Islet Amyloid Polypeptide/Amylin Contents in Pancreata Increase in Genetically Obese and Diabetic Mice

Tokuyama, Yoshiharu; Kanatsuka, Azuma; Yamaguchi, Tetsuro; Ohsawa, Haruhiko; Makino, Hírofumi; Nishimura, Masuhiro; Yoshida, Syohei

doi:10.1055/s-2007-1002100

Cited by 11 publications

(5 citation statements)

References 10 publications

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“…Increased secretion of IAPP was observed in individuals with obesity or pre-diabetic insulin resistance [88,89], and islet amyloid volume was correlated with BMI [11]. These findings, together with increased IAPP content in the pancreatic islet cells of obese and diabetic rodent models [27,28] and glucose-regulated proIAPP and proinsulin synthesis regulated by translational control [23,24], suggest that aberrant biosynthesis and secretion of IAPP might be related to obese and diabetic conditions. It seems likely that IAPP molecules are largely produced by obesity and insulin resistance as a consequence of both an unhealthy lifestyle and gene susceptibility, for example FTO, and hyperglycemia.…”

Section: Aberrant Biosynthesis Of Hiapp In Subjects With Obesity Insulin Resistance and Hyperglycemiamentioning

confidence: 98%

“…IAPP content and secretion in the pancreatic islet cells increase in addition to insulin in obese and diabetic rodent models, including ventromedial hypothalamic-lesioned obese rats, genetically obese Zucker rats [27], and genetically obese and diabetic mice, both ob/ob and db/db mice [28]. Also, IAPP contents change with increasing age in genetically obese and diabetic mice [29].…”

Section: Increase Of Iapp Synthesis Along With Aging and Under Obese And Diabetic Conditionsmentioning

confidence: 99%

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IAPP/amylin and β-cell failure: implication of the risk factors of type 2 diabetes

Kanatsuka¹,

Kou

Makino

2018

Diabetol Int

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In type 2 diabetes (T2D), the most significant pathological change in pancreatic islets is amyloid deposits, of which a major component is islet amyloid polypeptide (IAPP), also called amylin. IAPP is expressed in β-cells and co-secreted with insulin. Together with the inhibitory effects of synthetic human IAPP (hIAPP) on insulin secretion, our studies, using hIAPP transgenic mice, in which glucose-stimulated insulin secretion was moderately reduced without amyloid deposit, and hIAPP gene-transfected β-cell lines, in which insulin secretion was markedly impaired without amyloid, predicted that soluble hIAPP-related molecules would exert cytotoxicity on β-cells. Human IAPP is one of the most aggregation-prone peptides that interact with cell membranes. While it is widely reported that soluble hIAPP oligomers promote cytotoxicity, this is still a hypothesis since the mechanisms are not yet fully defined. Several hIAPP transgenic mouse models did not develop diabetes; however, in models with backgrounds characterized for diabetic phenotypes, β-cell function and glucose tolerance did worsen, compared to those in non-transgenic models with similar backgrounds. Together with these findings, many studies on metabolic and molecular disorders induced by risk factors of T2D suggest that in T2D subjects, toxic IAPP oligomers accumulate in β-cells, impair their function, and reduce mass through disruption of cell membranes, resulting in β-cell failure. IAPP might be central to β-cell failure in T2D. Anti-amyloid aggregation therapeutics will be developed to create treatments with more durable and beneficial effects on β-cell function. KeywordsIAPP/amylin • Type 2 diabetes • Islet amyloid • IAPP oligomer • Risk factors of T2D • β-Cell failure * Azuma Kanatsuka

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Section: Aberrant Biosynthesis Of Hiapp In Subjects With Obesity Insulin Resistance and Hyperglycemiamentioning

confidence: 98%

Section: Increase Of Iapp Synthesis Along With Aging and Under Obese And Diabetic Conditionsmentioning

confidence: 99%

IAPP/amylin and β-cell failure: implication of the risk factors of type 2 diabetes

