The association between hyperglycemia and inflammation and vascular complications in diabetes is now well established. Antidiabetes drugs may alleviate inflammation by reducing hyperglycemia; however, the anti-inflammatory effects of these medications are inconsistent and it is unknown whether their beneficial metabolic effects are mediated via modulation of chronic inflammation. Recent data suggest that immunomodulatory treatments may have beneficial effects on glycemia, β-cell function, and insulin resistance. However, the mechanisms underlying their beneficial metabolic effects are not always clear, and there are concerns regarding the specificity, safety, and efficacy of immune-based therapies. Herein, we review the anti-inflammatory and metabolic effects of current antidiabetes drugs and of anti-inflammatory therapies that were studied in patients with type 2 diabetes. We discuss the potential benefit of using anti-inflammatory treatments in diabetes and important issues that should be addressed prior to implementation of such therapeutic approaches.

The prevalence of diabetes is on the rise, with 415 million people affected worldwide according to recent data from the International Diabetes Federation (1). This number is predicted to increase further, with 642 million people expected to develop diabetes by 2040. While many factors are known to contribute to the development of diabetes and its complications, the involvement of the immune system in the pathogenesis of metabolic diseases has been gaining interest. It has long been appreciated that inflammation is central to the pathology of the pancreatic islet in type 1 diabetes. However, growing evidence suggests that inflammation also plays an important role in the pathogenesis of type 2 diabetes, including obesity-related insulin resistance, impaired insulin secretion, and diabetes-related vascular complications. Pioneering studies suggest that immunomodulatory treatments may improve glycemia, β-cell function, and/or insulin resistance in patients with type 2 diabetes (2,3). These studies constitute a proof of concept that chronic inflammation is implicated in the pathophysiology of type 2 diabetes, and therefore targeting inflammation may ameliorate diabetes, preventing its progression and vascular complications. However, the effects of immunomodulatory treatments are not limited to tissues involved in disease pathophysiology and thus might have unwarranted side effects. Moreover, current antidiabetes drugs may alleviate systemic and tissue-specific inflammation (412), and therefore the added value of using specific immunomodulatory treatments needs to be confirmed. Herein, we review the anti-inflammatory and metabolic effects of standard antidiabetes medications and of novel anti-inflammatory treatments. We further discuss issues that should be addressed prior to implementation of immune-based therapy in the treatment of diabetes.

Role of Inflammation in Metabolic Disorders

Multiple mechanisms are thought to contribute to β-cell dysfunction, insulin resistance, and vascular complications of diabetes. They have previously been extensively reviewed and are beyond the scope of the current review (13). We briefly refer to several key mechanisms regulating inflammation in diabetes and their translational implications. In diabetes, hyperglycemia and elevated free fatty acids may promote inflammation by stimulating glucose utilization along with alterations in oxidative phosphorylation (3,4,14). Such metabolic dysregulation has been shown to induce a proinflammatory trait in macrophages residing or invading the adipose tissue and other tissues including the islets and vasculature (1519). Glucotoxicity and lipotoxicity might also exert oxidative and endoplasmic reticulum stress, which in turn elicits an inflammatory response by activating thioredoxin-interacting protein (TXNIP) and the NLR family, pyrin domain containing 3 (NLRP3) inflammasome, which increase the release of active interleukin (IL)-1β (3,4,14,18,20). IL-1β further amplifies inflammation by inducing the expression of various cytokines and chemokines, resulting in the recruitment of immune cells including macrophages (“auto-stimulation”) (21). Similar mechanisms have been reported in diabetic β-cells, adipose tissue, and blood vessels (18,20,22,23). In type 2 diabetes, oligomers of islet amyloid polypeptide deposit in the pancreas and may trigger inflammation by stimulating the NLRP3 inflammasome and the generation of mature IL-1β (24). Stress and inflammation may eventually lead to apoptosis and contribute to β-cell dysfunction, insulin resistance, and atherosclerosis.

In addition, obesity is associated with alterations in the gut microbiome along with increased gut leakiness of bacterial wall lipopolysaccharides (endotoxins) that may further promote tissue inflammation (25,26). Endotoxins, free fatty acids (probably in conjunction with fetuin), and cholesterol induce inflammation by activating Toll-like receptor (TLR) pathways and, subsequently, nuclear factor-κB (NF-κB)-mediated release of a broad range of cytokines and chemokines including tumor necrosis factor (TNF), IL-1β, IL-8, and MCP-1 that promote the accumulation of various immune cells in different tissues (17,18). It has recently been reported that in obesity, alterations of the gut microbiome might stimulate not only the innate immune system but also the adaptive immune system, which might contribute to insulin resistance (27). Adipose tissue inflammation can also be triggered by local hypoxia caused by rapid expansion of adipose tissue with insufficient vascular adaptation (28).

The renin-angiotensin system may also play a role in inflammation, insulin resistance, and vascular damage (2932). Recent data suggest that this system may have a role in islet inflammation and β-cell dysfunction, independent of its effects on glucose metabolism. Angiotensin II has been shown to induce expression of chemokine MCP-1 and IL-6, leading to impaired mitochondrial function and insulin secretion, as well as increased β-cell apoptosis (33).

These findings shed new light on the mechanisms of inflammation in obesity and diabetes and open new venues for prevention of inflammation by modifying the proinflammatory microbiota or by using inhibitors of the renin-angiotensin system. Alternatively, it is possible to use treatments that target key molecules that regulate the inflammatory response.

Anti-inflammatory Properties of Antidiabetes Drugs

The link between nutrient metabolism and inflammation raises the hypothesis that correction of metabolic abnormalities by lifestyle modifications and/or antidiabetes medications may reduce inflammation, thereby improving β-cell function and insulin resistance while protecting against vascular complications, hence modifying the natural history of type 2 diabetes. The current available treatments for type 2 diabetes act through diverse mechanisms to improve glycemia. Many of these treatments also exert anti-inflammatory effects that might be mediated via their metabolic effects on hyperglycemia and hyperlipidemia or by directly modulating the immune system. Part of the findings as to the effects of different medications on systemic and tissue-specific inflammation was obtained in vitro or in animal models. Notably, in preclinical studies testing the anti-inflammatory effects of antidiabetes drugs, the drug concentrations used were much higher than those used in clinical practice; therefore, the findings should be interpreted with caution. Below, we summarize the current data on the anti-inflammatory properties of antidiabetes medications (Table 1).

