Current Diabetes Reports

, 15:82

Targeting Inflammation Through a Physical Active Lifestyle and Pharmaceuticals for the Treatment of Type 2 Diabetes


  • Sine Haugaard Knudsen
    • Centre of Inflammation and Metabolism/Centre of Physical Activity Research (CIM/CFAS), RigshospitaletUniversity of Copenhagen
    • Centre of Inflammation and Metabolism/Centre of Physical Activity Research (CIM/CFAS), RigshospitaletUniversity of Copenhagen
Pharmacologic Treatment of Type 2 Diabetes (HE Lebovitz and G Bahtiyar, Section Editors)

DOI: 10.1007/s11892-015-0642-1

Cite this article as:
Knudsen, S.H. & Pedersen, B.K. Curr Diab Rep (2015) 15: 82. doi:10.1007/s11892-015-0642-1
Part of the following topical collections:
  1. Topical Collection on Pharmacologic Treatment of Type 2 Diabetes


Evidence exists that interleukin (IL)-1β is involved in pancreatic β-cell damage, whereas TNF-α appears to be a key molecule in peripheral insulin resistance. Although increased plasma levels of IL-6 are seen in individuals with type 2 diabetes, mechanistic studies suggest that moderate acute elevations in IL-6, as provoked by exercise, exert anti-inflammatory effects by an inhibition of TNF-α and by stimulating IL-1 receptor antagonist (ra), thereby limiting IL-1β signaling. A number of medical treatments have anti-inflammatory effects. IL-1 antagonists have been tested in clinical studies and appear very promising. Also, there is a potential for anti-TNF-α strategies and salsalate has been shown to improve insulin sensitivity in clinical trials. Furthermore, the anti-inflammatory potential of statins, antagonists of the renin–angiotensin system, and glucose-lowering agents are discussed. While waiting for the outcome of long-term clinical pharmacological trials, it should be emphasized that physical activity represents a natural strong anti-inflammatory intervention with little or no side effects.


ExercisePhysical trainingAnti-inflammationMyokinesDrugs


Type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), colon cancer, breast cancer, dementia, and depression constitute a cluster of diseases [1]. During the past two decades, it has become increasingly clear that chronic inflammation is a crucial factor contributing to the development and progression of such chronic non-communicable diseases. Evidence suggests that chronic inflammation is involved in the pathogenesis of e.g. insulin resistance, pancreatic cell death, atherosclerosis, neurodegeneration, and tumor growth [2]. Obesity, in particular excess visceral adiposity, is associated with insulin resistance, hyperglycemia, dyslipidemia, and hypertension, which together are termed the “metabolic syndrome” [3]. These metabolic disorders are associated with an increased risk for the development of T2DM and CVD and contribute to high rates of mortality and morbidity [3]. T2DM is characterized by defects in insulin secretion as well as peripheral insulin resistance in skeletal muscle, adipose tissue, and liver. The progression from obesity-related insulin resistance to T2DM occurs when the pancreatic β-cells fail to compensate for insulin resistance [4].

The fact that chronic low-grade inflammation is involved in the development and/or progression of T2DM has been reviewed previously [58]. Several cross-sectional and prospective studies have described elevated circulating levels of acute-phase proteins, such as C-reactive protein (CRP) as well as cytokines and chemokines, in individuals with T2DM [914], and elevated levels of interleukin (IL)-1β, IL-6, IL-1 receptor antagonist (ra), and CRP are predictive of T2DM [10, 15, 16]. It has been well documented that inflammation influences the development of β-cell dysfunction. Inflammatory changes, including accumulation of macrophages and increased expression of IL-1β, have been documented in T2DM islets [6, 17, 18]. Moreover, it has been demonstrated that the depletion of resident islet macrophages in high-fat-fed transgenic mice with islet amyloid formation can reduce IL-1β expression, improve β-cell insulin secretion, and restore glucose tolerance [19]. Furthermore, therapeutic inhibition of IL-1β ameliorates β-cell dysfunction and glucose homeostasis in individuals with T2DM [20]. Thus, strong evidence exists that IL-1β is a key pro-inflammatory mediator of β-cell damage in T2DM.

