction.
Based on the United Kingdom Prospective Diabetes Study (UKPDS) and on the Belfast Diabetes Study, it is estimated that at diagnosis of T2DM, beta-cell function is already reduced by 50-60% and that this reduction of beta-cell function seems to start with 10-12 years before the appearance of hyperglycemia [11,12].
Consequently, intracellular metabolism of glucose by glycolysis, and further metabolism of pyruvate via the downstream tricarboxylic acid (TCA) cycle, leads to elevated NADH, FADH2 and ultimately ATP levels [4]. Several lines of evidence indicated that there is no hyperglycemia without beta-cell dysfunction [13,14].
The increased intracellular ATP:ADP ratio closes membrane-bound ATP-sensitive K+ channels, resulting in plasma membrane depolarisation and a subsequent opening of membrane-bound voltage activated Ca2+ channels. In most subjects with obesity-induced insulin resistance developing increased insulin secretion, insulin gene expression and beta-cell mass, these compensatory mechanisms can succeed to maintain glucose homeostasis and avoidance of diabetes mellitus [13-15]. A rapid influx of calcium ions is promoted, causing the exocytosis of insulin through fusion of the insulin containing vesicles with the plasma membrane via VAMP (vesicle-associated membrane protein) and SNARE (soluble NH2-ethylmaleimide-sensitive fusion protein attachment protein receptor) association [5]. This specific process of insulin secretion is known as KATP-dependent GSIS, and since ATP generation is critical, the metabolic control points of glycolysis, the TCA cycle and oxidative phosphorylation (i.e.
In the phase which precedes overt diabetes the decline of beta-cell function is slow but constant (2% per year) [19]. After the development of overt hyperglycemia there appears a significant acceleration (18% per year) in beta-cell failure, and the beta-cell function deteriorates regardless of the therapeutic regimen [11,19,20]. Consequent deterioration in metabolic equilibrium with increasing levels of glucose and free fatty acids, enhance and accelerate beta-cell dysfunction, lead to beta-cell apoptosis that does not seems to be adequately compensated by regenerative process and subsequent decrease of beta-cell mass.4. Potential mechanism and modulators of beta-cell failureThe main focus of the present chapter is on potential beta-cell failure mechanisms in T2DM.The initial alterations in beta-cell function are likely to reflect intrinsic defects, whereas the accelerated beta-cell dysfunction which mainly occurs after the development of overt hyperglycemia is the consequence of glucolipotoxicity [21]. This reflects a genetic predisposition for beta-cell defect, whereas the subsequent beta-cell failure may be a consequence of concomitant environmental conditions. Genetic factorsSeveral genes associated with increased risk of developing T2DM have been identified in genome-wide association studies [22]. Adapted from [3].However, there also remains the possibility that KATP-independent GSIS can occur in the ?-cell, although the exact methodology is still not fully understood. Genetic variation in this gene obviously affects the beta-cell excitability and insulin secretion [23].HHEX encodes a transcription factor necessary for the organogenesis of the ventral pancreas [49] and two SNPs (rs1111875, rs7923837) in HHEX were found to be associated with reduced insulin secretion [24-26]. GSIS was subsequently shown to be possible in a KATP-independent manner and it is believed that these two co-ordinate mechanisms of insulin secretion (i.e. SLC30A8 encodes the protein zinc transporter 8, which provide zinc for maturation, storage and exocytosis of the insulin granules [50].
KATP-dependent & KATP-independent GSIS), are responsible for the bi-phasic insulin response in animals.
Variants in this gene show to be associated with reduced glucose-stimulated insulin secretion [25,27] and alterations in proinsulin to insulin conversion [42].
It is thought that the initial rise in insulin secretion is KATP-dependent, while the second phase is mediated through KATP-independent interactions dependent on mitochondrial activity [4,9]. Mitochondrial, lipid and amino acid metabolism plays a significant role in regulation of insulin secretion and GSIS.
Lipid and amino acid metabolites can generate, or can directly become MCFs that enhance or inhibit GSIS. GlucolipotoxicityGrowing evidence indicated that long-term elevated plasma levels of glucose and fatty acids contribute to beta-cell function decline, a phenomenon known as glucolipotoxicity.
While individual amino acids alone at physiological concentrations do not enhance GSIS, some specific amino acids at higher concentrations, or in combination with others, can cause increments in GSIS [10]. Glucolipotoxicity differs from beta-cell exhaustion, which is a reversible phenomenon characterized by depletion of insulin granules due to prolonged exposure to secretagogues. Arginine, alanine, leucine and glutamine can increase GSIS, while homocysteine and cysteine at elevated concentration can inhibit GSIS [10].
