Inhibition of Insulin-Degrading Enzyme Does Not Increase Islet Amyloid Deposition in Vitro

Islet amyloid deposition in human type 2 diabetes results in β-cell loss. These amyloid deposits contain the unique amyloidogenic peptide human islet amyloid polypeptide (hIAPP), which is also a known substrate of the protease insulin-degrading enzyme (IDE). Whereas IDE inhibition has recently been demonstrated to improve glucose metabolism in mice, inhibiting it has also been shown to increase cell death when synthetic hIAPP is applied exogenously to a β-cell line. Thus, we wanted to determine whether a similar deleterious effect is observed when hIAPP is endogenously produced and secreted from islets. To address this issue, we cultured hIAPP transgenic mouse islets that have the propensity to form amyloid for 48 and 144 hours in 16.7 mM glucose in the presence and absence of the IDE inhibitor 1. At neither time interval did IDE inhibition increase amyloid formation or β-cell loss. Thus, the inhibition of IDE may represent an approach to improve glucose metabolism in human type 2 diabetes, without inducing amyloid deposition and its deleterious effects.

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β-Cell Loss and β-Cell Apoptosis in Human Type 2 Diabetes Are Related to Islet Amyloid Deposition

American Journal Of Pathology ◽

10.1016/j.ajpath.2011.02.036 ◽

2011 ◽

Vol 178 (6) ◽

pp. 2632-2640 ◽

Cited By ~ 179

Author(s):

Catherine A. Jurgens ◽

Mirna N. Toukatly ◽

Corinne L. Fligner ◽

Jayalakshmi Udayasankar ◽

Shoba L. Subramanian ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cell Apoptosis ◽

Cell Loss ◽

Amyloid Deposition ◽

Β Cell ◽

Islet Amyloid ◽

Human Type

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Up-Regulated Pancreatic Tissue MicroRNA-375 Associates With Human Type 2 Diabetes Through β-Cell Deficit and Islet Amyloid Deposition

Pancreas ◽

10.1097/mpa.0b013e3181d12613 ◽

2010 ◽

Vol 39 (6) ◽

pp. 843-846 ◽

Cited By ~ 67

Author(s):

Hailu Zhao ◽

Jing Guan ◽

Heung-Man Lee ◽

Yi Sui ◽

Lan He ◽

...

Keyword(s):

Type 2 Diabetes ◽

Pancreatic Tissue ◽

Amyloid Deposition ◽

Β Cell ◽

Islet Amyloid ◽

Human Type

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CHOP Contributes to, But Is Not the Only Mediator of, IAPP Induced β-Cell Apoptosis

Molecular Endocrinology ◽

10.1210/me.2015-1255 ◽

2016 ◽

Vol 30 (4) ◽

pp. 446-454 ◽

Cited By ~ 21

Author(s):

T. Gurlo ◽

J. F. Rivera ◽

A. E. Butler ◽

M. Cory ◽

J. Hoang ◽

...

Keyword(s):

Type 2 Diabetes ◽

Er Stress ◽

Cell Apoptosis ◽

Protein Misfolding ◽

Nuclear Translocation ◽

Cell Mass ◽

Cell Loss ◽

Β Cell ◽

Islet Amyloid

The islet in type 2 diabetes is characterized by β-cell loss, increased β-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). When protein misfolding protective mechanisms are overcome, human IAPP (h-IAPP) forms membrane permeant toxic oligomers that induce β-cell dysfunction and apoptosis. In humans with type 2 diabetes (T2D) and mice transgenic for h-IAPP, endoplasmic reticulum (ER) stress has been inferred from nuclear translocation of CCAAT/enhancer-binding protein homologous protein (CHOP), an established mediator of ER stress. To establish whether h-IAPP toxicity is mediated by ER stress, we evaluated diabetes onset and β-cell mass in h-IAPP transgenic (h-TG) mice with and without deletion of CHOP in comparison with wild-type controls. Diabetes was delayed in h-TG CHOP−/− mice, with relatively preserved β-cell mass and decreased β-cell apoptosis. Deletion of CHOP attenuates dysfunction of the autophagy/lysosomal pathway in β-cells of h-TG mice, uncovering a role for CHOP in mediating h-IAPP-induced dysfunction of autophagy. As deletion of CHOP delayed but did not prevent h-IAPP-induced β-cell loss and diabetes, we examined CHOP-independent stress pathways. JNK, a target of the IRE-1pTRAF2 complex, and the Bcl-2 family proapoptotic mediator BIM, a target of ATF4, were comparably activated by h-IAPP expression in the presence and absence of CHOP. Therefore, although these studies affirm that CHOP is a mediator of h-IAPP-induced ER stress, it is not the only one. Therefore, suppression of CHOP alone is unlikely to be a durable therapeutic strategy to protect against h-IAPP toxicity because multiple stress pathways are activated.

