60
BIOCHEMICAL SOCIETY TRANSACTIONS
action liberated from the membranc-associated glycolipid
precursor [33]. Clearly, more work is required to elucidate
both the intimate mode of action of POS upon insulin release
and the identity of those first messengers which could stimulate its production in islet cells.
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33. Saltiel, A. R. ( 1 987) Endocrinology 120. 967-972
Received 3 August I 9 8 8
How does glucose induce inositol lipid hydrolysis in pancreatic islets?
A considerable amount of work has focused on thc nature
of the coupling mechanism between nutrient oxidation and
islet cell depolarization. It is generally accepted that a rise in
cellular ATP concentration as a result of nutrient oxidation
Pancrcatic islets are one, if not the only, example of a tissue in depolarizes the cell membrane by reducing its permeability
which inositol lipid metabolism can be triggered by a nutrient
to K + [6, 71. There are, however, a number of observations
stimulus, in addition to hormonal and neurotransmitter-type which are not consistent with this as the sole mechanism for
agonists. Among the nutrients capable of eliciting such an nutrient-induced islet cell dcpolarization.
First, there is a lack of correlation between islet ATP
effect are glucose, glyceraldehyde and a-ketoisocaproate,
each of which are potent stimuli for insulin secretion. The levels and glucose-induced insulin secretion [S, 91. Second, a
initial response to these substances, as with neurotrans- maximal effect of glucose on K’ permcability is observed at
mitters, is hydrolysis of phosphatidylinositol 4,5-bisphos- approximately 7-8 mM of the sugar [ 101, whereas clcctrical
phatc and the formation of inositol 1,4,5-trisphosphate [ I ] activity and insulin secretion increase up to 20 mM 19, 111.
and phosphatidate 121 and of inositol 1,3,4,5-tetrakisphos- Consequently, it seems likely that an additional mechanism
exists which couples glucose oxidation to islet cell dcpolariphate and inositol 1,3,4-trisphosphate[3].
As is the case for insulin secretion, inositol lipid hydrolysis
zation and Ca2+entry.
Recent work in our laboratory has demonstrated that
in response to nutrients appears to require oxidation of that
nutrient [2] and also the presence of Ca2+( l o - ‘ M or above) addition of lactate to perifused islets results in a transient
in thc incubation medium [4]. lnositol lipid breakdown in stimulation of 4sCa2+and [‘H]inositol efflux (Fig. I ) , suggestislets can be induced by raising cytosolic Ca2+ concentra- ing Ca2 entry and inositol lipid breakdown, respectively.
tions, cither by K + depolarization [4] or by removing Na+ Furthermore, subsequent removal of lactate resulted in a
from the medium (L. Best, unpublished work). In addition, similar increase in jsCa2+and [3H]inositol efflux. It is highly
inositol lipid breakdown can be induced in digitonin- unlikely that the latter effect occurred as a result of increased
permeabilized islets by raising the concentration of C a 2 + oxidation of the substrate. An alternative explanation is that
from lo-’ to 1 V sM [4]. Taken as a whole, these observa- the flux of lactate across the islet cell plasma membrane is a
tions strongly suggest that nutrient-induced inositol lipid determinant of membrane potential. Thus, the production of
metabolism occurs as a result of depolarization and Ca2+ lactate from glucose, and the subsequent efflux of lactate
entry into the islet cell via voltage-sensitive Ca?+ channels from the islet cell, could be at least a part of the mechanism
whereby glucose depolarizes islet cells. In this respect, it is of
[51.
LEONARD BEST
Department of Medicitie, Utiiversity of Munchester, Oxford
Road, Munchester MI3 9l’T U.K .
+
1989
61
627th MEETING, NOTTINGHAM
0.025-
0.020
X
g 0.015’
3
+
m
,o 0.010
0.005
0’
0.~~~1
0.025
Fig. 2. A possible role for luctate formation arid efflux it7 the
depolurizution of islet cells by glucose
X
G
.-
0.020.
u
-s
sequestration of Ca?+ into endoplasmic reticulum [ 131,
whereas the other products of inositide hydrolysis, inositol
1,3,4,5-tetrakisphosphate and diacylglycerol, may exert an
additional regulatory function upon the secretory process
II 41.
y 0.01 5.