The effect of amino acids is also dependent on whether ?-cells are exposed acutely or chronically, as chronic exposure may influence the expression of genes involved in the control of insulin secretion [10,11]. Chronic exposure of beta-cells to hyperglycemia can also induce beta-cells apoptosis by increasing proapoptotic genes expression (Bad, Bid, Bik) while antiapoptotic gene expression Bcl-2 remains unaffected [54].There is a strong relationship between glucotoxicity and lipotoxicity.
In addition, another nutrient source, fatty acids, can also regulate GSIS in both a positive or negative manner depending on the level of saturation, carbon chain length, and whether exposure is under acute or chronic conditions.
Thus, hyperglycemia increases malonyl-CoA levels, leading to the inhibition of carnitine palmitoyl transferase-1 and subsequently to decreased oxidation of fatty acids and lipotoxicity [52]. Saturated fatty acids like palmitic and stearic acid are known to chronically decrease GSIS in vitro, but palmitic acid can acutely enhance GSIS [12-14]. Increased fatty acids in the pancreas leads to intrapancreatic accumulation of triglycerides [55]. Conversely, chronic exposure to monounsaturated oleic acid and polyunsaturated arachidonic acid can increase insulin production in ?-cells [13,15].
Lim E et al showed that the intrapancreatic fat is associated with beta-cell dysfunction and that sustained negative energy balance induces restoration of beta-cellular function [56].Elevated levels of glucose and saturated fatty acids in beta cells, stimulates AMP-activated protein kinase, which contributes to increased expression of sterolregulatory-element-binding-protein-1c (SREBP1c), leading to increased lipogenesis [57]. Fatty acids can amplify ?-cell GSIS, and it is likely that they elevate insulin levels by causing changes in calcium influx and proteins associated with ion channel activity [16].
Mitochondrial metabolism of amino and fatty acid is at the hub of the reported effects on insulin secretion and GSIS, mainly because TCA-mediated metabolism of both leads to increased ATP production and protein biosynthesis, which is a prerequisite for insulin secretion (Fig. Activation of the isoform of protein kinase C (PKC?) by free fatty acids which has been suggested as a possible candidate signaling molecule underlying the decrease in insulin secretion [60].Impaired insulin gene exepression by down-regulation of PDX-1 and MafA insulin gene promoter activity [61].
PDX-1 is affected in its ability to translocate to the nucleus, whereas MafA is affected at the level of its expression [61]. The intricacies of mitochondrial-mediated metabolism of amino and fatty acids will be discussed below.3. Free fatty acid impairs insulin gene expression only in the presence of hyperglycemia [62]. Pancreatic ?-cell metabolism and influencing factors Pancreatic ?-cells are unique and can be distinguished from other cell types by their metabolic profile.
Palmitate affects both insulin gene expression and insulin secretion, unlike oleate which affects only insulin secretion [63]. These adaptions are designed to specifically accelerate oxidative phosphorylation and TCA activity as a means to increase ATP output and consequently insulin exocytosis. Figure 2.Schematic diagram representing the metabolism of selected amino acids, highlighting related metabolic stimulus-secretion coupling factors involved in insulin release. Endoplasmic reticulum stressThe endoplasmic reticulum is responsible for the protein synthesis, being involved in protein translation, folding and assessing quality before protein secretion.
Accumulation of unfolded and misfolded protein in the endoplasmic reticulum lumen may impose endoplasmic reticulum stress [79,80].
Inflammatory cytokines such as IL-1? and IFN-?, can also cause endoplasmic reticulum stress [72].Endoplasmic reticulum stress induced beta-cell activation of an adaptive system named unfolded protein response by which it attenuates protein translation, increases protein folding and promotes misfolded protein degradation [81,82]. Briefly, the glycerol-3-phosphate shuttle consists of cytosolic and mitochondrial glycerol-3-phosphate dehydrogenase that operate in unison to convert dihydroxyacetone phosphate to glycerol-3-phosphate and NAD+, with a subsequent generation of FADH2 from NAD+ [4].
