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

Sauter, Nadine S.; Thienel, Constanze; Plutino, Yuliya; Kampe, Kapil; Dror, Erez; Traub, Shuyang; Timper, Katharina; Bédat, Benoît; Pattou, François; Kerr–Conte, Julie; Jehle, Andreas W.; Böni-Schnetzler, Marianne; Donath, Marc Y.

doi:10.2337/db14-1282

Cited by 55 publications

(60 citation statements)

References 54 publications

(59 reference statements)

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“…The high abundance of IL-1R1 on β-cells is likely the reason for higher sensitivity of β-cells to IL-1 action as compared to other islet cells [17], [18]. The contributing factors to islet inflammation and increased IL-1β levels in T2D are still not completely understood, but it appears that multiple factors such as elevated glucose, fatty acids, angiotensin II, and amyloid formation may contribute to this process [11], [12], [13], [14], [18], [19].…”

Section: Introductionmentioning

confidence: 99%

Amyloid formation disrupts the balance between interleukin-1β and interleukin-1 receptor antagonist in human islets

Hui

Asadi

Park

et al. 2017

Molecular Metabolism

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Objectivesβ-cell dysfunction and apoptosis associated with islet inflammation play a key role in the pathogenesis of type 2 diabetes (T2D). Growing evidence suggests that islet amyloid, formed by aggregation of human islet amyloid polypeptide (hIAPP), contributes to islet inflammation and β-cell death in T2D. We recently showed the role of interleukin-1β (IL-1β)/Fas/caspase-8 apoptotic pathway in amyloid-induced β-cell death. In this study, we used human islets in culture as an ex vivo model of amyloid formation to: (1) investigate the effects of amyloid on islet levels of the natural IL-1 receptor antagonist (IL-1Ra); (2) examine if modulating the IL-1β/IL-1Ra balance can prevent amyloid-induced β-cell Fas upregulation and apoptosis.MethodsIsolated human islets (n = 10 donors) were cultured in elevated glucose (to form amyloid) with or without a neutralizing human IL-1β antibody for up to 7 days. Parallel studies were performed with human islets in which amyloid formation was prevented by adeno-siRNA-mediated suppression of hIAPP expression (as control). β-cell levels of IL-1Ra, Fas, apoptosis as well as islet function, insulin- and amyloid-positive areas, and IL-1Ra release were assessed.ResultsProgressive amyloid formation in human islets during culture was associated with alterations in IL-1Ra. Islet IL-1Ra levels were higher at early stages but were markedly reduced at later stages of amyloid formation. Furthermore, IL-1Ra release from human islets was reduced during 7-day culture in a time-dependent manner. These changes in IL-1Ra production and release from human islets during amyloid formation adversely correlated with islet IL-1β levels, β-cell Fas expression and apoptosis. Treatment with IL-1β neutralizing antibody markedly reduced amyloid-induced β-cell Fas expression and apoptosis, thereby improving islet β-cell survival and function during culture.ConclusionsThese data suggest that amyloid formation impairs the balance between IL-1β and IL-1Ra in islets by increasing IL-1β production and reducing IL-1Ra levels thereby promoting β-cell dysfunction and death. Restoring the IL-1β/IL-1Ra ratio may provide an effective strategy to protect islet β-cells from amyloid toxicity in T2D.

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Section: Introductionmentioning

confidence: 99%

Amyloid formation disrupts the balance between interleukin-1β and interleukin-1 receptor antagonist in human islets

Hui

Asadi

Park

et al. 2017

Molecular Metabolism

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“…However, it is unclear if this improved glycemic control is a result of the normalization of vasoconstriction in tissues (e.g., muscle and pancreas) or due to the local inhibition of RAS. Sauter et al (17) show that chronic treatment with angiotensin II in high fat-fed mice that also received the vasodilator hydralazine (to prevent hypertension) caused impaired glucose-stimulated insulin secretion and deteriorated glucose tolerance that was not due to the changes in insulin sensitivity, supporting the direct effects of angiotensin II on b-cell function. Interestingly, neutralizing IL-1b signaling reduced angiotensin II-mediated islet inflammation, restored glucose-stimulated insulin secretion, and improved glucose homeostasis.…”

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confidence: 99%

“…In this issue of Diabetes, Sauter et al (17) report another interesting mechanism that contributes to islet inflammation and local IL-1b production in patients with T2D. Using in vitro islet studies and a mouse model of T2D, the authors show that the renin-angiotensin system (RAS), a major system in blood pressure regulation, contributes to islet inflammation and b-cell dysfunction independent of its effects on glucose homeostasis mediated via vasoconstriction.…”