Table 1

Anti-inflammatory effects of glucose-lowering agents used in the treatment of type 2 diabetes

DrugMechanism of actionMain findingsRemarks and limitationsReferences
Biguanides Activate AMPK ↓ or ↔ CRP; ↔ inflammatory biomarkers; ↓ markers of endothelial dysfunction and coagulation May have beneficial effects in chronic inflammatory diseases and cancer 3943  
SUs Close KATP channels on β-cell plasma membranes ↓ or ↔ inflammatory markers and markers of endothelial dysfunction; ↓ or ↔ CRP Conflicting data; modest effect, if any 4549  
TZDs Activate the nuclear transcription factor PPARγ ↓↓ CRP; ↓ inflammatory markers; ↑ adiponectin Consistent anti-inflammatory effect 46,48,49,5761  
DPP-4 inhibitors Inhibit DPP-4 activity, increasing postprandial active incretin concentrations ↓ Inflammatory cytokines and biomarkers; ↓ CRP Moderate effect; requires further study 10,6264,6670  
GLP-1 RAs Activate GLP-1 receptors ↓ Inflammatory cytokines and biomarkers; ↓ markers of endothelial dysfunction; ↓ CRP Moderate effect; requires further study 47,74,75  
SGLT2 inhibitors Inhibit SGLT2 in the proximal nephron Unknown Future studies needed — 
Insulins Activate insulin receptors ↓ or ↔ inflammatory cytokines and immune mediators; ↓ or ↔ CRP Moderate effect, although data conflicting 41,78,79  
DrugMechanism of actionMain findingsRemarks and limitationsReferences
Biguanides Activate AMPK ↓ or ↔ CRP; ↔ inflammatory biomarkers; ↓ markers of endothelial dysfunction and coagulation May have beneficial effects in chronic inflammatory diseases and cancer 3943  
SUs Close KATP channels on β-cell plasma membranes ↓ or ↔ inflammatory markers and markers of endothelial dysfunction; ↓ or ↔ CRP Conflicting data; modest effect, if any 4549  
TZDs Activate the nuclear transcription factor PPARγ ↓↓ CRP; ↓ inflammatory markers; ↑ adiponectin Consistent anti-inflammatory effect 46,48,49,5761  
DPP-4 inhibitors Inhibit DPP-4 activity, increasing postprandial active incretin concentrations ↓ Inflammatory cytokines and biomarkers; ↓ CRP Moderate effect; requires further study 10,6264,6670  
GLP-1 RAs Activate GLP-1 receptors ↓ Inflammatory cytokines and biomarkers; ↓ markers of endothelial dysfunction; ↓ CRP Moderate effect; requires further study 47,74,75  
SGLT2 inhibitors Inhibit SGLT2 in the proximal nephron Unknown Future studies needed — 
Insulins Activate insulin receptors ↓ or ↔ inflammatory cytokines and immune mediators; ↓ or ↔ CRP Moderate effect, although data conflicting 41,78,79  

ROS, reactive oxygen species.

Metformin

Currently the first-line treatment of type 2 diabetes, metformin improves diabetes control primarily by suppressing hepatic glucose production and by improving insulin sensitivity. Its effects are thought to be mediated in part though activation of AMPK, a key regulator of cellular energy homeostasis known to exert both anti-inflammatory and antioxidant effects (34). Metformin has also been shown to directly inhibit production of reactive oxygen species from complex I (NADH:ubiquinone oxidoreductase) of the mitochondrial electron transport chain. In lipopolysaccharide-activated macrophages, metformin inhibited production of the proform of IL-1β, while it boosted induction of the anti-inflammatory cytokine, IL-10 (35). Metformin has been shown to inhibit proinflammatory responses in vascular endothelial and smooth muscle cells (5,36). Recent reports have demonstrated that metformin may attenuate oxidized LDL-induced proinflammatory responses in monocytes and macrophages and inhibit monocyte-to-macrophage differentiation (37). In rodents, it decreased the expression of the proinflammatory and proapoptotic protein TXNIP in β-cells and hepatocytes (38). In human studies, however, the effects of metformin on inflammation are not well established. In the U.S. Diabetes Prevention Program, metformin modestly reduced C-reactive protein (CRP) levels in patients with impaired glucose tolerance (39). Others found that metformin decreased the levels of several markers of endothelial dysfunction and coagulation but did not affect TNF-α or CRP (40). In the LANCET Trial: A Trial of Long-acting Insulin Injection to Reduce C-reactive Protein in Patients With Type 2 Diabetes, metformin did not modify the levels of inflammatory biomarkers in patients with recent-onset type 2 diabetes, despite improved glycemia (41). Of note, recent studies suggest that metformin may have beneficial effects in chronic inflammatory diseases and cancers and may extend life span independent of its effects on glucose metabolism (42,43). Several clinical studies are currently assessing the effects of metformin in this context and whether these are mediated via modulation of the inflammatory state.

Sulfonylureas

While these agents directly stimulate insulin secretion by the β-cell, they have also been shown to have anti-inflammatory effects. As an example, glyburide has been shown to inhibit the NLRP3 inflammasome and subsequent IL-1β activation in macrophages (24,44). Similarly, gliclazide also decreased the expression of inflammatory markers and endothelial dysfunction in patients with type 2 diabetes (45). By contrast, in various comparative clinical trials, no significant changes in CRP were observed with sulfonylurea (SU) therapy, whereas significant reductions were found with the thiazolidinedione (TZD) pioglitazone and the glucagon-like peptide 1 (GLP-1) receptor agonist (GLP-1 RA) exanatide (4648). In a recent 52-week comparative study examining the effects of metformin, gliclazide, and pioglitazone on markers of inflammation, coagulation, and endothelial function, no improvements were seen in inflammatory markers (IL-1, IL-6, and TNF-α) with SU therapy compared with the other treatments, while similar glycemic control was attained (49).

TZDs

Extensive data support the direct role of peroxisome proliferator–activated receptor (PPAR)γ in the negative regulation of inflammation. TZDs are PPARγ agonists that improve metabolism by increasing insulin sensitivity primarily by increasing glucose utilization and decreasing hepatic glucose production. In rodents, they may have direct protective effects on the β-cell against oxidative stress and apoptosis, which may contribute to preservation of β-cell mass (50). Despite extensive research, the precise mechanism(s) underlying the beneficial metabolic effects of TZDs are still not well understood and may involve stimulation of AMPK; both PPARγ and AMPK are important regulators of inflammation (51). Indeed, TZDs have anti-inflammatory effects, which may affect both insulin resistance and cardiovascular risk. TZDs have been shown to decrease inflammatory markers in visceral adipose tissue, liver, atherosclerotic plaques, and circulating plasma (52). Pioglitazone treatment decreased invasion of adipose tissue by proinflammatory macrophages and increased hepatic and peripheral insulin sensitivity (53). Treatment with TZDs also decreased inflammation in nonalcoholic steatohepatitis and in atherosclerotic lesions (54,55).

Various clinical studies have examined the anti-inflammatory and antiatherogenic properties of TZDs. A meta-analysis showed that pioglitazone and rosiglitazone significantly decreased serum CRP levels in both people with and people without diabetes, irrespective of effects on glycemia (56). Treatment with TZDs improved endothelial function, decreased hs-CRP and inflammatory markers, and increased adiponectin levels (46,48,49,5759). In a study using 18F-fluorodeoxyglucose positron emission tomography imaging in subjects with impaired glucose tolerance or type 2 diabetes, pioglitazone treatment attenuated inflammation in atherosclerotic plaques (60). This was associated with increased HDL cholesterol level and decreased hs-CRP. This may explain the finding that treatment of subjects with type 2 diabetes with pioglitazone was associated with reduced cardiovascular morbidity (61).

