Islet Amyloid Polypeptide, Islet Amyloid, and Diabetes Mellitus

2011 ◽  
Vol 91 (3) ◽  
pp. 795-826 ◽  
Author(s):  
Per Westermark ◽  
Arne Andersson ◽  
Gunilla T. Westermark
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Islets ◽  
Amyloid Fibrils ◽  
Mammalian Species ◽  
Islet Amyloid Polypeptide ◽  
Glucagon Secretion ◽  
Β Cells ◽  
Islet Amyloid ◽  
Pancreatic Islets Of Langerhans

Islet amyloid polypeptide (IAPP, or amylin) is one of the major secretory products of β-cells of the pancreatic islets of Langerhans. It is a regulatory peptide with putative function both locally in the islets, where it inhibits insulin and glucagon secretion, and at distant targets. It has binding sites in the brain, possibly contributing also to satiety regulation and inhibits gastric emptying. Effects on several other organs have also been described. IAPP was discovered through its ability to aggregate into pancreatic islet amyloid deposits, which are seen particularly in association with type 2 diabetes in humans and with diabetes in a few other mammalian species, especially monkeys and cats. Aggregated IAPP has cytotoxic properties and is believed to be of critical importance for the loss of β-cells in type 2 diabetes and also in pancreatic islets transplanted into individuals with type 1 diabetes. This review deals both with physiological aspects of IAPP and with the pathophysiological role of aggregated forms of IAPP, including mechanisms whereby human IAPP forms toxic aggregates and amyloid fibrils.

scholarly journals Pancreatic beta-cell granule peptides form heteromolecular complexes which inhibit islet amyloid polypeptide fibril formation

2004 ◽  
Vol 377 (3) ◽  
pp. 709-716 ◽  
Author(s):  
Emma T. A. S. JAIKARAN ◽  
Melanie R. NILSSON ◽  
Anne CLARK
Keyword(s):  
Type 2 Diabetes ◽  
Amyloid Fibrils ◽  
Secretory Granules ◽  
Pancreatic Beta Cell ◽  
Islet Amyloid Polypeptide ◽  
Fibril Formation ◽  
Islet Amyloid ◽  
Β Sheet

Islet amyloid polypeptide (IAPP), or ‘amylin’, is co-stored with insulin in secretory granules of pancreatic islet β-cells. In Type 2 diabetes, IAPP converts into a β-sheet conformation and oligomerizes to form amyloid fibrils and islet deposits. Granule components, including insulin, inhibit spontaneous IAPP fibril formation in vitro. To determine the mechanism of this inhibition, molecular interactions of insulin with human IAPP (hIAPP), rat IAPP (rIAPP) and other peptides were examined using surface plasmon resonance (BIAcore), CD and transmission electron microscopy (EM). hIAPP and rIAPP complexed with insulin, and this reaction was concentration-dependent. rIAPP and insulin, but not pro-insulin, bound to hIAPP. Insulin with a truncated B-chain, to prevent dimerization, also bound hIAPP. In the presence of insulin, hIAPP did not spontaneously develop β-sheet secondary structure or form fibrils. Insulin interacted with pre-formed IAPP fibrils in a regular repeating pattern, as demonstrated by immunoEM, suggesting that the binding sites for insulin remain exposed in hIAPP fibrils. Since rIAPP and hIAPP form complexes with insulin (and each other), this could explain the lack of amyloid fibrils in transgenic mice expressing hIAPP. It is likely that IAPP fibrillogenesis is inhibited in secretory granules (where the hIAPP concentration is in the millimolar range) by heteromolecular complex formation with insulin. Alterations in the proportions of insulin and IAPP in granules could disrupt the stability of the peptide. The increase in the proportion of unprocessed pro-insulin produced in Type 2 diabetes could be a major factor in destabilization of hIAPP and induction of fibril formation.

PEG modified graphene oxide loaded with EALYLV peptides for inhibiting the aggregation of hIAPP associated with type-2 diabetes

2015 ◽  
Vol 3 (35) ◽  
pp. 7055-7067 ◽  
Author(s):  
Xianbo Zhou ◽  
Chengwen Cao ◽  
Qingchang Chen ◽  
Qianqian Yu ◽  
Yanan Liu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Graphene Oxide ◽  
Pancreatic Islets ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Islet Amyloid ◽  
Amyloid Aggregate ◽  
Modified Graphene Oxide ◽  
Modified Graphene

Human islet amyloid polypeptide (hIAPP) was found as amyloid aggregate deposits in the pancreatic islets of patients with type-2 diabetes and studies showed that insulin and its derivatives were the potent inhibitors of hIAPP aggregation.

scholarly journals Recent Insights in Islet Amyloid Polypeptide-Induced Membrane Disruption and Its Role inβ-Cell Death in Type 2 Diabetes Mellitus

