Ob Pomelo bei Diabetes

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Over a hundred years ago, high doses of salicylates were shown to lower glucose levels in diabetic patients.

This should have been an ob Pomelo bei Diabetes clue to link inflammation to the pathogenesis of type 2 diabetes T2Dbut the antihyperglycemic and antiinflammatory effects of salicylates were not connected ob Pomelo bei Diabetes the pathogenesis of insulin resistance until recently. Together with the discovery of an important role for tissue ob Pomelo bei Diabetes, these new findings are helping to reshape thinking about how obesity increases the risk for developing T2D and the metabolic syndrome.

The evolving concept of insulin resistance and T2D as having immunological components and an improving picture of how inflammation modulates metabolism provide new opportunities for using antiinflammatory strategies to correct the metabolic consequences of excess adiposity.

Clues to the involvement of ob Pomelo bei Diabetes in diabetes date back ob Pomelo bei Diabetes more than a century ago, when high doses of sodium salicylate 5. In Ebstein concluded that sodium salicylate could make the symptoms of diabetes mellitus totally disappear 13. The effect was rediscovered in ob Pomelo bei Diabetes an insulin-treated diabetic, given high-dose aspirin to treat the arthritis associated with rheumatic fever, no longer required daily insulin injections 4.

Fasting and postchallenge glucose concentrations were nearly normal, despite the discontinuation of insulin and treatment with aspirin alone.

Upon resolution of the ob Pomelo bei Diabetes symptoms, the aspirin was discontinued, and a repeat glucose tolerance test was grossly abnormal. Over a 2-week course of high-dose aspirin 5. Additional trials showed equivalent efficacy 56. Mechanistic studies focused on insulin secretion, undoubtedly because of the established importance of insulin secretion in the pathogenesis of diabetes, but the findings were inconclusive 7.

Insulin resistance and its role in the pathogenesis of T2D were less well appreciated, and, as a result, insulin sensitization was not considered as a potential mechanism for glucose lowering at the time.

Although epidemiological associations relating inflammation to T2D or obesity can be traced to the late s and s, when increases were found in circulating concentrations of fibrinogen and other acute-phase reactants 11 — 13the findings similarly failed to influence thoughts about pathogenesis.

More recently, additional epidemiological studies confirmed and extended these early findings Increased levels of markers and mediators of inflammation and acute-phase reactants such as fibrinogen, C-reactive protein CRPIL-6, plasminogen activator inhibitor-1 PAI-1sialic acid, and white cell count correlate with incident T2D 15 — This discovery gave the field a critical boost, because epidemiological studies, while highly informative, are correlative by nature and, alone, are unable to determine causality.

These different areas of research have coalesced sufficiently that credible hypotheses can now link inflammation to the development of insulin resistance and pathogenesis of T2D 30 This was a revolutionary idea, that a substance produced by fat — and overproduced by expanded fat — had local and potentially systemic effects on metabolism.

Adiponectin is similarly produced by fat, but expression decreases with increased adiposity The relative amount of each produced by the adipocyte versus associated adipose tissue macrophages remains unknown. Sites of resistin production are more complex; they include macrophages in humans but both adipocytes and macrophages in rodents MCP-1 and other chemokines have essential roles in the recruitment of macrophages to adipose tissue.

These cytokines and chemokines activate intracellular pathways that promote the development of insulin resistance and T2D. The investigations that focused on intracellular pathways activated by inflammation, instead of individual cytokines, have helped to restructure the framework for thinking about insulin resistance.

The fact that TLRs recognize microbial lipid conjugates ob Pomelo bei Diabetes led to speculation that endogenous lipids or lipid conjugates might also activate 1 or more of the TLRs in obesity, a possibility supported by experiments showing that saturated fatty acids bind and activate TLR4 Likewise, RAGE binds a variety of ligands, including endogenous advanced glycation end products AGEs and a distinct set of microbial products 46 AGEs are nonenzymatic adducts formed between glucose and targeted proteins, particularly ob Pomelo bei Diabetes with slow rates of turnover.

Examples include serine pS and serine ob Pomelo bei Diabetes By contrast, evidence has not been reported for obesity-induced effects on transcription factors such as AP-1 that are regulated by JNK.

