Islet amyloid polypeptide acts on glucose‐ stimulated beta cells to reduce voltage‐gated calcium channel activation, intracellular Ca<sup>2+</sup> concentration, and insulin secretion

Zhu, Tiehong; Wang, Yinxia; He, Bin; Zang, J.; He, Qing; Zhang, Weihua

doi:10.1002/dmrr.1140

Cited by 19 publications

(16 citation statements)

References 39 publications

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“…IAPP is produced by the beta cells [6] and co-secreted with insulin upon stimulation [7]. IAPP acts as a modulator for insulin release and reduces voltage-gated calcium channel activation and insulin secretion [8]. IAPP is synthesized as a 67 residues prohormone, and undergoes posttranslational processing to become biologically active.…”

Section: Introductionmentioning

confidence: 99%

Drosophila Melanogaster as a Model System for Studies of Islet Amyloid Polypeptide Aggregation

2011

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BackgroundRecent research supports that aggregation of islet amyloid polypeptide (IAPP) leads to cell death and this makes islet amyloid a plausible cause for the reduction of beta cell mass, demonstrated in patients with type 2 diabetes. IAPP is produced by the beta cells as a prohormone, and proIAPP is processed into IAPP by the prohormone convertases PC1/3 and PC2 in the secretory granules. Little is known about the pathogenesis for islet amyloid and which intracellular mechanisms are involved in amyloidogenesis and induction of cell death.Methodology/Principal FindingsWe have established expression of human proIAPP (hproIAPP), human IAPP (hIAPP) and the non-amyloidogenic mouse IAPP (mIAPP) in Drosophila melanogaster, and compared survival of flies with the expression driven to different cell populations. Only flies expressing hproIAPP in neurons driven by the Gal4 driver elavC155,Gal4 showed a reduction in lifespan whereas neither expression of hIAPP or mIAPP influenced survival. Both hIAPP and hproIAPP expression caused formation of aggregates in CNS and fat body region, and these aggregates were both stained by the dyes Congo red and pFTAA, both known to detect amyloid. Also, the morphology of the highly organized protein granules that developed in the fat body of the head in hIAPP and hproIAPP expressing flies was characterized, and determined to consist of 15.8 nm thick pentagonal rod-like structures.Conclusions/SignificanceThese findings point to a potential for Drosophila melanogaster to serve as a model system for studies of hproIAPP and hIAPP expression with subsequent aggregation and developed pathology.

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Section: Introductionmentioning

confidence: 99%

Drosophila Melanogaster as a Model System for Studies of Islet Amyloid Polypeptide Aggregation

2011

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“…They found that VCCs were inhibited by high concentration of extracellular hIAPP, and they proposed that the reduction of GSIS in hIAPP-treated islets is the result of IAPP inhibition of VCCs (29). The mechanism was not described, but the authors suggested that it could also be involved in the activity of K ATP channels.…”

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confidence: 99%

Involvement of ATP-sensitive Potassium (KATP) Channels in the Loss of Beta-cell Function Induced by Human Islet Amyloid Polypeptide

Soty

Visa

Soriano

et al. 2011

Journal of Biological Chemistry

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Islet amyloid polypeptide (IAPP) is a major component of amyloid deposition in pancreatic islets of patients with type 2 diabetes. It is known that IAPP can inhibit glucose-stimulated insulin secretion; however, the mechanisms of action have not yet been established. In the present work, using a rat pancreatic beta-cell line, INS1E, we have created an in vitro model that stably expressed human IAPP gene (hIAPP cells). These cells showed intracellular oligomers and a strong alteration of glucose-stimulated insulin and IAPP secretion. Taking advantage of this model, we investigated the mechanism by which IAPP altered beta-cell secretory response and contributed to the development of type 2 diabetes. We have measured the intracellular Ca 2؉ mobilization in response to different secretagogues as well as mitochondrial metabolism. The study of calcium signals in hIAPP cells demonstrated an absence of response to glucose and also to tolbutamide, indicating a defect in ATP-sensitive potassium (K ATP ) channels. Interestingly, hIAPP showed a greater maximal respiratory capacity than control cells. These data were confirmed by an increased mitochondrial membrane potential in hIAPP cells under glucose stimulation, leading to an elevated reactive oxygen species level as compared with control cells. We concluded that the hIAPP overexpression inhibits insulin and IAPP secretion in response to glucose affecting the activity of K ATP channels and that the increased mitochondrial metabolism is a compensatory response to counteract the secretory defect of beta-cells.Type 2 diabetes is characterized by impaired insulin secretion with a progressive decline in beta-cell mass and function (1, 2). A main characteristic of type 2 diabetes is the extracellular accumulation of amyloid fibrils in pancreatic islets (3, 4). The main component of these deposits is the islet amyloid polypeptide (IAPP).2 Specifically, human IAPP (hIAPP) but not rodent IAPP is amyloidogenic (5). Pancreatic beta-cells co-express and co-secrete IAPP and insulin in response to several secretagogue stimuli (6 -8). It is well established that IAPP is implicated in the pathogenesis of diabetes because it forms amyloid deposits leading to beta-cell death (9 -12). In addition, although different studies have demonstrated that IAPP can inhibit glucose-stimulated insulin secretion (GSIS) (13-15), the mechanisms of action have not been established. In pancreatic beta-cells, GSIS depends critically on the activity of ATP-sensitive potassium channels (K ATP ), which serve as a coupling factor between changes in glucose metabolism and membrane electrical activity (16,17). These channels are hetero-octameric complexes comprising four inward-rectifier potassium ion channels (Kir6.2) and four regulatory sulfonylurea receptors (SUR1) (18). Gain-of-function mutations of Kir6.2 are associated with defective GSIS and the development of type 2 diabetes (19,20), whereas loss of function mutations of Kir6.2 and SUR1 are the most common causes of congenital hyperinsulinism of infancy, ...

