Detrimental effect of protracted hyperglycaemia on beta-cell neogenesis in a mouse murine model of diabetes

• Published in: Diabetologia 2002-12, Vol.45 (12), p.1689-1696
• Main Authors: GUZ, Y, TORRES, A, TEITELMAN, G
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blood Glucose - analysis; Cell Count; Cell Differentiation; Cell Division - drug effects; Cell Survival; Cells; Diabetes; Diabetes Mellitus, Experimental - blood; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glucose; Glucose Transporter Type 2; Hyperglycemia; Hyperglycemia - blood; Hyperglycemia - etiology; Hyperglycemia - pathology; Insulin; Insulin - metabolism; Insulin - pharmacology; Islets of Langerhans - metabolism; Islets of Langerhans - pathology; Male; Medical sciences; Mice; Mice, Inbred Strains; Monosaccharide Transport Proteins - metabolism; Time Factors
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-002-0970-y

Previous studies have shown that new beta cells differentiate from intra-islet precursors in pancreatic islets of mice in which diabetes is induced by injecting a high dose of the beta-cell toxin streptozotocin. Moreover, the re-establishment of euglycaemia by insulin therapy 1 day after streptozotocin treatment improved the process of regeneration. We sought to assess whether a 1-week delay in the restoration of euglycaemia would affect beta-cell regeneration. Adult CD-1 mice were injected with 200 mg/kg of streptozotocin. One group of mice remained hyperglycaemic throughout the experiment while a second group became normoglycaemic following the administration of insulin therapy 1 week after the injection of streptozotocin. Pancreata removed at different times after treatment were processed for visualization ofbeta precursor-cell markers and insulin by confocal microscopy. New beta cells appeared in islets of streptozotocin-treated mice after restoration of normoglycaemia. Like islets of streptozotocin mice in which blood glucose concentrations were rapidly restored, islets of mice that became normoglycaemic 1 week after streptozotocin treatment also had two potential insulin precursor cell types. Protracted hyperglycaemia however, had several harmful effects on insulin cell neogenesis, such as a reduction in the number of euglycaemic mice with successful beta-cell regeneration and a decrease in the number and survival of the newly differentiated insulin-containing cells. These results indicate that islets gradually lose their regenerative potential when they are exposed to high circulating glucose concentrations for an extended period of time.