IL-12 serum levels in patients with type 2 diabetes treated with sulphonylureas

Wegner, Małgorzata; Winiarska, Hanna; Bobkiewicz-Kozlowska, T.; Dworacka, Marzena

doi:10.1016/j.cyto.2008.02.014

Cited by 58 publications

(64 citation statements)

References 41 publications

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“…The effect of sitagliptin was selective in obese mice, with no effect in lean mice with lower levels of cytokine expression. Interestingly, a recent report shows that IL-12 is increased in serum of type 2 diabetic patients and is correlated with BMI and homeostatic model assessment of insulin resistance (52). Therefore, sitagliptin may have beneficial effects on insulin secretion by also reducing islet IL-12 expression and production.…”

Section: Discussionmentioning

confidence: 99%

Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice

Dobrian¹,

Ma²,

Lindsay³

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

146

100

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Adipose tissue inflammation and reduced pancreatic β-cell function are key issues in the development of cardiovascular disease and progressive metabolic dysfunction in type 2 diabetes mellitus. The aim of this study was to determine the effect of the DPP IV inhibitor sitagliptin on adipose tissue and pancreatic islet inflammation in a diet-induced obesity model. C57Bl/6J mice were placed on a high-fat (60% kcal fat) diet for 12 wk, with or without sitagliptin (4 g/kg) as a food admix. Sitagliptin significantly reduced fasting blood glucose by 21% as well as insulin by ∼25%. Sitagliptin treatment reduced body weight without changes in overall body mass index or in the epididymal and retroperitoneal fat mass. However, sitagliptin treatment led to triple the number of small adipocytes despite reducing the number of the very large adipocytes. Sitagliptin significantly reduced inflammation in the adipose tissue and pancreatic islet. Macrophage infiltration in adipose tissue evaluated by immunostaining for Mac2 was reduced by sitagliptin ( P < 0.01), as was the percentage of CD11b+/F4/80+ cells in the stromal vascular fraction ( P < 0.02). Sitagliptin also reduced adipocyte mRNA expression of inflammatory genes, including IL-6, TNFα, IL-12(p35), and IL-12(p40), 2.5- to fivefold as well as 12-lipoxygenase protein expression. Pancreatic islets were isolated from animals after treatments. Sitagliptin significantly reduced mRNA expression of the following inflammatory cytokines: MCP-1 (3.3-fold), IL-6 (2-fold), IL-12(p40) (2.2-fold), IL-12(p35) (5-fold, P < 0.01), and IP-10 (2-fold). Collectively, the results indicate that sitagliptin has anti-inflammatory effects in adipose tissue and in pancreatic islets that accompany the insulinotropic effect.

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Section: Discussionmentioning

confidence: 99%

Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice

Dobrian¹,

Ma²,

Lindsay³

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

146

100

View full text Add to dashboard Cite

show abstract

“…However, the IL-12p40 homodimer has also been shown to antagonize IL-12p70 activity in murine (49) cells and human cell lines (50), which would argue for a rather antiinflammatory function for this subunit. Because associations have been described between increased serum levels of IL-12p70 and insulin resistance in humans (51,52), a reduction of IL-12p40 in serum could result in increased action of IL-12p70 and subsequent insulin resistance. In an attempt to translate our findings to systemic IL-12p40 levels, we measured serum IL-12p40 levels in 12 lean and 12 obese individuals.…”

