Inflammatory Signaling: Another Drug Target to Improve Glycemic Control in Type 2 Diabetes

Ever since major clinical outcomes studies proved that tight control of Type 2 diabetes can delay or prevent the devastating long-term microvascular complications of the disease, clinicians have been challenged to use all of the treatment options available in their armamentaria to help patients achieve appropriate glucose goals 1. However, in spite of more aggressive treatment guidelines in recent years, many patients are still falling short of these universally accepted goals, in spite of earlier or in some cases the initial use of combinations of oral therapies. A world-wide epidemic of Type 2 diabetes is underway that shows no signs of remitting in the next several years 2. In order to address the basic therapeutic needs of these millions of patients, additional treatment options will need to be made available, especially to have some hope of getting the majority to patients to accepted glucose treatment goals. How can translational research help in the practical development of new therapeutic agents for Type 2 diabetes? Many of the common medications now used to treat diabetes were first discovered as natural products or by drug screening for glucose-lowering effects in diabetic animal models, including metformin, sulfonylureas and thiazolidinediones. More recently, however, newer oral agents have been developed that target a specific therapeutic pathway. Perhaps the best examples of this approach includes agents that affect the incretin pathway 3. Administering agonists of GLP-1 receptors, such as exenatide, or increasing endogenous GLP-1 in the circulation by inhibiting the enzyme responsible for its degradation, dipeptidyl peptidase-4 (DPP-4), have both become common additions to the management of Type 2 diabetes in recent years. In this issue of CTS, Goldfine et al. 4, describe early clinical trials that apply salicylates as a potential hypoglycemic agent for the management of Type 2 diabetes. These studies capitalize on the historical use of these agents as a natural product as well as the more recently appreciated targeting of salicylates as inhibitors of the IKK-β signaling pathway, which contributes to tissue insulin resistance 5. The testing of a commonly used class of drugs, with a well-known safety profile, offers an exciting translational approach that promises to help in the management of glycemia in Type 2 diabetes. One might wonder why the aggressive management of high glucose in Type 2 diabetes has posed such a therapeutic conundrum? In its simplest view, obesity-related Type 2 diabetes results from a combination of two major factors: tissue resistance to the action of insulin combined with inadequate pancreatic β-cell insulin secretion. In recent years, a detailed characterization of the underlying pathogenic defects in Type 2 diabetes has progressed rapidly, and multiple pathways have been identified, each contributing significantly to the underlying disease state 6. In the majority of patients, it is known that a multigenic predisposition progresses to overt Type 2 diabetes in the setting of overfeeding and obesity because of a panoply of abnormalities, each of which contributes its part to the underlying insulin resistance that, along with β-cell defects, ultimately leads to hyperglycemia. Obesity-related Type 2 diabetes is associated with increased circulating non-esterified fatty acids and inflammatory cytokines as well as a decrease in the insulin-sensitizing adipokine, adiponectin. Each of these components contributes to signaling abnormalities and mitochondrial dysfunction in liver, skeletal muscle and adipose tissue that result in tissue resistance to insulin action. The balance of insulin signaling is determined by insulin receptor-stimulated protein tyrosine phosphorylation which promotes insulin responses, and serine phosphorylation of insulin receptor substrate (IRS) proteins elicited by various kinases in the cell that oppose the insulin action cascade 7. Among the IRS serine kinases associated with insulin resistance are the c-Jun amino-terminal kinases (JNK), protein kinase C (PKC) isoforms and IκB kinase-β (IKK-β). IKK-β is the target of salicylate therapy in the studies by Goldfine et al. and of particular interest since it not only contributes to a block in cellular insulin signaling, but also contributes to the activation of an inflammatory signaling cascade. IKK-β phosphorylates the cellular protein for which it is named, inhibitor of κB (IκB), an event that promotes IκB degradation and frees up the transcription factor NF-κB for translocation to the nucleus and stimulation of inflammatory responses. Thus, IKK-β lies at the crossroads of intrinsic pathways linking inflammation and immune responses with metabolic disorders that are highly conserved between mammals and lower species. Recent studies have suggested that these ancient pathways can be perturbed in pathogenic directions by the modern excesses of caloric intake and sedentary lifestyles 7. In addition, unforeseen interrelationships have now been identified between more classic immune system responses and metabolic regulation. Myeloid-specific deletion of IKK-β alone can result in a partial protection against obesity- or lipopolysaccharide-induced insulin resistance in animal models, identifying a fascinating link between the function of circulating leukocytes and physiologic insulin action 8. Thus, inhibition of IKK-β offers a potential means of enhancing insulin signaling, while at the same time reducing systemic inflammatory responses that contribute to endothelial dysfunction and the long-term vascular complications of diabetes. Goldfine et al. 4 provide a good rationalization for the use of non-acetylated salicylates to inhibit the IKKβ/NF-κB axis, since they do not inhibit cyclooxygenases, as does aspirin and related salicylate derivatives. The only adverse effect noted in these early short-term studies is dose-related tinnitus. Although not unexpected, this might be a significant limitation to the clinical use of salsalate in Type 2 diabetes, since this can reduce the effectiveness of the drug in its anticipated magnitude of glucose lowering. The anti-inflammatory effects of salsalate in these early studies are of interest, and include substantial reductions in C-reactive protein (CRP) and CD40 ligand as well as increases in adiponectin, which may engender further vascular protection with salicylate therapy. The lipid effects, with a predominant reduction in free fatty acids and triglycerides are also generally favorable. Interestingly, salsalate therapy increased non-oxidative glucose utilization by clamp studies, as might be expected of an insulin sensitizer, but at the same time it resulted in a reduced insulin clearance. The mechanism of the latter effect is not well understood, but if confirmed, it may provide a unique means of prolonging and enhancing the effect of endogenous insulin secretion, which is an important limiting factor in patients with Type 2 diabetes. Salicylates have also been shown to have positive effects on insulin secretion at the β-cell 9. The early “proof-of-concept” short duration translational studies presented here are now being followed-up by Drs. Goldfine and Shoelson and colleagues in the multicenter, randomized, NIH-sponsored “Targeting Inflammation with Salsalate in T2D” (TINSAL-T2D) trial (see http://tinsalt2d.org/). The multiple effects of salsalate on insulin action and insulin secretion portend its likely value in clinical Type 2 diabetes, although the magnitude of the therapeutic response remains to be proven, especially at the lower doses that are better tolerated. The international community has recently begun an all-out awareness campaign for screening and diagnosis of diabetes as well as convincing practitioners of the need to use aggressive therapeutic approaches to prevent its long-term complications (see www.worlddiabetesday.org). Prompted by the International Diabetes Federation, the United Nations has taken up the cause of this world-wide epidemic by identifying Type 2 diabetes as the first non-communicable disease of such devastating proportions as to require attention by the World Health Organization. Ongoing guideline revisions have also highlighted the need for early and aggressive combination therapies in order to maximize the clinical benefit of the available drugs in attempts to achieve glycemic goals 10. Aside from weight loss and maintenance strategies and lasting lifestyle changes, a magic bullet for normalizing blood glucose in diabetes does not appear to be on the foreseeable horizon. To that end, however, safe, inexpensive and well-tolerated agents such as salicylates, with their unique mechanism(s) of action, should work well in various combinations with other oral and parenteral therapies to help patients move towards the now well-accepted tight glucose management goals for Type 2 diabetes.