Glucokinase activation is beneficial or toxic to cultured rat pancreatic islets depending on the prevailing glucose concentration.
(2015) American Journal of Physiology: Endocrinology and Metabolism — Vol. 309, n° 7, p. E632-E639 (2015)
Files
Roma2015_GKApaper.pdf
Open Access - Adobe PDF
- 706.28 KB
Details
- Authors
- Abstract
- BACKGROUND/AIM: In rat pancreatic islets, beta-cell gene expression, survival and subsequent acute glucose stimulation of insulin secretion (GSIS) are optimally preserved by prolonged culture at 10 mM glucose (G10) and markedly altered by culture at G5 or G30. Here we tested whether pharmacological glucokinase (GK) activation prevents these alterations during culture or improves GSIS after culture. METHODS: Rat pancreatic islets were cultured 1-7 days at G5, G10 or G30 with or without 3 µM of the GK activator Ro 28-0450 (Ro). After culture, beta-cell apoptosis and islet gene mRNA levels were measured, and the acute glucose-induced increase in NAD(P)H autofluorescence, intracellular calcium concentration and insulin secretion were tested in the absence or presence of Ro 28-0450. RESULTS: Prolonged culture of rat islets at G5 or G30 instead of G10 triggered beta-cell apoptosis and reduced their glucose responsiveness. Addition of Ro during culture differently affected beta-cell survival and glucose responsiveness depending on the glucose concentration during culture: it was beneficial to beta-cell survival and function at G5, detrimental at G10, and ineffective at G30. In contrast, acute GK activation with Ro increased the glucose sensitivity of islets cultured at G10, but failed at restoring beta-cell glucose responsiveness after culture at G5 or G30. CONCLUSIONS: Pharmacological GK activation prevents the alteration of beta-cell survival and function by long-term culture at G5, but mimics glucotoxicity when added to G10. The complex effects of glucose on the beta-cell phenotype result from changes in glucose metabolism and not from an effect of glucose per se.
- Affiliations
diabète et nutrition
Citations
Roma, L. P., Duprez, J., & Jonas, J.-C. (2015). Glucokinase activation is beneficial or toxic to cultured rat pancreatic islets depending on the prevailing glucose concentration. American Journal of Physiology: Endocrinology and Metabolism, 309(7), E632-E639. https://doi.org/10.1152/ajpendo.00154.2015 (Original work published 2015)