2008 ◽  
Vol 2008 ◽  
pp. 1-9 ◽  
Author(s):  
Lucie Khemtémourian ◽  
J. Antoinette Killian ◽  
Jo W. M. Höppener ◽  
Maarten F. M. Engel
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Cell Death ◽  
Type 2 Diabetes Mellitus ◽  
Membrane Damage ◽  
Islet Amyloid Polypeptide ◽  
Islet Amyloid ◽  
Induced Membrane ◽  
Pancreatic Islets Of Langerhans

The presence of fibrillar protein deposits (amyloid) of human islet amyloid polypeptide (hIAPP) in the pancreatic islets of Langerhans is thought to be related to death of the insulin-producing isletβ-cells in type 2 diabetes mellitus (DM2). The mechanism of hIAPP-inducedβ-cell death is not understood. However, there is growing evidence that hIAPP-induced disruption ofβ-cell membranes is the cause of hIAPP cytotoxicity. Amyloid cytotoxicity by membrane damage has not only been suggested for hIAPP, but also for peptides and proteins related to other misfolding diseases, like Alzheimer’s disease, Parkinson’s disease, and prion diseases. Here we review the interaction of hIAPP with membranes, and discuss recent progress in the field, with a focus on hIAPP structure and on the proposed mechanisms of hIAPP-induced membrane damage in relation toβ-cell death in DM2.

Azadirachtin inhibits amyloid formation, disaggregates pre-formed fibrils and protects pancreatic β-cells from human islet amyloid polypeptide/amylin-induced cytotoxicity

2019 ◽  
Vol 476 (5) ◽  
pp. 889-907 ◽  
Author(s):  
Richa Dubey ◽  
Ketaki Patil ◽  
Sarath C. Dantu ◽  
Devika M. Sardesai ◽  
Parnika Bhatia ◽  
...  
Keyword(s):  
Pancreatic Islets ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Dynamics Simulation ◽  
Major Constituent ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide

Abstract The human islet amyloid polypeptide (hIAPP) or amylin is the major constituent of amyloidogenic aggregates found in pancreatic islets of type 2 diabetic patients that have been associated with β-cell dysfunction and/or death associated with type 2 diabetes mellitus (T2DM). Therefore, developing and/or identifying inhibitors of hIAPP aggregation pathway and/or compound that can mediate disaggregation of preformed aggregates holds promise as a medical intervention for T2DM management. In the current study, the anti-amyloidogenic potential of Azadirachtin (AZD)—a secondary metabolite isolated from traditional medicinal plant Neem (Azadirachta indica)—was investigated by using a combination of biophysical and cellular assays. Our results indicate that AZD supplementation not only inhibits hIAPP aggregation but also disaggregates pre-existing hIAPP fibrils by forming amorphous aggregates that are non-toxic to pancreatic β-cells. Furthermore, AZD supplementation in pancreatic β-cells (INS-1E) resulted in inhibition of oxidative stress; along with restoration of the DNA damage, lipid peroxidation and the associated membrane damage, endoplasmic reticulum stress and mitochondrial membrane potential. AZD treatment also restored glucose-stimulated insulin secretion from pancreatic islets exposed to hIAPP. All-atom molecular dynamics simulation studies on full-length hIAPP pentamer with AZD suggested that AZD interacted with four possible binding sites in the amyloidogenic region of hIAPP. In summary, our results suggest AZD to be a promising candidate for combating T2DM and related amyloidogenic disorders.

Photodegradation of porphyrin-bound hIAPP(1–37) fibrils

2020 ◽  
Vol 44 (22) ◽  
pp. 9438-9443
Author(s):  
Yongxiu Song ◽  
Ping Li ◽  
Zhiming Zhang ◽  
Yin Wang ◽  
Zhefei Zhang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Pancreatic Islets ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Preventive Strategy ◽  
Islet Amyloid ◽  
Amyloid Deposits

Amyloid deposits in pancreatic islets of type 2 diabetes mellitus (T2DM) are mainly comprised of human islet amyloid polypeptide (hIAPP), the degradation of hIAPP fibrils by photoactive porphyrin could be a preventive strategy against T2DM.

scholarly journals Inhibition of the malate–aspartate shuttle in mouse pancreatic islets abolishes glucagon secretion without affecting insulin secretion

2015 ◽  
Vol 468 (1) ◽  
pp. 49-63 ◽  
Author(s):  
Jelena A. Stamenkovic ◽  
Lotta E. Andersson ◽  
Alice E. Adriaenssens ◽  
Annika Bagge ◽  
Vladimir V. Sharoyko ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Glucagon Secretion ◽  
Nutrient Sensing ◽  
Β Cells ◽  
Mouse Pancreatic Islets ◽  
Glucagon And Insulin ◽  
Malate Aspartate Shuttle

Secretion of both glucagon and insulin is perturbed in Type 2 diabetes (T2D). In the present study, we identify a difference in mitochondrial shuttling between α- and β-cells that adjusts nutrient sensing and which potentially could be employed to specifically target secretion of either hormone.

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