Oscillations of insulin secretion can be triggered by imposed oscillations of cytoplasmic Ca2+ or metabolism in normal mouse islets.
Open accessAbstract
Glucose-induced insulin secretion depends on an acceleration of glucose metabolism, requires a rise in the cytoplasmic free Ca2+ concentration ([Ca2+]i), and is modulated by activation of protein kinases in beta-cells. Normal mouse islets were used to determine whether oscillations of these three signals are able and necessary to trigger oscillations of insulin secretion. The approach was to minimize or abolish spontaneous oscillations and to compare the impact of forced oscillations of each signal on insulin secretion. In a control medium, repetitive increases in the glucose concentration triggered oscillations in metabolism [NAD(P)H fluorescence], [Ca2+]i (fura-PE3 method), and insulin secretion. In the presence of diazoxide, metabolic oscillations persisted, but [Ca2+]i and insulin oscillations were abolished. When the islets were depolarized with high K+ with or without diazoxide, [Ca2+]i was elevated, and insulin secretion was stimulated. Forced metabolic oscillations transiently decreased or did not affect [Ca2+]i and potentiated insulin secretion with oscillations of small amplitude. These oscillations of secretion followed metabolic oscillations only when [Ca2+]i did not change. When [Ca2+]i fluctuated, these changes prevailed over those of metabolism for timing secretion. Repetitive depolarizations with high K+ in the presence of stable glucose (10 mmol/l) induced synchronous pulses of [Ca2+]i and insulin secretion with only small oscillations of metabolism. Continuous stimulation of protein kinase A (PKA) and protein kinase C (PKC) did not dissociate the [Ca2+]i and insulin pulses from the high K+ pulses. However, the amplitude of the insulin pulses was consistently increased, whereas that of the [Ca2+]i pulses was either increased (PKA) or decreased (PKC). In conclusion, metabolic oscillations can induce oscillations of insulin secretion independently of but with a lesser effectiveness than [Ca2+]i oscillations. Although oscillations in metabolism may cyclically influence secretion through an ATP-sensitive K+ channel (K+-ATP channel)-independent pathway, their regulatory effects are characterized by a hysteresis that makes them unlikely drivers of fast oscillations, unless they also involve [Ca2+]i changes through the K+-ATP channel-dependent pathway.
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Increased metabolism can stimulate insulin release independent of [Ca2+]i elevation.
“In addition, there is evidence that increased metabolism can stimulate insulin release independent of [Ca 2ϩ ] i elevation (36,37).”
From Paradoxical Stimulation of Glucagon Secretion by High Glucose Concentrations (2006) · cites this paper as [37]
Cited by
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Triggering and amplifying pathways of regulation of insulin secretion by glucose.
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Self-citationRegulation of insulin secretion: a matter of phase control and amplitude modulation
Henquin, J. C. (2009) · Diabetologia · doi:10.1007/s00125-009-1314-y · Cited by 493 · see citing works
“Moreover, imposed metabolic oscillations at stably elevated [Ca]c are poorly able to induce pulsatile insulin secretion compared with imposed [Ca]c oscillations [88].”
BackgroundSelf-citationGlucose-sensing mechanisms in pancreatic β-cells
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“…of lipid-derived signals (Deeney et al. 1996; Pinton et al. 2002), lipid-derived signals may still be important for activating or augmenting PKC activity since phorbol esters enhance insulin secretion even when intracellular Ca2C is raised by direct depolarization with high KC (Ravier et al. 1999).”
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“Experiments were performed at 37 °C as previously described (35).”
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Self-citationSignals and pools underlying biphasic insulin secretion.
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“Similar observations have been made with single or groups of islets when [Ca(2) ]i was intermittently raised in the presence of higher glucose concentrations (39,40).”
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Henquin, J. C., Ravier, M. A., Nenquin, M., Jonas, J., & Gilon, P. (2003) · European Journal of Clinical Investigation · doi:10.1046/j.1365-2362.2003.01207.x · Cited by 177 · see citing works
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“In addition, there is evidence that increased metabolism can stimulate insulin release independent of [Ca 2+ ]i elevation (36, 37).”
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“Furthermore, imposed metabolic oscillations give rise to small insulin secretion oscillations when compared with imposed [Ca(2) ]i oscillations (90).”
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“system using batches of 15 islets (35).”
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Self-citationEndocrine cells and blood vessels work in tandem to generate hormone pulses
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“In particular, it has been demonstrated that insulin release kinetics in response to glucose challenge, are biphasic and oscillatory in nature (Bergsten et al. 1994; Gilon et al. 2002; Ravier et al. 1999).”
BackgroundComplex Patterns of Metabolic and Ca2+ Entrainment in Pancreatic Islets by Oscillatory Glucose
Pedersen, M. G., Mosekilde, E., Polonsky, K. S., et al. (2013) · Biophysical Journal · doi:10.1016/j.bpj.2013.05.036 · Cited by 35 · see citing works
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Self-citationReduced Cytochrome c Is an Essential Regulator of Sustained Insulin Secretion by Pancreatic Islets*
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“Consequently, it seems as though oscillations in either the ATP/ADP ratio or [Ca(21)]i can support pulsatile secretion when the other factor remains stable (41,43).”
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Signaling Underlying Pulsatile Insulin Secretion
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“have reported that pulsatile secretion disappears when [Ca2+], is stable [45] but these authors have later confirmed our suggestion that pulsatile secretion can be accounted for by oscillations either in [Ca2+], or metabolism [70].”
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“…the [Ca2 ]i oscillation in response to glucose is apparently important for insulin secretion because it is associated with cell-membrane electrical bursting activity and, according to some studies, pulsatile insulin secretion (Bergsten et al., 1994; Ravier et al., 1999; Kjems et al., 2002).”
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“Subsequent opening of voltage-dependent Ca(2) channels ensues and allows an increase of the cytosolic Ca(2) concentration that finally triggers an increase in insulin secretion (28).”
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MIND-DEPENDENT CONFORMATIONAL CHANGES IN MINE REGULATE THE MIN OSCILLATION
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- Authors
- Ravier, M. A., Gilon, P., & Henquin, J. C.
- Affiliations
- UCLouvain (BE)
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 1999-12-01
- Volume
- 48
- Issue
- 12
- Pages
- 2374-2382
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2067542515
- Cited by
- 48
- References
- 0
- Citations by year
- 2022: 1 · 2021: 1 · 2020: 1 · 2018: 1 · 2017: 1 · 2015: 2 · 2014: 1 · 2013: 1 · 2012: 2
- FWCI
- 6.66
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- other-oa
- Locations
- Diabetes (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)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- metabolic oscillations, pancreatic beta cells, glucose-stimulated insulin secretion, diazoxide, potassium depolarization, protein kinase A, protein kinase C, ATP-sensitive potassium channels, NAD(P)H fluorescence, pancreatic islets, hysteresis
- MeSH terms
- Insulin Secretion, Animals, Calcium, Cells, Cultured, Diazoxide, Female, Glucose, Insulin, Islets of Langerhans, Kinetics, Mice, Inbred Strains, NAD, NADP, Oscillometry, Potassium, Protein Kinase C, Protein Kinases, Cyclic AMP-Dependent Protein Kinases, Mice
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