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Islet Amyloid in Type 2 Diabetes, and the Toxic Oligomer Hypothesis

Endocrine Reviews ◽

10.1210/er.2007-0037 ◽

2008 ◽

Vol 29 (3) ◽

pp. 303-316 ◽

Cited By ~ 393

Author(s):

Leena Haataja ◽

Tatyana Gurlo ◽

Chang J. Huang ◽

Peter C. Butler

Keyword(s):

Type 2 Diabetes ◽

Neurodegenerative Diseases ◽

Cell Mass ◽

Cell Loss ◽

Β Cell ◽

Islet Amyloid ◽

Amyloidogenic Proteins ◽

Toxic Oligomer

Abstract Type 2 diabetes (T2DM) is characterized by insulin resistance, defective insulin secretion, loss of β-cell mass with increased β-cell apoptosis and islet amyloid. The islet amyloid is derived from islet amyloid polypeptide (IAPP, amylin), a protein coexpressed and cosecreted with insulin by pancreatic β-cells. In common with other amyloidogenic proteins, IAPP has the propensity to form membrane permeant toxic oligomers. Accumulating evidence suggests that these toxic oligomers, rather than the extracellular amyloid form of these proteins, are responsible for loss of neurons in neurodegenerative diseases. In this review we discuss emerging evidence to suggest that formation of intracellular IAPP oligomers may contribute to β-cell loss in T2DM. The accumulated evidence permits the amyloid hypothesis originally developed for neurodegenerative diseases to be reformulated as the toxic oligomer hypothesis. However, as in neurodegenerative diseases, it remains unclear exactly why amyloidogenic proteins form oligomers in vivo, what their exact structure is, and to what extent these oligomers play a primary or secondary role in the cytotoxicity in what are now often called unfolded protein diseases.

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4-Phenylbutyrate (PBA) treatment reduces hyperglycemia and islet amyloid in a mouse model of type 2 diabetes and obesity

Scientific Reports ◽

10.1038/s41598-021-91311-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sara de Pablo ◽

Júlia Rodríguez-Comas ◽

Daniela Díaz-Catalán ◽

Gema Alcarraz-Vizán ◽

Carlos Castaño ◽

...

Keyword(s):

Type 2 Diabetes ◽

Glucose Metabolism ◽

Cell Mass ◽

Amyloid Deposition ◽

Islet Amyloid ◽

Chemical Chaperone ◽

Amyloid Deposits ◽

And Function ◽

Diabetes And Obesity

AbstractAmyloid deposits in pancreatic islets, mainly formed by human islet amyloid polypeptide (hIAPP) aggregation, have been associated with loss of β-cell mass and function, and are a pathological hallmark of type 2 diabetes (T2D). Treatment with chaperones has been associated with a decrease in endoplasmic reticulum stress leading to improved glucose metabolism. The aim of this work was to investigate whether the chemical chaperone 4-phenylbutyrate (PBA) prevents glucose metabolism abnormalities and amyloid deposition in obese agouti viable yellow (Avy) mice that overexpress hIAPP in β cells (Avy hIAPP mice), which exhibit overt diabetes. Oral PBA treatment started at 8 weeks of age, when Avy hIAPP mice already presented fasting hyperglycemia, glucose intolerance, and impaired insulin secretion. PBA treatment strongly reduced the severe hyperglycemia observed in obese Avy hIAPP mice in fasting and fed conditions throughout the study. This effect was paralleled by a decrease in hyperinsulinemia. Importantly, PBA treatment reduced the prevalence and the severity of islet amyloid deposition in Avy hIAPP mice. Collectively, these results show that PBA treatment elicits a marked reduction of hyperglycemia and reduces amyloid deposits in obese and diabetic mice, highlighting the potential of chaperones for T2D treatment.

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