Islet amyloid and type 2 diabetes: overproduction or inadequate clearance and detoxification?
Open accessAbstract
A hallmark of type 2 diabetes is the reduction of pancreatic islet β cell mass through induction of apoptosis and lack of regeneration. In most patients, β cell dysfunction is associated with the presence of extracellular amyloid plaques adjacent to β cells and intracellular toxic oligomers that are comprised of islet amyloid polypeptide (IAPP). In this issue of the JCI, three independent research groups reveal that a functional autophagy system normally prevents the accumulation of toxic IAPP oligomers in human IAPP-expressing murine models. Furthermore, mice expressing human IAPP but deficient for β cell autophagy through genetic deletion of the autophagy initiator ATG7 developed β cell apoptosis and overt diabetes. Together, these studies indicate that autophagy protects β cells from the accumulation of toxic IAPP oligomers and suggest that enhancing autophagy may be a novel target for prevention of type 2 diabetes.
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IAPP (amylin) is co-secreted with insulin from islet beta-cells in healthy individuals during the fed state and acts as an anti-hyperglycaemic agent by decreasing gastric motility, promoting satiety and inhibiting glucagon secretion.
“Islet amyloid polypeptide (IAPP) (more commonly known as amylin) is co-secreted with insulin from islet beta-cells in healthy individuals during the fed state and acts as an anti-hyperglycaemic agent by decreasing gastric motility, promoting satiety and inhibiting glucagon secretion.128”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [128]
Transgenic mice producing human IAPP have islet amyloid accumulation, increased beta-cell apoptosis, decreased beta-cell mass, impaired glucose tolerance, and some develop diabetes.
“Several lines of transgenic mice have been generated which produce human IAPP, and they were shown to have islet amyloid accumulation, increased beta-cell apoptosis, decreased beta-cell mass, impaired glucose tolerance, and some developed diabetes.128”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [128]
Defective autophagy is likely pivotal for the pathogenesis of T2D.
“It has been elucidated that beta-cells are usually protected from IAPP oligomers by autophagy processes, so it seems that these processes are defective in prediabetes and T2D, which is likely pivotal for the pathogenesis of T2D.128,132”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [128]
Virtually all T2D patients have IAPP-containing plaques in their islets.
“Virtually all T2D patients have IAPP-containing plaques in their islets.128”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [128]
Extracellular plaques of IAPP are not causative of beta-cell pathology; intracellular oligomers of IAPP observed in T2D patients (but not T2D-free individuals) produce cytotoxic effects.
“The current consensus in the literature is that extracellular plaques of IAPP are not causative of beta-cell pathology, but rather intracellular oligomers of this protein observed in T2D patients (but not in T2D-free individuals) produce the cytotoxic effects.128,131”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [128]
Beta-cells are usually protected from IAPP oligomers by autophagy processes.
“It has been elucidated that beta-cells are usually protected from IAPP oligomers by autophagy processes, so it seems that these processes are defective in prediabetes and T2D, which is likely pivotal for the pathogenesis of T2D.128,132”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [128]
Autophagy processes are defective in prediabetes and T2D.
“It has been elucidated that beta-cells are usually protected from IAPP oligomers by autophagy processes, so it seems that these processes are defective in prediabetes and T2D, which is likely pivotal for the pathogenesis of T2D.128,132”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [128]
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References 21 · Cited by 27
Research works printed but not linked: 1
- Singh R, et al. Autophagy regulates lipid metabo- lism. Nature. 2009;458(7242):1131-1135.
- Authors
- Gupta, D., & Leahy, J. L.
- Venue
- Journal of Clinical Investigation
- Published
- 2014-07-18
- Volume
- 124
- Issue
- 8
- Pages
- 3292-3294
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC4109527
- OpenAlex
- W2140661828
- Cited by
- 27
- References
- 21
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 4 · 2022: 1 · 2021: 4 · 2020: 3 · 2019: 1 · 2018: 1 · 2017: 2 · 2016: 1 · 2015: 4
- FWCI
- 2.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R56DK056818, DK 56818, R01DK056818)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- amylin, type 2 diabetes, autophagy, beta-cell apoptosis, ATG7, beta-cell mass, amyloid plaques
- MeSH terms
- Animals, Autophagy, Diabetes Mellitus, Type 2, Female, Humans, Male, Insulin-Secreting Cells, Islet Amyloid Polypeptide
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