Interplay between cytoplasmic Ca2+ and the ATP/ADP ratio: a feedback control mechanism in mouse pancreatic islets
Open accessAbstract
In pancreatic β cells, the increase in the ATP/ADP ratio that follows a stimulation by glucose is thought to play an important role in the Ca2+-dependent increase in insulin secretion. Here we have investigated the possible interactions between Ca2+ and adenine nucleotides in mouse islets. Measurements of both parameters in the same single islet showed that the rise in the ATP/ADP ratio precedes any rise in the cytoplasmic free-Ca2+ concentration ([Ca2+]i) and is already present during the initial transient lowering of [Ca2+]i produced by the sugar. Blockade of Ca2+ influx with nimodipine did not prevent the concentration-dependent increase in the ATP/ADP ratio produced by glucose and even augmented the ratio at all glucose concentrations which normally stimulate Ca2+ influx. In contrast, stimulation of Ca2+ influx by 30 mM K+ or 100 µM tolbutamide lowered the ATP/ADP ratio. This lowering was of rapid onset and reversibility, sustained and prevented by nimodipine or omission of extracellular Ca2+. It was, however, not attenuated after blockade of secretion by activation of α2-adrenoceptors. The difference in islet ATP/ADP ratio during blockade and stimulation of Ca2+ influx was similar to that observed between threshold and submaximal glucose concentrations. The results suggest that the following feedback loop could control the oscillations of membrane potential and [Ca2+]i in β cells. Glucose metabolism increases the ATP/ADP ratio in a Ca2+-independent manner, which leads to closure of ATP-sensitive K+ channels, depolarization and stimulation of Ca2+ influx. The resulting increase in [Ca2+]i causes a larger consumption than production of ATP, which induces reopening of ATP-sensitive K+ channels and arrest of Ca2+ influx. Upon lowering of [Ca2+]i the ATP/ADP ratio increases again and a new cycle may start.
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After 25-30 action potentials, the fall in cytoplasmic/submembrane ATP/ADP-ratio results in sufficient activation of KATP channels to terminate the burst and fully repolarize the β-cell to -70 mV.
“Eventually, after 25-30 action potentials, the fall in the cytoplasmic/submembrane ATP/ADP-ratio results in sufficient activation of KATP channels to terminate the burst and fully repolarize the β-cell to -70 mV (143, 675) (Figure 12A-B).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [143]
The ‘Functional significance of the changes in the ATP/ADP ratio induced by Ca2+’ section and its Figure 4 caption (page not provided) propose that a falling ATP/ADP ratio reopens KATP channels and arrests Ca2+ influx. The caption specifies partial membrane repolarization, not full repolarization to −70 mV; our copy also does not give a count of 25–30 action potentials or establish a submembrane ATP/ADP change. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAs intracellular ATP levels never fall below 1 mM in β-cells, even in the absence of glucose, KATP channels are largely closed even at resting glucose concentrations.
“As intracellular ATP levels never fall below 1 mM in β-cells, even in the absence of glucose (143, 422), KATP channels are largely closed, even at resting glucose concentrations.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [143]
The citation is attached to the assertion that intracellular ATP never falls below 1 mM, even without glucose. The Results report an ATP/ADP ratio at 1 mM glucose, and Table 1 reports ATP content in pmol per islet at 3 and 10 mM glucose; neither establishes an intracellular ATP concentration or a minimum in glucose-free conditions. I searched for intracellular ATP concentration and glucose-free ATP measurements. (LLM, conf=0.73)
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Gylfe, E. (1988) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)68305-x · Cited by 61 · see citing works
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Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men
Rorsman, P., & Ashcroft, F. M. (2018) · Physiological Reviews · doi:10.1152/physrev.00008.2017 · Cited by 793 · see citing works
Regulation of ATP production by mitochondrial Ca2+
Tarasov, A. I., Griffiths, E. J., & Rutter, G. A. (2012) · Cell Calcium · doi:10.1016/j.ceca.2012.03.003 · Cited by 319 · see citing works
The dynamic plasticity of insulin production in β-cells
Boland, B. B., Rhodes, C. J., & Grimsby, J. S. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.04.010 · Cited by 194 · see citing works
Göpel, S. O., Kanno, T., Barg, S., Eliasson, L., Galvanovskis, J., Renström, E., & Rorsman, P. (1999) · The Journal of General Physiology · doi:10.1085/jgp.114.6.759 · Cited by 137 · see citing works
Bertram, R., Satin, L. S., Pedersen, M. G., Luciani, D. S., & Sherman, A. (2007) · Biophysical Journal · doi:10.1529/biophysj.106.097154 · Cited by 105 · see citing works
Closing in on the mechanisms of pulsatile insulin secretion
Bertram, R., Satin, L. S., & Sherman, A. S. (2018) · Diabetes · doi:10.2337/dbi17-0004 · Cited by 83 · see citing works
- Authors
- DETIMARY, P., GILON, P., & HENQUIN, J.-C.
- Affiliations
- UCLouvain (BE)
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 1998-07-15
- Volume
- 333
- Issue
- 2
- Pages
- 269-274
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC1219582
- OpenAlex
- W1901140894
- Cited by
- 170
- References
- 1
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 6 · 2022: 7 · 2021: 6 · 2020: 4 · 2019: 1 · 2018: 1 · 2017: 8 · 2016: 5 · 2015: 4 · 2014: 14 · 2013: 5 · 2012: 7
- FWCI
- 7.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B)) (submittedVersion, other-oa)
- Funders
- Fédération Wallonie-Bruxelles
- Services Fédéraux des Affaires Scientifiques, Techniques et Culturelles
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- intracellular calcium, ATP/ADP ratio, pancreatic beta cells, pancreatic islets, insulin secretion, calcium influx, ATP-sensitive potassium channels, glucose stimulation, nimodipine, tolbutamide, alpha2-adrenoceptors, membrane potential oscillations, feedback control, adenine nucleotides
- MeSH terms
- Adenosine Diphosphate, Adenosine Triphosphate, Animals, Calcium, Calcium Channel Blockers, Cytoplasm, Female, Glucose, Hypoglycemic Agents, Insulin, Islets of Langerhans, Nimodipine, Potassium, Tolbutamide, Mice
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