Dipeptidyl Peptidase-4 Inhibitors

There is substantial evidence that dipeptidyl peptidase (DPP)-4 inhibitors can improve a variety of cardiovascular risk factors and inflammation (6264). DPP-4 inhibitors were found to suppress NLRP3, TLR4, and IL-1β expression in human macrophages (65). High-fat diet–fed obese rodents of advanced age treated with vildagliptin for 11 months had improved glucose tolerance, enhanced insulin secretion, and higher survival rate (9). Furthermore, treatment with the DPP-4 inhibitor prevented peri-insulitis, typically observed in rodents fed a high-fat diet. In clinical studies, a potent anti-inflammatory effect has been reported with sitagliptin in patients with type 2 diabetes. Treatment with sitagliptin for 12 weeks reduced mRNA expression of CD26, TNF-α, TLR2, TLR4, proinflammatory kinases c-Jun N-terminal kinase-1 and inhibitory κB kinase, and inhibitor of chemokine receptor CCR-2 in mononuclear cells, as well as of plasma CRP, IL-6, and free fatty acids (10). In a cohort of Japanese patients with uncontrolled diabetes and coronary artery disease, sitagliptin improved the inflammatory state and endothelial function (66). Furthermore, sitagliptin added to the antidiabetes regimen of patients with type 2 diabetes already treated with metformin, and pioglitazone reduced hs-CRP and other inflammatory markers (67,68). Studies examining the effects of the DPP-4 inhibitors vildagliptin and linagliptin showed that they also reduce inflammation (69,70). However, large randomized controlled prospective studies analyzing the cardiovascular safety of different DPP-4 inhibitors, including Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction (SAVOR-TIMI 53), Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE), and Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), have not demonstrated cardiovascular benefit with DPP-4 inhibitors (7173). Of note, in these studies follow-up was relatively short, the patients already had established cardiovascular disease, and the studies were designed to show noninferiority rather than superiority. The findings should therefore be interpreted with caution.

GLP-1 RAs

GLP-1 RAs induce weight loss and improve glycemia and cardiovascular risk factors, which may be partially mediated by their anti-inflammatory effects. In patients with type 2 diabetes, treatment with GLP-1 analogs may modulate the proinflammatory activity of the innate immune system, leading to reduced proinflammatory activation of macrophages and consequently the expression and secretion of proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6 and increased adiponectin (74). With regard to the effects of GLP-1 analogs on CRP, a small placebo-controlled study demonstrated a significant reduction in CRP levels with exenatide (75). In a 12-month comparative study, exenatide demonstrated a significant decrease in hs-CRP compared with SU (47). However, the effects of GLP-1 RAs on cardiovascular morbidity and mortality are currently unknown.

Insulin

Several studies have suggested that insulin may exert an anti-inflammatory response, independent of its effects on glycemia (76,77). Insulin has been shown to alleviate inflammation through several mechanisms, including increased endothelial nitric oxide release and decreased expression of proinflammatory cytokines and immune mediators, such as NF-κB, intracellular adhesion molecule-1, and MCP-1, as well as several TLRs (76). In a randomized parallel-group study in patients with type 2 diabetes, serum concentrations of hs-CRP and IL-6 were markedly reduced in insulin-treated patients compared with metformin, despite similar glycemic control (78). This may suggest that insulin reduces inflammation, irrespective of its effects on glycemia. In contrast, in LANCET, treatment with insulin compared with placebo or metformin did not provide an anti-inflammatory benefit, despite improved glycemia (41). Similarly, in Outcome Reduction with an Initial Glargine Intervention (ORIGIN), insulin treatment did not affect cardiovascular mortality (79). Overall, the findings as to the anti-inflammatory effects of insulin are controversial and inconclusive.

Sodium–Glucose Cotransporter 2 Inhibitors

Sodium–glucose cotransporter (SGLT) 2 inhibitors improve glycemia by inhibiting reabsorption of glucose in the proximal tubule of the kidney, inducing glucosuria and lowering plasma glucose levels. Currently, there are limited data available with regard to the anti-inflammatory properties of SGLT2 inhibitors. Treatment with the SGLT inhibitor phlorizin in Psammomys obesus gerbils was shown to decrease islet inflammation, possibly related to the improvement in glucotoxicity (3). In type 2 diabetic mice, the SGLT2 inhibitor ipraglifloxin was shown to improve hyperglycemia, insulin secretion, hyperlipidemia, and liver levels of oxidative stress biomarkers and reduce markers of inflammation including IL-6, TNF-α, MCP-1, and CRP levels (80). While no clinical trial has reported the effects of SGLT2 inhibitors on inflammatory markers, the recent EMPA-REG OUTCOME [BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients] demonstrated a 38% reduction in cardiovascular death in patients with type 2 diabetes and cardiovascular disease after treatment with empagliflozin (81). It is of interest whether this effect is in part mediated by anti-inflammatory properties.

Metabolic Effects of Anti-inflammatory Drugs

Targeted anti-inflammatory therapy has been suggested for both prevention and treatment of diabetes; this has previously been extensively reviewed (82). Herein, we briefly summarize the current data on the metabolic effects of different anti-inflammatory treatments (Table 2).

Table 2

Metabolic effects of anti-inflammatory drugs

DrugMechanism of actionMain findingsRemarks and limitationsReferences
Anti–TNF-α antibody, soluble TNF receptor:Fc fusion protein TNF-α antagonism No effect on insulin sensitivity; ↑ insulin secretion; ↓ CRP Studies underpowered and of short duration 8387  
IL-1 receptor antagonist, IL-1β–specific antibody IL-1β antagonism ↓ HbA1c; ↑ insulin sensitivity; ↑ insulin secretion; ↓ CRP Effects persisted several weeks after treatment cessation; long-term studies ongoing 8892  
Salsalate IKK-β–NF-κB inhibition ↓ HbA1c; ↓ FBG; ↑ insulin sensitivity; ↑ insulin secretion; ↓ CRP; ↑ adiponectin Increased LDL cholesterol and urine albumin levels; further studies needed to confirm cardiovascular and renal safety 94100  
Diacerein Reduces TNF-α and IL-1β by unknown mechanism of action ↓ HbA1c; ↓ FBG; ↑ insulin secretion Single study in drug-naïve patients; further studies warranted to clarify long-term efficacy and safety 101  
Chloroquine/HCQ Unknown ↓ HbA1c; ↓ FBG; ↑ insulin secretion; ↓ insulin degradation Observational or small-scale prospective RCT 106111  
DrugMechanism of actionMain findingsRemarks and limitationsReferences
Anti–TNF-α antibody, soluble TNF receptor:Fc fusion protein TNF-α antagonism No effect on insulin sensitivity; ↑ insulin secretion; ↓ CRP Studies underpowered and of short duration 8387  
IL-1 receptor antagonist, IL-1β–specific antibody IL-1β antagonism ↓ HbA1c; ↑ insulin sensitivity; ↑ insulin secretion; ↓ CRP Effects persisted several weeks after treatment cessation; long-term studies ongoing 8892  
Salsalate IKK-β–NF-κB inhibition ↓ HbA1c; ↓ FBG; ↑ insulin sensitivity; ↑ insulin secretion; ↓ CRP; ↑ adiponectin Increased LDL cholesterol and urine albumin levels; further studies needed to confirm cardiovascular and renal safety 94100  
Diacerein Reduces TNF-α and IL-1β by unknown mechanism of action ↓ HbA1c; ↓ FBG; ↑ insulin secretion Single study in drug-naïve patients; further studies warranted to clarify long-term efficacy and safety 101  
Chloroquine/HCQ Unknown ↓ HbA1c; ↓ FBG; ↑ insulin secretion; ↓ insulin degradation Observational or small-scale prospective RCT 106111  

FBG, fasting blood glucose; IKK-β, inhibitory κB kinase-β; RCT, randomized controlled trials.

Anti–TNF-α

TNF-α was the first proinflammatory cytokine implicated in the pathogenesis of insulin resistance and type 2 diabetes; this has been confirmed in preclinical studies in various animal models (2). However, to date, TNF-α antagonism has not demonstrated any clear benefit in type 2 diabetes in man (8387). Careful analysis of these clinical studies suggests that all have serious limitations, as they were underpowered and of short duration (13). A number of observational studies have demonstrated that treatment of subjects without diabetes and with inflammatory diseases, such as rheumatoid arthritis, psoriasis, and Crohn disease, with TNF-α antagonists has improved glycemia and reduced the risk for developing diabetes. While the majority of these studies are not prospective, and the improvement is not a direct effect on glucose metabolism necessarily but, rather, improvement in the underlying disease, these observations warrant a well-designed clinical study of TNF antagonism in patients with type 2 diabetes.