TNF-α has been identified as a key molecule in peripheral insulin resistance. This evidence is based on classical studies in cultured cells [21] and in TNF-α knockout mice [22]. Further evidence was found when TNF-α infusion was shown to inhibit whole-body insulin-mediated glucose uptake and signal transduction in healthy humans [23]. The latter study showed that TNF-α directly impairs peripheral insulin-stimulated glucose uptake via an impaired phosphorylation of Akt substrate 160, the most proximal step identified in the canonical insulin signaling cascade regulating GLUT4 translocation and glucose uptake [23].

Here, we discuss different anti-inflammatory strategies both with regard to a physically active lifestyle and with regard to pharmaceutical agents that specifically aim at blocking cytokine signaling pathways or appear to have anti-inflammatory side effects, which may be useful for individuals with T2DM.

The Role of Physical Activity in Inflammation

Several studies have proven that fewer inflammatory markers are detectable after long-term behavioral changes involving both reduced energy intake and increased physical activity [24].

More specifically, it is well-described in both longitudinal and cross-sectional studies that regular physical activity, also without weight loss, diminishes systemic chronic inflammation [24]. However, the prescription of exercise as a potential anti-inflammatory tool is a relatively new concept [24, 25].

The anti-inflammatory effects of exercise may at least in part be mediated by secretory peptides, so-called myokines, produced by working skeletal muscle. Skeletal muscle can communicate with other organs by secreting these myokines and this muscle “secretome” consists of several hundred peptides that are the conceptual basis for a new paradigm of muscle communication with tissues including adipose tissue, liver, pancreas, and brain [26•, 27]. Myokines include various muscle-secreted cytokines such as IL-6, IL-7, and leukemia inhibitory factor, and other peptides such as brain-derived neurotropic factor, insulin-like growth factor 1, fibroblast growth factor 2, follistatin-related protein 1 (FSTL-1), and irisin [28••, 29].

Some myokines can induce an anti-inflammatory response with each bout of exercise. For example, during exercise, IL-6 is the first detectable cytokine released into the blood from the contracting skeletal muscle fibers. IL-6 increases in an exponential fashion with exercise and contributes to a marked increase in circulating levels of IL-6. Of note, in contrast to the cytokine response elicited by sepsis, muscle-derived IL-6 occurs without a preceding increase in TNF-α. In relation to exercise, IL-6 induces a subsequent increase in the production of IL-1ra and IL-10 by blood mononuclear cells, thus stimulating the occurrence of anti-inflammatory cytokines [30].

A model of low-grade inflammation was previously established in our laboratory [31]. A very low dose of Escherichia coli endotoxin was administered to healthy subjects, who were randomized to either rest or exercise prior to endotoxin administration. In resting subjects, endotoxin induced a two- to threefold increase in circulating levels of TNF-α. In contrast, when participants performed 3 hours of ergometer cycling and received the endotoxin bolus at 2.5 hours, the TNF-α response was totally blunted, suggesting that acute exercise may inhibit TNF-α production. The effects of exercise could be mimicked by an infusion of IL-6, which suppressed the endotoxin-induced TNF-α production [32]. The latter study was in agreement with studies demonstrating that IL-6 inhibits lipopolysaccharide (LPS)-induced TNF-α production in cultured human monocytes [33] and that levels of TNF-α are elevated in anti-IL-6-treated mice and in IL-6-deficient knockout mice [34]. Thus, an acute bout of exercise induces a strong anti-inflammatory effect, which at least in part is mediated by IL-6.

