The role of macrophages in obesity-associated islet inflammation and β-cell abnormalities.

Chronic, unresolved tissue inflammation is a well-described feature of obesity, type 2 diabetes mellitus (T2DM) and other insulin-resistant states. In this context, adipose tissue and liver inflammation have been particularly well studied; however, abundant evidence demonstrates that inflammatory processes are also activated in pancreatic islets from obese animals and humans with obesity and/or T2DM. In this Review, we focus on the characteristics of immune cell-mediated inflammation in islets and the consequences of this with respect to β-cell function. In contrast to type 1 diabetes mellitus, the dominant immune cell type causing inflammation in obese and T2DM islets is the macrophage. The increased macrophage accumulation in T2DM islets primarily arises through local proliferation of resident macrophages, which then provide signals (such as platelet-derived growth factor) that drive β-cell hyperplasia (a classic feature of obesity). In addition, islet macrophages also impair the insulin secretory capacity of β-cells. Through these mechanisms, islet-resident macrophages underlie the inflammatory response in obesity and mechanistically participate in the β-cell hyperplasia and dysfunction that characterizes this insulin-resistant state. These findings point to the possibility of therapeutics that target islet inflammation to elicit beneficial effects on β-cell function and glycaemia

Metabolic and transcriptomic analysis of Huntington's disease model reveal changes in intracellular glucose levels and related genes.

Huntington's Disease (HD) is a neurodegenerative disorder caused by an expansion in a CAG-tri-nucleotide repeat that introduces a poly-glutamine stretch into the huntingtin protein (mHTT). Mutant huntingtin (mHTT) has been associated with several phenotypes including mood disorders and depression. Additionally, HD patients are known to be more susceptible to type II diabetes mellitus (T2DM), and HD mice model develops diabetes. However, the mechanism and pathways that link Huntington's disease and diabetes have not been well established. Understanding the underlying mechanisms can reveal potential targets for drug development in HD. In this study, we investigated the transcriptome of mHTT cell populations alongside intracellular glucose measurements using a functionalized nanopipette. Several genes related to glucose uptake and glucose homeostasis are affected. We observed changes in intracellular glucose concentrations and identified altered transcript levels of certain genes including Sorcs1, Hh-II and Vldlr. Our data suggest that these can be used as markers for HD progression. Sorcs1 may not only have a role in glucose metabolism and trafficking but also in glutamatergic pathways affecting trafficking of synaptic components

Paradoxical roles of antioxidant enzymes:Basic mechanisms and health implications

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated from aerobic metabolism, as a result of accidental electron leakage as well as regulated enzymatic processes. Because ROS/RNS can induce oxidative injury and act in redox signaling, enzymes metabolizing them will inherently promote either health or disease, depending on the physiological context. It is thus misleading to consider conventionally called antioxidant enzymes to be largely, if not exclusively, health protective. Because such a notion is nonetheless common, we herein attempt to rationalize why this simplistic view should be avoided. First we give an updated summary of physiological phenotypes triggered in mouse models of overexpression or knockout of major antioxidant enzymes. Subsequently, we focus on a series of striking cases that demonstrate “paradoxical” outcomes, i.e., increased fitness upon deletion of antioxidant enzymes or disease triggered by their overexpression. We elaborate mechanisms by which these phenotypes are mediated via chemical, biological, and metabolic interactions of the antioxidant enzymes with their substrates, downstream events, and cellular context. Furthermore, we propose that novel treatments of antioxidant enzyme-related human diseases may be enabled by deliberate targeting of dual roles of the pertaining enzymes. We also discuss the potential of “antioxidant” nutrients and phytochemicals, via regulating the expression or function of antioxidant enzymes, in preventing, treating, or aggravating chronic diseases. We conclude that “paradoxical” roles of antioxidant enzymes in physiology, health, and disease derive from sophisticated molecular mechanisms of redox biology and metabolic homeostasis. Simply viewing antioxidant enzymes as always being beneficial is not only conceptually misleading but also clinically hazardous if such notions underpin medical treatment protocols based on modulation of redox pathways

MicroRNAs and the functional β cell mass: For better or worse.

Insulin secretion from pancreatic β cells plays a central role in the control of blood glucose levels. The amount of insulin released by β cells is precisely adjusted to match organism requirements. A number of conditions that arise during life, including pregnancy and obesity, can result in a decreased sensitivity of insulin target tissues and a consequent rise in insulin needs. To preserve glucose homoeostasis, the augmented insulin demand requires a compensatory expansion of the pancreatic β cell mass and an increase in its secretory activity. This compensatory process is accompanied by modifications in β cell gene expression, although the molecular mechanisms underlying the phenomenon are still poorly understood. Emerging evidence indicates that at least part of these compensatory events may be orchestrated by changes in the level of a novel class of gene regulators, the microRNAs. Indeed, several of these small, non-coding RNAs have either positive or negative impacts on β cell proliferation and survival. The studies reviewed here suggest that the balance between the actions of these two groups of microRNAs, which have opposing functional effects, can determine whether β cells expand sufficiently to maintain blood glucose levels in the normal range or fail to meet insulin demand and thus lead, as a consequence, towards diabetes manifestation. A better understanding of the mechanisms governing changes in the microRNA profile will open the way for the development of new strategies to prevent and/or treat both type 2 and gestational diabetes