Anti–IL-1β

Since the discovery of the central role of IL-1β in the pathogenesis of type 2 diabetes, numerous studies have investigated the role of IL-1β blockade on insulin resistance and type 2 diabetes. To date, eight independent clinical studies conducted with an IL-1 receptor antagonist (anakinra) or IL-1β–specific antibody (gevokizumab, canakizumab, and LY21891020) have demonstrated beneficial effects on metabolic parameters including decreased HbA1c and enhanced insulin sensitivity and β-cell secretory function, with concomitant improvement in inflammatory markers (82,8891). In a double-blind, placebo-controlled, parallel-group study involving 70 patients with type 2 diabetes, IL-1 blockade with anakinra reduced HbA1c, CRP, IL-6 levels, and the proinsulin-to-insulin ratio, while enhancing C-peptide secretion, indicating improved β-cell function; these beneficial effects persisted up to several weeks after treatment cessation (92). Although the duration of these studies does not provide definitive proof, the findings suggest a role for IL-1β blockade in modulating diabetes-associated inflammation and metabolic dysregulation. With regard to safety, IL-1β antagonism was generally well tolerated, with the main concern being that anakinra requires daily injections and often causes adverse reactions at the injection site. The humanized antibodies against IL-1β allow for monthly injections, which minimize these localized reactions.

Salsalate

Salsalate, a prodrug of salicylate, with fewer adverse reactions than aspirin and sodium salicylate, has demonstrated beneficial effects on glycemia and insulin sensitivity, probably through inhibition of the NF-κB pathway (93). To date, there are seven independent clinical trials that consistently demonstrate improvement in glycemia with salsalate (94100). These data support the role of inflammation and of the NF-κB pathway in the pathogenesis of type 2 diabetes that might become novel therapeutic targets for type 2 diabetes. Salsalate also reduces insulin clearance and may therefore partly improve glycemia via noninflammatory mechanisms. The safety of salsalate was studied in a well-designed multicenter, placebo-controlled study of 48 weeks’ duration (96). While the drug was well tolerated, a small increase in LDL cholesterol level was observed. Further, urinary albumin secretion was also increased and returned to baseline upon discontinuation of treatment. While salsalate may be an effective and inexpensive adjunct to type 2 diabetes treatment, further studies are needed to confirm its long-term cardiovascular and renal safety and to determine whether these effects are sustainable with continued administration.

Diacerein

A drug currently used in the treatment of arthritis, diacerein decreases levels of IL-1β, although its mechanism of action is unknown. In drug-naïve patients with type 2 diabetes, diacerein treatment improved insulin secretion and HbA1c levels, while reducing IL-1β and TNF-α levels (101). Further studies are warranted to clarify its long-term efficacy and safety.

Chloroquine/Hydroxychloroquine

Antimalarials such as hydroxychloroquine (HCQ) are commonly used to treat autoimmune rheumatic diseases, including rheumatoid arthritis and lupus. The precise anti-inflammatory mechanism of HCQ is not known and is probably related to alkalinization of endosomal organelles in immune cells. HCQ has been shown to reduce the incidence of diabetes among patients with rheumatoid arthritis and lupus and to improve glycemia in patients with rheumatic disorders and diabetes (102,103). Animal studies have shown that antimalarials improve insulin secretion and peripheral insulin sensitivity in diabetic rats (104). HCQ also has been shown to inhibit insulin degradation in rat hepatocytes (105). A few small randomized controlled trials showed that HCQ lowers HbA1c and LDL cholesterol levels in patients with type 2 diabetes (106110). The mechanisms of hypoglycemia with HCQ are inferred from studies of the parent drug, chloroquine, which has been shown to increase insulin levels in man by both increasing insulin secretion and inhibiting its degradation (111). Well-designed clinical studies are needed to further evaluate the effect of HCQ in individuals with type 2 diabetes and whether its beneficial metabolic effects are related to its anti-inflammatory properties.

Discussion

The association between hyperglycemia, inflammation, and vascular complications in diabetes is now well established. Different antidiabetes drugs, such as TZDs, DPP-4 inhibitors, GLP-1 RAs, and insulin, have bona fide anti-inflammatory effects. Since metabolic dysregulation itself induces inflammation, effective antidiabetes treatments may alleviate inflammation by virtue of improving the metabolic state. It is therefore difficult to clearly differentiate the effects of the drugs on metabolism from their direct effects on the immune system. However, the anti-inflammatory effects of different medications are partial and inconsistent, probably due to incomplete normalization of metabolic dysregulation or because diabetes-associated inflammation is multifactorial; the mechanisms involved include, but are not limited to, hyperglycemia. This rationalizes testing the impact of anti-inflammatory treatments on glycemia, diabetes progression, and cardiovascular morbidity. Exciting new data show that different treatments designed to modulate the immune response have beneficial metabolic effects; this opens new venues for the treatment of diabetes. However, it should be emphasized that the impact of such treatments on glycemia over long periods of time and more importantly on cardiovascular complications is still unknown. Moreover, a number of the anti-inflammatory drugs may have metabolic effects that are unrelated to their anti-inflammatory effects. This complicates the interpretation of the findings as to the metabolic effects of anti-inflammatory medications. It also remains a challenge to adequately assess inflammation in man, since crude surrogate markers are being used, and it is currently difficult to appreciate tissue-specific variations in the level and type of inflammation. Preclinical studies in animal models are most helpful in this regard; however, it may be difficult to extrapolate from findings in animal models to the clinical setting. Finally, there are important questions as to the safety and cost of these treatments.

Inflammation may have an important role in the development and progression of diabetes and its complications; however, the impact of experimental anti-inflammatory treatments on diabetes deterioration over time and cardiovascular outcomes is still elusive. To date, there is limited evidence showing that current antidiabetes medications have sustainable effects on glycemia and are able to prevent cardiovascular events. EMPA-REG showed that treatment with the SGLT2 inhibitor empagliflozin dramatically decreased cardiovascular mortality (81). It is of great interest to see whether empagliflozin has anti-inflammatory effects and if this plays a role in mediating its effects on mortality. It remains to be shown whether anti-inflammatory treatments administered alone or together with current antidiabetes drugs can prevent the vascular complications of diabetes. Further studies are required to clarify the role of anti-inflammatory therapy in the management of type 2 diabetes. Better understanding of the inflammatory basis for diabetes may provide for improved modalities for diabetes prevention and treatment, using novel targeted approaches in conjunction with current pharmacologic and lifestyle interventions.

