Autophagy defends pancreatic β cells from human islet amyloid polypeptide-induced toxicity

Rivera, Jacqueline; Costes, Safia; Gurlo, Tatyana; Glabe, Charles G.; Butler, Peter C.

doi:10.1172/jci71981

Cited by 198 publications

(184 citation statements)

References 54 publications

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“…We hypothesized that 1 mechanism might be the KEAP-1/nuclear factor erythroid-derived-2-related-factor (Nrf2)/antioxidant pathway, widely recognized as a prominent regulator of antioxidant enzyme gene expression (32)(33)(34)(35)(36). Several reports involving mouse models of diabetes appeared midway through our study and supported this possibility (6,(37)(38)(39). Our current work used Zucker diabetic fatty rats (ZDF rats) that are known to develop severe hyperglycemia and oxidative stress when fed a HFD (40).…”

Section: Introductionmentioning

confidence: 64%

Nrf2/antioxidant pathway mediates β cell self-repair after damage by high-fat diet–induced oxidative stress

Abebe¹,

Mahadevan²,

Bogachus³

et al. 2017

JCI Insight

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Section: Introductionmentioning

confidence: 64%

Nrf2/antioxidant pathway mediates β cell self-repair after damage by high-fat diet–induced oxidative stress

Abebe¹,

Mahadevan²,

Bogachus³

et al. 2017

JCI Insight

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“…Shigihara et al (6) demonstrated that the proliferation rate of β cells in vitro and in vivo is lowered when autophagy is defective, suggesting that autophagy regulates β cell division; however, they did not provide a mechanism for this effect. Rivera et al (7) showed that the IAPP present in p62-dependent vacuoles is exclusively nontoxic IAPP fibrils and did not identify insulin within the p62 inclusions. Moreover, Rivera and colleagues determined that enhanced oxidative stress induces β cell apoptosis in the human IAPP-expressing autophagy-deficient mice through reduction of nuclear factor erythroid-2-related factor 2 (NRF2), which induces antioxidant enzyme expression.…”

Section: Islet Amyloidmentioning

confidence: 98%

“…There are many additional mechanisms that have been proposed for β cell dysfunction and death in type 2 diabetes, including ER stress, oxidative stress, and autoimmune damage, all of which have been linked to IAPP toxicity (7,8,16). While it is tempting to try and connect the dots through a single, unified mechanism, all of these proposed pathways of β cell dysfunction have been recapitulated and extensively studied in rodent models of diabetogenic systems, such as high-fat feeding and partial pancreatectomy, or through genetic modification.…”

Section: Islet Amyloidmentioning

confidence: 99%

Islet amyloid and type 2 diabetes: overproduction or inadequate clearance and detoxification?

Gupta¹,

Leahy²

2014

J. Clin. Invest.

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C o m m e n t a r y 3 2 9 2 jci.org Volume 124 Number 8 August 2014Islet amyloid and type 2 diabetes: overproduction or inadequate clearance and detoxification?Dhananjay Gupta and Jack L. LeahyDivision of Endocrinology, Diabetes and Metabolism and Department of Medicine, University of Vermont, Burlington, Vermont, USA. Type 2 diabetes mellitus and the pancreatic islet β cellType 2 diabetes mellitus is a complex metabolic disorder that is comprised of defective insulin action in the periphery as well as within the liver and adipose tissue. Numerous cross-sectional and prospective studies have shown that what determines whether a person develops diabetes resides within their pancreatic β cells (1, 2). Insulin resistance is common in our modern society due to extenuating factors, including obesity, poor dietary and lifestyle habits, disordered sleep, and emotional stress. However, β cell compensation, the normal biological counter response of hyperinsulinemia, prevents most individuals from becoming diabetic. In turn, a defining feature of those at risk for type 2 diabetes is a defective β cell compensation response, with subtle β cell dysfunction evident even when blood glucose is still in the normal glucose tolerance range (1-3). As metabolic demands exceed an individual's capacity for β cell compensation, glucose levels rise along with the onset of a multidimensional pathogenic response in β cells that is likely driven by glucotoxicity, lipotoxicity, ER and oxidative stress, inflammation, and dedifferentiation. Once the pathogenic cascade is initiated, there is a progressive loss of β cell mass and function that results in worsening hyperglycemia and a waning response to therapy, which are both typical of this disease.Research into the mechanisms that promote β cell dysfunction has been performed mostly in isolated cells, cell lines, or animal models, given the inability to perform pancreas biopsies on healthy subjects for clinical research purposes. While these models are useful to probe the biology of the β cell pathogenic processes, it remains unclear which β cell dysfunction-promoting mechanism is most active for induction of the inadequate β cell compensation in human type 2 diabetes. Studies performed with isolated islets from brain-dead pancreas donors and pathological pancreas specimens -from nondiabetic and type 2 diabetic subjects -have provided evidence that supports multiple pathways for β cell dysfunction. Unfortunately, these studies lack the ability to identify the initial steps in this process that occur before the onset of diabetes and directly cause the β cell dysfunction. It is clear that both reduced β cell mass and lowered insulin secretory function are elements of the β cell pathophysiology of type 2 diabetes. Furthermore, a defective β cell compensation system, which predisposes patients to type 2 diabetes, is operative well before the diagnosis of abnormal blood glucose values by current criteria (1, 2). As such, the hunt continues for mechanisms for β cell dysfunction that are independen...