Thus, it prevents additional protein misfolding and further accumulation of unfolded protein; increase the folding capacity of the endoplasmic reticulum to deal with misfolded proteins via the induction of endoplasmic reticulum chaperones. Here, cytosolic malate dehydrogenase reduces oxaloacetate to malate and NAD+, with a subsequent generation of NADH inside the mitochondria. Using an amino group provided by glutamate, mitochondrial oxaloacetate can be converted back to aspartate maintaining this cyclic event. Mitochondrial dysfunction and ROS productionBeta cell mitochondria play a key role in the insulin secretion process, not only by providing energy in the form of ATP to support insulin secretion, but also by synthesising metabolites that can act as factors that couple glucose sensing to insulin granule exocytosis [3].Mitochondrial dysfunction and abnormal morphology occur before the onset of hyperglycemia and play an important role in beta-cell failure [89]. In diabetic state, the proteins from the mitochondrial inner membrane are decreased, and also may exist transcriptional changes of the mitochondrial proteins [89]. Mitochondrial dysfunction, induced by glucolipotoxicity, plays a pivotal role in beta-cell failure and leads to increased ROS production as a result of metabolic stress. Levels of antioxidant enzymes in beta cells are very low (catalase and glutathione peroxide levels were much lower than those of superoxide dismutase), making beta cells be vulnerable to oxidative stress [92].Low concentrations of ROS contribute to increased glucose-stimulated insulin secretion, but only in the presence of glucose-induced elevations in ATP [93].
Adapted from [11].As alluded to previously, amino acid metabolism is essential for nutrient- and glucose-stimulated insulin secretion, and the effects of several amino acids have been reviewed extensively [3,10,11].
To summarise these findings briefly, both arginine and alanine have been shown to promote insulin release through changes in electrogenic transport, progressing to activation of Ca2+ ion channels [10,23,24].
All these effects are reversible in time after transient increase ROS.Chronic and significant elevation of ROS, resulted from an imbalance between ROS production and scavenging by endogenous antioxidants, may lead to beta-cell failure [95,96]. Persistent oxidative stress mediates beta-cell failure through several different mechanisms, including:Decreased insulin secretion. Therefore, both arginine and alanine may protect ?-cells from oxidative insult in addition to promoting insulin secretion. However, prolonged exposure of ?-cells to alanine results in decreased alanine-induced insulin secretion, while reaction of arginine with inducible nitric oxide synthase (iNOS) can promote nitric oxide (NO) production [10,19].
Beta-cells lipid accumulation via SREBP1c [108].The antioxidant effect varies depending on the type of exposure of beta cells to ROS. NO is an important signalling molecule, which is essential for ?-cell glucose uptake at low levels, but at high concentration may be toxic [26]. Thus, under beta-cells exposure to low concentrations of ROS, antioxidants lower the insulin secretion [109,110]. Interaction of NO with superoxide (O -) can also lead to the formation of peroxynitrite (ONOO-), a damaging free radical that can disrupt mitochondrial function [27]. Instead, under the glucolipotoxicity, antioxidants increase the insulin secretion and reduce beta cell apoptosis [108].9.
In fact, ONOO-, which is in equilibrium with its conjugate peroxynitrous acid (ONOOH, pKa ? 6.8) [28], is a highly reactive oxidant species produced by the combination of the oxygen free radical O2- and NO [29] and has been demonstrated to be a more potent oxidant and cytotoxic mediator than NO or O2- individually, in a variety of inflammatory conditions [30].
ONOO- is extremely cytotoxic to rat and human islet cells in vitro [31] and its in vivo formation has been reported in pancreatic islets where it has been associated with ?-cell destruction and development of T1DM in NOD mice [32]. Additionally, beta-cells dysfunction and apoptosis may also be triggered by pro-inflammatory signals from other organs, such as adipose tissue [111,112]. High levels of homocysteine and cysteine have also been shown to elicit a negative effect on ?-cell function. In obese hyperinsulinaemic T2DM patients, homocysteine levels are increased, while they are increased in T1DM patients, but only following disease-related complications such as diabetic nephropathy [11,33].
Chronic exposure of beta-cell to inflammatory cytokines, like Il-1?, IFN-? or TNF-?, can cause endoplasmic reticulum stress and the unfolded protein response activation in beta-cells, and also beta-cells apoptosis [72,115]. It has been suggested that homocysteine can decrease GSIS in rat pancreatic ?-cells [34], although the inhibitory mechanism is still not fully understood. Because, as indicated by Donath et al, the apoptotic beta-cells can provoke, in turn, an immune response, a vicious cycle may develop [115]. Another cytokine involved in beta-cells dysfunction is the PANcreatic DERived factor (PANDER). In addition, homocysteine can be converted to asymmetric dimethylarginine, which is inhibitor of neuronal NOS and can also inhibit iNOS to a lesser extent and therefore may reduce NO production, which is important for ?-cell insulin secretion and function [10,37].