Section: Discussionmentioning

confidence: 99%

Adipocytes Modulate the Phenotype of Human Macrophages through Secreted Lipids

Klein-Wieringa

Andersen

Kwekkeboom

et al. 2013

The Journal of Immunology

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Previous studies have shown accumulation and an enhanced proinflammatory profile of macrophages in adipose tissue of obese mice, indicating the presence of an interaction between adipocytes and macrophages in this tissue. However, the consequences of this interaction in humans are yet incompletely understood. In this study, we explored the modulating effects of adipocytes on the phenotype of macrophages in humans and studied the possible molecular pathways involved. Adipocyte-conditioned media (ACM) treatment of macrophages for 48 h strongly reduced the LPS-induced IL-12p40 secretion by macrophages, whereas the production of TNF-α and other cytokines remained largely unaffected. This effect was independent of the source of adipocytes. Interestingly, the level of inhibition correlated directly with body mass index (BMI) of the adipocyte donor. Because adipocytes release many different cytokines, adipokines, and lipids, we have separated the protein and lipid fractions of ACM, to obtain insight into the molecular nature of the soluble mediators underlying the observed effect. These experiments revealed that the inhibitory effect resided predominantly in the lipid fraction. Further studies revealed that PGE2 and linoleic and oleic acid were potent inhibitors of IL-12p40 secretion. Interestingly, concentrations of these ACM-derived lipids increased with increase in BMI of the adipocyte donor, suggesting that they could mediate the BMI-dependent effects of ACM. To our knowledge, these results provide first evidence that obesity-related changes in adipose tissue macrophage phenotype could be mediated by adipocyte-derived lipids in humans. Intriguingly, these changes appear to be different from those in murine obesity.

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“…In obesity, however, WAT recruits M1 macrophages that secrete proinflammatory cytokines such as TNF-a (13) and IL-12 (36)(37)(38).…”

Section: Endogenous Oils Enhance the Production Of Proinflammatory Cymentioning

confidence: 99%

Endogenous Oils Derived From Human Adipocytes Are Potent Adjuvants That Promote IL-1α–Dependent Inflammation

et al. 2014

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Obesity is characterized by chronic inflammation associated with neutrophil and M1 macrophage infiltration into white adipose tissue. However, the mechanisms underlying this process remain largely unknown. Based on the ability of oil-based adjuvants to induce immune responses, we hypothesized that endogenous oils derived from necrotic adipocytes may function as an immunological "danger signal." Here we show that endogenous oils of human origin are potent adjuvants, enhancing antibody responses to a level comparable to Freund's incomplete adjuvant. The endogenous oils were capable of promoting interleukin (IL)-1a-dependent recruitment of neutrophils and M1-like macrophages, while simultaneously diminishing M2-like macrophages. We found that endogenous oils from subcutaneous and omental adipocytes, and from healthy and unhealthy obese individuals, promoted comparable inflammatory responses. Furthermore, we also confirmed that white adipocytes in visceral fat of metabolically unhealthy obese (MUO) individuals are significantly larger than those in metabolically healthy obese individuals. Since adipocyte size is positively correlated with adipocyte death, we propose that endogenous oils have a higher propensity to be released from hypertrophied visceral fat in MUO individuals and that this is the key factor in driving inflammation. In summary, this study shows that adipocytes contain a potent oil adjuvant which drives IL1a-dependent proinflammatory responses in vivo.Obesity is characterized by chronic, low-grade inflammation resulting in insulin resistance. Understanding the mechanisms underlying this inflammation would provide valuable insights into the disease and potentially offer new therapeutic targets. Early studies showing that sodium salicylate can reverse the symptoms of type 2 diabetes (1) highlighted roles for inhibitor of kB kinase b (IKKb) and Jun N-terminal kinase (JNK) in this process. JNK can directly phosphorylate Serine307 on insulin receptor substrate 1, thus impairing insulin signaling and mediating obesity-induced insulin resistance (2). IKKb can also phosphorylate insulin receptor substrate 1 (3), and myeloid-specific deletion of IKKb in obese mice protects against insulin resistance (4). In addition, IKKbmediated translocation of nuclear factor-kB into the nucleus

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IL-12 serum levels in patients with type 2 diabetes treated with sulphonylureas

Cited by 58 publications

References 41 publications

Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice

Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice

Adipocytes Modulate the Phenotype of Human Macrophages through Secreted Lipids

Endogenous Oils Derived From Human Adipocytes Are Potent Adjuvants That Promote IL-1α–Dependent Inflammation

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