Abstract
Smoking is widely regarded as a risk factor for type 2 diabetes because nicotine contributes to insulin resistance by desensitizing the insulin receptors in muscle, liver, or fat. Little is known, however, about the immediate regulation of islet hormonal output by nicotine, an agonist of ionotropic cholinergic receptors. We investigated this by imaging cytosolic Ca 2+ dynamics in mouse and human islets using confocal microscopy and measuring glucagon secretion in response to the alkaloid from isolated mouse islets. Nicotine acutely stimulated cytosolic Ca 2+ in glucagonsecreting α-cells but not in insulin-secreting β-cells. The 2.8-± 0.5-fold (P < 0.05) increase in Ca 2+, observed in >70% of α-cells, correlated well with a 2.5-± 0.3-fold stimulation of glucagon secretion. Nicotine-induced elevation of cytosolic Ca 2+ relied on influx from the extracellular compartment rather than release of the cation from intracellular depots. Metabotropic cholinergic signaling, monitored at the level of intracellular diacylglycerol, was limited to 69% of α-cells versus 94% of β-cells. We conclude that parasympathetic regulation of pancreatic islet hormone release uses different signaling pathways in β-cells (metabotropic) and α-cells (metabotropic and ionotropic), resulting in the fine-tuning of acetylcholine-induced glucagon exocytosis. Sustained nicotinic stimulation is, therefore, likely to attenuate insulin sensitivity by increasing glucagon release.
Original language | English |
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Pages (from-to) | 53-64 |
Number of pages | 12 |
Journal | Diabetes |
Volume | 74 |
Issue number | 1 |
Early online date | 30 Oct 2024 |
DOIs | |
Publication status | Published (in print/issue) - 1 Jan 2025 |
Bibliographical note
Publisher Copyright:© 2024 by the American Diabetes Association.
Keywords
- Nicotine
- pancreatic α-cells
- glucagon secretion
- cholinergic signaling
- diabetes
- Humans
- Insulin-Secreting Cells/metabolism
- Mice, Inbred C57BL
- Male
- Glucagon-Secreting Cells/metabolism
- Glucagon/metabolism
- Signal Transduction/drug effects
- Calcium/metabolism
- Animals
- Nicotine/pharmacology
- Mice
- Receptors, Nicotinic/metabolism