New therapeutic targets for T2DM Targeting inflammation: NF- B, salsalate Gwanpyo Koh Department of Internal Medicine Jeju National University School of Medicine
Introduction Obesity is occurring at epidemic rates worldwide is associated with type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) Multiple lines of evidence suggest inflammatory pathways as pathogenic mediators for both T2DM and CVD Obesity-induced inflammation is chronic and indolent, features differentiate it from the more acute types of inflammation commonly associated with infections, injury, and autoimmunity
Clinical measures of inflammation White blood cell count higher total leukocyte counts precede and predict the incident risk of T2DM and CHD primarily the granulocyte subpopulation, rather than the lymphocyte and monocyte subpopulations High-sensitivity C-reactive protein (hscrp), Interleukin-6 (IL-6) associated with the development of T2DM and CVD A variety of circulating proinflammatory cytokines and acutephase reactants are increased in obesity, MetS, HTN, NASH, PCOS, T2DM, and CVD
High white blood cell count predicts the development of type 2 diabetes Vozarova et al. Diabetes. 2002;51:455 61.
The higher risk for CVD associated with increased total leucocyte count seems to be accounted for by the increased granulocyte count EPIC-Norfolk Prospective Population Study. J Intern Med. 2007;262(6):678-89.
Elevated levels of CRP and IL-6 predict the development of type 2 DM Women's Health Study. JAMA. 2001;286(3):327-34.
Intracellular inflammatory pathway activated in obesity and T2DM Nuclear factor B (NF- B) the inflammation master switch that controls the synthesis of many proteins critical for the activation and maintenance of the inflamed state Hypothesis Obesity stimulates NF- B activity and additional stress pathways in adipose tissue, liver, and leukocytes, thereby promoting insulin resistance Adipokines TNF-, adiponectin, leptin, IL-6, resistin, monocyte chemoattractant protein 1 (MCP-1), plasminogen activator inhibitor 1 (PAI-1), angiotensinogen, visfatin, retinol-binding protein 4 (RBP-4), serum amyloid A (SAA) True adipokines: leptin and adiponectin They activate intracellular pathways that promote the development of insulin resistance and T2DM
The relative amounts of each adipokine produced by the adipocyte and associated adipose tissue macrophages remain unknown regular chow C57BL/6J mice a diet high in fat Goldfine et al. Clin Chem. 2011;57(2):162-7.
Adipose expression of TNF- : Neutralization of TNF-alpha in obese fa/fa rats caused a significant increase in the peripheral uptake of glucose in response to insulin Lean mice Obese mice Adipocytes 1 2 Stroma-vessels 3 4 TNFR, TNF- receptor-immunoglobulin G (IgG) chimeric protein Hotamisligil et al. Science. 1993;259(5091):87-91.
NF- B mechanism of action http://en.wikipedia.org/wiki/file:nfkb_mechanism_of_action.png
Potential cellular mechanisms for activating inflammatory signaling Shoelson et al. J Clin Invest. 2006;116(7):1793-801.
Local, portal, and systemic effects of inflammation in insulin resistance and atherogenesis Shoelson et al. J Clin Invest. 2006;116(7):1793-801.
Antiinflammatory strategies for treating type 2 diabetes A retrospective study suggested that the use of chloroquine to treat rheumatoid arthritis is associated with a lower incidence of type 2 diabetes High doses of aspirin used for rheumatoid arthritis were noted to lower the fasting glucose concentration in patients with type 2 diabetes In a double-masked, randomized parallel-group trial, the blockade of interleukin-1 with anakinra improved glycemia and beta-cell secretory function and reduced markers of systemic inflammation A recent series of studies suggests, however, that the nonacetylated salicylates, an older class of antiinflammatory drugs infrequently used today, show promise as potential new treatments for diabetes
The blockade of interleukin-1 with anakinra improved glycemia and β-cell secretory function in T2D patients Larsen et al. N Engl J Med. 2007;356(15):1517-26
Salicylates They inhibit the IKKβ/NF- B axis Two different forms acetylated (aspirin) the acetyl group covalently inhibits COX enzymes nonacetylated (sodium salicylate, salsalate, and salsalate trisilate or triflusal) Salsalate not associated with increased bleeding risk It has been marketed since 1972 as an oral analgesic, antipyretic, and antirheumatic drug The usual dosage is 3 4.5 g daily in divided doses
Structure and properties of salsalate Desouza. Drugs Today (Barc). 2010;46(11):847-53.
Williamson. Br Med J. 1901;1(2100):760-2.
Preclinical studies with salicylates The use of high-dose salicylates in Zucker fatty rats and ob/ob mice significantly lowered blood glucose concentrations and increased insulin sensitivity IKKβ ( /+) mice also improved blood glucose concentrations and insulin sensitivity Activation of NF- B in the liver, fat, or macrophages causes insulin resistance similar to that seen in obesity NF- B inhibition decreases obesity-induced insulin resistance The molecular effects of salicylates in modulating inflammatory metabolic processes are thought in principle to be mediated through IKK/NF- B signaling
High-dose salicylates lowered blood glucose concentrations and improved insulin signaling in ZDF rats Yuan et al. Science. 2001;293(5535):1673-7.
Heterozygous deletion of IκB kinase (IKK) improved blood glucose concentrations and insulin sensitivity in obese mice Yuan et al. Science. 2001;293(5535):1673-7.
Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB Liver-specific IKK-beta (LIKK) transgenic mice Cai et al. Nat Med. 2005;11(2):183-90.