Given that TNF-α is a key molecule in insulin resistance, the finding that exercise inhibits TNF-α may contribute to explain why exercise enhances insulin sensitivity. In parallel, it is well documented that IL-1β is involved in pancreatic β-cell damage. The finding that exercise provokes an increase in circulating IL-1ra may contribute to protect against IL-1-mediated destruction of β-cells. It has been shown that IL-6 stimulates α-cell proliferation, prevents apoptosis caused by metabolic stress, and regulates α-cell mass in vivo [35]. Thus, it appears that exercise-induced IL-6 production may be involved in the expansion of pancreatic α-cell mass that is needed for functional β-cell compensation when an increased metabolic demand is present [35]. It has furthermore been shown that elevated IL-6 concentrations in response to exercise stimulate glucagon-like peptide-1 (GLP-1) secretion from intestinal L-cells and pancreatic α-cells, improving insulin secretion and glycemia [36]. This suggests that IL-6 is involved in an endocrine loop implicating IL-6 in a beneficial regulation of insulin secretion, which may be useful in T2DM [36]. Thus, although the role of IL-6 in metabolism is still debated [1] and although increased plasma levels of IL-6 have been associated with T2DM in correlational studies [9, 13], mechanistic studies in humans suggest that moderate acute elevations in IL-6, as provoked by exercise, exert anti-inflammatory effects by an inhibition of TNF-α and by stimulating IL-1ra, thereby limiting IL-1β signaling.

Moreover, IL-6 and other myokines, such as IL-15 and FSTL-1, mediate long-term exercise-induced improvements in cardiovascular risk factors (for example, fat distribution and endothelial function), thus potentially having indirect anti-inflammatory effects [26•, 28••, 29]. We suggest that exercise may induce anti-inflammatory effects by limiting the amount of ectopic fat accumulation.

Whereas subcutaneous adipose tissue, particularly in lower body fat depots, might be protective against chronic diseases, strong evidence exists that the detrimental effects of the accumulation of visceral fat, and fat in the liver and in the skeletal muscle, might stimulate an inflammatory response [28••, 37]. It seems well documented that physical inactivity is a BMI-independent cause of central obesity and evidence exists that visceral fat is more inflammatory than subcutaneous fat [38]. Moreover, both physical inactivity [39] and abdominal adiposity [38] are associated with persistent, systemic low-grade inflammation, and a direct link between physical inactivity and visceral fat has been established [1, 4042]. In a study in which healthy men reduced their daily activity levels from >10,000 to <1500 “steps” for 14 days, intra-abdominal fat mass increased without a change in total fat mass. The accumulation of visceral fat was accompanied by impaired glucose and fat metabolism [41]. Thus, avoiding a physical inactive lifestyle will limit the amount of visceral fat and hence lower chronic low-grade inflammation.

Taken together, there is good evidence to suggest that regular exercise mediates anti-inflammatory actions of benefit for individuals with T2DM.

Anti-inflammatory Pharmaceutical Treatment in Type 2 Diabetes

Potential Anti-inflammatory Agents

Current drug treatment in T2DM is aimed at lowering glycemia, while lacking disease-modifying characteristics, such as slowing the progressive decline in insulin secretory function. With the well-established role of inflammation in the pathogenesis of both insulin resistance and β-cell dysfunction [43], targeting inflammation may be a superior treatment strategy in T2DM that not only lowers glycemia but also prevents the progression of the disease, targets its comorbidities, and has long-lasting effects as recently reviewed [44••]. Various anti-inflammatory drugs have been approved or are in the late stages of development for the treatment of conditions driven by inflammatory processes, and these may also present useful in the treatment of T2DM. In addition, drugs already used in individuals with T2DM targeting glycemia, dyslipidemia, and hypertension may display additional anti-inflammatory properties of potential further exploitation.


The role of IL-1β in the pathogenesis of T2DM is increasingly accepted and targeting IL-1β inflammation has shown promising clinical diabetes-related outcomes [20, 45, 46••, 4753]. As described, IL-1β is a pro-inflammatory cytokine that is implicated in the development of obesity-induced systemic inflammation in particular leading to β-cell dysfunction and destruction in T2DM [45]. This is mediated by inducing NF-κB-mediated release of various cytokines, including IL-1β, leading to the recruitment of macrophages and other immune cells [18, 54], thereby creating a vicious cycle of IL-1 auto-induction [55].

