Anti-inflammatory effects of glucose-lowering agents in DM Introduction The prevalence of diabetes is on the rise

Anti-inflammatory effects of glucose-lowering agents in DM

Introduction
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. Although many factors contribute, of late involvement of the immune system in the pathogenesis of diabetes has been gaining interest. 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, b-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. Current antidiabetes drugs may alleviate systemic and tissue-specific inflammation (4)

Pathogenesis of the Diabetes – Role of Inflammation:
Type 2 diabetes tends to increasingly affect people as they age, especially those with genetic and epigenetic predispositions. It is strongly promoted by over-nutrition and physical inactivity. In predisposed individuals, a defect in insulin secretion can be detected concomitantly with a reduced response to insulin-stimulated glucose uptake in liver and adipose tissues, a condition known as insulin resistance (5). At the individual level, insulin resistance remains relatively constant over time and increases only mildly with age. By contrast, a deterioration of the insulin-secretory capacity of pancreatic ?-cells is continuous, after an initial increase in insulin production, thereby causing the onset and progression of type 2 diabetes. Thus, insulin secretion no longer compensates for the increased peripheral insulin demand.
Multiple mechanisms underlie defective insulin secretion and responses in type 2 diabetes. These include glucotoxicity, lipotoxicity, oxidative stress, endoplasmic reticulum (ER) stress, alterations of the gut microbiota, endocannabinoids and the formation of amyloid deposits in the islets (6). They probably all participate in the pathology of the disease, with inter-individual differences depending on genetic background, nutrition, physical activity, the use of antibiotics and other environmental factors. Interestingly, all of these mechanisms are associated with inflammatory responses (7). In pancreatic islets, elevated glucose concentrations increase the metabolic activity of islet cells, leading to elevated formation of reactive oxygen species (ROS), which promotes the activation of the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome and caspase 1, thus enabling the production of mature interleukin?1? (IL?1?) (8) Increased insulin demand and production induces ER stress, which also activates the inflammasome (9). Furthermore, lipopolysaccharides from bacterial cell walls (endotoxins) or free fatty acids bound to Fetuin?A activate Toll-like receptor 2 (TLR2) and TLR4, leading to the translocation of nuclear factor??B (NF??B) and the induction of inflammation (10). All of these components induce very low concentrations of islet-derived IL?1?.
IL?1? induces various cytokines and chemokines — including IL?6, IL?8, tumour necrosis factor (TNF) and monocyte chemoattractant protein 1 (MCP1; also known as CCL2) — that lead to the attraction of macrophages and other immune cells(11). Furthermore, islets produce amyloid polypeptide, which aggregates to form amyloid fibrils in patients with type 2 diabetes. Human islet amyloid polypeptide interacts with immune cells to promote the synthesis of IL?1? via the inflammasome (12). Finally, endocannabinoids, which mediate satiety in the hypothalamus and are upregulated in the liver during obesity, may also promote macrophage activation(13).
The underlying mechanisms of insulin resistance are also associated with an inflammatory response, although the aetiology of insulin resistance partly differs from the one causing defective insulin secretion. By storing excessive nutrients, adipocytes experience ER stress and hypertrophy — both of which have been associated with the production of cytokines and chemokines(14). Eventually, lipid overload may lead to adipocyte death, further triggering an inflammatory response. Additionally, inflammation can be triggered by local hypoxia caused by the rapid expansion of adipose tissues without sufficient vascular adaptation (15). Obesity is also associated with increased gut leakiness for bacterial products (endotoxins) that, along with inducing changes to the gut flora, may further trigger tissue inflammation (16). These stresses trigger several intracellular inflammatory pathways. Indeed, endotoxins, free fatty acids and other lipids recruit Fetuin?A, which, together with the recruiting agent, activates TLR2 and TLR4, thereby leading to the NF??B?mediated release of cytokines and chemokines such as TNF, IL?1?, IL?8 and MCP1 (17). These cytokines then promote the accumulation of various immune cells. In macrophages, hyperglycaemia and lipids promote the formation of inflammasomes that lead to the splicing of pro?IL?1? to active IL?1?(18). This potent cytokine then activates multiple immune cells and thereby promotes insulin resistance. Similar alterations have been observed in other insulin-sensitive tissues, particularly the liver and muscle.
The renin-angiotensin system may also play a role in inflammation, insulin resistance, and vascular damage (19). 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 ?-cell apoptosis (20).

