Glucose-induced β cell production of IL-1β contributes to glucotoxicity in human pancreatic islets

Maedler, Kathrin; Сергеев, П. В.; Ris, Frédéric; Oberholzer, José; Joller‐Jemelka, H. I.; Spinas, Giatgen A.; Kaiser, Nurit; Halban, Philippe A.; Donath, Marc Y.

doi:10.1172/jci200215318

Cited by 1,012 publications

(459 citation statements)

References 56 publications

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“…However, the inflammatory pathway is better represented in islet cell death in autoimmune type 1 diabetes than in T2DM. Increased expression of IL-1β has been observed in islets in T2DM (Boni-Schnetzler et al 2008) and associated with glucotoxicity (Maedler et al 2002). These data suggest that inflammation could be a factor in the pathogenesis of type 2 diabetes (Donath & Shoelson 2011).…”

Section: Cellular Pathways Of Cytotoxicitymentioning

confidence: 97%

The β-cell assassin: IAPP cytotoxicity

Raleigh

Zhang

Hastoy

et al. 2017

Journal of Molecular Endocrinology

118

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Islet amyloid polypeptide (IAPP) forms cytotoxic oligomers and amyloid fibrils in islets in type 2 diabetes (T2DM). The causal factors for amyloid formation are largely unknown. Mechanisms of molecular folding and assembly of human IAPP (hIAPP) into β-sheets, oligomers and fibrils have been assessed by detailed biophysical studies of hIAPP and non-fibrillogenic, rodent IAPP (rIAPP); cytotoxicity is associated with the early phases (oligomers/multimers) of fibrillogenesis. Interaction with synthetic membranes promotes β-sheet assembly possibly via a transient α-helical molecular conformation. Cellular hIAPP cytotoxicity can be activated from intracellular or extracellular sites. In transgenic rodents overexpressing hIAPP, intracellular pro-apoptotic signals can be generated at different points in β-cell protein synthesis. Increased cellular trafficking of proIAPP, failure of the unfolded protein response (UPR) or excess trafficking of misfolded peptide via the degradation pathways can induce apoptosis; these data indicate that defects in intracellular handling of hIAPP can induce cytotoxicity. However, there is no evidence for IAPP overexpression in T2DM. Extracellular amyloidosis is directly related to the degree of β-cell apoptosis in islets in T2DM. IAPP fragments, fibrils and multimers interact with membranes causing disruption in vivo and in vitro. These findings support a role for extracellular IAPP in β-sheet conformation in cytotoxicity. Inhibitors of fibrillogenesis are useful tools to determine the aberrant mechanisms that result in hIAPP molecular refolding and islet amyloidosis. However, currently, their role as therapeutic agents remains uncertain.

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Section: Cellular Pathways Of Cytotoxicitymentioning

confidence: 97%

The β-cell assassin: IAPP cytotoxicity

Raleigh

Zhang

Hastoy

et al. 2017

Journal of Molecular Endocrinology

118

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“…We focused on hsCRP, IL6, IL1Ra and adiponectin as pro-and anti-inflammatory biomarkers because of their well-established associations with incident type 2 diabetes in prospective studies (1, 2, 31). Based on experimental data and other epidemiological studies, cytokines such as IL1β (32,33,34), tumour necrosis factor (TNF)-α (35,36) and transforming growth factor (TGF)-β (37,38) and chemokines such as monocyte chemoattractant protein-1/chemokine (C-C motif) ligand 2 (MCP-1/CCL2) (39,40) undoubtedly represent interesting candidates because of their impact on insulin sensitivity and/or beta-cell function. However, circulating levels of IL1β are below the limit of detection for a large proportion of individuals in population-based studies with currently available assays, and experimental data on TNFα and insulin resistance do not appear to be translated into an association between circulating levels of this protein and risk of type 2 diabetes in cohort studies (41,42).…”

Section: Strengths and Limitationsmentioning

confidence: 99%

Biomarkers of subclinical inflammation and increases in glycaemia, insulin resistance and beta-cell function in non-diabetic individuals: the Whitehall II study

