Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress

Hasnain, Sumaira Z.; Borg, Danielle J.; Harcourt, Brooke E.; Tong, Hui; Sheng, Yonghua; Ng, Choa Ping; Das, Indrajit; Wang, Ran; Chen, Alice C.‐H.; Loudovaris, Thomas; Kay, Thomas W. H.; Thomas, Helen E.; Whitehead, Jonathan P.; Forbes, Josephine M.; Prins, Johannes B.; McGuckin, Michael A.

doi:10.1038/nm.3705

Cited by 221 publications

(302 citation statements)

References 68 publications

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“…New approaches or improved agents are required to suppress oxidative stress. For example, we have found that the cytokine, IL‐22, drives a robust natural anti‐oxidant programme in secretory cells,113 including respiratory epithelial cells, potentially providing a more effective mechanism to protect cells from both environmental and intrinsically‐generated ROS/RNS.…”

Section: Therapeutic Approaches To Resolve Oxidative and Er Stress Inmentioning

confidence: 99%

Oxidative and endoplasmic reticulum stress in respiratory disease

2018

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Oxidative stress and endoplasmic reticulum (ER) stress are related states that can occur in cells as part of normal physiology but occur frequently in diseases involving inflammation. In this article, we review recent findings relating to the role of oxidative and ER stress in the pathophysiology of acute and chronic nonmalignant diseases of the lung, including infections, cystic fibrosis, idiopathic pulmonary fibrosis and asthma. We also explore the potential of drugs targeting oxidative and ER stress pathways to alleviate disease.

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Section: Therapeutic Approaches To Resolve Oxidative and Er Stress Inmentioning

confidence: 99%

Oxidative and endoplasmic reticulum stress in respiratory disease

2018

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“…In prediabetes and the early phases of diabetes, insulin hypersecretion is evident with progressive serum hyperinsulinaemia and hyperproinsulinaemia. Similarly, mice fed high fat diets show serum hyperinsulinaemia and hyperproinsulinaemia, and their islets hypersecrete insulin on ex vivo glucose challenge (Hasnain et al 2014). In chronic ER stress, quality control mechanisms that retain misfolded proteins in the ER are relaxed or overwhelmed, allowing misfolded proteins to move to the Golgi and be packaged for secretion .…”

Section: Intrinsic Er Functionsmentioning

confidence: 99%

“…As discussed above, the chronic ER stress that develops with prediabetes and early diabetes is associated with increasing serum insulin, which is typically accompanied by decreasing intracellular stores of insulin in b-cells (Hasnain et al 2014). Under these conditions, the b-cells are manufacturing large quantities of insulin under suboptimal conditions within the ER and almost continuously secreting some insulin, although secretion still surges post-prandially.…”

Section: Increased Insulin Biosynthesismentioning

confidence: 99%

Oxidative and endoplasmic reticulum stress in β-cell dysfunction in diabetes

Hasnain¹,

Prins²,

McGuckin³

2015

Journal of Molecular Endocrinology

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The inability of pancreatic b-cells to make sufficient insulin to control blood sugar is a central feature of the aetiology of most forms of diabetes. In this review we focus on the deleterious effects of oxidative stress and endoplasmic reticulum (ER) stress on b-cell insulin biosynthesis and secretion and on inflammatory signalling and apoptosis with a particular emphasis on type 2 diabetes (T2D). We argue that oxidative stress and ER stress are closely entwined phenomena fundamentally involved in b-cell dysfunction by direct effects on insulin biosynthesis and due to consequences of the ER stress-induced unfolded protein response. We summarise evidence that, although these phenomenon can be driven by intrinsic b-cell defects in rare forms of diabetes, in T2D b-cell stress is driven by a range of local environmental factors including increased drivers of insulin biosynthesis, glucolipotoxicity and inflammatory cytokines. We describe our recent findings that a range of inflammatory cytokines contribute to b-cell stress in diabetes and our discovery that interleukin 22 protects b-cells from oxidative stress regardless of the environmental triggers and can correct much of diabetes pathophysiology in animal models. Finally we summarise evidence that b-cell dysfunction is reversible in T2D and discuss therapeutic opportunities for relieving oxidative and ER stress and restoring glycaemic control.