In initial clinical testing, IL-1β was targeted by the naturally occurring IL-1ra [20, 51, 52] that potentially interrupts the vicious cycle of IL-1 auto-induction. In individuals with T2DM, 13 weeks of treatment with the recombinant human IL-1ra, anakinra, reduced systemic inflammation and improved glycemia and β-cell secretory function [20]. In addition, anakinra has been shown to improve β-cell function in obese individuals and individuals with pre-diabetes [51, 52]. Thus, data from independent clinical studies show the effectiveness of IL-1 receptor blockade by anakinra not only in lowering hyperglycemia but also in preserving β-cell function.

IL-1 receptor blockade has shown good long-term effects. After anakinra withdrawal for ∼10 months, improvement in β-cell function as well as markers of systemic inflammation was preserved in individuals with T2DM [48]. Since anakinra requires daily injections and in some cases show adverse effects at the injection site, humanized IL-1β-specific antibodies (gevokizumab, canakinumab, and LY2189102) with much longer half-life (∼3 weeks) have been developed, allowing less frequent dosing. In several independent studies, these antibodies have shown very promising anti-diabetic effects [46••, 56, 49, 50]. In individuals with T2DM, glycated hemoglobin (HbA1c) and markers of systemic inflammation were reduced while insulin secretion and sensitivity was increased 3 months after a single dose of treatment with gevokizumab [56]. Furthermore, a single dose of canakinumab tended to improve insulin secretion in individuals with impaired glucose tolerance or well-controlled T2DM [49]. Four monthly canakinumab injections were effective in reducing HbA1c in individuals with T2DM [46••]. Finally, 12 weeks of treatment with LY2189102 once a week also decreased HbA1c, increased insulin secretion, and reduced inflammatory markers [50].

Interpreting all data from these independent clinical studies demonstrate the effectiveness of targeting IL-1β in reducing inflammation and improving both glucose metabolism as well as insulin secretory function in individuals with impaired glucose tolerance and T2DM. This identifies a potential anti-diabetic drug target that not only reduces glycemia but also delays progression of β-cell dysfunction. A sub-study of a larger ongoing clinical trial (the Canakinumab Anti-inflammatory Thrombosis Outcomes Study [CANTOS]; Identifier: NCT01327846 [57]) will determine if canakinumab on top of standard-of-care treatment can increase insulin secretion and insulin sensitivity in individuals with T2DM. These results will bring us closer to confirming a potential new anti-inflammatory drug in the treatment of T2DM.

A point to consider involves the inter-subject variation in response to treatment. Interestingly, studies have shown that carriers of a common (allelic frequency 44 %) 5′ promoter polymorphism of the IL-1ra gene (C-allele) are highly responsive to anti-IL-1 treatment because of relative endogenous IL-1ra deficiency [48, 58]. This variation in responders to anti-IL-1 treatment must be acknowledged as a limitation in the potential as general anti-inflammatory treatment and future studies should look into this when testing in larger clinical cohorts.


The levels of TNF-α are elevated in obesity and T2DM, and the direct link to muscle insulin resistance is well established [21, 22, 59], arguing that antagonizing TNF-α is an obvious inflammatory target in treating T2DM. The protecting effects of lacking TNF-α in mice [22] and the reversing effects of neutralization [59] or inhibition [60] in rats have led to several clinical studies investigating the role of this inflammatory target in reducing human insulin resistance. Even though initial clinical testing of TNF-α antagonism has failed to confirm the promising pre-clinical data [6164], several limitations may preclude definitive conclusions, suggesting that TNF-α should not yet be excluded as a potential anti-inflammatory target in T2DM.