This publication is based on the presentations at the 5th World Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension (CODHy). The Congress and the publication of this supplement were made possible in part by unrestricted educational grants from AstraZeneca.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

1.
International Diabetes Federation. IDF Diabetes Atlas, 7 ed. Brussels, Belgium, International Diabetes Federation, 2015
2.
Hotamisligil
GS
,
Shargill
NS
,
Spiegelman
BM
.
Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance
.
Science
1993
;
259
:
87
91
[PubMed]
3.
Maedler
K
,
Sergeev
P
,
Ris
F
, et al
.
Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets
.
J Clin Invest
2002
;
110
:
851
860
[PubMed]
4.
Zhou
R
,
Tardivel
A
,
Thorens
B
,
Choi
I
,
Tschopp
J
.
Thioredoxin-interacting protein links oxidative stress to inflammasome activation
.
Nat Immunol
2010
;
11
:
136
140
[PubMed]
5.
Isoda
K
,
Young
JL
,
Zirlik
A
, et al
.
Metformin inhibits proinflammatory responses and nuclear factor-kappaB in human vascular wall cells
.
Arterioscler Thromb Vasc Biol
2006
;
26
:
611
617
[PubMed]
6.
Lee
HM
,
Kim
JJ
,
Kim
HJ
,
Shong
M
,
Ku
BJ
,
Jo
EK
.
Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes
.
Diabetes
2013
;
62
:
194
204
[PubMed]
7.
Ricote
M
,
Li
AC
,
Willson
TM
,
Kelly
CJ
,
Glass
CK
.
The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation
.
Nature
1998
;
391
:
79
82
[PubMed]
8.
Jiang
C
,
Ting
AT
,
Seed
B
.
PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines
.
Nature
1998
;
391
:
82
86
[PubMed]
9.
Omar
BA
,
Vikman
J
,
Winzell
MS
, et al
.
Enhanced beta cell function and anti-inflammatory effect after chronic treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin in an advanced-aged diet-induced obesity mouse model
.
Diabetologia
2013
;
56
:
1752
1760
[PubMed]
10.
Makdissi
A
,
Ghanim
H
,
Vora
M
, et al
.
Sitagliptin exerts an antinflammatory action
.
J Clin Endocrinol Metab
2012
;
97
:
3333
3341
[PubMed]
11.
Chaudhuri
A
,
Ghanim
H
,
Vora
M
, et al
.
Exenatide exerts a potent antiinflammatory effect
.
J Clin Endocrinol Metab
2012
;
97
:
198
207
[PubMed]
12.
Ferdaoussi
M
,
Abdelli
S
,
Yang
JY
, et al
.
Exendin-4 protects beta-cells from interleukin-1 beta-induced apoptosis by interfering with the c-Jun NH2-terminal kinase pathway
.
Diabetes
2008
;
57
:
1205
1215
[PubMed]
13.
Donath
MY
,
Dalmas
É
,
Sauter
NS
,
Böni-Schnetzler
M
.
Inflammation in obesity and diabetes: islet dysfunction and therapeutic opportunity
.
Cell Metab
2013
;
17
:
860
872
[PubMed]
14.
Böni-Schnetzler
M
,
Boller
S
,
Debray
S
, et al
.
Free fatty acids induce a proinflammatory response in islets via the abundantly expressed interleukin-1 receptor I
.
Endocrinology
2009
;
150
:
5218
5229
[PubMed]
15.
Ehses
JA
,
Perren
A
,
Eppler
E
, et al
.
Increased number of islet-associated macrophages in type 2 diabetes
.
Diabetes
2007
;
56
:
2356
2370
[PubMed]
16.
Richardson
SJ
,
Willcox
A
,
Bone
AJ
,
Foulis
AK
,
Morgan
NG
.
Islet-associated macrophages in type 2 diabetes
.
Diabetologia
2009
;
52
:
1686
1688
[PubMed]
17.
Nguyen
MT
,
Favelyukis
S
,
Nguyen
AK
, et al
.
A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways
.
J Biol Chem
2007
;
282
:
35279
35292
[PubMed]
18.
Vandanmagsar
B
,
Youm
YH
,
Ravussin
A
, et al
.
The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance
.
Nat Med
2011
;
17
:
179
188
[PubMed]
19.
Cai
D
,
Yuan
M
,
Frantz
DF
, et al
.
Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB
.
Nat Med
2005
;
11
:
183
190
[PubMed]
20.
Dinarello
CA
.
Immunological and inflammatory functions of the interleukin-1 family
.
Annu Rev Immunol
2009
;
27
:
519
550
[PubMed]
21.
Böni-Schnetzler
M
,
Thorne
J
,
Parnaud
G
, et al
.
Increased interleukin (IL)-1beta messenger ribonucleic acid expression in beta -cells of individuals with type 2 diabetes and regulation of IL-1beta in human islets by glucose and autostimulation
.
J Clin Endocrinol Metab
2008
;
93
:
4065
4074
[PubMed]
22.
Williams
MD
,
Nadler
JL
.
Inflammatory mechanisms of diabetic complications
.
Curr Diab Rep
2007
;
7
:
242
248
[PubMed]
23.
Kim
JA
,
Montagnani
M
,
Koh
KK
,
Quon
MJ
.
Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms
.
Circulation
2006
;
113
:
1888
1904
[PubMed]
24.
Masters
SL
,
Dunne
A
,
Subramanian
SL
, et al
.
Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes
.
Nat Immunol
2010
;
11
:
897
904
[PubMed]
25.
Cani
PD
,
Bibiloni
R
,
Knauf
C
, et al
.
Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice
.
Diabetes
2008
;
57
:
1470
1481
[PubMed]
26.
Ley
RE
,
Bäckhed
F
,
Turnbaugh
P
,
Lozupone
CA
,
Knight
RD
,
Gordon
JI
.
Obesity alters gut microbial ecology
.
Proc Natl Acad Sci U S A
2005
;
102
:
11070
11075
[PubMed]
27.
Sell
H
,
Habich
C
,
Eckel
J
.
Adaptive immunity in obesity and insulin resistance
.
Nat Rev Endocrinol
2012
;
8
:
709
716
[PubMed]
28.
Ye
J
.
Emerging role of adipose tissue hypoxia in obesity and insulin resistance
.
Int J Obes
2009
;
33
:
54
66
[PubMed]
29.
van der Zijl
NJ
,
Moors
CC
,
Goossens
GH
,
Blaak
EE
,
Diamant
M
.
Does interference with the renin-angiotensin system protect against diabetes? Evidence and mechanisms
.
Diabetes Obes Metab
2012
;
14
:
586
595
[PubMed]
30.
Jandeleit-Dahm
KA
,
Tikellis
C
,
Reid
CM
,
Johnston
CI
,
Cooper
ME
.
Why blockade of the renin-angiotensin system reduces the incidence of new-onset diabetes
.
J Hypertens
2005
;
23
:
463
473
[PubMed]
31.
Fliser
D
,
Buchholz
K
,
Haller
H
;
EUropean Trial on Olmesartan and Pravastatin in Inflammation and Atherosclerosis (EUTOPIA) Investigators
.
Antiinflammatory effects of angiotensin II subtype 1 receptor blockade in hypertensive patients with microinflammation
.
Circulation
2004
;
110
:
1103
1107
[PubMed]
32.
Manabe
S
,
Okura
T
,
Watanabe
S
,
Fukuoka
T
,
Higaki
J
.