The anti-inflammatory agents aspirin and salicylate inhibit the activity of I B kinase-β 1 2 3 4 5 6 ASA: acetylsalicylic acid, Sal: sodium salicylate, Dex: dexamethasone, Indo: indomethacin. Yin et al. Nature. 1998;396(6706):77-80.
An inhibitor of the protein kinases TBK1 and IKK-ɛ improves obesity-related metabolic dysfunctions in mice Four different IκB kinases (IKKs): IKK-α, IKK-β, IKK-ε and TBK1 Amlexanox: a selective IKK-ε and TBK1 inhibitor Reilly et al. Nat Med. 2013;19(3):313-21.
Clinical trials of salicylates Pilot clinical trials showed that the 2-4 week administration of salsalate to patients with type 2 diabetes or to obese prediabetic patients reduced the blood concentrations of glucose, triglycerides, and nonesterified fatty acids The results of these small proof-of-concept studies were sufficiently encouraging that the NIH funded larger clinical trials for both type 2 diabetes and cardiovascular disease TINSAL-T2D (Targeting Inflammation Using Salsalate in Type 2 Diabetes), TINSAL-FMD, TINSAL-CVD Randomized, placebo-controlled trials showed that salsalate decreased glucose levels in people with newly diagnosed and advanced type 2 diabetes and prediabetes The magnitude of change in HbA1c levels with salsalate (-0.37~-0.49%) was similar to that seen in recent studies for other marketed drugs Reduced insulin clearance may contribute to decreasing glucose levels Salsalate also reduced triglycerides, nonesterified fatty acids and leukocytes counts and increased adiponectin Some participants who took higher doses experienced tinnitus
Salsalate decreased NF- B activity and glucose level in T2D patients No serious adverse events were associated with administration of salsalate Dose-dependent and dose-limiting tinnitus (4.5 g/day) A tendency toward increased anion gap Small but significant increases in serum creatinine Goldfine et al. Clin Transl Sci. 2008;1(1):36-43.
Salsalate decreased insulin clearance and increased insulin secretion Triflusal metabolite [2-hydroxy-4-trifluoromethylbenzoic acid (HTB)] Goldfine et al. Clin Transl Sci. 2008;1(1):36-43. Fernández-Real et al. J Clin Endocrinol Metab. 2008;93(7):2523-30.
To compare the efficacy and safety of salsalate at different doses in patients with type 2 diabetes (Stage 1 of TINSAL-T2D) Stage 1 of TINSAL-T2D. Ann Intern Med. 2010;152(6):346-57.
Circulating triglyceride and adiponectin concentrations also improved in the 3 salsalate groups Stage 1 of TINSAL-T2D. Ann Intern Med. 2010;152(6):346-57.
Other measures of efficacy and safety (Stage 1 of TINSAL-T2D) Mean low density lipoprotein cholesterol levels increased by 15 mg/dl (p=0.002) in the 3.0-g/d group compared with placebo, but did not differ from placebo in the other salsalate groups Median urinary albumin concentration increased in all salsalate groups compared with placebo No serious adverse events were attributable to salsalate. Mild gastrointestinal symptoms were more frequent among patients receiving salsalate Tinnitus, an expected side effect of high-dose salicylates, occurred less frequently than anticipated Three patients (11%) in the placebo group and 5 to 6 patients (19% to 22%) Stage 1 of TINSAL-T2D. Ann Intern Med. 2010;152(6):346-57.
To assess 1-year efficacy and safety of 3.5- g salsalate in 286 pts with T2DM (Stage 2 of TINSAL-T2D) HbA 1c : -0.37% Stage 2 of TINSAL-T2D. Ann Intern Med. 2013;159(1):1-12.
The paradoxical increase in fasting insulin and decrease in C-peptide concentrations for salsalate compared with placebo Stage 2 of TINSAL-T2D. Ann Intern Med. 2013;159(1):1-12.
Leukocyte count was lowered and adiponectin level increased with salsalate, but LDL-C level also increased Stage 2 of TINSAL-T2D. Ann Intern Med. 2013;159(1):1-12.
Urinary albumin levels increased but reversed on discontinuation Stage 2 of TINSAL-T2D. Ann Intern Med. 2013;159(1):1-12.
Other findings and adverse events Tinnitus was reported by 16 (11%) patients receiving salsalate and 7 (5%) receiving placebo (p=0.082) Tinnitus resolved or returned to baseline in all participants by the end of the study Body weight and hematocrit levels actually increased (p<0.001) Serum creatinine levels were greater with salsalate than with placebo (p=0.008) However, estimated GFR did not change within or between groups (p=0.176) Adverse events that occurred with frequencies of 5% or greater and numerically more frequently in salsalate recipients than placebo recipients No serious adverse events were attributed to salsalate Gastrointestinal side effects did not differ between groups Stage 2 of TINSAL-T2D. Ann Intern Med. 2013;159(1):1-12.
Salsalate does not change flow-mediated dilation in peripheral conduit arteries in patients with T2D (TINSAL-FMD) TINSAL-FMD. Diabetes Care. 2013;36(12):4132-9.
Potential benefits of salicylates in cardiovascular disease are being tested
Conclusion Inflammation appears to participate in the pathogenesis of both type 2 diabetes Multiple basic-science laboratories are investigating the underlying mechanisms that initiate inflammation and link it to insulin resistance and vascular impairment Salsalate improves glycemia in patients with type 2 diabetes & abnormal glucose tolerance and decreases inflammatory mediators The number of patients studied and the trial duration were insufficient to warrant recommending the use of salsalate for T2D Considerations of cardiorenal safety will require further evaluation Ongoing trials with salsalate will determine whether this particular antiinflammatory agent is effective for the prevention of CVD
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