In contrast, cysteine has been shown to increase ?-cell GSIS at low concentrations [38] and is essential for antioxidant defence and glutathione synthesis, along with glycine and glutamate.
Cysteine supplementation was found to protect ?-cells from hydrogen peroxide (H2O2)-induced cell death and prevented glucotoxicity in mouse ?-cells [39,40]. There have not been revealed significant effects of adiponectin on basal or glucose-stimulated insulin secretion [112].Leptin is another adipocytokine that may interfere with beta-cell function and survival.
However, at elevated concentrations, it impaired GSIS through excessive hydrogen sulphide (H2S) formation [41].
In studies on animal model, leptin has been shown to inhibit insulin secretion via activation of ATP-regulated potassium channels and reduction in cellular cAMP level [116], inhibit insulin biosynthesis by activating suppressor of cytokine signalling 3 (SOCS3) [119], suppress acetylcholine-induced insulin secretion [116] and induce the expression of inflammatory genes [120]. Glutamine is required for ?-cell metabolism and function, and is consumed at rapid rates [10]. Studies performed on human islets indicated that chronic exposure to leptin stimulates the release of IL-1? and inhibits UCP2 expression, leading to beta-cell dysfunction and apoptosis [111].


Glutamine supplementation does not induce insulin release [10], but co-treatment with leucine significantly enhances GSIS via activation of glutamate dehydrogenase (GDH), allowing entry of glutamine into the TCA cycle (Fig. Other adipocytokines including TNF-?, IL-6, resistin, visfatin may also modulate beta-cell function and survival, although it is unclear whether the amount released into the circulation is sufficient to affect beta-cells [111].10. Islet amyloid polypeptideHuman islet amyloid polypeptide (amylin) is expressed almost exclusively in beta-cells and is costored and coreleased with insulin in response to beta-cells secretagogues.
It has been suggested that glutamine alone does not induce insulin secretion because it is not oxidised during its metabolism. Glucolipotoxicity causes increased insulin requirement and those lead to increased production of both insulin and amylin. Instead, metabolism of glutamine may yield aspartate and GABA (?-aminobutyric acid), a potent inhibitor of glucagon secretion (Fig. High concentrations of amyloid are toxic to beta-cells and have been implicated in beta-cell dysfunction and apoptosis [121,122].The effect of Islet amyloid polypeptide on beta-cell function is not fully elucidated.
Studies in vivo have shown that the islet amyloid polypeptide inhibits the first and second phase of glucose-stimulated insulin secretion, but this occurs only at concentrations of islet amyloid polypeptide above physiological range [77]. However, using NMR studies, we found that the major products of glutamine metabolism were aspartate and glutamate.
Here, glutamate entered the ?-glutamyl cycle and increased the synthesis of the antioxidant, glutathione [43].
Beta-cell failure — Implication for treatmentUnderstanding the causes for beta-cell failure is of capital importance to develop new and more effective therapeutic strategies.Taking into consideration the existence of early beta-cell dysfunction and the significant reduction of beta-cell mass in the natural history of T2DM as well as the progressive character of these pathophysiological modifications, insulin therapy could be an important option for obtaining and maintaining an optimal glycemic control. Consequently, glutamine may function to enhance ATP production and insulin release by changes in down-stream metabolism, most notably via glutamine-derived glutamate.
Alternatively, glutamate can be transported externally from the cell and into the surrounding matrix, which may cause glutamate receptor activation and desensitisation if the rate of release is over extended periods [44].
Since glucagon secretion from pancreatic ?-cells is sensitive to glutamate exposure, its release may represent a novel paracrine control mechanism for modulation of blood carbohydrate levels [44].
Several lines of evidence indicated that metformin could improve beta-cell function and survival. Some groups have reported that total intracellular glutamate levels increased in response to glucose, while others reported no significant change [25,45,46].
Incubation of T2DM islets with metformin was associated with increased insulin content, insulin mRNA expression and glucose responsiveness, and also with reduced cell apoptosis by normalization of caspase 3 and caspase 8 activities [103].
Recently, it has been suggested that glutamate is transported into insulin-containing vesicles, thereby promoting Ca2+-dependent insulin secretion [47].
It has been shown that metformin, and also the PPAR gamma agonists can protect beta-cell from deleterious effects of glucolipotoxicity [126,127].Other therapeutic options for beta-cell protection, such as incretins are actually under debate.