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“…There is some evidence that secreted insulin from high-fat diet-induced obese C57BL/6 (HFDIO) mice islets is less functional in insulin bioassays (10), such that functional quality of secreted insulin deserves more attention. Furthermore, within the same study, treatment of the HFDIO mice with the anti-inflammatory interleukin-22 improved the degree of hyperinsulinemia, the pattern of glucose-stimulated insulin release, and the quality of the insulin released, suggesting that pharmacological interventions aimed at reducing islet b-cell inflammation may have the potential to reverse proinsulin processing defects (10). Insulin hypersecretion has been proposed as a causative factor for type 2 diabetes and obesity, as well as a risk factor for islet b-cell failure, such that therapies to prevent this may be protective (11)(12)(13)(14).…”

Section: Diabetesdiabetesjournalsorgmentioning

confidence: 99%

Reversibility of Defects in Proinsulin Processing and Islet β-Cell Failure in Obesity-Related Type 2 Diabetes

Nolan

Delghingaro-Augusto

2016

Diabetes

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Islet b-cell failure is mostly progressive in type 2 diabetes, resulting in the need for serial escalations in glucoselowering therapies for many patients with this condition (1-4). This failure is a consequence of impaired b-cell function and loss of b-cell mass, with varying contributions of each likely to relate to the heterogeneity in causative factors from patient to patient (1-5). It is a commonly held view that impaired proinsulin synthesis contributes to the b-cell dysfunction aspect of b-cell failure (1,2). This can be a consequence of the endoplasmic reticulum (ER) stress response that inhibits protein synthesis (including proinsulin) and/or b-cell dedifferentiation in which the expression of the essential elements required for a mature b-cell function, including the transcription of the insulin gene, are reduced or absent (1,2).In this issue of Diabetes, however, Alarcon et al. (6) convincingly show that islet b-cell proinsulin synthesis is increased rather than decreased in two obese mouse models of type 2 diabetes. They do find severe depletion in the number of mature insulin granules in the b-cells of these obese diabetic mice, but the evidence is that this results from accelerated, dysfunctional proinsulin processing and trafficking rather than the consequence of deficient proinsulin synthesis (6). Furthermore, these defects can be rapidly reversed by a short period of b-cell rest, at least in vitro (6). These findings are important, as reversibility of this form of islet b-cell dysfunction, if better understood, may lead to improved approaches for the prevention of progressive b-cell failure in affected patients with type 2 diabetes.Alarcon et al. (6) used the C57BL/6J db/db and the C57BLKS/J db/db obese diabetic mouse models (referred to hereon as 6J db/db and KS db/db ), the difference between them being that KS db/db , compared with 6J db/db mice, are less able to compensate for insulin resistance by b-cell mass expansion. At 16 weeks of age, both db/db strains were shown to have diabetes with fasting hyperglycemia and hyperinsulinemia. Following an intraperitoneal glucose load, however, only the 6J db/db mice were able to mount a glucose-stimulated insulin secretory response, indicating that 6J db/db mice have less severe islet failure than KS db/db mice (6). The fasting hyperinsulinemia of both these obese mouse strains, however, is consistent with them having some capacity to synthesize and release insulin, even though this is poorly regulated.Ultrastructural analysis of the islet b-cells of both db/db mouse strains showed marked reduction in the number of mature insulin granules, an increased number of immature granules, and the expansion of both the Golgi apparatus and the ER (6). Also seen were some very complex multivesicular bodies (MVBs), which are elaborated on further in the Supplementary Data online (see ref. 6) using elegant tomographic electron microscopy methods. The authors speculate that the appearance of these MVBs may be a consequence of increased requirements for membrane b...

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Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress

Cited by 221 publications

References 68 publications

Oxidative and endoplasmic reticulum stress in respiratory disease

Oxidative and endoplasmic reticulum stress in respiratory disease

Oxidative and endoplasmic reticulum stress in β-cell dysfunction in diabetes

Reversibility of Defects in Proinsulin Processing and Islet β-Cell Failure in Obesity-Related Type 2 Diabetes

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