We recently demonstrated the mitogenic and secretagogic actions of lithium in the insulin-producing pancreatic β-cell (Sjöholm Å, Welsh N, Hellerström C: Lithium increases DNA replication, polyamine content and insulin secretion by rat pancreatic β-cells in vitro. Am J Physiol 262:C391-C395, 1992). In this study, the influence of lithium on β-cell signal transduction pathways was monitored and their importance for the stimulated cell replication and hormone secretion was elucidated by selective pharmacological probes. To this end, fetal rat pancreatic islets enriched in β-cells were isolated and cultured for 3 days with or without 10 mmol/l LiCl. This resulted in a marked mitogenic response by the β-cells, of similar magnitude to that obtained by pharmacological activation of cAMP-dependent protein kinases by forskolin or the Sp-diastereomer of cAMP or protein kinase C stimulation by phorbol ester. However, neither did lithium affect the islet content of cAMP (whereas forskolin did), nor was the mitogenic response to the ion impeded when islets were pretreated with the Rp-diastereomer of cAMP, a specific antagonist of cAMP-dependent protein kinases, or by the Ca2+ channel blocker D-600. The protein kinase C inhibitor l-(5′-isoquinolinesulfonyl)-2-methylpiperazine prevented the mitogenicity of phorbol ester, but not that of lithium. Conversely, addition of increasing concentrations of inositol along with lithium also did not affect the mitogenicity of the ion, providing indirect evidence against the involvement of protein kinase C in mediating the growth-promoting effect of lithium in this system. It was found that pretreatment of islets with pertussis toxin, which inactivates GTP-binding proteins by ADP-ribosylation, prevented the mitogenicity and part of the secretagogic action of lithium. It is concluded that although specific activation of the cAMP and protein kinase C signaling systems appears sufficient to trigger a mitogenic response of the β-cell, lithium seemingly does not work through any of these systems nor via Ca2+ influx in promoting β-cell mitogenesis. Our results, moreover, suggest that the actions of lithium are conveyed by pertussis toxin-sensitive GTP-binding proteins.
Skip Nav Destination
Article navigation
Original Articles|
August 01 1996
Lithium Stimulation of Rat Pancreatic β-Cell Replication Is Mediated Through Pertussis Toxin-Sensitive GTP-Binding Proteins and Occurs Independently of Ca2+ Influx, cAMP, or Protein Kinase C Activation
Åke Sjöholm
Åke Sjöholm
Department of Molecular Medicine, The Endocrine and Diabetes Unit, The Rolf Luft Center for Diabetes Research, Karolinska Institute, Karolinska Hospital, Stockholm, and the Department of Internal Medicine, Lowenstromska Hospital
Upplands Vasby, Sweden
Search for other works by this author on:
Address correspondence and reprint requests to Dr. Ake Sjoholm, Department of Molecular Medicine (L6:01B), The Endocrine and Diabetes Unit, The Rolf Luft Center for Diabetes Research, Karolinska Institute, Karolinska Hospital, S-171 76 Stockholm, Sweden. [email protected]
Diabetes 1996;45(8):1057–1062
Article history
Received:
November 14 1995
Revision Received:
March 07 1996
Accepted:
March 07 1996
PubMed:
8690152
Citation
Åke Sjöholm; Lithium Stimulation of Rat Pancreatic β-Cell Replication Is Mediated Through Pertussis Toxin-Sensitive GTP-Binding Proteins and Occurs Independently of Ca2+ Influx, cAMP, or Protein Kinase C Activation. Diabetes 1 August 1996; 45 (8): 1057–1062. https://doi.org/10.2337/diab.45.8.1057
Download citation file:
47
Views