Taken together, this evidence suggests that a variety of amino acids may contribute significantly to regulation of pancreatic ?-cell insulin secretion. However, other ?-cell metabolic processes are important to insulin secretion and must be considered. Here, the authors have clearly demonstrated that under glucose stimulus, ?-cells strongly enhance metabolic flux towards glycolysis and TCA cycle. Indeed, there is a very delicate poise to coordinately regulate the flux of glucose towards the formation of NADPH (through the pentose-phosphate shunt) avoiding excessive formation of sorbitol (via the polyol-aldose reductase shunt) which would empty glycolytic flux (Fig.
Finally, glucose may be deviated from ultimate metabolism through further glycolytic steps via the reaction of fructose-6-phosphate with glutamine through the hexosamine biochemical pathway (HBP) (Fig. Over-enhanced flux through HBP is an inducer of endoplasmic reticulum (ER) stress, while being associated with insulin-resistance [55].PC and PDH are both highly expressed in ?-cells and allow conversion of pyruvate to oxaloacetate (PC) and acetyl-CoA (PDH), with subsequent entry into the TCA cycle [4]. Interestingly, siRNA inhibition of PC reduces cell proliferation and GSIS in insulinoma cells and rat islets, while overexpression in rat islets could enhance GSIS and cell proliferation [56,57]. The role of PDH is less understood and it is thought to support PC activity by providing acetyl-CoA for citrate production. Common to each pathway is the conversion of glycolytic-derived pyruvate to oxaloacetate by PC, as described above.
Pyruvate can re-enter the mitochondria to repeat the cycle with further generation of NADPH [4]. Translocation of citrate to the cytosol results in oxaloacetate and acetyl CoA regeneration from citrate by ATP-citrate lyase (ACL). Malonyl CoA is then converted to long chain acyl CoA by fatty acid synthase leading to fatty acid production. Additionally, malonyl CoA can also inhibit carnitine palmitoyl transferase 1 (CPT-1), which in a low glucose state, transports fatty acids into the mitochondria to generate ATP by oxidation [4,10].
However, in high glucose situations, inhibition of CPT-1 leads to fatty acid accumulation in the cytosol and this accumulation may increase insulin exocytosis by augmenting calcium influx and ion channel proteins [10,16]. These concepts again fully illustrate the inherent relationship between ?-cell metabolism of glucose, amino acids and lipids with insulin exocytosis [11,58,59]. AMPK is crucial in lipid metabolism control and can chronically regulate ?-cell function by altering the expression of vital transcription factors that govern lipogenic and glycolytic enzymes [10]. The exact metabolic mechanisms of how lipids can augment GSIS are still not fully understood but are believed to involve modulation of Ca2+ mobilisation via interaction with G-protein coupled receptors [60].
Recent evidence has shown that these G-protein coupled receptors are highly expressed in ?-cells and correlated with insulinogenic index [10,61]. It has also been demonstrated that interaction of omega-3 fatty acids and the GPR120 receptor, plays an instrumental role in mediating insulin-sensitisation and anti-inflammatory effects in obese mice models [62]. AMPK also occupies a central position in metabolic regulation in order to avoid inflammatory dysregulation.
Accordingly, in different cell types, AMPK phosphorylates and inhibit glutamine:fructose-6-phosphate amidotransferase-1 (GFAT-1), the flux-generating step of HBP (Fig.
4), thus allowing for the down-regulation of such a shunt from glycolysis under low glucose situations [63], while chronic hexosamine flux stimulates fatty acid oxidation by activating AMPK [64].
However, regulatory pathways under AMPK control are not solely intended to divert metabolic fluxes.
Rather, AMPK regulation of GSK-3? allows the concomitant regulation of inflammatory cytokine production, since the inhibition of GSK-3? elicits the deinhibition of HSF-1, thus triggering the expression of HSP70, which is an intracellular anti-inflammatory protein. It is of note that, besides the now classical molecular chaperone action, the most remarkable intracellular effect of HSP70 is the inhibition of NF- ?B activation, which has profound implications for immunity, inflammation, cell survival and apoptosis. This may also be unequivocally demonstrated by treating cells or tissues with HSP70 antisense oligonucleotides that completely reverse the beneficial NF-?B-inhibiting effect of HSP70 and inducible HSP70 expression (see [68,69]). Hence, HSP70 is anti-inflammatory per se, when intracellularly located, which also explains why cyclopentenone prostaglandins (cp-PGs), which are the most powerful physiological inducers of HSP70 by activating HSF-1, are at the same time powerful anti-inflammatory autacoids [71-73].Another striking effect of HSP70 is the inhibition of apoptosis. The intrinsic apoptotic pathway is characterized by the release of mitochondrial pro-apoptotic factors and activation of caspase enzymes, while stimulation of cell surface receptors triggers the extrinsic death-pathway.
