PERSONAL SUMMARY OF:

INTERACTION OF GLYCOLYSIS
AND MITOCHONDRIAL RESPIRATION
IN METABOLIC OSCILLATIONS OF PANCREATIC ISLETS
Original Paper: Richard Bertram, Leslie S. Satin, Morten Gram Pedersen,
Dan S. Luciani, and Arthur Sherman
Biophysical Journal (2007) Vol. 92 pp.15441555.
2011-10879

Contents
1. Introduction
Biological oscillations
Glucose-stimulated insulin secretio
n from
pancreatic beta cells
Competing hypotheses
Dual oscillator model
2. Models
The glycolytic model
The mitochondrial model
The electrical/calcium model

3. Results
Fast, slow, and compound bursting
Plasma membrane hyperpolarizati
on
A mechanism for fast and slow mic
e
Limitations of the model
4. Conclusion
5. Further Research
6. References

Biological oscillations

Theoretical models can tell

many features of the biologi

cal oscillation
Molecular mechanisms
The conditions for oscillation
Physiological implications
Relations to other oscillatory p

henomena

Goldbeter, Berridge, Biochemical Oscillations and Cellular Rhythms, Cambridge

University Press, 1997

Glucose-stimulated insulin secretion from

pancreatic beta cells

Conventional model of insulin secretion

The conventional model fails to capture

the dynamic aspect of the insulin secreti

on
Oscillation in insulin secretion occurs in
several time scale
Faster component (15 sec ~ 2 min)
Slower component (2~7 min)
Lost in type 2 diabetes patients
Bertram et al., Metabolic and electrical oscillations: partners in
controlling pulsatile insulin secretion, Am J Physiol Endocrinol Metab
293: E890E900, 2007.

Competing hypotheses
Glycolysis-driven mechanism

Ca2+-driven mechanism
Ca2+ influx depolarizes the memb

Positive feedback of FBP on PFK-M

Oscillation in [ATP] and [ADP]
Oscillation in conductance of KATP

channel
The role of Ca2+ is mediatory and/or
nonessential

rane
Burst of Ca2+ influx is stopped by
negative feedback
K(Ca) channel activation
decrease of [ATP]/[ADP] that will cause

KATP channels to open

Ca2+ actively initiates the oscillati

on

Dual oscillator model

Fast component:

Ca2+ feedback onto cha

nnels and metabolism
Slow component:
oscillation in glycolysis

Bertram et al., Interaction of Glycolysis and Mitochondrial Respiration in Metabolic

Oscillations of Pancreatic Islets, Biophysical Journal Volume 92 March 2007 15441555.

The glycolytic model

is the average rate of considering the

cooperative activation/inhibition of PFK

subunits (Smolen, 1995)

Bertram et alCalcium and Glycolysis Mediate Multiple

Bursting Modes in Pancreatic Islets, Biophysical Journal
Volume 87 November 2004 30743087.

The mitochondrial model

NADH is produced in pyruvate dehydrogenase and citric acid cycle, and then c

onsumed in oxidative phosphorylation.

: O2 consumption at the electron transport chain

ADP is consumed and ATP is produced in mitochondria

General form of the flux equation (c: adjustable parameter)

The mitochondrial model

affects oxidative phosphorylation rate and ionic flow across the membrane

Ca2+ enters the mitochondria by Ca2+ uniporter and leaves through Na+/Ca2+ ex

changer.
: The fraction of free Ca2+

The electrical/calcium model

Plasma membrane potential determines the conductance of ions across the pl

asma membrane and vice versa

The ionic currents are in general given by

The electrical/calcium model

n: activation variable for the delayed rectifying K+ channel

,
: The conductance across the KATP channel

The electrical/calcium model

The cytosolic adenine nucleotide concentrations and cytosolic Ca2+ concentrati

ons are related

Fast, slow, and compound bursting

Only intermediate value of promote gl

ycolytic oscillation in this model

Only fast oscillation is observed when
is high
Increase in Ca2+ level rapidly turns off it
self by activating K(Ca) channel, KATP
channel, and ER Ca2+ ATPase
Bertram et al., Interaction of Glycolysis and Mitochondrial
Respiration in Metabolic Oscillations of Pancreatic Islets,
Biophysical Journal Volume 92 March 2007 15441555.

Fast, slow, and compound bursting

Both components are superimposed

when has intermediate value

Cellular O2 consumption rate is in pha
se with Ca2+ level and therefore with i
nsulin secretion

Bertram et al., Interaction of Glycolysis and Mitochondrial

Respiration in Metabolic Oscillations of Pancreatic Islets,
Biophysical Journal Volume 92 March 2007 15441555.

Plasma membrane hyperpolarization

When membrane Ca2+ oscillation is te

rminated by setting the fraction of ope

n K(ATP) channel 1, all metabolic osci
llation is terminated

Bertram et al., Interaction of Glycolysis and Mitochondrial

Respiration in Metabolic Oscillations of Pancreatic Islets,
Biophysical Journal Volume 92 March 2007 15441555.

Plasma membrane hyperpolarization

Experiments showed that metabolic oscillations

pause when the cell membrane is hyperpolarize

d by diazoxide
However, this is not necessarily a case against
glycolytic mechanism for slow oscillations
When membrane is hyperpolarized, cytosolic AT
P level increases enough to stall glycolysis
Bertram et al., Interaction of Glycolysis and
Mitochondrial Respiration in Metabolic Oscillations of
Pancreatic Islets, Biophysical Journal Volume 92
March 2007 15441555.