Effects of angiotensin II receptor blockade with valsartan on pro-inflammatory cytokines in patients with essential hypertension
.
J Cardiovasc Pharmacol
2005
;
46
:
735
739
[PubMed]
33.
Sauter
NS
,
Thienel
C
,
Plutino
Y
, et al
.
Angiotensin II induces interleukin-1β-mediated islet inflammation and β-cell dysfunction independently of vasoconstrictive effects
.
Diabetes
2015
;
64
:
1273
1283
[PubMed]
34.
Foretz
M
,
Guigas
B
,
Bertrand
L
,
Pollak
M
,
Viollet
B
.
Metformin: from mechanisms of action to therapies
.
Cell Metab
2014
;
20
:
953
966
[PubMed]
35.
Kelly
B
,
Tannahill
GM
,
Murphy
MP
,
O’Neill
LA
.
Metformin inhibits the production of reactive oxygen species from NADH:ubiquinone oxidoreductase to limit induction of interleukin-1β (IL-1β) and boosts interleukin-10 (IL-10) in lipopolysaccharide (LPS)-activated macrophages
.
J Biol Chem
2015
;
290
:
20348
20359
[PubMed]
36.
Kim
SA
,
Choi
HC
.
Metformin inhibits inflammatory response via AMPK-PTEN pathway in vascular smooth muscle cells
.
Biochem Biophys Res Commun
2012
;
425
:
866
872
[PubMed]
37.
Vasamsetti
SB
,
Karnewar
S
,
Kanugula
AK
,
Thatipalli
AR
,
Kumar
JM
,
Kotamraju
S
.
Metformin inhibits monocyte-to-macrophage differentiation via AMPK-mediated inhibition of STAT3 activation: potential role in atherosclerosis
.
Diabetes
2015
;
64
:
2028
2041
[PubMed]
38.
Shaked
M
,
Ketzinel-Gilad
M
,
Cerasi
E
,
Kaiser
N
,
Leibowitz
G
.
AMP-activated protein kinase (AMPK) mediates nutrient regulation of thioredoxin-interacting protein (TXNIP) in pancreatic beta-cells
.
PLoS One
2011
;
6
:
e28804
[PubMed]
39.
Haffner
S
,
Temprosa
M
,
Crandall
J
, et al.;
Diabetes Prevention Program Research Group
.
Intensive lifestyle intervention or metformin on inflammation and coagulation in participants with impaired glucose tolerance
.
Diabetes
2005
;
54
:
1566
1572
[PubMed]
40.
Caballero
AE
,
Delgado
A
,
Aguilar-Salinas
CA
, et al
.
The differential effects of metformin on markers of endothelial activation and inflammation in subjects with impaired glucose tolerance: a placebo-controlled, randomized clinical trial
.
J Clin Endocrinol Metab
2004
;
89
:
3943
3948
[PubMed]
41.
Pradhan
AD
,
Everett
BM
,
Cook
NR
,
Rifai
N
,
Ridker
PM
.
Effects of initiating insulin and metformin on glycemic control and inflammatory biomarkers among patients with type 2 diabetes: the LANCET randomized trial
.
JAMA
2009
;
302
:
1186
1194
[PubMed]
42.
Gallagher
EJ
,
LeRoith
D
.
Diabetes, cancer, and metformin: connections of metabolism and cell proliferation
.
Ann N Y Acad Sci
2011
;
1243
:
54
68
[PubMed]
43.
Koh
SJ
,
Kim
JM
,
Kim
IK
,
Ko
SH
,
Kim
JS
.
Anti-inflammatory mechanism of metformin and its effects in intestinal inflammation and colitis-associated colon cancer
.
J Gastroenterol Hepatol
2014
;
29
:
502
510
[PubMed]
44.
Lamkanfi
M
,
Mueller
JL
,
Vitari
AC
, et al
.
Glyburide inhibits the Cryopyrin/Nalp3 inflammasome
.
J Cell Biol
2009
;
187
:
61
70
[PubMed]
45.
Räkel
A
,
Renier
G
,
Roussin
A
,
Buithieu
J
,
Mamputu
JC
,
Serri
O
.
Beneficial effects of gliclazide modified release compared with glibenclamide on endothelial activation and low-grade inflammation in patients with type 2 diabetes
.
Diabetes Obes Metab
2007
;
9
:
127
129
[PubMed]
46.
Derosa G, Cicero AF, Fogari E, D'Angelo A, Bianchi L, Maffioli P: Pioglitazone compared to glibenclamide on lipid profile and inflammation markers in type 2 diabetic patients during an oral fat load. Horm Metab Res 2011;43:505–512
47.
Derosa
G
,
Maffioli
P
,
Salvadeo
SA
, et al
.
Exenatide versus glibenclamide in patients with diabetes
.
Diabetes Technol Ther
2010
;
12
:
233
240
[PubMed]
48.
Schöndorf
T
,
Musholt
PB
,
Hohberg
C
, et al
.
The fixed combination of pioglitazone and metformin improves biomarkers of platelet function and chronic inflammation in type 2 diabetes patients: results from the PIOfix study
.
J Diabetes Sci Technol
2011
;
5
:
426
432
[PubMed]
49.
Erem
C
,
Ozbas
HM
,
Nuhoglu
I
,
Deger
O
,
Civan
N
,
Ersoz
HO
.
Comparison of effects of gliclazide, metformin and pioglitazone monotherapies on glycemic control and cardiovascular risk factors in patients with newly diagnosed uncontrolled type 2 diabetes mellitus
. Exp Clin Endocrinol Diabetes
2014
;
122
:
295
302
50.
Wajchenberg
BL
.
beta-Cell failure in diabetes and preservation by clinical treatment
.
Endocr Rev
2007
;
28
:
187
218
[PubMed]
51.
LeBrasseur
NK
,
Kelly
M
,
Tsao
TS
, et al
.
Thiazolidinediones can rapidly activate AMP-activated protein kinase in mammalian tissues
.
Am J Physiol Endocrinol Metab
2006
;
291
:
E175
E181
[PubMed]
52.
Ceriello
A
.
Thiazolidinediones as anti-inflammatory and anti-atherogenic agents
.
Diabetes Metab Res Rev
2008
;
24
:
14
26
[PubMed]
53.
Esterson YB, Zhang K, Koppaka S, et al. Insulin sensitizing and anti-inflammatory effects of thiazolidinediones are heightened in obese patients. J Investig Med 2013;61:1152–1160
54.
Boettcher
E
,
Csako
G
,
Pucino
F
,
Wesley
R
,
Loomba
R
.
Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis
.
Aliment Pharmacol Ther
2012
;
35
:
66
75
[PubMed]
55.
Reiss
AB
,
Vagell
ME
.
PPARgamma activity in the vessel wall: anti-atherogenic properties
.
Curr Med Chem
2006
;
13
:
3227
3238
[PubMed]
56.
Zhao
Y
,
He
X
,
Huang
C
, et al
.
The impacts of thiazolidinediones on circulating C-reactive protein levels in different diseases: a meta-analysis
.
Diabetes Res Clin Pract
2010
;
90
:
279
287
[PubMed]
57.
Esposito
K
,
Ciotola
M
,
Carleo
D
, et al
.
Effect of rosiglitazone on endothelial function and inflammatory markers in patients with the metabolic syndrome
.
Diabetes Care
2006
;
29
:
1071
1076
[PubMed]
58.
Stocker DJ, Taylor AJ, Langley RW, Jezior MR, Vigersky RA. A randomized trial of the effects of rosiglitazone and metformin on inflammation and subclinical atherosclerosis in patients with type 2 diabetes. Am Heart J 2007;153:445.e1–6
59.
Hanefeld
M
,
Pfützner
A