Initial clinical studies testing the role of targeting TNF-α in insulin resistance, using a single dose of TNF-α antagonism, failed to show any effects on insulin sensitivity [61, 62]. Similarly, 4 weeks of TNF-α antagonism by etanercept decreased C-reactive protein (CRP) levels, but did not alter insulin sensitivity [63, 64]. This, however, may be attributed to small sample sizes (7–10 subjects) in these studies. Due to the large genetic and metabolic heterogeneity of individuals with T2DM, it could be argued that these studies were underpowered. Recently, the effect of prolonged (6 month) TNF-α antagonism by etanercept was assessed in obese non-diabetic individuals [65]. Etanercept decreased fasting glucose and increased the ratio of high molecular weight to total adiponectin, both potentially indicative of improved insulin sensitivity [65]. This could imply that previous studies may have used insufficient treatment durations (between 2 days and 4 weeks). Furthermore, while ongoing clinical trials are investigating TNF-α antagonism in the treatment of the metabolic syndrome ( Identifier: NCT00409318 and Identifier: NCT00413400), the potential of TNF-α antagonism as an anti-inflammatory and anti-diabetic treatment remains to be investigated in individuals with T2DM. Interestingly, inhibition of TNF-α by pentoxifylline has been shown to produce an additive antiproteinuric effect associated with a reduction of urinary TNF-α excretion in individuals with T2DM [66].


In contrast to the common belief of IL-6 as a deleterious pro-inflammatory cytokine, the described potential beneficial effects of exercise-mediated acutely elevated IL-6 plasma levels suggest a positive metabolic role for IL-6 in health and potentially in the treatment of a disease such as T2DM. In short, in addition to its anti-inflammatory actions, an acute challenge with IL-6 enhances peripheral glucose uptake and induces lipid oxidation via a mechanism that includes activation of AMP-activated protein kinase (AMPK) [39]. The Bruning group has recently identified signaling via IL-6 as an important determinant of the alternative activation of macrophages and assigns an unexpected homeostatic role to IL-6 in limiting inflammation [67]. Furthermore, strong evidence exists that IL-6 is an essential regulator of satellite cell-mediated skeletal muscle hypertrophy [68, 69].

In states of increased insulin demand such as obesity and pre-diabetes, chronically elevated IL-6 levels may enhance the immune response that contributes to β-cell adaptation by increasing L-cell GLP-1 secretion, expanding β-cell mass and reprogramming α-cells to process pro-glucagon to GLP-1 [36]. Furthermore, increased IL-6 mRNA in insulin-resistant tissues may be an attempt to overcome the metabolic dysfunction [70]. Supporting the notion that IL-6 exerts beneficial effects on metabolism, IL-6 knockout mice develop late-onset obesity and glucose intolerance [71].

Acute high levels of IL-6 can induce fever, release of catecholamines, and elevated plasma glucose [72, 73]. However, along the line with the above described effects of acutely elevated IL-6 plasma levels in response to exercise, a mild elevation of plasma IL-6 stimulates CRP, IL-1ra, and IL-10, without increasing TNF-α [30]. In fact, IL-6 infusion inhibits endotoxin-induced TNF-α production in healthy subjects [32]. Thus, moderate levels and/or acute administration of IL-6 seems to induce an anti-inflammatory rather than an inflammatory response in healthy individuals. In resting individuals, IL-6 infused at physiological concentrations did, however, not influence whole-body glucose disposal, glucose uptake, or endogenous glucose production [74]. Interestingly, IL-6 administration increased insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMPK [75]. This later finding support clinical implications of IL-6 in metabolism, but confirmation in individuals with T2DM is lacking [76]. In particular, it has been reported that IL-6 increases glucose uptake in myotubes from healthy individuals, but not from obese individuals with T2DM, perhaps reflecting a state of IL-6 resistance [77, 78]. In addition to the different effect of chronically elevated IL-6 levels as compared to an acute rise mediated by infusion or exercise, the beneficial effects of IL-6 may be dependent on metabolic health. In fact, blocking IL-6/IL-6 antagonism is a therapeutic target for many pro-inflammatory diseases, and Actemra (tocilizumab, a humanized IL-6 receptor inhibiting monoclonal antibody) is approved for clinical use for the treatment of pro-inflammatory diseases, such as rheumatoid arthritis, and may also be beneficial in diverse cancers [79, 80]. However, the side effects of blocking IL-6 appear to be hyperlipidemia and weight gain [79].