The pancreatic beta cell surface proteome

The pancreatic beta cell is responsible for maintaining normoglycaemia by secreting an appropriate amount of insulin according to blood glucose levels. The accurate sensing of the beta cell extracellular environment is therefore crucial to this endocrine function and is transmitted via its cell surface proteome. Various surface proteins that mediate or affect beta cell endocrine function have been identified, including growth factor and cytokine receptors, transporters, ion channels and proteases, attributing important roles to surface proteins in the adaptive behaviour of beta cells in response to acute and chronic environmental changes. However, the largely unknown composition of the beta cell surface proteome is likely to harbour yet more information about these mechanisms and provide novel points of therapeutic intervention and diagnostic tools. This article will provide an overview of the functional complexity of the beta cell surface proteome and selected surface proteins, outline the mechanisms by which their activity may be modulated, discuss the methods and challenges of comprehensively mapping and studying the beta cell surface proteome, and address the potential of this interesting subproteome for diagnostic and therapeutic applications in human disease

The pancreatic beta cell surface proteome

The pancreatic beta cell is responsible for maintaining normoglycaemia by secreting an appropriate amount of insulin according to blood glucose levels. The accurate sensing of the beta cell extracellular environment is therefore crucial to this endocrine function and is transmitted via its cell surface proteome. Various surface proteins that mediate or affect beta cell endocrine function have been identified, including growth factor and cytokine receptors, transporters, ion channels and proteases, attributing important roles to surface proteins in the adaptive behaviour of beta cells in response to acute and chronic environmental changes. However, the largely unknown composition of the beta cell surface proteome is likely to harbour yet more information about these mechanisms and provide novel points of therapeutic intervention and diagnostic tools. This article will provide an overview of the functional complexity of the beta cell surface proteome and selected surface proteins, outline the mechanisms by which their activity may be modulated, discuss the methods and challenges of comprehensively mapping and studying the beta cell surface proteome, and address the potential of this interesting subproteome for diagnostic and therapeutic applications in human diseas

Brain energy rescue:an emerging therapeutic concept for neurodegenerative disorders of ageing

The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner — a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes

Modern roles for an ancient system. Intracellular Complement in the regulation of β cell function

Type 2 diabetes (T2D) is characterised by defective insulin exocytosis from the pancreatic β cells, accompanied by insulin resistance. Reduced β cells mass is often seen in T2D individuals, caused by enhanced β cells apoptosis. It is now understood that several components drive β cells dysfunction and apoptosis. These are glucose-and lipo-toxicity, ER stress, pro-inflammatory cytokines, dysfunctions in autophagy, and β cells dedifferentiation. Our studies revealed novel functions of intracellular complement components in β cells, presenting a new link between complement and diabetes development. We found that C3 is upregulated in pancreatic islets during T2D as a factor against β cells dysfunction caused by attenuated autophagy. In paper I, we revealed a high expression of C3 in human pancreatic islets. C3 was found intracellularly in isolated human pancreatic β cells. We verified the binding between C3 and ATG16L1 within the cytosol. C3 was required to maintain autophagy activity in β cells, as evidenced by the massive accumulation of LC3-II puncta, indicating that in the absence of C3 autophagosomes do not fuse with lysosomes. Autophagy protects the β cells from injuries caused by exposure to stressors, such as lipotoxicity. When exposing the C3-knockout INS-1 cells to β cells autophagy inducers (palmitate and IAPP), we observed significantly increased cell death caused by autophagy insufficiency. In paper II, we showed that silencing of CD59 expression in rat β cells significantly suppressed insulin secretion. Moreover, removing the membrane-bound CD59 did not affect insulin secretion, suggesting that intracellular CD59 is involved in this function. We found that the CD59 mutant, lacking the GPI-anchor, was present intracellularly in the β cell line. Non-GPI anchored CD59 interacts with SNARE protein: VAMP2 and rescues insulin secretion. We showed that the GPI-anchor, which is necessary for CD59 complement inhibitory function, is not necessary for its ability to mediate insulin secretion. Two other mutations: W40E and C64Y, rescued insulin secretion. Studies showed that these mutations result in a loss of CD59 complement inhibitory functions. Our data suggest that there are different structural requirements for separate functions of CD59, which are: MAC inhibition and insulin secretion. In papers III and IV, using RNA sequencing, we revealed the presence of two CD59 isoforms lacking the GPI anchoring domain (replaced with the unique C-terminal domains). We named these isoforms IRIS-1 and IRIS-2 (Isoforms Rescuing Insulin Secretion 1 and 2). Both isoforms exist in human and mouse pancreatic islets. They colocalize with insulin granules and interact with SNARE exocytotic machinery, allowing for insulin secretion. Induction of glucotoxicity in primary, healthy human islets led to a significant decrease in IRIS-1 protein-level expression. We found that expression of both IRIS-1 and IRIS-2 is markedly reduced in islets isolated from T2D patients compared to healthy controls, suggesting that hyperglycaemia may be one of the factors resulting in reduced IRIS-1 and IRIS-2 expression in T2D individuals. Next, an electropositive patch was found in the C-terminal region of IRIS-1, suggesting potential interaction with DNA. We found that IRIS-1 localizes in the nuclei of pancreatic β cells. We confirmed that the C-terminal domain of IRIS-1 is localising it to the nucleus. Since robust localisation of IRIS-1 in the nucleus is observed only in some nuclei, it can suggest that IRIS-1 is localising in the nucleus depending on the differentiation state of the cells or in a subset of cells with different functional relevance. We found that IRIS-1 expressing cells displayed significantly higher expression levels of Urocortin 3 and Pdx 1 (markers of mature β cells, which loss marks the beginning of β cells dedifferentiation), suggesting that IRIS-1 may be required for maintaining β cells identity and function