Glucose desensitization in INS-1 cells: Evidence of impaired function caused by glucose metabolite(s) rather than by the glucose molecule per se

• Published in: Metabolism, clinical and experimental Vol. 51; no. 6; pp. 671 - 677
• Main Authors: Brock, Birgitte, Mogensen, Jane H., Gregersen, S[oslash]ren, Hermansen, Kjeld
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.06.2002; Elsevier
• Subjects: Animals; Biological and medical sciences; Cell Line; Deoxyglucose - pharmacology; Diabetes. Impaired glucose tolerance; Dose-Response Relationship, Drug; Drug Tolerance - physiology; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme Inhibitors - pharmacology; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glucokinase - antagonists & inhibitors; Glucose - metabolism; Glucose - pharmacology; Glucose-6-Phosphate Isomerase - antagonists & inhibitors; Glyceraldehyde - pharmacology; Insulin - genetics; Insulin - metabolism; Insulin Secretion; Intracellular Fluid - metabolism; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Mannoheptulose - pharmacology; Medical sciences; Rats; RNA, Messenger - metabolism; Time Factors; Endocrinopathy; Human; Cell culture; Pancreatic hormone; Desensitization; RNA; Metabolite; Pathogenesis; Glucose; Experimental study; Gene expression; Non insulin dependent diabetes; In vitro; Insulin; Biological activity; Endocrine secretion; β Cell; High dose; Endocrine pancreas
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1053/meta.2002.32722

Type 2 diabetes characteristically involves disturbances of the [beta ]-cell function including reduced insulin secretion in response to elevated glucose. In experimental diabetes, [beta ] cells are often [ldquo ]blind[rdquo ] to glucose, and clonal [beta ]-cell lines chronically exposed to glucose show impaired glucose sensing. The present study focuses on the effect of long-term exposure to high-glucose concentrations on insulin secretion, insulin store, and insulin mRNA content in the [beta ]-cell line INS-1. The cellular insulin mRNA content has been shown to be reduced by approximately 90% on such exposure for 4 days. This decrement could be partly counteracted by subsequent culture for 4 days at low glucose, while daily alternate culture in high and low glucose did not prevent the insulin mRNA content from being reduced. The insulin release from cells cultured at high glucose was simultaneously reduced by 50%. This change was, however, not reversed by subsequent culture at low glucose, a pattern also found for the intracellular insulin stores. The suppression of insulin mRNA, insulin release, and intracellular insulin stores induced by high glucose was completely neutralized by the metabolic glucokinase blocker, mannoheptulose, while 2-deoxyglucose, a phosphoglucose isomerase blocker, had no impact. This suggests that glucokinase activity may have a negative regulatory effect. Addition of D-glyceraldehyde (DG) induced an increase in insulin release, while insulin mRNA remained unaltered. It would therefore seem that at least one glucose metabolite is involved in the glucose desensitization in INS-1 cells, which opens the prospect of regulatory factor(s), which possess(es) negative, as well as positive, actions.