Salsalate (salicylate) is a pro-drug form of salicylic acid that has fewer adverse effects than sodium salicylate and is approved for human use. In addition, several independent clinical studies have shown that salsalate treatment can improve the glycemic and inflammatory profiles in obese individuals and individuals with T2DM [81•, 8284]. In particular, salsalate has the potential to target T2DM via inhibition of the NF-κB pathway and thereby reducing inflammation [85].

In a larger (n = 286) randomized placebo-controlled clinical trial (TINSAL-T2D), Goldfine and colleagues have confirmed that 1 year of salsalate treatment (3.5 g/day) can reduce hyperglycemia (HbA1c) and circulating inflammatory markers in individuals with T2DM [81•]. Thus, there is good evidence for the potential of salsalate to decrease hyperglycemia by targeting inflammation. While endothelial function is unaltered from reducing inflammation, salsalate reduces insulin clearance, suggesting that the glucose-lowering effects of salsalate also occur via non-inflammatory mechanisms [8284]. With the additional findings of increased LDL-cholesterol and urinary albumin level in individuals with T2DM after 48 weeks of salsalate treatment [81•], the long-term effects of salsalate should be further investigated in order to establish safety and magnitude of such side effects.

Resveratrol, naturally occurring in several plants, has by some been reported to positively affect glucose metabolism and has anti-inflammatory effects [8689]. In specific, resveratrol treatment has been found to protect glucose homeostasis in animals fed a high-fat diet [86]. Furthermore, resveratrol reduced IL-6, IL-8, and MCP-1 levels in a concentration-dependent manner in human adipocytes under inflammatory condition, and this is mainly due to its NF-κB inhibitory potential [89]. Confirmation of these promising effects from in vitro and animal studies is, however, inconsistent. In obese individuals, 30 days of resveratrol treatment (150 mg/day) decreased glucose level as well as circulating inflammatory markers [87]. In a 1-year clinical trial, resveratrol supplementation modulated expression of inflammatory microRNAs and cytokines in individuals with T2DM [88]. On contrary, 4 weeks of high-dose resveratrol treatment (1500 mg/day) in obese healthy individuals had no effects on insulin sensitivity or inflammatory markers [90], and in aged men, no improvement in metabolic and inflammatory status could be detected [91]. In fact, resveratrol was found to blunt the positive effects of exercise on cardiovascular health in aged men [92]. Therefore, the potential of resveratrol as anti-inflammatory treatment in obesity and T2DM remains questionable.

Anti-diabetic Drugs With Anti-inflammatory Effects

As recently reviewed [93•], some of the drugs which are routinely used as anti-diabetic treatment possess anti-inflammatory effects in addition to their intended metabolic effects.

First of all, anti-inflammatory effects of incretin-based treatments, including dipeptidylpeptidase-4 inhibitors and GLP-1 receptor agonists, have repeatedly been found [9498, 99•], and some clinical data support this potential in individuals with T2DM [94, 96, 99•].

Thiazolidinediones are peroxisome proliferator-activated receptor-gamma agonists that lower glucose level partly by inhibition of a molecular pathway implicated in insulin resistance [100]. Based on substantial evidence, these are also effective in lowering inflammation in the visceral fat tissue, in the liver, and in the circulation (reviewed in [93•]). Anti-inflammatory effects of the biguanide metformin are reflected by reduced IL-1β-induced inflammation in vascular cells [101] and in macrophages from individuals with T2DM [102]. The effect of metformin on circulating inflammatory markers in individuals with T2DM is, however, modest and less pronounced than treatment with thiazolidinediones [103].