Systemic markers of oxidative stress increase with adiposity, consistent with a role for ROS in the development of obesity-induced insulin resistance Consistent with this, the antioxidant N -acetyl cysteine can reduce ROS and improve insulin resistance in a hyperglycemia-induced model Lipid accumulation also activates ob Pomelo bei Diabetes unfolded protein response to increase ER stress in fat and liver Ceramides may form under conditions of cell stress and promote cellular signaling, including the ob Pomelo bei Diabetes of apoptosis.

Saturated fats may also promote the synthesis of ceramides, which accumulate in tissues such as muscle and ob Pomelo bei Diabetes correlate with the degree of insulin resistance Lipid excess increases the activities of various PKC isoforms.

Consistent with these findings, salicylates improve muscle insulin resistance after lipid infusion 56although the relevance of the acute lipid infusion model to the pathology of obesity-induced insulin resistance is questionable. Once activated, however, the processes can be self-perpetuating through a positive-feedback loop created by the produced proinflammatory cytokines. JNK is a stress kinase that normally phosphorylates the c-Jun component of the AP-1 transcription factor, ob Pomelo bei Diabetes to date there ob Pomelo bei Diabetes no known links between this well-established transcriptional pathway and JNK-induced insulin resistance.

In addition to the cytokines, there is upregulated expression of transcriptions factors, receptors, and other relevant proteins including chemokines that recruit monocytes and stimulate their differentiation into macrophages Box 1.

Inflammation is also closely linked to the pathogenesis of ob Pomelo bei Diabetes, suggesting that inflammation might be a common denominator that links obesity to many of its pathological sequelae.

Overlapping collections of transcriptionally regulated inflammatory proteins participate in the pathogenesis of these disorders Box 1. Signs of inflammation accompany even the earliest accumulation of lipid within the arterial wall, including the upregulation of the cell adhesion molecules P- and E-selectin, ICAM-1, and VCAM-1, which localizes circulating immune cells 60 The adherent cells can migrate into the subendothelial space, where they contribute to the local inflammatory response.

The latter can break down collagen and tissue factor, an important mediator of thrombosis As vascular remodeling progresses, the accumulation of foam cells leads to the formation of a lipid pool, rich in prothrombotic tissue factor. Activated macrophages secrete MMPs, which degrade collagen and render the fibrous cap weak and prone to rupture Thus a dynamic balance is maintained between collagen synthesis and breakdown.

If proinflammatory forces predominate, the fibrous cap may thin and eventually rupture, with release of prothrombotic lipids into the lumen. This may herald the onset of an acute ischemic event. This also suggests the corollary that pharmacological decreases in inflammatory activity ob Pomelo bei Diabetes coordinately downregulate the production of a number of proteins involved in the pathogenesis of insulin resistance, T2D, and cardiovascular disease CVD.

Adipose tissue has attracted a great deal of attention as a pathogenic site of ob Pomelo bei Diabetes insulin resistance, partly because changes in adiposity are easy to see but also because fat produces bioactive proteins that are readily detected and reflect the inflammatory state of the organ. However, it has also been firmly established that all fat is not equal; adipose tissue in the subcutaneous versus abdominal or visceral depots differs by cell size 69 ob Pomelo bei Diabetes, 70metabolic activity, and potential ob Pomelo bei Diabetes in insulin resistance 71 Visceral fat is more pathogenic.

The adipocyte itself is integral to the development of obesity-induced inflammation. Since the bulk of accumulated lipid is stored in adipocytes, it is generally assumed that the adipocyte initiates the process and the macrophage serves to amplify the signal. Endothelial adhesion molecules e. The monocytes that differentiate into macrophages produce many of the same inflammatory cytokines and chemokines as those listed above, and additional ones, to further promote local inflammation ob Pomelo bei Diabetes propagate the inflammatory diathesis systemically.

It is important to understand how increasing adiposity leads to the recruitment of immune cells to adipose tissue. MCP-1 CCL2a chemoattractant for monocytes, DCs, and memory T cells, is produced by adipocytes in parallel with increasing adiposity 7475suggesting that MCP-1 might play a role in recruitment of monocytes.

Consistent with this, mice lacking CCR2, an important receptor for MCP-1, are partly protected from developing high-fat diet—induced insulin resistance and exhibit reductions in adipose tissue macrophage recruitment and inflammatory gene expression The fact that protection is incomplete implies that additional chemoattractant ligand-receptor pairs might be involved.

It is also interesting that some macrophages found in the adipose tissue of obese rodents are large and multinucleated 7475 Such multinucleate giant cells are often found at sites of chronic inflammation and result from the fusion or engulfment of macrophages by each other.