The inhibitory potential of HSP70 over apoptosis occurs via many intracellular downstream pathways (e.g.
JNK, NF-?B and Akt), which are both directly and indirectly blocked by HSP70, or through inhibition of mitochondrial Bcl-2 release.
Together, these mechanisms are responsible for HSP70’s anti-apoptotic function in stressed-cells [74].In conclusion, intracellularly activated HSPs of the 70-kDa family are cytoprotective and anti-inflammatory by avoiding protein denaturation and excessive NF-?B activation which may be damaging to the cells [75]. These observations link energy sensing (AMPK) to anti-inflammation (HSP70) and points out to the complexity of the impact of metabolic regulation for cell survival and function.
Therefore, agents or nutrients that promote anti-inflammatory responses may be beneficial as anti-diabetic therapies.
Since interaction of the immune system with pancreatic islets is central to T1DM and is becoming increasing linked to T2DM, the precise mechanisms of pancreatic cell death in relation to immunological function will now be discussed.4. Immune-like characteristics of ?-cells and response to cytokinesThe pathophysiology of pancreatic islets in T1 and T2DM is characterised by an inflammatory process that includes immune cell infiltration, presence of apoptotic cells, expression of cytokines or adipokines and even amyloid deposits [76].
Although the aetiology of T1DM differs from T2DM, a common feature of both is an immune system-mediated destruction of pancreatic ?-cells, ultimately leading to pancreatic dysfunction and reduced ?-cell mass. In fact, it also stems from local production of pro-inflammatory cytokines by the pancreatic ?-cells themselves.
The similarity between pancreatic ?-cells and immune cells is an intriguing characteristic. Pancreatic ?-cells have been shown to express biologically active cytokines like the pro-inflammatory cytokine IL-1? in hyperglycaemic conditions [77,78].
However, expression of the biologically active form of IL-1? was evident in pancreatic ?-cells, indicating that similar to immune cells, these cells possess the necessary cellular machinery to allow expression of immunologically active cytokines [77]. IL-1? elicits its potent cytotoxic effects through activation of NF?B, and a subsequent initiation of the extrinsic cell-death pathway [78]. Additionally, chronic exposure to IL-1? results in increased iNOS expression, and consequently excess NO production. High levels of NO inhibit mitochondrial ATP synthesis and up-regulate the expression of pro-inflammatory genes in ?-cells, which may potentiate ?-cell failure [78]. Similar to macrophages and dendritic cells, ?-cells also express TLR’s that normally function to regulate the immune system [80]. TLR’s interact with a wide variety of pathogen-related molecules, including lipopolysaccharide (LPS), a component of bacterial cell walls. However, in ?-cells, it is believed that TLR’s play a role in insulin-resistance and inflammation in T2DM. TLR2 and TLR4 have been suggested as receptors for fatty acids, and may alter insulin signalling during dyslipidaemia. We have shown that ?-cells express a range of TLR’s and could indeed respond to LPS via TLR’s, and this interaction decreased insulin exocytosis accordingly [80]. Glutamine also up-regulates nuclear factor of activated T cells (NFAT), and thus promotes ?-cell growth, while suppressing ?-cell death. Mutations in NFAT-dependent genes have been demonstrated to result in hereditary forms of T2DM [11].
Moreover, as discussed above, glutamine can enter HBP thus regulating GSK-3? activity and HSP70 expression which promotes anti-inflammation and cytoprotection [53,54].Pancreatic ?-cells are also reported to express other cytokines, including IL-6, IL-8, granulocyte colony-stimulating factor (G-CSP) and MIP-1 (macrophage inflammatory protein-1) that not only induce apoptotic ?-cell death, but also signal patrolling macrophages, enhancing islet immune cell infiltration [76]. Macrophages, monocytes, neutrophils and dendritic cells perform their function by engulfing invading foreign matter including bacteria or dead cells, and degrade them using super oxide (O2 -) generated from plasma membrane-bound NOX [27]. ?-Cells also express NOX in large quantities, and utilise controlled NOX-derived ROS to drive mitogenic signalling and proliferation [27]. However, during hyperglycaemia or dyslipidaemia as occurs in T2DM, levels of NOX-derived ROS may increase and overwhelm antioxidant defences, leading to mitochondrial dysfunction, DNA oxidation, lipid peroxidation and ?-cell death.