Sulphonylureas stimulate insulin secretion, and anti-inflammatory effects are elicited by preventing IL-1β but not IL-6 and TNF-α secretion from macrophages [104]. However, such anti-inflammatory effects have not been confirmed in individuals with T2DM [105, 106]. While the thiazolidinedione, pioglitazone was associated with reduction in CRP levels, treatment with either glibenclamide [105] or glimepiride [106] showed no alteration.

For other glucose-lowering agents such as glinides [107] and α-glucosidase inhibitors [108], anti-inflammatory effects in humans may be limited and still need further investigation. Finally, it must be acknowledged that even though some potential anti-inflammatory effects are related to direct actions of a given pharmacological agent, others may result from better glucose control.

Other Drugs With Anti-inflammatory Effects

To target comorbidities such as dyslipidaemia and hypertension, individuals with T2DM are often treated with aspirin, antagonists of the renin–angiotensin system, and statins in addition to their anti-diabetic drugs. Interestingly, some of these drugs have also demonstrated anti-inflammatory effects.

Antagonists of the renin–angiotensin system are used in the treatment of hypertension and diabetic nephropathy. Interestingly, this antagonism also displays anti-inflammatory effects that may have anti-diabetic properties [109, 110]. Angiotensin receptor blocking in fat-fed mice improved insulin sensitivity and changed inflammatory status to an anti-inflammatory state [111]. Using angiotensin receptor blockers in individuals with hypertension [112] or T2DM [113] have been found to reduce serum levels of inflammatory markers. Thus, the protective effects of renin–angiotensin system antagonism may not only be due to the blood pressure-lowering activity but also to improved glycemic control that is in part explained by anti-inflammatory effects.

Aspirin (acetylsalicylic acid) is used in prevention of CVD due to its antiplatelet effect but at higher doses also as an anti-inflammatory agent. Interestingly, a low dose of aspirin has been found to decrease serum platelet-cyclo-oxygenase-1 activity [114]. Even though this was not accompanied by a decrease in CRP levels, this suggests that aspirin may also show anti-inflammatory effects even when used as an antiplatelet agent.

Statins are part of the standard treatment for elevated blood cholesterol levels, but have additionally been shown to lower systemic inflammation [115, 116]. In individuals with coronary disease, pravastatin therapy resulted in decreased systemic inflammation, reflected as a reduction in CRP levels [115]. Furthermore, simvastatin reduced CRP levels and inhibited the release of TNF-α, IL-6, and IL-8 from monocytes in individuals with type 1 diabetes [116]. These data suggest that the protective effects of statins may in part be due to anti-inflammatory effects. In addition, the finding that statins had no effect on endotoxin-induced inflammation in healthy subjects with normal lipid levels may suggest that a possible anti-inflammatory effect of statins is mediated via an inhibition of lipid-induced-inflammation [117]. However, conflicting results showing that statins may increase IL-1β secretion from human monocytes and macrophages [118, 119] may be one possible explanation to why statin therapy in some studies is associated with a slightly increased risk of diabetes development [120, 121].


Targeting inflammation with anti-inflammatory drugs has a lot of potential in the future treatment of patients with T2DM. As diabetic vascular complications are partly mediated by inflammatory processes [4], targeting inflammation may not only improve glycemic control and slow the progressive β-cell secretory dysfunction but also prevent such comorbidities ([5] in [93•]). However, novel anti-inflammatory treatment strategies for diabetes still remain to be tested in long-term studies with large, multi-ethnic patient populations. While waiting for the outcome of such studies, it is important to highlight the fact that lifestyle modification such as regular physical activity can have a significant effect on low-grade chronic inflammation.

Compliance with Ethics Guidelines

Conflict of Interest

Sine Haugaard Knudsen and Bente Klarlund Pedersen declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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© Springer Science+Business Media New York 2015