The Once and Future Cure for Diabetes

Dr. Weeks’ Comment: Anti-inflammatory agents were curing diabetes a century ago but unfortunately they were killing patients also…. a not altogether atypical response in medicine).  Current research confirms that inflammation fuels diabetes.

 “…The anti-inflammatory properties of TZDs and statins are side effects distinct from their primary modes of action. By contrast, high-dose salicylates directly target inflammation by inhibiting NF-κB (3840). The glucose-lowering effects of salicylates, seen decades ago in patients with diabetes (17), are now recognized as well to be due at least in part to NF-κB inhibition…”


What we need is a “centsible” (safe, effective and cost effective) anti-inflammatory food.  Got SOUL?




Inflammation and insulin resistance

Steven E. Shoelson, Jongsoon Lee and Allison B. Goldfine

Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Published in Volume 116, Issue 7 (July 3, 2006) J Clin Invest. 2006;116(7):1793-1801. doi:10.1172/JCI29069.



Over a hundred years ago, high doses of salicylates were shown to lower glucose levels in diabetic patients. This should have been an important clue to link inflammation to the pathogenesis of type 2 diabetes (T2D), but the antihyperglycemic and antiinflammatory effects of salicylates were not connected to the pathogenesis of insulin resistance until recently. Together with the discovery of an important role for tissue macrophages, 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.


Historical perspectives on the link between inflammation and insulin resistance

Clues to the involvement of inflammation in diabetes date back to more than a century ago, when high doses of sodium salicylate (5.0-7.5 g/d) were first demonstrated to diminish glycosuria in diabetic patients having “the milder form of the disease,” presumably type 2 diabetes (T2D) (1-3). In 1876 Ebstein concluded that sodium salicylate could make the symptoms of diabetes mellitus totally disappear (1, 3). Similarly, in 1901 Williamson found that “sodium salicylate had a definite influence in greatly diminishing the sugar excretion” (2). The effect was rediscovered in 1957 when 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 joint symptoms, the aspirin was discontinued, and a repeat glucose tolerance test was grossly abnormal. Intrigued by these findings, Reid and colleagues prospectively studied 7 additional patients, 4 the “overweight mild type” and three “lean more severe diabetics” (4). Over a 2-week course of high-dose aspirin (5.0-8.0 g/d), fasting blood glucose levels fell from an average of more than 190 mg/dl before treatment to 92 mg/dl; every patient responded. Additional trials showed equivalent efficacy (5, 6). 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. It wasn’t until much later that studies looking at a role for inflammation in the pathogenesis of insulin resistance reinvestigated the hypoglycemic actions of salicylates and identified the molecular target to be the IκB kinase-β (IKKβ)/NF-κB axis (8-10).

Although epidemiological associations relating inflammation to T2D or obesity can be traced to the late 1950s and 1960s, when increases were found in circulating concentrations of fibrinogen and other acute-phase reactants (11-13), the findings similarly failed to influence thoughts about pathogenesis. More recently, additional epidemiological studies confirmed and extended these early findings (14). Increased levels of markers and mediators of inflammation and acute-phase reactants such as fibrinogen, C-reactive protein (CRP), IL-6, plasminogen activator inhibitor-1 (PAI-1), sialic acid, and white cell count correlate with incident T2D (15-25). Markers of inflammation and coagulation are reduced with intensive lifestyle intervention, as was performed in the diabetes prevention program (26), but experiments showing that adipose tissue-derived proinflammatory cytokines such as TNF-α could actually cause insulin resistance in experimental models provided the necessary impetus to begin thinking in terms of pathogenesis (27-29). 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, 31).