These reports illustrate the immune-like characteristics of pancreatic ?-cells and clearly demonstrate the ability of these cells to not only respond to cytokines, but to be capable of producing endogenous cytokines in an autocrine fashion. This suggests that the immune system plays an integral part in progression of DM and may offer potential therapeutic targets. However, to develop immune-related treatments, more research is required into understanding the mechanisms of islet inflammation in both T1 and T2DM. Macrophages play a critical role since they phagocytose apoptotic and necrotic ?-cells, as well as produce ROS and cytokines (TNF?, INF-? and IL-1?), that can promote ?-cell death, which leads to patient insulin-dependence.
However, effector CD4-helper and CD8-cytotoxic T-cells represent the predominant pancreatic infiltrate for this disease, and recent evidence has suggested that T1DM progression may be dependent on a precarious equilibrium between migration and activation of effector and regulatory T-cells (Treg) [82]. An important element in T1DM disease development is the generation of autoreactive effector T-cells that kill pancreatic ?-cells through expression of Fas, lytic granules and cytokines such as INF-? [82]. Research into formation of these autoimmune cell types is still at an early stage, and it was only definitively shown in 2012, that autoreactive effector cytotoxic-CD8 T-cells were indeed present in T1DM human pancreatic islets [81]. Furthermore, the means by which these "homicidal" immune cells are generated and go on to attack ?-cells is still not fully understood. However, part of the process is believed to involve dendritic cell migration to draining lymph nodes following antigen presentation, and stimulation of autoreactive T-cell differentiation [82,83].
T-cells sub-sets such as Th1, Th2 and Th17 are thus formed and they express the necessary weaponry that is responsible for ?-cell death in T1DM [82], this being exacerbated by strong psychological stress [84], one of the possible triggering factors for the onset of T1DM (for review, please see [85]). Additionally, T-cell–mediated release of INF-? and TNF? can up-regulate expression of pro-apoptotic proteins (Bim and PUMA) leading to ?-cell death, along with promoting recruitment and clearance of damaged-cells by macrophages [77,86]. On the other hand, in normal individuals, activity of these autoimmune cells is normally controlled by Treg cells and it is the failure to control the action of effector T-cells that result in autoimmune disease.
The mechanisms by which Treg cells prevent autoimmune attack is also not fully elucidated, but they are thought to prevent cytotoxic action of T-cells by use of contact inhibition and release of soluble signalling factors, such as IL-10 and TGF? (transforming growth factor?) [82]. It is also unclear whether the precise causes of inflammation in T1DM are a consequence of T-cell failure to respond to Treg, or whether defective or low Treg numbers are to blame for disease progression.
Nonetheless, the interplay between these cell populations offers a potential therapeutic strategy for T1DM treatment [82]. Interestingly, an autoimmune element has also been reported in patients with T2DM, along with the accepted thesis of insulin-resistance [76,87].
Hyperglycaemia, dyslipidaemia and low-grade inflammation (consisting of circulating inflammatory cytokines or adipokines released by adipocyte expansion), are considered important factors in the progression of T2DM and are generally present in obese individuals who are at risk of T2DM development [77].
Moreover, concomitant down-regulation of the receptor antagonist IL-1Ra was also observed in ?-cells cultured in hyperglycaemic conditions [76]. In addition, IL-1? can promote the local expression of other cytokines, for example IL-6 and IL-8. These cytokines aid in the recruitment of patrolling macrophages, which may subsequently become activated by high microenvironment levels of IL-1? and amplify IL-1? content in their own right [76].
In terms of islet inflammation, IL-1? expression and its effects on ?-cell death appears to be a uniting factor, in both T1 and T2DM and is being considered a possible therapeutic target [77,89]. While inflammation is essential to maintain tissue homeostasis, it is also beneficial and allows repair of damaged organs. However, it is the presence of chronic, out of control and unchecked inflammatory factors that contribute to ?-cell death and ensuing DM.
Ultimately, increased local microenvironment cytokine production in islets is detrimental and understanding the mechanisms of cytokine release and regulation, and also suppression of ?-cell function, will allow the development of new treatment regimens. Inflammatory mediators and suppression of ?-cell functionSince inflammation and ?-cell death is common to both T1 and T2DM, it is reasonable to assume that shared inflammatory mediators may exist between the two conditions.
