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Nicotinic Signaling Stimulates Glucagon Secretion in Mouse and Human Pancreatic α-Cells

Hamilton, Alexander LU ; Zhang, Quan ; Gao, Rui ; Hill, Thomas G. ; Salehi, Albert LU orcid ; Knudsen, Jakob G. ; Draper, Matthew B. ; Johnson, Paul R.V. ; Rorsman, Patrik LU and Tarasov, Andrei I. (2025) In Diabetes 74(1). p.53-64
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 Ca2+ 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 Ca2+ in glucagonsecreting α-cells but not in insulin-secreting β-cells. The 2.8-± 0.5-fold (P < 0.05) increase in Ca2+, observed in >70% of α-cells,... (More)

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 Ca2+ 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 Ca2+ in glucagonsecreting α-cells but not in insulin-secreting β-cells. The 2.8-± 0.5-fold (P < 0.05) increase in Ca2+, observed in >70% of α-cells, correlated well with a 2.5-± 0.3-fold stimulation of glucagon secretion. Nicotine-induced elevation of cytosolic Ca2+ 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.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetes
volume
74
issue
1
pages
12 pages
publisher
American Diabetes Association Inc.
external identifiers
  • pmid:39475504
  • scopus:85213393784
ISSN
0012-1797
DOI
10.2337/db23-0809
language
English
LU publication?
yes
id
31b73d67-95eb-4168-ab8b-9ad655d4a351
date added to LUP
2026-01-12 08:16:24
date last changed
2026-01-26 09:39:39
@article{31b73d67-95eb-4168-ab8b-9ad655d4a351,
  abstract     = {{<p>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<sup>2+</sup> 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<sup>2+</sup> in glucagonsecreting α-cells but not in insulin-secreting β-cells. The 2.8-± 0.5-fold (P &lt; 0.05) increase in Ca<sup>2+</sup>, observed in &gt;70% of α-cells, correlated well with a 2.5-± 0.3-fold stimulation of glucagon secretion. Nicotine-induced elevation of cytosolic Ca<sup>2+</sup> 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.</p>}},
  author       = {{Hamilton, Alexander and Zhang, Quan and Gao, Rui and Hill, Thomas G. and Salehi, Albert and Knudsen, Jakob G. and Draper, Matthew B. and Johnson, Paul R.V. and Rorsman, Patrik and Tarasov, Andrei I.}},
  issn         = {{0012-1797}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{53--64}},
  publisher    = {{American Diabetes Association Inc.}},
  series       = {{Diabetes}},
  title        = {{Nicotinic Signaling Stimulates Glucagon Secretion in Mouse and Human Pancreatic α-Cells}},
  url          = {{http://dx.doi.org/10.2337/db23-0809}},
  doi          = {{10.2337/db23-0809}},
  volume       = {{74}},
  year         = {{2025}},
}