β Cell–specific increased expression of calpastatin prevents diabetes induced by islet amyloid polypeptide toxicity

Gurlo, Tatyana; Costes, Safia; Hoang, Jonathan D.; Rivera, Jacqueline; Butler, Alexandra E.; Butler, Peter C.

doi:10.1172/jci.insight.89590

Cited by 17 publications

(16 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pseudo-hypoxic activation of HIF1α may occur due to mitochondrial dysfunction or adaptive quiescence of mitochondria to protect the mitochondrial network, as previously described in response to increased cytosolic Ca 2+ 26 . It is of interest that β-cells in T2D are characterized by a fragmented mitochondrial network, altered mitochondrial function, and disrupted Ca 2+ dynamics 4,7,11 . Therefore, we next sought to examine the impact of hIAPP toxicity on the mitochondrial network and β-cell function.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

IAPP toxicity activates HIF1α/PFKFB3 signaling delaying β-cell loss at the expense of β-cell function

Montemurro¹,

Nishimura²,

Pei³

et al. 2019

Nat Commun

Self Cite

View full text Add to dashboard Cite

The islet in type 2 diabetes (T2D) is characterized by amyloid deposits derived from islet amyloid polypeptide (IAPP), a protein co-expressed with insulin by β-cells. In common with amyloidogenic proteins implicated in neurodegeneration, human IAPP (hIAPP) forms membrane permeant toxic oligomers implicated in misfolded protein stress. Here, we establish that hIAPP misfolded protein stress activates HIF1α/PFKFB3 signaling, this increases glycolysis disengaged from oxidative phosphorylation with mitochondrial fragmentation and perinuclear clustering, considered a protective posture against increased cytosolic Ca 2+ characteristic of toxic oligomer stress. In contrast to tissues with the capacity to regenerate, β-cells in adult humans are minimally replicative, and therefore fail to execute the second pro-regenerative phase of the HIF1α/PFKFB3 injury pathway. Instead, β-cells in T2D remain trapped in the pro-survival first phase of the HIF1α injury repair response with metabolism and the mitochondrial network adapted to slow the rate of cell attrition at the expense of β-cell function.

show abstract

Section: Resultsmentioning

confidence: 99%

“…In common with other protein misfolding diseases, the most toxic forms of IAPP aggregates are small membrane permeant oligomers 4–6 . These oligomers are considered the likely cause of aberrant Ca 2+ signaling manifest as calpain hyperactivation characteristic of cells affected by misfolded proteins 7–10 .…”

Section: Introductionmentioning

confidence: 99%

IAPP toxicity activates HIF1α/PFKFB3 signaling delaying β-cell loss at the expense of β-cell function

Montemurro¹,

Nishimura²,

Pei³

et al. 2019

Nat Commun

Self Cite

View full text Add to dashboard Cite

show abstract

“…Autophagy has been suggested as a defending mechanism in β cells against the proteotoxicity of amylin, and a known dysfunction of the ALP in T2D may further contribute to detrimental effects [148, 149]. Interestingly, toxic amylin oligomers were shown to lead to intracellular membrane disruption, increased cytoplasmic Ca 2+ concentrations, and, consequently, overactivation of the calpain system, specifically calpain-2, in cell models, mice, and pancreatic tissues from humans with T2D [150, 151]. This overactivation ultimately leads to critical autophagic dysfunctions [150].…”

Section: Calpains and Autophagy In Neurodegeneration And Other Medmentioning

confidence: 99%

“…Interestingly, toxic amylin oligomers were shown to lead to intracellular membrane disruption, increased cytoplasmic Ca 2+ concentrations, and, consequently, overactivation of the calpain system, specifically calpain-2, in cell models, mice, and pancreatic tissues from humans with T2D [150, 151]. This overactivation ultimately leads to critical autophagic dysfunctions [150].…”

Section: Calpains and Autophagy In Neurodegeneration And Other Medmentioning

confidence: 99%

“…Typical genetic strategies comprise the overexpression of the endogenous calpain inhibitor CAST, or the knockdown and knockout of calpain isoforms as well as of CSS1. In a human IAPP transgenic mouse model of T2D, overexpression of CAST was shown to be protective against the loss and dysfunction of pancreatic β cells and preventing diabetes onset by restoring the vital ALP [150]. Moreover, the intravitreal injection of siRNA directed against CSS1 reduced calpain activation and beclin-1 cleavage in an in vivo model for retinal ischemic injuries [136].…”

Section: Calpains and Autophagy In Neurodegeneration And Other Medmentioning

confidence: 99%

See 1 more Smart Citation

Killing Two Angry Birds with One Stone: Autophagy Activation by Inhibiting Calpains in Neurodegenerative Diseases and Beyond

Weber

Sena

Singer

et al. 2019

BioMed Research International

View full text Add to dashboard Cite

Proteolytic machineries execute vital cellular functions and their disturbances are implicated in diverse medical conditions, including neurodegenerative diseases. Interestingly, calpains, a class of Ca2+-dependent regulatory proteases, can modulate the degradational system of autophagy by cleaving proteins involved in this pathway. Moreover, both machineries are common players in many molecular pathomechanisms and have been targeted individually or together, as a therapeutic strategy in experimental setups. In this review, we briefly introduce calpains and autophagy, with their roles in health and disease, and focus on their direct pathologically relevant interplay in neurodegeneration and beyond. The modulation of calpain activity may comprise a promising treatment approach to attenuate the deregulation of these two essential mechanisms.

show abstract

Islet amyloid toxicity: From genesis to counteracting mechanisms

Marmentini

Branco

Boschero

et al. 2021

Journal Cellular Physiology

View full text Add to dashboard Cite

Islet amyloid polypeptide (IAPP or amylin) is a hormone co-secreted with insulin by pancreatic β-cells and is the major component of islet amyloid. Islet amyloid is found in the pancreas of patients with type 2 diabetes (T2D) and may be involved in β-cell dysfunction and death, observed in this disease. Thus, investigating the aspects related to amyloid formation is relevant to the development of strategies towards β-cell protection. In this sense, IAPP misprocessing, IAPP overproduction, and disturbances in intra-and extracellular environments seem to be decisive for IAPP to form islet amyloid. Islet amyloid toxicity in β-cells may be triggered in intra-and/or extracellular sites by membrane damage, endoplasmic reticulum stress, autophagy disruption, mitochondrial dysfunction, inflammation, and apoptosis. Importantly, different approaches have been suggested to prevent islet amyloid cytotoxicity, from inhibition of IAPP aggregation to attenuation of cell death mechanisms. Such approaches have improved β-cell function and prevented the development of hyperglycemia in animals. Therefore, counteracting islet amyloid may be a promising therapy for T2D treatment.

show abstract

β Cell–specific increased expression of calpastatin prevents diabetes induced by islet amyloid polypeptide toxicity

Cited by 17 publications

References 59 publications

IAPP toxicity activates HIF1α/PFKFB3 signaling delaying β-cell loss at the expense of β-cell function

IAPP toxicity activates HIF1α/PFKFB3 signaling delaying β-cell loss at the expense of β-cell function

Killing Two Angry Birds with One Stone: Autophagy Activation by Inhibiting Calpains in Neurodegenerative Diseases and Beyond

Islet amyloid toxicity: From genesis to counteracting mechanisms

Contact Info

Product

Resources

About