It is these mediators that promote infiltration of immune cells, suppression of ?-cell function, culminating in reduced insulin exocytosis and increased ?-cell apoptosis. However, it must be noted that the activity of these modulators can be heavily influenced by nutrient availability, such as in hyperglycaemia and dyslipidaemia conditions.
Further to this, there is significant crossover between the molecules in these categories, and several can significantly impact on the others, indicating a complex role in both T1 and T2DM.
T1DM is an autoimmune disease and it comes as no surprise that cytokine expression is elevated in these patients [79].
Interestingly, it is becoming more evident that cytokines also play a critical role in T2DM progression, and increased levels have been reported in T2DM patients [76,87]. The most obvious source of cytokine production is from islet invading immune cells, although other researchers have illustrated that islet ?-cells could also express cytokines [76,79].
Cytokine and adipokine release also occurs from adipose tissue since it expands rapidly in obese patients. Here, hypoxia also plays a key part in cytokine release due to an inflammatory response to lack of vasculature in rapidly growing adipose tissue [90,91]. Recent evidence has suggested that adipocyte invading macrophages are a significant supplier of TNF? to the circulation in obese T2DM patients, and this could be a contributing-factor that modulates inflammation in disease progression [92,93]. It is likely that all sources contribute in some way or another to elevate cytokine levels, and consequently compound inflammation in DM patients. The main cytokines that are responsible for inflammation in T1 and T2DM, include IL-1?, TNF?, INF-?, IL-6 and IL-8. This factor targets transcription of genes associated with inflammation, and can cause subsequent up-regulation and release of IL-1?, TNF?, IL-6 and IL-8 [94,95]. Therefore, the aforementioned cytokines can initiate an auto-stimulatory or feed-forward inflammatory effect through NF?B-signalling in ?-cells, resulting in amplification of inflammation. NF?B can play either a pro-survival or pro-death role given the correct circumstances [98]. Both NF?B and JNK are intrinsically connected, and NF?B can prevent JNK-mediated cell death, the regulatory interactions of which have been reviewed expertly elsewhere [99]. Cellular ROS can be generated from Electron Transport Chain (ETC) respiratory complexes or from specific enzymes (e.g. As a result of unavoidable oxidative chemistry and prolonged ETC activity, superoxide (O2 -) anions can be formed and may “leak” from the mitochondria and elicit cellular damage [100].
Additionally, excess glucose can cause increased intracellular calcium, which may enhance mitochondrial O2 - output, but also activate NOX-derived ROS via protein kinase C (PKC) [100]. High glucose can also induce NOX activity through NADPH production from the conversion of glucose-6-phosphate to pentose leading to increased O2 - [100]. Superoxide is a precursor reactive species and can be converted to other forms of strong oxidants including H2O2, and free radicals such as hydroxyl radicals and also peroxynitrite following reaction with NO [27,100].
In T2DM patients, dyslipidaemia occurs along with hyperglycaemia and consequently vascular circulation and intracellular accumulation of lipids can have a profound effect on the inflammatory response. They can also increase O2 - and NO production via activation of NOX and iNOS, respectively, all potentially activating the NF?B pathway [97,100,102]. Formation of ceramide from long chain fatty acids also contributes to precipitation of lipotoxicity in ?-cells and results in ROS generation and apoptotic death [97,100]. Ceramide, synthesised by serine palmitoyltransferase from long chain fatty acids like palmitic acid [100], is capable of inhibiting the pro-survival PI3K pathway, activating caspase-9 [100]. Like other fatty acids, ceramide can associate with and activate TLR’s, which may elicit an immune response [90].
Since adipose tissue expands in obese patients, increased adipose-derived factors have been detected in patient serum, including leptin, TNF? and IL-6. Leptin, an appetite control endocrine factor, inhibits feeding by interaction with receptors in the hypothalamus and a subsequent stimulation of neurotransmitter release, for example norepinephrine [103]. It is considered a cytokine due to its homology in structure with IL-6, and its receptor-mediated effects [77,103,104].
It has been shown to induce ?-cell death by up-regulating IL-1?, and has also been implicated in exacerbation of T1DM in animal models [77,105]. Conversely, adiponectin is considered an anti-inflammatory protein, and enhances IL-1Ra and IL-10 expression [90,106], leading to reduced IL-1? and enhanced suppression of T-cell mediated inflammation. Chemokines can also be secreted from adipose tissue and are elevated in the adipose tissue of obese mice and humans [90,107].



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