Kanatsuka¹,

Kou

Makino

2018

Diabetol Int

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“…Islet amyloid deposition is rare in non-diabetic humans (37). Synthesis and secretion of IAPP are increased aber¬ rantly in obese rats (14) and obese diabetic mice (15). The IAPP response during oral glucose loading was enhanced in glucose-intolerant relatives of subjects with NIDDM (16).…”

Section: Resultsmentioning

confidence: 99%

“…This peptide is co-secreted with insulin in response to several secretagogues (8,9), and inhibits glucosestimulated insulin secretion from islets (10,11) and insulin actions in peripheral tissues (12,13). Islet amyloid polypeptide is synthesized aberrantly in obese and diabetic animals (14,15), and the secretion is The authors contributed equally to this work. enhanced in glucose-intolerant relatives of subjects with NIDDM (16).…”

mentioning

confidence: 99%

Formation of islet amyloid fibrils in beta-secretory granules of transgenic mice expressing human islet amyloid polypeptide/amylin

Yagui

Yamaguchi

Kanatsuka

et al. 1995

European Journal of Endocrinology

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To investigate the relationship between human islet amyloid polypeptide (IAPP)/amylin expression and islet amyloid deposits in the pathogenesis of human non-insulin-dependent diabetes mellitus (NIDDM), we developed transgenic mice using a human IAPP cDNA connected to an insulin promoter. Ribonucleic acid blotting and immunohistochemistry revealed the expression of the transgene in the pancreatic beta cells. Immunogold electron microscopy showed that beta-secretory granules contained the human C-terminal flanking peptide of the IAPP precursor. Reverse-phase HPLC demonstrated human and mouse IAPP amide in the pancreas. Electron microscopy showed the accumulation of fibril-like material in a considerable number of beta-secretory granules. These results suggest that in transgenic mice, the human IAPP precursor is expressed in beta cells and becomes normally sorted into beta-secretory granules in which normal conversion to mature human IAPP takes place. The human IAPP molecules, because of their amyloidogenesis, aggregate into amyloid fibrils in secretory granules. Glucose tolerance was normal at 7 months old and islet amyloid was not observed. A longer time may be required for islet amyloid deposits and hyperglycemia to develop in mice. Our working hypothesis is that in human NIDDM, IAPP aggregates into amyloid fibrils in beta-secretory granules, and that the fibrils are released into the extracellular space and islet amyloid deposits become substantial with time.

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“…There is an excessive firing of cytoplasmic Ca 2+ transients when OM ß-cells are stimulated with glucagon [55]. Islet amyloid polypeptide is increased in islets from OM [56]. OM islets also have a reduced capacity to increase blood flow to meet metabolic demands [57].…”

Section: Pancreatic Isletsmentioning

confidence: 99%

The Physiology of Obese-Hyperglycemic Mice [ob/obMice]

Lindström

2007

The Scientific World JOURNAL

298

254

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This review summarizes key aspects of what has been learned about the physiology of leptin deficiency as it can be observed in obese-hyperglycemic ob/ob mice. These mice lack functional leptin. They are grossly overweight and hyperphagic, particularly at young ages, and develop severe insulin resistance. They have been used as a model for obesity and as a rich source of pancreatic islets with high insulin release capacity. The leptin deficiency manifests also with regard to immune function, the cardiovascular system including angiogenesis, supportive tissue function, malignancies, and reproductive function. ob/ob Mice are well suited for studies on the interaction between leptin and insulin, and for studies on initial aspects of metabolic disturbances leading to type-2diabetes.

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Islet Amyloid Polypeptide/Amylin Contents in Pancreata Increase in Genetically Obese and Diabetic Mice

Cited by 11 publications

References 10 publications

IAPP/amylin and β-cell failure: implication of the risk factors of type 2 diabetes

IAPP/amylin and β-cell failure: implication of the risk factors of type 2 diabetes

Formation of islet amyloid fibrils in beta-secretory granules of transgenic mice expressing human islet amyloid polypeptide/amylin

The Physiology of Obese-Hyperglycemic Mice [ob/obMice]

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