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

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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Islet Amyloid in Patients With Diabetes Due to Exocrine Pancreatic Disorders, Type 2 Diabetes, and Nondiabetic Patients

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa176 ◽

2020 ◽

Vol 105 (8) ◽

pp. 2595-2605

Author(s):

Sandra Ueberberg ◽

Michael A Nauck ◽

Waldemar Uhl ◽

Chiara Montemurro ◽

Andrea Tannapfel ◽

...

Keyword(s):

Type 2 Diabetes ◽

Pancreatic Tissue ◽

Amyloid Formation ◽

Β Cell ◽

Islet Amyloid ◽

Amyloid Deposits ◽

Typical Finding ◽

Patients With Diabetes ◽

Pancreatic Disorders

Abstract Background Amyloid deposits are a typical finding in pancreatic islets from patients with type 2 diabetes. Whether this is linked to the pathogenesis of type 2 diabetes is currently unknown. Therefore, we compared the occurrence of islet amyloid in patients with type 2 diabetes, diabetes secondary to pancreatic disorders, and nondiabetic individuals. Patients and methods Pancreatic tissue from 15 nondiabetic patients, 22 patients with type 2 diabetes, and 11 patients with diabetes due to exocrine pancreatic disorders (chronic pancreatitis, pancreatic carcinoma) were stained for insulin, amyloid, and apoptosis. β-cell area, amyloid deposits, and β-cell apoptosis were quantified by morphometric analysis. Results The proportion of islets containing amyloid deposits was significantly higher in both type 2 diabetes and diabetes due to exocrine pancreatic disorders than in healthy subjects. Islets with both amyloid and apoptosis were observed more frequently in type 2 diabetes and significantly more so in diabetes due to exocrine pancreatic disorders. In both diabetic groups, apoptotic ß-cells were found significantly more frequently in islets with more prominent amyloid deposits. Conclusions The occurrence of amyloid deposits in both type 2 diabetes and diabetes secondary to exocrine pancreatic disorders suggests that islet amyloid formation is a common feature of diabetes mellitus of different etiologies and may be associated with a loss of pancreatic ß-cells.

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Faculty Opinions recommendation of Evidence of β-Cell Dedifferentiation in Human Type 2 Diabetes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726044256.793513932 ◽

2016 ◽

Author(s):

Rosemarie Heyn

Keyword(s):

Type 2 Diabetes ◽

Β Cell ◽

Cell Dedifferentiation ◽

Human Type

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The β-Cell in Human Type 2 Diabetes

Advances in Experimental Medicine and Biology - The Islets of Langerhans ◽

10.1007/978-90-481-3271-3_22 ◽

2010 ◽

pp. 501-514 ◽

Cited By ~ 42

Author(s):

Piero Marchetti ◽

Roberto Lupi ◽

Silvia Del Guerra ◽

Marco Bugliani ◽

Lorella Marselli ◽

...

Keyword(s):

Type 2 Diabetes ◽

Β Cell ◽

Human Type

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β-Cell Dysfunctional ERAD/Ubiquitin/Proteasome System in Type 2 Diabetes Mediated by Islet Amyloid Polypeptide–Induced UCH-L1 Deficiency

Diabetes ◽

10.2337/db10-0522 ◽

2010 ◽

Vol 60 (1) ◽

pp. 227-238 ◽

Cited By ~ 71

Author(s):

Safia Costes ◽

Chang-jiang Huang ◽

Tatyana Gurlo ◽

Marie Daval ◽

Aleksey V. Matveyenko ◽

...

Keyword(s):

Type 2 Diabetes ◽

Islet Amyloid Polypeptide ◽

Ubiquitin Proteasome System ◽

Β Cell ◽

Islet Amyloid ◽

Ubiquitin Proteasome

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Evidence of β-Cell Dedifferentiation in Human Type 2 Diabetes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2015-2860 ◽

2016 ◽

Vol 101 (3) ◽

pp. 1044-1054 ◽

Cited By ~ 198

Author(s):

Francesca Cinti ◽

Ryotaro Bouchi ◽

Ja Young Kim-Muller ◽

Yoshiaki Ohmura ◽

P. R. Sandoval ◽

...

