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Amyloid fibril formation is progressive and correlates with beta-cell secretion in transgenic mouse isolated islets
- Source :
- Diabetologia. 42(10)
- Publication Year :
- 1999
-
Abstract
- Aims/hypothesis. Amyloid fibrils are formed in islets isolated from transgenic mice expressing the gene for human islet amyloid polypeptide (IAPP) by an unknown mechanism. This model of islet amyloidosis in Type II (non-insulin-dependent) diabetes mellitus has been used to investigate the temporal and glucose dependency of fibril formation. Methods. To determine the time course and nature of amyloid-like accumulations and the role of glucose, transgenic mouse islets were cultured for 2‐12 days in medium containing glucose (4.2 mmol/l, 11.1 mmol/l or 16.7 mmol/l) or 3.3 mmol/l glucose plus non-glucose secretagogues, 10 mmol/l leucine, 10 mmol/l leucine + 0.1 mmol/l tolbutamide, 10 mmol/l alpha-ketoisocaproic acid + 10 mmol/l glutamine. The extent of fibril formation was determined by quantitative immuno-electron microscopy. Insulin and islet amyloid polypeptide secretion into the media was measured by radioimmunoassay. Results. Extracellular amyloid fibrils immunoreactive for islet amyloid polypeptide were visible initially after 6 days of culture in 11.1 mmol/l glucose and formed 2.3 ‐ 0.8 % of the islet area after 12 days; small accumulations of intracellular fibrils and amorphous extracellular islet amyloid polypeptide-immunoreactive material were present at 6‐12 days. Beta-cell secretion was increased significantly by 16.7 mmol/l glucose and by alpha-ketoisocaproic acid + glutamine. The proportion of fibrillar amyloid (amyloid area/islet area%) correlated with the amount of insulin (r = 0.55, p < 0.05) and IAPP (r = 0.5, p < 0.05) in the culture media. Evidence of cellular damage was present in less than 10 % cells and correlated with the degree of fibril deposition (r = 0.8, p < 0.0001). Conclusion/interpretation. These data suggest that islet amyloid polypeptide amyloid is formed primarily at extracellular sites in isolated transgenic mouse islets and progressive fibril formation correlates with beta-cell secretion. [Diabetologia (1999) 42: 1219‐ 1227]
- Subjects :
- Male
endocrine system
medicine.medical_specialty
Amyloid
Time Factors
Cell Survival
Endocrinology, Diabetes and Metabolism
Glutamine
Tolbutamide
Amylin
Mice, Transgenic
Biology
Fibril
Islets of Langerhans
Mice
Leucine
Internal medicine
Internal Medicine
medicine
Extracellular
Animals
Humans
Hypoglycemic Agents
Insulin
Cells, Cultured
geography
geography.geographical_feature_category
Dose-Response Relationship, Drug
Amyloidosis
Islet
medicine.disease
Keto Acids
Islet Amyloid Polypeptide
Endocrinology
Glucose
Culture Media, Conditioned
Female
Beta cell
Extracellular Space
Subjects
Details
- ISSN :
- 0012186X
- Volume :
- 42
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Diabetologia
- Accession number :
- edsair.doi.dedup.....f965453172dd0c530ce935a7d03d18a8