Anti-inflammatory properties of Anti Diabetic agents :
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.

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 through activation of AMPK, a key regulator of cellular energy homeostasis known to exert both anti-inflammatory and antioxidant effects (21). Metformin also directly inhibit production of reactive oxygen species from complex I (NADH:ubiquinone oxidoreductase) of the mitochondrial electron transport chain. Inlipopolysaccharide activated macrophages, metformin inhibited production of the proform of IL-1b, while it boosted induction of the anti-inflammatory cytokine, IL-10 (22). Metformin may attenuate oxidized LDL-induced proinflammatory responses in monocytes and macrophages and inhibit monocyte-to-macrophage differentiation (23). In the U.S. Diabetes Prevention Program, metformin modestly reduced C-reactive protein (CRP) levels in patients with impaired glucose tolerance (24). Krysiak and Okopien showed that patients with IGT treated with metformin reduced release of various pro-inflammatory cytokines from monocyte and lymphocytes.(25) In the BARI 2D trial, treatment of metformin in patients with T2DM and coronary artery disease showed anti-inflammatory effects as indicated by reduction in plasma insulin, plasminogen activator inhibitor type 1 antigen, CRP, and fibrinogen levels.(26) However 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 (27). Thus, the anti-inflammatory effect of metformin remains unclear and may be an indirect effect mediated through the improvement of insulin sensitivity and hyperglycemia.

Sulfonylureas

While these agents directly stimulate insulin secretion by the b-cell, they have also been shown to have anti-inflammatory effects. The K-ATP channels in monocytes/macrophages are upregulated and stimulate inflammatory reactions mediated by MAPKs/NF-?B pathways, while glibenclamide, a generic sulfonylurea, rescues this progression.(28) Cai et al found that glibenclamide could attenuate LPS-induced myocardial injury in diabetic mice, possibly through inhibiting inflammation.(29) Glibenclamide has been shown to inhibit the NLRP3 inflammasome and subsequent IL-1? activation in macrophages (30). Similarly, gliclazide also decreased the expression of inflammatory markers and endothelial dysfunction in patients with type 2 diabetes (31). 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 (32). 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-a) with SU therapy compared with the other treatments, while similar glycemic control was attained (33). Studies on sulfonylureas provide evidence for safety in patients with diabetes combined with asthma by downregulation of allergic inflammation via IL-4/IL-13/p-STAT6/VCAM-1 signaling pathway or by inhibiting cytokine-induced eosinophil survival and activation.(34)

TZDs

TZDs are PPAR? 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 ?-cell against oxidative stress and apoptosis, which may contribute to preservation of ?-cell mass (35). Beneficial effects may also involve stimulation of AMPK. TZDs have been shown to decrease inflammatory markers in visceral adipose tissue, liver, atherosclerotic plaques, and circulating plasma (36). Pioglitazone treatment decreased invasion of adipose tissue by proinflammatory macrophages and increased hepatic and peripheral insulin sensitivity (37). Treatment with TZDs also decreased inflammation in nonalcoholic steatohepatitis and in atherosclerotic lesions (38). 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 (39). Treatment with TZDs improved endothelial function, decreased hs-CRP and inflammatory markers, and increased adiponectin levels (40).
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 (41). 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.(42)

DPP4-inhibitors

DPP-4 inhibitors were found to suppress NLRP3, TLR4, and IL-1b expression in human macrophages (43). 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 (44). 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-a, TLR2, TLR4, proinflammatory kinases c-Jun N-terminal kinase-1 and inhibitory kB kinase, and inhibitor of chemokine receptor CCR-2 in mononuclear cells, as well as of plasma CRP, IL-6, and free fatty acids (45). In a cohort of Japanese patients with uncontrolled diabetes and coronary artery disease, sitagliptin improved the inflammatory state and endothelial function (46). 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 (47). In hemodialysis patients with T2DM, linagliptin decreased levels of prostaglandin E2, IL-6, hsCRP, glycated albumin, and blood glucose which was associated with an increase in active GLP-1.(48)
However, large randomized controlled prospective studies analyzing the cardiovascular safety of different DPP-4 inhibitors, including Saxagliptin Assessment of VascularOutcomes Recorded in Patientswith 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 (49-51). 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.