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confidence: 99%

New Insights Into the Mechanisms of Islet Inflammation in Type 2 Diabetes

Marzban

2015

Diabetes

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Impaired function and reduced mass of pancreatic islet b-cells are two hallmarks of type 2 diabetes (T2D) (1,2). However, clinical onset of T2D does not occur until b-cells fail to secrete sufficient insulin to maintain normoglycemia in the face of insulin resistance (1,2). While studies performed on isolated human islets have identified multiple pathways that may contribute to b-cell failure in T2D, these studies lack the ability to investigate the initial steps that occur in vivo before or at early stages of onset of T2D and the sequence of events that result in b-cell failure in patients with T2D.Growing evidence from recent studies suggests that chronic islet inflammation, in addition to its key role in the pathogenesis of type 1 diabetes, also plays an important role in b-cell dysfunction and failure in T2D (3-9). Impaired b-cell function precedes the clinical onset of T2D, suggesting an early role for islet inflammation in the process of b-cell failure in this disease. The association between chronic activation of the innate immune system and T2D has long been appreciated (10) but recently has gained high attention due to increasing evidence supporting its importance. The elevated number of islet-associated macrophages and increased expression of interleukin (IL)-1b have been reported in the pancreatic islets from patients with T2D (4,11). Moreover, it was recently demonstrated that depletion of resident islet macrophages in high fat-fed transgenic mice with islet amyloid formation can reduce IL1b expression, improve b-cell insulin secretion, and restore glucose tolerance (8). Accordingly, animal studies and clinical trials targeting IL-1b signaling have been shown to improve b-cell function and glucose homeostasis in T2D (12)(13)(14). Taken together, these findings support the idea that IL-1b is likely a key proinflammatory mediator of b-cell damage in T2D. Thus, identifying the factors that contribute to local generation of IL-1b in the islets of patients with T2D is of great interest.Increased islet IL-1b levels have been reported following chronic exposure of human islets to elevated glucose, fatty acids, or leptin-three factors that are closely associated with T2D (3,15,16). Moreover, it was recently shown that biosynthetic amyloid formation in human islets causes b-cell dysfunction and death via induction of Fas upregulation and activation of the Fas-mediated apoptotic pathway initiated by caspase-8, which closely correlates with increased islet IL-1b levels (6,9). These studies provided evidence that amyloid-induced Fas upregulation is likely mediated by IL-1b. In line with these findings, Westwell-Roper et al. (8) have reported b-cell dysfunction associated with increased islet IL-1b expression in high fat-fed transgenic mice with islet amyloid formation. These findings support the idea that local IL-1b production, likely induced by multiple factors during prediabetic state and/or early stages of T2D, may play a key role in b-cell failure in T2D. However, other factors that contribute to this proce...

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“…In a recent study, it was reported that a 4 week chronic infusion of angiotensin II impaired glucose tolerance in vivo and abolished glucose stimulated insulin secretion independent of changes in blood pressure (86). Angiotensin II also had deleterious effects on pancreatic islet mitochondrial function and insulin secretion due to IL-1β and NF-κB mediated inflammation in islets (86).…”

Section: Relevance To Shock Trauma and Critical Illnessmentioning

confidence: 99%

“…Angiotensin II also had deleterious effects on pancreatic islet mitochondrial function and insulin secretion due to IL-1β and NF-κB mediated inflammation in islets (86). Since components of the RAS, including angiotensin-converting enzyme 2 (ACE2), are found in rodent and human pancreatic islets (87–89), and overexpression of ACE2 in pancreas of diabetic mice improve glycemic control (89), the efficacy of RAS blockade to ameliorate insulin resistance in burn injury may also be due to improvements in pancreatic islet function.…”

Section: Relevance To Shock Trauma and Critical Illnessmentioning

confidence: 99%

Pancreatic Islet Responses to Metabolic Trauma

Burke

Karlstad

Collier

2016

Shock

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Carbohydrate, lipid, and protein metabolism are largely controlled by the interplay of various hormones, which includes those secreted by the pancreatic islets of Langerhans. While typically representing only 1–2% of the total pancreatic mass, the islets have a remarkable ability to adapt to disparate situations demanding a change in hormone release, such as peripheral insulin resistance. There are many different routes to the onset of insulin resistance, including obesity, lipodystrophy, glucocorticoid excess, and the chronic usage of atypical anti-psychotic drugs. All of these situations are coupled to an increase in pancreatic islet size, often with a corresponding increase in insulin production. These adaptive responses within the islets are ultimately intended to maintain glycemic control and to promote macronutrient homeostasis during times of stress. Herein, we review the consequences of specific metabolic trauma that lead to insulin resistance and the corresponding adaptive alterations within the pancreatic islets.

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

Cited by 55 publications

References 54 publications

Amyloid formation disrupts the balance between interleukin-1β and interleukin-1 receptor antagonist in human islets

Amyloid formation disrupts the balance between interleukin-1β and interleukin-1 receptor antagonist in human islets

New Insights Into the Mechanisms of Islet Inflammation in Type 2 Diabetes

Pancreatic Islet Responses to Metabolic Trauma

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