Anti-inflammatory effects of glucose-lowering agents in DMIntroductionThe 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.MetforminCurrently 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)TZDsTZDs 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.ConclusionObesity 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.References1. International Diabetes Federation. IDF Diabetes Atlas, 7 ed. Brussels, Belgium, International Diabetes Federation, 20152. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor alpha: direct role in obesity-linked insulin resistance.
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