GLP-1 receptor agonists

GLP-1RAs and other analogs have been shown to activate GLP-1 receptor to increase intracellular cAMP in pancreatic acinar cells to stimulate insulin secretion while suppressing glucagon secretion and functions identically to GLP-1.(52) Additionally GLP-1RAs decrease waist circumference, fat content, and intra-hepatic lipids in patients with nonalcoholic fatty liver diseases and T2DM.(53) 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-a, IL-1b, and IL-6 and increased adiponectin (54). In a small placebo-controlled study demonstrated a significant reduction in CRP levels with exenatide (55).

Insulin

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-kB, intracellular adhesion molecule-1, and MCP-1, as well as several TLRs (56). 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 (57). 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 (27). Similarly, in Outcome Reduction with an Initial Glargine Intervention (ORIGIN), insulin treatment did not affect cardiovascular mortality (58). Overall, the findings as to the anti-inflammatory effects of insulin are controversial and inconclusive.
Insulin has a major drawback in terms of inducing weight gain. This increase in fat mass can bring distinct morphological changes including adipocyte enlargement and macrophage influx leading to a more pronounced inflammatory status reflected by an increased secretion of pro-inflammatory mediators and a reduction in secretion of the insulin-sensitizing protein adiponectin (ADN). Therefore, the systemic anti-inflammatory effects of insulin may be counteracted by the pro-inflammatory changes associated with an increased fat mass, which is reinforced by a study from Jansen et al where patients characterized by a pronounced insulin-associated weight gain had an influx of macrophages into the adipose tissue and it was accompanied by a more pronounced inflammatory status.(59)

SGLT-2 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-a,MCP-1, and CRP levels (59). 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 (60). It is of interest whether this effect is in part mediated by anti-inflammatory properties.

Conclusion
Obesity and T2DM cause an increase in inflammatory markers (hsCRP, TNF-?, IL-6) and a decrease in anti-inflammatory factors, including ADN, leading to metabolic dysfunction. Thus, targeting inflammation is important for the management of diabetes and related disorders. Multiple studies have demonstrated an anti-inflammatory potential for various hypoglycemic drugs, which can contribute to improved clinical outcomes. Hypoglycemic agents exert their anti-inflammatory effects either by controlling hyperglycemia or directly, by acting on inflammatory pathways, independent of glucose control.