Keyword(s):

Type 2 Diabetes ◽

Β Cell ◽

Cell Dedifferentiation ◽

Human Type

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Amyloid damage to islet β-cells in type 2 diabetes: hypoxia or pseudo-hypoxia?

10.1101/810747 ◽

2019 ◽

Cited By ~ 2

Author(s):

Vittorio Bellotti ◽

Alessandra Corazza ◽

Beatrice Foglia ◽

Erica Novo ◽

J. Paul Simons ◽

...

Keyword(s):

Type 2 Diabetes ◽

Amyloid Deposition ◽

Β Cells ◽

Islet Amyloid ◽

Good Tool ◽

Amyloid Deposits ◽

Oxygen Perfusion

ABSTRACTAggregation of islet amyloid polypeptide (IAPP) and amyloid deposition in the islets of Langerhans may significantly contribute to the multifactorial pathogenic mechanisms leading to type 2 diabetes. A direct toxic effect on β-cells of oligomeric IAAP has been demonstrated in in vitro models, but the mechanism operating in vivo is still unclear. Mice models presenting amyloid deposition and glucose intolerance represent a good tool for exploring in vivo a putative mechanism of toxicity directly related to the physical expansion of the extracellular matrix by the amyloid fibrillar aggregates. Based on our hypothesis that deposition of amyloid may influence the oxygen perfusion, we have calculated that the mean distribution of oxygen partial pressure would drop by more than 50 % in the presence of amyloid deposits in the islet. This condition of hypoxia caused by the remodelling of the extracellular space may explain the metabolic abnormalities in the Langerhans islets, otherwise interpreted as pseudo-hypoxic response to IAPP oligomers.

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Vaccination Against Amyloidogenic Aggregates in Pancreatic Islets Prevents Development of Type 2 Diabetes Mellitus

Vaccines ◽

10.3390/vaccines8010116 ◽

2020 ◽

Vol 8 (1) ◽

pp. 116 ◽

Cited By ~ 3

Author(s):

Elisa S. Roesti ◽

Christina N. Boyle ◽

Daniel T. Zeman ◽

Marcos Sande-Melon ◽

Federico Storni ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Pancreatic Islets ◽

Hormone Secretion ◽

Β Cell ◽

Islet Amyloid ◽

Disease Modifying

Type 2 diabetes mellitus (T2DM) is a chronic progressive disease characterized by insulin resistance and insufficient insulin secretion to maintain normoglycemia. The majority of T2DM patients bear amyloid deposits mainly composed of islet amyloid polypeptide (IAPP) in their pancreatic islets. These—originally β-cell secretory products—extracellular aggregates are cytotoxic for insulin-producing β-cells and are associated with β-cell loss and inflammation in T2DM advanced stages. Due to the absence of T2DM preventive medicaments and the presence of only symptomatic drugs acting towards increasing hormone secretion and action, we aimed at establishing a novel disease-modifying therapy targeting the cytotoxic IAPP deposits in order to prevent the development of T2DM. We generated a vaccine based on virus-like particles (VLPs), devoid of genomic material, coupled to IAPP peptides inducing specific antibodies against aggregated, but not monomeric IAPP. Using a mouse model of islet amyloidosis, we demonstrate in vivo that our vaccine induced a potent antibody response against aggregated, but not soluble IAPP, strikingly preventing IAPP depositions, delaying onset of hyperglycemia and the induction of the associated pro-inflammatory cytokine Interleukin 1β (IL-1β). We offer the first cost-effective and safe disease-modifying approach targeting islet dysfunction in T2DM, preventing pathogenic aggregates without disturbing physiological IAPP function.

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