Herder

Færch

Carstensen‐Kirberg

et al. 2016

European Journal of Endocrinology

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Objective: Higher systemic levels of pro-inflammatory biomarkers and low adiponectin are associated with increased risk of type 2 diabetes, but their associations with changes in glycaemic deterioration before onset of diabetes are poorly understood. We aimed to study whether inflammation-related biomarkers are associated with 5-year changes in glucose and insulin, HbA1c, insulin sensitivity and beta-cell function before the diagnosis of type 2 diabetes and whether these associations may be bidirectional. Design and methods: We used multiple repeat measures (17 891 person-examinations from 7683 non-diabetic participants) from the Whitehall II study to assess whether circulating high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL6), IL1 receptor antagonist (IL1Ra) and adiponectin are associated with subsequent changes in glycaemia, insulin, insulin resistance and beta-cell function (based on oral glucose tolerance tests). We examined bidirectionality by testing if parameters of glucose metabolism at baseline are associated with changes in inflammation-related biomarkers. Results: Higher hsCRP and IL6 were associated with increases in fasting insulin, insulin resistance and, for IL6, with beta-cell function after adjustment for confounders. Higher adiponectin was associated with decreases in fasting glucose, HbA1c, fasting insulin, insulin resistance and beta-cell function. The reverse approach showed that 2-h glucose and insulin sensitivity were associated with changes in IL1Ra. Fasting insulin and insulin resistance showed inverse associations with changes in adiponectin. Conclusions: Subclinical inflammation is associated with development of increased glycaemia, insulin resistance and beta-cell function in non-diabetic individuals. These findings are consistent with the hypothesis that inflammationrelated processes may increase insulin resistance and lead to a compensatory upregulation of beta-cell function. European Journal of Endocrinology175:5 368 Clinical Study C Herder and others Inflammation and glucose metabolism

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“…Recombinant IL-1Ra protects from glucose-induced apoptosis and improves β-cell function (fig. 3) [39]. Therefore, the balance between IL-1 and its naturally occurring antagonist IL-1Ra is likely to be central to the pathogenesis of both type 1 and type 2 diabetes [40].…”

Section: The Interplay Of Interleukin (Il)-1β and Il-1 Receptor Antagmentioning

confidence: 99%

β-Cells in Type 2 Diabetes: A Loss of Function and Mass

Maedler

Donath²

2004

Horm Res Paediatr

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Type 2 diabetes mellitus manifests itself in individuals who lose the ability to produce sufficient amounts of insulin to maintain normoglycaemia in the face of insulin resistance. The ability to secrete adequate amounts of insulin depends on β-cell function and mass. Chronic hyperglycaemia is detrimental to pancreatic β-cells, causing impaired insulin secretion and playing an essential role in the regulation of β-cell turnover. This paper will address the effect of chronically elevated glucose levels on β-cell turnover and function. In previous studies we have shown that elevated glucose concentrations induce apoptosis in human β-cells due to an interaction between constitutively expressed Fas ligand and upregulated Fas. Human β-cells produce interleukin (IL)-1β in response to high glucose concentrations, independently of an immune-mediated process. This was antagonized by the IL-1 receptor antagonist (IL-1Ra), a naturally occurring anti-inflammatory cytokine also found in the β-cell. Therefore the balance of IL-1β and IL-1Ra may play a crucial role in the pathogenesis of diabetes. Inhibition of glucotoxicity represents a promising therapeutic stratagem in diabetes therapy to preserve functional β-cell mass.

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Glucose-induced β cell production of IL-1β contributes to glucotoxicity in human pancreatic islets

Cited by 1,012 publications

References 56 publications

The β-cell assassin: IAPP cytotoxicity

The β-cell assassin: IAPP cytotoxicity

Biomarkers of subclinical inflammation and increases in glycaemia, insulin resistance and beta-cell function in non-diabetic individuals: the Whitehall II study

β-Cells in Type 2 Diabetes: A Loss of Function and Mass

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