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“…6 Induced autophagy maintains the amino acid pool inside cells to adapt to starvation while constitutive autophagy has been shown to function as a cell-repair mechanism that is important for long-lived postmitotic cells. [7][8][9][10][11] Defects in autophagy have been associated with neurodegenerative diseases, [12][13][14][15] diabetes, 16,17 lysosomal storage disease 18 and the loss of vision. 19 In addition to macroautophagy, microautophagy and chaperone-mediated autophagy (CMA) have been described.…”

mentioning

confidence: 99%

Autophagy supports survival and phototransduction protein levels in rod photoreceptors

et al. 2015

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Damage and loss of the postmitotic photoreceptors is a leading cause of blindness in many diseases of the eye. Although the mechanisms of photoreceptor death have been extensively studied, few studies have addressed mechanisms that help sustain these non-replicating neurons for the life of an organism. Autophagy is an intracellular pathway where cytoplasmic constituents are delivered to the lysosomal pathway for degradation. It is not only a major pathway activated in response to cellular stress, but is also important for cytoplasmic turnover and to supply the structural and energy needs of cells. We examined the importance of autophagy in photoreceptors by deleting the essential autophagy gene Atg5 specifically in rods. Loss of autophagy led to progressive degeneration of rod photoreceptors beginning at 8 weeks of age such that by 44 weeks few rods remained. Cone photoreceptor numbers were only slightly diminished following rod degeneration but their function was significantly decreased. Rod cell death was apoptotic but was not dependent on daily light exposure or accelerated by intense light. Although the light-regulated translocation of the phototransduction proteins arrestin and transducin were unaffected in rods lacking autophagy, Atg5-deficient rods accumulated transducin-α as they degenerated suggesting autophagy might regulate the level of this protein.This was confirmed when the light-induced decrease in transducin was abolished in Atg5-deficient rods and the inhibition of autophagy in retinal explants cultures prevented its degradation. These results demonstrate that basal autophagy is essential to the long-term health of rod photoreceptors and a critical process for maintaining optimal levels of the phototransduction protein transducin-α. As the lack of autophagy is associated with retinal degeneration and altered phototransduction protein degradation in the absence of harmful gene products, this process may be a viable therapeutic target where rod cell loss is the primary pathologic event. Autophagy is an intracellular pathway where cytoplasmic constituents are delivered to the lysosomes for degradation. Defective autophagy can contribute to the age-dependent accumulation of damaged proteins and organelles leading to altered cellular homeostasis and loss of function. [1][2][3][4][5] The metabolic roles of autophagy can be classified into two types, basal and induced. In nutrient-rich conditions, autophagy is suppressed but still occurs at low levels (basal autophagy); however, when cells are subjected to stress (starvation, injury, hypoxia), autophagy is activated immediately (induced autophagy). 6 Induced autophagy maintains the amino acid pool inside cells to adapt to starvation while constitutive autophagy has been shown to function as a cell-repair mechanism that is important for long-lived postmitotic cells. 7-11 Defects in autophagy have been associated with neurodegenerative diseases, 12-15 diabetes, 16,17 lysosomal storage disease 18 and the loss of vision. 19 In addition to macroautophagy, m...

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Autophagy defends pancreatic β cells from human islet amyloid polypeptide-induced toxicity

Cited by 198 publications

References 54 publications

Nrf2/antioxidant pathway mediates β cell self-repair after damage by high-fat diet–induced oxidative stress

Nrf2/antioxidant pathway mediates β cell self-repair after damage by high-fat diet–induced oxidative stress

Islet amyloid and type 2 diabetes: overproduction or inadequate clearance and detoxification?

Autophagy supports survival and phototransduction protein levels in rod photoreceptors

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