References

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
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
4. Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. Thioredoxin-interacting protein links oxidativestress to inflammasome activation. Nat Immunol 2010;11:136–140
5 5.Kahn, S. E., Hull, R. L. & Utzschneider, K. M. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444, 840–846 (2006)
6 Hull, R. L., Westermark, G. T., Westermark, P. & Kahn, S. E. Islet amyloid: a critical entity in the pathogenesis of type 2 diabetes. J. Clin. Endocrinol. Metab. 89, 3629–3643 (2004)
7 Westwell-Roper, C. Y., Ehses, J. A. & Verchere, C. B. Resident macrophages mediate islet amyloid polypeptide-induced islet IL?1? production and ? cell dysfunction. Diabetes 63, 1698–1711 (2014)
8 Zhou, R., Tardivel, A., Thorens, B., Choi, I. & Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nature Immunol. 11, 136–140 (2010)
9 Oslowski, C. M. et al. Thioredoxin-interacting protein mediates ER stress-induced ? cell death through initiation of the inflammasome. Cell Metab. 16, 265–273 (2012)
10 Pal, D. et al. Fetuin?A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nature Med. 18, 1279–1285 (2012)
11 Butcher, M. J. et al. Association of proinflammatory cytokines and islet resident leucocytes with islet dysfunction in type 2 diabetes. Diabetologia 57, 491–501 (2014)
12 Masters, S. L. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL?1? in type 2 diabetes. Nature Immunol. 11, 897–904 (2010)
13 Jourdan, T. et al. Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates ? cell loss in type 2 diabetes. Nature Med. 19, 1132–1140 (2013)
14 Martinez, J., Verbist, K., Wang, R. & Green, D. R. The relationship between metabolism and the autophagy machinery during the innate immune response. Cell Metab.17, 895–900 (2013)
15 Ye, J. Emerging role of adipose tissue hypoxia in obesity and insulin resistance. Int. J. Obes. 33, 54–66 (2009)
16 Cox, L. M. & Blaser, M. J. Pathways in microbe-induced obesity. Cell Metab. 17, 883–894 (2013)
17 Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nature Med. 17, 179–188 (2011)
18 Koenen, T. B. et al. Hyperglycemia activates caspase?1 and TXNIP-mediated IL?1? transcription in human adipose tissue. Diabetes 60, 517–524 (2011)
19 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
20 Sauter NS, Thienel C, Plutino Y, et al. Angiotensin II induces interleukin-1b-mediated islet inflammation and b-cell dysfunction independently of vasoconstrictive effects. Diabetes 2015;64:1273–1283
21 Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B. Metformin: from mechanisms of action to therapies. Cell Metab 2014;20:953–966
22 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-1b (IL-1b) and boosts interleukin-10 (IL-10) in lipopolysaccharide (LPS)-activated macrophages. J Biol Chem 2015;290:20348–20359
23 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
24 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
25 Krysiak R, Okopien B. Lymphocyte-suppressing and systemic anti-inflammatory effects of high-dose metformin in simvastatin-treated patients with impaired fasting glucose. Atherosclerosis. 2012;225:403–407
26 Sobel BE, Hardison RM, Genuth S, et al. Profibrinolytic, antithrombotic, and antiinflammatory effects of an insulin-sensitizing strategy in patients in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Circulation. 2011;124:695–703
27 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
28 Ling MY, Ma ZY, Wang YY, et al. Up-regulated ATP-sensitive potassium channels play a role in increased inflammation and plaque vulnerability in macrophages. Atherosclerosis. 2013;226:348–355.
29 Cai J, Lu S, Yao Z, Deng YP, et al. Glibenclamide attenuates myocardial injury by lipopolysaccharides in streptozotocin-induced diabetic mice. 30.Cardiovasc Diabetol. 2014;13:106 Lamkanfi M, Mueller JL, Vitari AC, et al. Glyburide inhibits the Cryopyrin/Nalp3 inflammasome. J Cell Biol 2009;187:61–70
30 R¨akel 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
31 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
32 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
33 Cui W, Zhang S, Cai Z, et al. The antidiabetic agent glibenclamide protects airway hyperresponsiveness and inflammation in mice. Inflammation. 2015;38:835–845
34 Wajchenberg BL. beta-Cell failure in diabetes and preservation by clinical treatment. Endocr Rev 2007;28:187–218
35 Ceriello A. Thiazolidinediones as anti-inflammatory and anti-atherogenic agents. Diabetes Metab Res Rev 2008;24:14–26
36 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
37 Reiss AB, Vagell ME. PPARgamma activity in the vessel wall: anti-atherogenic properties. Curr Med Chem 2006;13:3227–3238
38 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
39 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
40 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
41 Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a metaanalysis of randomized trials. JAMA 2007;298: 1180–1188
42 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
43 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 advancedaged diet-induced obesity mousemodel. Diabetologia 2013;56:1752–1760
44 Makdissi A, Ghanim H, Vora M, et al. Sitagliptin exerts an antinflammatory action. J Clin Endocrinol Metab 2012;97:3333–3341
45 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
46 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
47 Nakamura Y, Tsuji M, Hasegawa H, et al. Anti-inflammatory effects of linagliptin in hemodialysis patients with diabetes. Hemodial Int. 2014;18:433–442
48 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
49 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
50 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
51 Wang XC, Gusdon AM, Liu H, et al. Effects of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease and
52 inflammation. World J Gastroenterol. 2014;20:14821–14830.
53 Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med. 2015;373:11–22
54 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
55 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
56 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
57 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
58 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
59 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
60 Zinman B,Wanner C, Lachin JM, et al.; EMPAREG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–2128