,
Forst
T
,
Kleine
I
,
Fuchs
W
.
Double-blind, randomized, multicentre, and active comparator controlled investigation of the effect of pioglitazone, metformin, and the combination of both on cardiovascular risk in patients with type 2 diabetes receiving stable basal insulin therapy: the PIOCOMB study
.
Cardiovasc Diabetol
2011
;
10
:
65
[PubMed]
60.
Nitta
Y
,
Tahara
N
,
Tahara
A
, et al
.
Pioglitazone decreases coronary artery inflammation in impaired glucose tolerance and diabetes mellitus: evaluation by FDG-PET/CT imaging
.
JACC Cardiovasc Imaging
2013
;
6
:
1172
1182
[PubMed]
61.
Lincoff
AM
,
Wolski
K
,
Nicholls
SJ
,
Nissen
SE
.
Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials
.
JAMA
2007
;
298
:
1180
1188
[PubMed]
62.
Scheen
AJ
.
Cardiovascular effects of gliptins
.
Nat Rev Cardiol
2013
;
10
:
73
84
[PubMed]
63.
Ussher
JR
,
Drucker
DJ
.
Cardiovascular biology of the incretin system
.
Endocr Rev
2012
;
33
:
187
215
[PubMed]
64.
Zhao
Y
,
Yang
L
,
Zhou
Z
.
Dipeptidyl peptidase-4 inhibitors: multitarget drugs, not only antidiabetes drugs
.
J Diabetes
2014
;
6
:
21
29
[PubMed]
65.
Dai
Y
,
Wang
X
,
Ding
Z
,
Dai
D
,
Mehta
JL
.
DPP-4 inhibitors repress foam cell formation by inhibiting scavenger receptors through protein kinase C pathway
.
Acta Diabetol
2014
;
51
:
471
478
[PubMed]
66.
Matsubara J, Sugiyama S, Akiyama E, et al. Dipeptidyl peptidase-4 inhibitor, sitagliptin, improves endothelial dysfunction in association with its anti-inflammatory effects in patients with coronary artery disease and uncontrolled diabetes. Circ J 2013;77:1337–1344
67.
Derosa
G
,
Maffioli
P
,
Salvadeo
SA
, et al
.
Effects of sitagliptin or metformin added to pioglitazone monotherapy in poorly controlled type 2 diabetes mellitus patients
.
Metabolism
2010
;
59
:
887
895
[PubMed]
68.
Derosa
G
,
Carbone
A
,
D’Angelo
A
, et al
.
Variations in inflammatory biomarkers following the addition of sitagliptin in patients with type 2 diabetes not controlled with metformin
.
Intern Med
2013
;
52
:
2179
2187
[PubMed]
69.
Khan
S
,
Khan
S
,
Imran
M
,
Pillai
KK
,
Akhtar
M
,
Najmi
AK
.
Effects of pioglitazone and vildagliptin on coagulation cascade in diabetes mellitus--targeting thrombogenesis
.
Expert Opin Ther Targets
2013
;
17
:
627
639
[PubMed]
70.
Yamagishi
S
,
Ishibashi
Y
,
Ojima
A
,
Sugiura
T
,
Matsui
T
.
Linagliptin, a xanthine-based dipeptidyl peptidase-4 inhibitor, decreases serum uric acid levels in type 2 diabetic patients partly by suppressing xanthine oxidase activity
.
Int J Cardiol
2014
;
176
:
550
552
[PubMed]
71.
Scirica
BM
,
Bhatt
DL
,
Braunwald
E
, et al.;
SAVOR-TIMI 53 Steering Committee and Investigators
.
Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus
.
N Engl J Med
2013
;
369
:
1317
1326
[PubMed]
72.
White WB, Bakris GL, Bergenstal RM, et al. EXamination of cArdiovascular outcoMes with alogliptIN versus standard of carE in patients with type 2 diabetes mellitus and acute coronary syndrome (EXAMINE): a cardiovascular safety study of the dipeptidyl peptidase 4 inhibitor alogliptin in patients with type 2 diabetes with acute coronary syndrome. Am Heart J 2011;162:620–626.e1
73.
Green
JB
,
Bethel
MA
,
Armstrong
PW
, et al.;
TECOS Study Group
.
Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes
.
N Engl J Med
2015
;
373
:
232
242
[PubMed]
74.
Hogan
AE
,
Gaoatswe
G
,
Lynch
L
, et al
.
Glucagon-like peptide 1 analogue therapy directly modulates innate immune-mediated inflammation in individuals with type 2 diabetes mellitus
.
Diabetologia
2014
;
57
:
781
784
[PubMed]
75.
Wu
JD
,
Xu
XH
,
Zhu
J
, et al
.
Effect of exenatide on inflammatory and oxidative stress markers in patients with type 2 diabetes mellitus
.
Diabetes Technol Ther
2011
;
13
:
143
148
[PubMed]
76.
Sun
Q
,
Li
J
,
Gao
F
.
New insights into insulin: the anti-inflammatory effect and its clinical relevance
.
World J Diabetes
2014
;
5
:
89
96
[PubMed]
77.
Dandona
P
,
Aljada
A
,
Mohanty
P
.
The anti-inflammatory and potential anti-atherogenic effect of insulin: a new paradigm
.
Diabetologia
2002
;
45
:
924
930
[PubMed]
78.
Mao
XM
,
Liu
H
,
Tao
XJ
,
Yin
GP
,
Li
Q
,
Wang
SK
.
Independent anti-inflammatory effect of insulin in newly diagnosed type 2 diabetes
.
Diabetes Metab Res Rev
2009
;
25
:
435
441
[PubMed]
79.
Gerstein
HC
,
Bosch
J
,
Dagenais
GR
, et al.;
ORIGIN Trial Investigators
.
Basal insulin and cardiovascular and other outcomes in dysglycemia
.
N Engl J Med
2012
;
367
:
319
328
[PubMed]
80.
Tahara
A
,
Kurosaki
E
,
Yokono
M
, et al
.
Effects of SGLT2 selective inhibitor ipragliflozin on hyperglycemia, hyperlipidemia, hepatic steatosis, oxidative stress, inflammation, and obesity in type 2 diabetic mice
.
Eur J Pharmacol
2013
;
715
:
246
255
[PubMed]
81.
Zinman
B
,
Wanner
C
,
Lachin
JM
, et al.;
EMPA-REG OUTCOME Investigators
.
Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes
.
N Engl J Med
2015
;
373
:
2117
2128
[PubMed]
82.
Donath
MY
.
Targeting inflammation in the treatment of type 2 diabetes: time to start
.
Nat Rev Drug Discov
2014
;
13
:
465
476
[PubMed]
83.
Ofei
F
,
Hurel
S
,
Newkirk
J
,
Sopwith
M
,
Taylor
R
.
Effects of an engineered human anti-TNF-alpha antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM
.
Diabetes
1996
;
45
:
881
885
[PubMed]
84.
Paquot
N
,
Castillo
MJ
,
Lefèbvre
PJ
,
Scheen
AJ
.
No increased insulin sensitivity after a single intravenous administration of a recombinant human tumor necrosis factor receptor: Fc fusion protein in obese insulin-resistant patients
.
J Clin Endocrinol Metab
2000
;
85
:
1316
1319
[PubMed]
85.
Stanley
TL
,
Zanni
MV
,
Johnsen
S
, et al
.
TNF-alpha antagonism with etanercept decreases glucose and increases the proportion of high molecular weight adiponectin in obese subjects with features of the metabolic syndrome
.
J Clin Endocrinol Metab
2011
;
96
:
E146
E150
[PubMed]