?,
I
0.010
0.005’
20
25
30
35
40
45
50
55
Time (min)
Fig. I . Fractional o u ~ l o w rutes (t;OR) for 45Ca2+ Ulld
/~’I-t]iiiositoI
froin pre-loudecl puricreutic islets: eflects of mdditiori mid sirbseqireiit withdrawal of luctute
Groups of 150 islets were perifused in the presence of 5.6
mM-glucose and exposed to 40 mwlactate during the period
designated by the vertical lines.
interest that the conversion of glucose to lactate is approximately linear within the range 2.5-20 mwglucose. The
extrusion of protons, produced during glycolysis, could
occur in exchange for Na+; we have previously demonstrated an amiloride-sensitive N a + / H + exchange system in
islets [12]. The efflux of lactate via such a system would constitute a net loss of negative charge (see Fig. 2) and, theoretically, result in a depolarization of the islet cell membrane and
Ca?+ entry via voltage-sensitive Ca2+ channels. One of the
consequences of a rise in cytosolic Ca?+ concentration
would be the initiation of inositol lipid breakdown. The inositol 1,4,5-trisphosphate produced as a result could limit the
I . Best, L. & Malaisse, W. J. (1984) Enr/ocrino/ogy 115,
I8 14- I820
2. Best. L. & Malaisse, W. J. (1983) Mol. Cell. Endocrinol. 32,
205-2 14
3. Best, L., Tomlinson, S., Hawkins, P. T. & Downes, C. P. (1987)
Biochim. Biophp. Acrcr 927, 1 12- I 16
4. Best, L. ( 1986) Biochem. J. 235,773-779
5. Findlay, I. & Dunne, M. J. ( 1 985) FEBSLetr. 189,28 1-285
6 . Sturgess. N. C.. Hales. C. N. & Ashford. M. L. J . ( 1987) I’j7ugers
Arch. 409,607-6 15
7. Arkhammar, P., Nilsson. T., Korsman, P. & Berggren, P.-0.
( 1 987) J. Biol. Chem. 262.5448-5454
8. Hellman, B.. Idahl, L.-A. & Danielsson, A. ( 1969) Diuberes 18,
509-5 16
9. Malaisse, W. J., Sener, A.. Herchuelz. A. & Hutton, J . C. (1979)
Mercrbolism 28.373-386
10. Boschero, A. C. & Malaisse. W. J. ( I98 1 ) J. f’hysiol. (London)
315, 143-156
I I . Mcissner, H. P. & Schmelz. H. ( I 974) I’Jiigers Archiv. 351,
195-206
12. Best, L., Bone, E. A.. Meats, J. E. 6( Tomlinson, S. (1988) J.
Mol. Eticlocritiol. 1, 33-38
13. Nilsson. T., Arkhammar, P., Hallberg. A,, Hellman. B. &
Berggren. P.-0. ( I 987) Biocheni. J. 248,329-336
14. Metz, S. ( 1988) Dirrberes 37,3-7
Kcceived 3 August 1988
Role of protein kinase C in the regulation of insulin secretion
PETER M. JONES and SIMON L. HOWELL
Department of Physiology, Kirig’s College Loiidori,
Kerairigtori, London W8 7AH, U.K .
The Ca2+/phospholipid-dependent protein kinase C (PKC)
has been implicated in a variety of physiological systems,
Abbreviations used: PKC. protein kinase C; DAG, diacylglycerol;
PMXB. polymyxin B; PMA. phorbol 12-myristate 13-acetate; PDD,
4u-phorbol I2,13-didecanoate; PS, phosphatidylserine.
Vol. 17
including the control of insulin secretion from @-cellsof pancreatic islets of Langerhans (see Nishizuka, 1984). PKC has
been identified.and characterized in islets of Langerhans and
insulin-secreting tumour cells (for review, see Harrison et al.,
1984), and a number of endogenous substrates have been
reported for PKC in studies using intact, homogcnized or
clectrically permeabilized islets (Harrison el al., 1984; Jones
et al., 1988).
The activity of PKC in sirir is thought to be regulated by
the availability of diacylglyccrols (DAG) which can be