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

Hensen, J.; Howard, Craig D.; Walter, Verena; Thurén, Tom

doi:10.1016/j.diabet.2013.07.003

Cited by 100 publications

(65 citation statements)

References 26 publications

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“…To date, eight independent clinical studies conducted with an IL-1 receptor antagonist (anakinra) or IL-1b-specific antibody (gevokizumab, canakizumab, and LY21891020) have demonstrated beneficial effects on metabolic parameters including decreased HbA 1c and enhanced insulin sensitivity and b-cell secretory function, with concomitant improvement in inflammatory markers (82,(88)(89)(90)(91). In a double-blind, placebocontrolled, parallel-group study involving 70 patients with type 2 diabetes, IL-1 blockade with anakinra reduced HbA 1c , CRP, IL-6 levels, and the proinsulin-toinsulin ratio, while enhancing C-peptide secretion, indicating improved b-cell function; these beneficial effects persisted up to several weeks after treatment cessation (92).…”

Section: Anti-il-1bmentioning

confidence: 99%

Anti-inflammatory Agents in the Treatment of Diabetes and Its Vascular Complications

et al. 2016

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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, b-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, 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. 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 (4-12), 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.

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Section: Anti-il-1bmentioning

confidence: 99%

Anti-inflammatory Agents in the Treatment of Diabetes and Its Vascular Complications

et al. 2016

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“…This contributes to the formation of insulitis by recruiting and activating IL-1b-producing macrophages. Treatment of type 2 diabetes or obese patients with anakinra, the recombinant form of IL-1Ra, or specific anti-IL-1b antibodies improved glycemia and b-cell function and reduced circulating inflammatory indicators (29)(30)(31)(32)(33)(34).…”

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confidence: 99%

Angiotensin II Induces Interleukin-1β–Mediated Islet Inflammation and β-Cell Dysfunction Independently of Vasoconstrictive Effects

et al. 2014

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Pathological activation of the renin-angiotensin system (RAS) is associated with the metabolic syndrome, and the new onset of type 2 diabetes can be delayed by RAS inhibition. In animal models of type 2 diabetes, inhibition of the RAS improves insulin secretion. However, the direct effects of angiotensin II on islet function and underlying mechanisms independent of changes in blood pressure remain unclear. Here we show that exposure of human and mouse islets to angiotensin II induces interleukin (IL)-1-dependent expression of IL-6 and MCP-1, enhances b-cell apoptosis, and impairs mitochondrial function and insulin secretion. In vivo, mice fed a high-fat diet and treated with angiotensin II and the vasodilator hydralazine to prevent hypertension showed defective glucose-stimulated insulin secretion and deteriorated glucose tolerance. Application of an anti-IL-1b antibody reduced the deleterious effects of angiotensin II on islet inflammation, restored insulin secretion, and improved glycemia. We conclude that angiotensin II leads to islet dysfunction via induction of inflammation and independent of vasoconstriction. Our findings reveal a novel role for the RAS and an additional rationale for the treatment of type 2 diabetic patients with an IL-1b antagonist.Obesity and type 2 diabetes are related to hypertension and to increased activation of the renin-angiotensin system (RAS) (1-3). Multiple trials have shown that RAS blockade reduces the incidence of new-onset type 2 diabetes in high-risk populations (4). On the basis of several meta-analyses, this reduction ranges between 22% and 30% (5,6). In addition, in different animals models of type 2 diabetes, treatment with either angiotensinreceptor blockers or ACE inhibitors improves glucose tolerance and b-cell function (2,7-10). All of this suggests a role for angiotensin II in the development of type 2 diabetes.The RAS is classically known as a systemic hormonal system regulating blood pressure, fluid balance, and electrolyte absorption (11). Finding a local RAS in various tissues and organs such as brain, kidney (12), heart (13), liver, and adipose tissue (14) has expanded its role to diverse physiological functions in addition to its effects on circulation. All key components of the RAS also have been localized to the endocrine pancreas, including the precursor angiotensinogen and the angiotensin II type 1 receptor (15,16). Furthermore, obesity and hyperglycemia increases the expression of the local RAS in pancreatic islets (17), adipose tissue (18), and skeletal muscle.

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“…В связи с этим представляют интерес данные о важной роли ИЛ1 в пато-генезе СД 2-го типа и связанных с ним кардиоваскуляр-ных осложнений [32]. Предварительные результаты дру-гих исследований свидетельствуют о том, что на фоне ле-чения канакинумабом отмечено снижение концентрации Hb A1 и уменьшение числа и выра-женности признаков диабетической ретинопатии сетчатки [33][34][35]. К сожалению, различия в груп-пах пациентов, получавших канаки-нумаб и ПЛ, в отношении общей ле-тальности отсутствовали (р=0,31).…”

Section: канакинумабunclassified

Anti-Inflammatory Therapy for Atherosclerosis: Contribution to and Lessons of Rheumatology

Насонов¹,

Попкова²

2017

rsp

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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

Cited by 100 publications

References 26 publications

Anti-inflammatory Agents in the Treatment of Diabetes and Its Vascular Complications

Anti-inflammatory Agents in the Treatment of Diabetes and Its Vascular Complications

Angiotensin II Induces Interleukin-1β–Mediated Islet Inflammation and β-Cell Dysfunction Independently of Vasoconstrictive Effects

Anti-Inflammatory Therapy for Atherosclerosis: Contribution to and Lessons of Rheumatology

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