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“…However, the same final results would be achieved indirectly if hIAPP inhibits of the ATP-sensitive potassium channel (K ATP ) closure which would prevent the ␤-cell membrane depolarization required to induce Ca 2+ channel opening. This interesting problem was addressed by Soty et al [94] who, working with an hIAPP transgenic rat pancreatic ␤-cell line, found that membrane depolarization with 30 mM KCl, raises the intracellular Ca 2+ concentration and induces a very strong secretion of insulin, discarding the proposal that the reduction of GSIS in hIAPP-treated islets could be the result of hIAPP inhibition of voltage-gated Ca 2+ channels [93]. However it should be kept in mind that GSIS may be affected differently by hIAPP if it is added externally to islets or if it is overexpressed endogeneously in transgenic cells.…”

Section: Effect Of Hiapp On Plasma Membrane Channelsmentioning

confidence: 97%

“…Zhu et al [93] investigated the secretion of insulin in rat islet ␤-cells stimulated with a high glucose concentration (16.7 mM) in the presence or absence of externally added hIAPP. At the same time, they studied the activity of the high voltage-gated calcium channels and the intracellular calcium concentration.…”

Section: Effect Of Hiapp On Plasma Membrane Channelsmentioning

confidence: 99%

Human IAPP amyloidogenic properties and pancreatic β-cell death

Fernández

2014

Cell Calcium

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Islet amyloid polypeptide acts on glucose‐ stimulated beta cells to reduce voltage‐gated calcium channel activation, intracellular Ca²⁺ concentration, and insulin secretion

Abstract: glucose-stimulated islet beta-cell high voltage-gated calcium channels were activated in conjunction with insulin secretion, while high extracellular concentrations of IAPP inhibited beta-cell high voltage-gated calcium channel activation and insulin secretion in a dose-dependent manner.

Cited by 19 publications

References 39 publications

Drosophila Melanogaster as a Model System for Studies of Islet Amyloid Polypeptide Aggregation

Drosophila Melanogaster as a Model System for Studies of Islet Amyloid Polypeptide Aggregation

Involvement of ATP-sensitive Potassium (KATP) Channels in the Loss of Beta-cell Function Induced by Human Islet Amyloid Polypeptide

Human IAPP amyloidogenic properties and pancreatic β-cell death

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Islet amyloid polypeptide acts on glucose‐ stimulated beta cells to reduce voltage‐gated calcium channel activation, intracellular Ca2+ concentration, and insulin secretion

Abstract: glucose-stimulated islet beta-cell high voltage-gated calcium channels were activated in conjunction with insulin secretion, while high extracellular concentrations of IAPP inhibited beta-cell high voltage-gated calcium channel activation and insulin secretion in a dose-dependent manner.

Cited by 19 publications

References 39 publications

Drosophila Melanogaster as a Model System for Studies of Islet Amyloid Polypeptide Aggregation

Drosophila Melanogaster as a Model System for Studies of Islet Amyloid Polypeptide Aggregation

Involvement of ATP-sensitive Potassium (KATP) Channels in the Loss of Beta-cell Function Induced by Human Islet Amyloid Polypeptide

Human IAPP amyloidogenic properties and pancreatic β-cell death

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Islet amyloid polypeptide acts on glucose‐ stimulated beta cells to reduce voltage‐gated calcium channel activation, intracellular Ca²⁺ concentration, and insulin secretion