Macrophages including multinucleate giant cells may aggregate at sites of adipocyte necrosis Other cell types in adipose tissue may also participate in the inflammatory process. Vascular cells are an obvious place to look. Adipose tissue is highly vascularized, with multiple capillaries in contact with each adipocyte Moreover, adipose tissue rapidly proliferates and expands as nutrient stores increase, possibly using processes similar to the angiogenesis that supports tumor growth In addition to being important for fat expansion, the microvasculature undoubtedly ob Pomelo bei Diabetes important roles in adipose tissue inflammation.

For example, circulating leukocytes do not adhere to normal endothelium, but after initiation of a high-fat Western diet the endothelium expresses cell adhesion molecules that bind leukocytes ob Pomelo bei Diabetes As mentioned earlier, MCP-1 induces the migration of blood monocytes into the subendothelial space and augments differentiation into macrophages. Thus changes are predicted in adipose tissue endothelial cells in response to altered adiposity.

As macrophages rarely function alone, other types of immune cells are likely to participate in ob Pomelo bei Diabetes tissue inflammation, although this has not yet been reported. In ob Pomelo bei Diabetes to cytokine and protease release, the actions of macrophages in inflammation include antigen presentation and T cell activation.

Classical inflammation involves the added presence of neutrophils, DCs, NK cells, mast cells, and various subtypes of T lymphocytes. Potential roles for these other immune cells in adipose tissue inflammation will doubtless be topics for future investigation.

Nonalcoholic fatty liver disease NAFLD often accompanies abdominal adiposity, and its prevalence is increasing and closely parallels the prevalence of the comorbid conditions T2D and hyperlipidemia. The pathological spectrum of NAFLD ranges from simple steatosis to steatohepatitis, advanced fibrosis, and cirrhosis. Inflammation clearly plays a pivotal role in the progression of this disease process. While inadequate suppression of hepatic glucose production, due at least in part to hepatic insulin resistance, is an established contributor to hyperglycemia in T2D, the role of inflammation in the pathogenesis of these processes has only recently been explored.

Inflammatory gene expression increases in liver with increasing adiposity This suggests that hepatocyte lipid accumulation steatosis might induce a subacute inflammatory response in liver that is similar to the adipose tissue ob Pomelo bei Diabetes that follows adipocyte lipid accumulation.

Alternatively, proinflammatory substances in the portal circulation, potentially produced in abdominal fat, might initiate hepatic inflammation. The proinflammatory cytokines participate in the development of insulin resistance and activate Kupffer cells, the resident hepatic macrophages. The number of Kupffer cells does not increase with adiposity, but their activation state does A wide variety of other immune cells are present in normal liver and may also play roles in inflammation-induced insulin resistance, including T and B lymphocytes, NK cells, and DCs as well as hepatic stellate cells and liver sinusoidal endothelial cells Healthy liver contains a broad repertoire of cells that participate in inflammatory and immune responses, including resident hepatic macrophages Kupffer ob Pomelo bei DiabetesB and T cells, NK and NKT cells, DCs, liver sinusoidal endothelial cells, hepatic stellate cells, and hepatocytes.

Hepatic steatosis and obesity are accompanied by the ob Pomelo bei Diabetes of inflammatory signaling pathways in liver. Proinflammatory cytokines and FFAs, produced either by hepatocytes in response to steatosis or by abdominal fat tissue, ob Pomelo bei Diabetes activate Kupffer cells. Numbers of regulatory NKT cells decrease in parallel with the Kupffer cell activation.

Skeletal muscle is another major site of insulin resistance in obesity and T2D. However, increasing ob Pomelo bei Diabetes does not appear to activate inflammatory cascades in ob Pomelo bei Diabetes muscle, as it does in fat and liver. Inflammation is activated in muscle by intralipid infusion, but this is distinct from the effects of increasing adiposity.

The lipid infusion model is a research tool used to acutely raise circulating and intratissue fatty acid levels and induce insulin resistance. Increasing adiposity activates inflammatory responses in fat and liver, with associated increases in the production of cytokines and chemokines. Portal delivery of abdominal fat—derived cytokines and lipids contributes to hepatic inflammation and insulin resistance. Proinflammatory and proatherogenic mediators are produced in the adipose tissue and liver and associated immune cells.

This creates a systemic inflammatory diathesis that promotes insulin resistance in skeletal muscle and other tissues and atherogenesis in the vasculature.