86.
Bernstein
LE
,
Berry
J
,
Kim
S
,
Canavan
B
,
Grinspoon
SK
.
Effects of etanercept in patients with the metabolic syndrome
.
Arch Intern Med
2006
;
166
:
902
908
[PubMed]
87.
Dominguez
H
,
Storgaard
H
,
Rask-Madsen
C
, et al
.
Metabolic and vascular effects of tumor necrosis factor-alpha blockade with etanercept in obese patients with type 2 diabetes
.
J Vasc Res
2005
;
42
:
517
525
[PubMed]
88.
van Asseldonk
EJ
,
Stienstra
R
,
Koenen
TB
,
Joosten
LA
,
Netea
MG
,
Tack
CJ
.
Treatment with Anakinra improves disposition index but not insulin sensitivity in nondiabetic subjects with the metabolic syndrome: a randomized, double-blind, placebo-controlled study
.
J Clin Endocrinol Metab
2011
;
96
:
2119
2126
[PubMed]
89.
Cavelti-Weder
C
,
Babians-Brunner
A
,
Keller
C
, et al
.
Effects of gevokizumab on glycemia and inflammatory markers in type 2 diabetes
.
Diabetes Care
2012
;
35
:
1654
1662
[PubMed]
90.
Sloan-Lancaster
J
,
Abu-Raddad
E
,
Polzer
J
, et al
.
Double-blind, randomized study evaluating the glycemic and anti-inflammatory effects of subcutaneous LY2189102, a neutralizing IL-1β antibody, in patients with type 2 diabetes
.
Diabetes Care
2013
;
36
:
2239
2246
[PubMed]
91.
Hensen
J
,
Howard
CP
,
Walter
V
,
Thuren
T
.
Impact of interleukin-1β antibody (canakinumab) on glycaemic indicators in patients with type 2 diabetes mellitus: results of secondary endpoints from a randomized, placebo-controlled trial
.
Diabetes Metab
2013
;
39
:
524
531
[PubMed]
92.
Larsen
CM
,
Faulenbach
M
,
Vaag
A
,
Ehses
JA
,
Donath
MY
,
Mandrup-Poulsen
T
.
Sustained effects of interleukin-1 receptor antagonist treatment in type 2 diabetes
.
Diabetes Care
2009
;
32
:
1663
1668
[PubMed]
93.
Yuan
M
,
Konstantopoulos
N
,
Lee
J
, et al
.
Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta
.
Science
2001
;
293
:
1673
1677
[PubMed]
94.
Fleischman
A
,
Shoelson
SE
,
Bernier
R
,
Goldfine
AB
.
Salsalate improves glycemia and inflammatory parameters in obese young adults
.
Diabetes Care
2008
;
31
:
289
294
[PubMed]
95.
Goldfine
AB
,
Conlin
PR
,
Halperin
F
, et al
.
A randomised trial of salsalate for insulin resistance and cardiovascular risk factors in persons with abnormal glucose tolerance
.
Diabetologia
2013
;
56
:
714
723
[PubMed]
96.
Goldfine
AB
,
Fonseca
V
,
Jablonski
KA
, et al.;
Targeting Inflammation Using Salsalate in Type 2 Diabetes Study Team
.
Salicylate (salsalate) in patients with type 2 diabetes: a randomized trial
.
Ann Intern Med
2013
;
159
:
1
12
[PubMed]
97.
Goldfine
AB
,
Fonseca
V
,
Jablonski
KA
,
Pyle
L
,
Staten
MA
,
Shoelson
SE
;
TINSAL-T2D (Targeting Inflammation Using Salsalate in Type 2 Diabetes) Study Team
.
The effects of salsalate on glycemic control in patients with type 2 diabetes: a randomized trial
.
Ann Intern Med
2010
;
152
:
346
357
[PubMed]
98.
Goldfine
AB
,
Silver
R
,
Aldhahi
W
, et al
.
Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes
.
Clin Transl Sci
2008
;
1
:
36
43
[PubMed]
99.
Koska
J
,
Ortega
E
,
Bunt
JC
, et al
.
The effect of salsalate on insulin action and glucose tolerance in obese non-diabetic patients: results of a randomised double-blind placebo-controlled study
.
Diabetologia
2009
;
52
:
385
393
[PubMed]
100.
Faghihimani
E
,
Aminorroaya
A
,
Rezvanian
H
,
Adibi
P
,
Ismail-Beigi
F
,
Amini
M
.
Salsalate improves glycemic control in patients with newly diagnosed type 2 diabetes
.
Acta Diabetol
2013
;
50
:
537
543
[PubMed]
101.
Ramos-Zavala
MG
,
González-Ortiz
M
,
Martínez-Abundis
E
,
Robles-Cervantes
JA
,
González-López
R
,
Santiago-Hernández
NJ
.
Effect of diacerein on insulin secretion and metabolic control in drug-naive patients with type 2 diabetes: a randomized clinical trial
.
Diabetes Care
2011
;
34
:
1591
1594
[PubMed]
102.
Wasko
MC
,
Hubert
HB
,
Lingala
VB
, et al
.
Hydroxychloroquine and risk of diabetes in patients with rheumatoid arthritis
.
JAMA
2007
;
298
:
187
193
[PubMed]
103.
Chen
YM
,
Lin
CH
,
Lan
TH
, et al
.
Hydroxychloroquine reduces risk of incident diabetes mellitus in lupus patients in a dose-dependent manner: a population-based cohort study
.
Rheumatology (Oxford)
2015
;
54
:
1244
1249
[PubMed]
104.
Emami
J
,
Gerstein
HC
,
Pasutto
FM
,
Jamali
F
.
Insulin-sparing effect of hydroxychloroquine in diabetic rats is concentration dependent
.
Can J Physiol Pharmacol
1999
;
77
:
118
123
[PubMed]
105.
Emami
J
,
Pasutto
FM
,
Mercer
JR
,
Jamali
F
.
Inhibition of insulin metabolism by hydroxychloroquine and its enantiomers in cytosolic fraction of liver homogenates from healthy and diabetic rats
.
Life Sci
1999
;
64
:
325
335
[PubMed]
106.
Gerstein
HC
,
Thorpe
KE
,
Taylor
DW
,
Haynes
RB
.
The effectiveness of hydroxychloroquine in patients with type 2 diabetes mellitus who are refractory to sulfonylureas--a randomized trial
.
Diabetes Res Clin Pract
2002
;
55
:
209
219
[PubMed]
107.
Rekedal
LR
,
Massarotti
E
,
Garg
R
, et al
.
Changes in glycosylated hemoglobin after initiation of hydroxychloroquine or methotrexate treatment in diabetes patients with rheumatic diseases
.
Arthritis Rheum
2010
;
62
:
3569
3573
[PubMed]
108.
Quatraro
A
,
Consoli
G
,
Magno
M
, et al
.
Hydroxychloroquine in decompensated, treatment-refractory noninsulin-dependent diabetes mellitus. A new job for an old drug
?
Ann Intern Med
1990
;
112
:
678
681
[PubMed]
109.
Kang L, Mikuls TR, O'Dell JR. Hydroxychloroquine: a diabetic drug in disguise? BMJ Case Rep 2009;pii: bcr08.2008.0654. DOI: 10.1136/bcr.08.2008.0654
110.
Shojania
K
,
Koehler
BE
,
Elliott
T
.
Hypoglycemia induced by hydroxychloroquine in a type II diabetic treated for polyarthritis
.
J Rheumatol
1999
;
26
:
195
196
[PubMed]
111.
Powrie
JK
,
Smith
GD
,
Shojaee-Moradie
F
,
Sönksen
PH
,
Jones
RH
.
Mode of action of chloroquine in patients with non-insulin-dependent diabetes mellitus
.
Am J Physiol
1991
;
260
:
E897
E904
[PubMed]