Molecular pathways that link inflammation and insulin resistance

Hotamisligil and colleagues (27) and Karasik and colleagues (28) first showed that the proinflammatory cytokine TNF-α was able to induce insulin resistance. This was a revolutionary idea, that a substance produced by fat ”” and overproduced by expanded fat ”” had local and potentially systemic effects on metabolism. The concept of fat as a site for the production of cytokines and other bioactive substances quickly extended beyond TNF-α to include leptin, IL-6, resistin, monocyte chemoattractant protein-1 (MCP-1), PAI-1, angiotensinogen, visfatin, retinol-binding protein-4, serum amyloid A (SAA), and others (32-36). Adiponectin is similarly produced by fat, but expression decreases with increased adiposity (37). While leptin and adiponectin are true adipokines that appear to be produced exclusively by adipocytes, TNF-α, IL-6, MCP-1, visfatin, and PAI-1 are expressed as well at high levels in activated macrophages and/or other cells. 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 (34). TNF-α, IL-6, resistin, and undoubtedly other pro- or antiinflammatory cytokines appear to participate in the induction and maintenance of the subacute inflammatory state associated with obesity. 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. As mentioned above, the antihyperglycemic effects of salicylates focused attention on IKKβ and NF-κB (38-40). However, increasing adiposity activates both JNK and IKKβ (8, 41-43). Many of the more typical proinflammatory stimuli simultaneously activate JNK and IKKβ pathways, including cytokines and TLRs (Figure 1). Concordantly, genetic or chemical inhibition of either JNK or IKKβ/NF-κB can improve insulin resistance. The several hypothesized mechanisms that might explain how obesity activates JNK and NF-κB can be separated into receptor and nonreceptor pathways (Figure 1). Proinflammatory cytokines such as TNF-α and IL-1β activate JNK and IKKβ/NF-κB through classical receptor-mediated mechanisms that have been well characterized (Figure 1). JNK and IKKβ/NF-κB are also activated by pattern recognition receptors, defined as surface proteins that recognize foreign substances. These include the TLRs and the receptor for advanced glycation end products (RAGE) (44). Many TLR ligands are microbial products, including LPS and lipopeptides derived from bacteria (44). The fact that TLRs recognize microbial lipid conjugates has 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 (45). Likewise, RAGE binds a variety of ligands, including endogenous advanced glycation end products (AGEs) and a distinct set of microbial products (46, 47). AGEs are nonenzymatic adducts formed between glucose and targeted proteins, particularly those with slow rates of turnover. Prolonged hyperglycemia and the accompanying production of excess quantities of AGEs can activate NF-κB.

Potential cellular mechanisms for activating inflammatory signaling. Obesity and high-fat diet activate IKKβ/NF-κB and JNK pathways in adipocytes, hepatocytes, and associated macrophages. Stimuli that have been shown to activate these pathways during metabolic dysregulation include ligands for TNF-α, IL-1, Toll, or AGE receptors (TNFR, IL-1R, TLR, or RAGE, respectively), intracellular stresses including ROS and ER stress, ceramide, and various PKC isoforms. Obesity-induced IKKβ activation leads to NF-κB translocation and the increased expression of numerous markers and potential mediators of inflammation that can cause insulin resistance. Obesity-induced JNK activation promotes the phosphorylation of IRS-1 at serine sites that negatively regulate normal signaling through the insulin receptor/IRS-1 axis. Examples include serine-302 (pS302) and serine-307 (pS307). By contrast, evidence has not been reported for obesity-induced effects on transcription factors such as AP-1 that are regulated by JNK. IKKβ and/or NF-κB are inhibited or repressed by the actions of salicylates, TZDs, and statins.


In addition to proinflammatory cytokine and pattern recognition receptors, cellular stresses activate JNK and NF-κB, including ROS and ER stress. Systemic markers of oxidative stress increase with adiposity, consistent with a role for ROS in the development of obesity-induced insulin resistance (48). One potential mechanism is through the activation of NADPH oxidase by lipid accumulation in the adipocyte, which increases ROS production (49). This mechanism was shown to increase the production of TNF-α, IL-6, and MCP-1, and decrease the production of adiponectin. Consistent with this, the antioxidant N-acetyl cysteine can reduce ROS and improve insulin resistance in a hyperglycemia-induced model (50). Lipid accumulation also activates the unfolded protein response to increase ER stress in fat and liver (51). ER stress was shown to activate JNK to lead to serine phosphorylation of insulin receptor substrate-1 (IRS-1), but as with all of the stimuli described in Figure 1, ER stress similarly activates NF-κB…….


…….In summary, obesity, T2D, and CVD share a metabolic milieu characterized by insulin resistance and chronic subacute inflammation. While drugs that secondarily alter the inflammatory process are undoubtedly of great clinical importance, several lines of evidence suggest it might also be possible to directly target inflammation with pharmacological interventions to treat and/or prevent insulin resistance and T2D and modulate risk for CVD and other metabolic conditions. These approaches may provide clinical benefits to a large number of persons affected by the obesity epidemic and the related cluster of metabolic disorders.


…..  (for the complete article including references   see this link to entire article

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