A mechanism for fast and slow mice

Individual mice differs in the oscill

ation period of pancreatic beta cell

The differences in glycolytic oscill
ation threshold comes from differe
nces in PFK isoform composition
M-isoform is oscillatory, while C-isofor

m is not oscillatory
Bertram et al., Interaction of Glycolysis and Mitochondrial Respiration in
Metabolic Oscillations of Pancreatic Islets, Biophysical Journal Volume 92
March 2007 15441555.

Limitations of the model

The model omitted large part of the glycolysis and citric acid cycle
The model does not preserve stoichiometry of the aerobic respiration
The far from ~6

Conclusion
A mathematical model of the beta cell that can account for fast(15 sec ~ 2 mi

n) and slow(2~7 min) oscillations in insulin was demonstrated

The glycolytic component produces slow oscillation and the electrical/calcium
component generates fast oscillation, and the two communicate through the a
ction of mitochondria (and ER)
Plasma membrane hyperpolarization can terminate metabolic oscillation, but it
is not an evidence against glycolytic oscillations
The differences between individual mices insulin oscillation period was ascrib
ed to differences in the isoform composition of PFK, which will be a possible e
xperimental test for this model

Further studies
Experimental and few theoretical investigations on the function of different mol

ecular components
Affect of the different SERCA isoforms using islets from SERCA3(relatively low Ca 2+ affinity)

knockout mice (Bertram & Arceo II, 2008)

Modulation of oscillation by phosphofructo-2-kinase and fructose-2,6-bisphosphate (Merrins
et al., 2012)
The role of Ca2+ oscillations (Merrins et al., 2010; Pedersen et al., 2013)
The role of KATP conductance in compound bursting (Watts et al., 2011; Ren et al., 2013)

Interislet synchronization (Zhang et al., 2008)

References
Bertram et al., Calcium and glycolysis mediate multiple bursting modes in pancreati

c islets, Biophys. J. (2004) Vol. 87, pp. 3074-3087.

Bertram et al., A simplified model for mitochondrial ATP production, J. Theor. Biol. (2
006) Vol. 243, pp. 575-586.
Bertram et al., Interaction of Glycolysis and Mitochondrial Respiration in Metabolic
Oscillations of Pancreatic Islets, Biophys. J. (2007) Vol. 92 pp. 15441555.
Bertram et al., Metabolic and electrical oscillations: partners in controlling pulsatile i
nsulin secretion, Am J Physiol Endocrinol Metab (2007) Vol. 293, pp. E890E900.
Bertram, Arceo II, A mathematical study of the differential effects of two SERCA Isof
orms on Ca2+ oscillations in pancreatic islets, Bull. Math. Biol. (2008) Vol. 70, pp. 12
511271.
Bertram et al., Response to the comment by F. Diederichs, Biophys. J. (2008) Vol. 9
4, pp. 5080.

References
Goldbeter, Berridge, Biochemical Oscillations and Cellular Rhythms, Cambridge Universit

y Press, 1997.
Jung et al., Correlated oscillations in glucose consumption, oxygen consumption, and intr
acellular free Ca2+ in single islets of Langerhans, J. Biol. Chem. (2000) Vol. 275 pp. 6642
6650.
Kennedy et al., Metabolic oscillations in -cells, Diabetes (2002) Vol. 51, Supplement 1, p
p. S152-S161.
Kindmark et al., Glucose-induced oscillations in cytoplasmic free Ca 2+ concentration prece
de oscillations in mitochondrial membrane potential in the pancreatic cell, J. Biol. Che
m. (2001) Vol. 276, pp. 3453034536.
Merrins et al., Metabolic oscillations in pancreatic islets depend on the intracellular Ca2+ l
evel but not Ca2+ oscillations, Biophys. J. (2010) Vol. 99, pp. 76-84.
Merrins et al., Phosphofructo-2-kinase/fructose-2,6-bisphosphatase modulates oscillation
s of pancreatic islet metabolism, PLoS ONE (2012) Vol. 7, No. 4, e34036.

References
Nunemaker et al., Individual mice can be distinguished by the period of their islet

calcium oscillations: Is there an intrinsic islet period that is imprinted in vivo?, Dia
betes (2005) Vol. 54 pp. 35173522.
Pedersen et al., Complex patterns of metabolic and Ca2+ entrainment in pancreat
ic islets by oscillatory glucose, Biophys. J. (2013) Vol. 105, pp. 29-39.
Ren et al., Slow oscillations of KATP conductance in mouse pancreatic islets pro
vide support for electrical bursting driven by metabolic oscillations, Am. J. Physio
l. Endocrinol. Metab. (2013) Vol. 305, pp. E805-E817.
Tornheim, Are metabolic oscillations responsible for normal oscillatory insulin sec
retion?, Diabetes (1997) Vol. 46, pp. 1375-1380.
Watts et al., Mathematical modeling demonstrates how multiple slow processes
can provide adjustable control of islet bursting, Islets (2011) Vol. 3, pp. 320-326.

References
Zhang et al., Long lasting synchronization of calcium oscillations by cholinergic

stimulation in isolated pancreatic islets, Biophys. J. (2008) Vol. 95, pp. 4676-4
688.