Department of Molecular Medicine, The Rolf Luft Center for Diabetes Research, Karolinska Institutet, S-171 76 Stockholm, Sweden
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ABSTRACT |
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Pancreatic
-cell function is essential for the regulation of glucose
homeostasis in humans, and its impairment leads to the development of
type 2 diabetes. Inputs from glucose and cell surface receptors act
together to initiate the
-cell stimulus-response coupling that
ultimately leads to the release of insulin. Phosphorylated inositol
compounds have recently emerged as key players at all levels of the
stimulus-secretion coupling process. In this current review, we seek to
highlight recent advances in
-cell phosphoinositide research by
dividing our examination into two sections. The first involves the
events that lead to insulin secretion. This includes both new roles for
inositol polyphosphates, particularly inositol hexakisphosphate, and
both conventional and 3-phosphorylated inositol lipids. In the second
section, we deal with the more novel concept of the autocrine role of
insulin. Here, released insulin initiates signal transduction cascades,
principally through the activity of phosphatidylinositol 3-kinase. This
new round of signal transduction has been established to activate key
-cell genes, particularly the insulin gene itself. More
controversially, this insulin feedback has also been suggested to
either terminate or enhance insulin secretion events.
inositol polyphosphates; inositol lipids; insulin receptor; insulin
secretion; pancreatic -cell
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INTRODUCTION |
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PANCREATIC -CELL
stimulus-response coupling plays an essential role in the regulation of
blood glucose concentration because of the
-cell's ability to sense
and respond to external stimuli and to integrate the resulting
signaling into a stimulatory signal for insulin release. Although
glucose is often seen as the main signal in this process, in reality,
because of the relatively narrow physiological blood glucose
concentration range, a plethora of different factors, including other
nutrients, neurotransmitters, islet-generated factors, and systemic
growth factors, act in a concerted manner to control the release of
insulin (reviewed in Ref. 11). In most cases the action of
these factors is mediated by membrane receptors coupled to either G
proteins or tyrosine kinases, many of which subsequently activate the
phosphoinositide-derived second messenger cascades. Nonetheless, the
coupling of glucose metabolism to electrical activity remains central
in all models of
-cell stimulus-secretion coupling. The resting
membrane potential of the
-cell is thought to be set by the
ATP-sensitive K+ (KATP) channel (reviewed in
Ref. 4). Incubation of pancreatic
-cells with
stimulatory glucose concentrations leads to the activation of a cascade
of reactions that ends in the exocytosis of stored insulin. Briefly,
this complex of processes starts with the uptake of glucose by the
-cell high-Km/low-affinity glucose
transporter GLUT2 and proceeds with the conversion into glucose
6-phosphate by the
-cell isoform of glucokinase (reviewed in Refs.
62 and 75). The following metabolism of glucose in
glycolysis and the tricarboxylic acid cycle results in the generation
of ATP. Elevation in the ATP-to-ADP ratio leads to closure of
KATP channels, which in turn results in depolarization of
the plasma membrane. The subsequent opening of voltage-gated L-type
Ca2+ channels leads to an increase in the cytoplasmic free
Ca2+ concentration ([Ca2+]i),
which promotes insulin secretion (reviewed in Ref. 10).
In recent years, new information has emerged that suggests that
phosphorylated inositol compounds (Fig.
1), in addition to their established
roles in conveying signals from cell membrane receptors, also regulate
the KATP channel, the L-type Ca2+ channel,
exocytosis, and endocytosis and thus have become center stage in the
unfolding drama of -cell stimulus-response coupling.
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The aim of this current review is to examine the role of a diverse
family of phosphorylated inositol derivatives that are associated with
both the events following glucose metabolism and signaling pathways
associated with cell surface receptors. Interestingly, this family of
phosphorylated inositol derivatives is now emerging as a key mediator
of stimulus-response coupling. We will divide the contribution of these
molecules into two overall themes. The first is the role of
phosphorylated inositols in the pathways leading to secretion. The
second is the more novel concept of inositol lipids, mediating the
autocrine effect of insulin. The concept of an autocrine function for
insulin in -cells brings with it the need to reassess how many of
the functions previously ascribed to glucose are actually secondary to
insulin release and are, in fact, insulin-driven events.
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NEW ROLES FOR INOSITOL PHOSPHATES AND LIPIDS IN INSULIN STIMULUS-SECRETION COUPLING |
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Inositol polyphosphates and lipids serve a central and still
expanding role in cellular regulation (38, 72, 85).
Historically, inositol polyphosphates, both membrane lipids and
water-soluble phosphates, have been key mediators of -cell
stimulus-secretion coupling, mainly resulting from the activation of G
protein-coupled receptors (GPCR) but also in response to glucose
directly (28, 89, 101). Thus their principal sphere of
influence has been seen in terms of the GPCR-mediated breakdown of
phosphatidylinositol 4,5-bisphosphate
[PtdIns(4,5)P2] to the second
messengers diacylglycerol (DAG), which activates protein kinase C
(PKC), and inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], which
subsequently mobilizes Ca2+ from intracellular stores
(13, 71). However, glucose metabolism itself can also
stimulate inositol lipid turnover and the increase of
Ins(1,4,5)P3 (14).
The stimulatory effect of glucose on
Ins(1,4,5)P3 is largely thought to
be secondary to the influx of extracellular Ca2+ after
membrane depolarization and the Ca2+ activation of
phospholipase C (PLC; see Ref. 14). This finding has been
substantiated by subsequent work, with the proviso that direct
voltage-dependent production of
Ins(1,4,5)P3 (76, 30) may also contribute. What is less clear is the relative contribution of
the extracellular Ca2+-independent component of
glucose-induced inositol phosphate production (101). One
novel mechanism whereby
Ins(1,4,5)P3 could be enhanced irrespective of the method of production is the blockade of
Ins(1,4,5)P3 metabolism by
glycolytic intermediates, like fructose 1,6-bisphosphate. These can
enhance Ins(1,4,5)P3 accumulation
and lead to Ca2+ mobilization (73, 74).
Although it is not the intention of the current review to focus on this
area in detail, it is important to note that there is still a
considerable debate about the significance of this glucose-induced
Ins(1,4,5)P3 production. The debate
has been fueled by differences in experimental protocols, for example, variability in the length of myo-inositol labeling and the
lack of studies that have measured
Ins(1,4,5)P3 by HPLC or by specific mass assay. These methodological variations have been compounded by the
different experimental models used, ranging from -cell lines to
intact islets. Arguably, islets represent the most physiological system
to answer these questions, but even here dramatic differences in the
inositol phosphate responses to glucose occur, dependent on the length
of islet culture and the species used (rat and human vs. mouse; see
Ref. 101). Thus the glucose-stimulated accumulation of
Ins(1,4,5)P3 is still an area
requiring ongoing investigation.
More recently, new aspects of this established second messenger family have emerged, all of which may play a role in the final release of insulin. These include new substrates for PLC, including phosphatidylinositol (PtdIns), and the possibility that the GPCR-linked PLC-mediated breakdown of PtdIns(4,5)P2 can serve to mediate the closure of the KATP channel, enhancing stimulus-response coupling (3, 51). By contrast, increases in PtdIns 3-kinase activity mediated by secreted insulin are suggested to increase the opening of the KATP channel, thus repolarizing the membrane and acting as an off switch of the stimulus-response coupling (45). The most likely product of PtdIns 3-kinase mediating this effect is PtdIns(3,4,5)P3 (34, 51, 81). Novel roles for highly phosphorylated inositol polyphosphates, particularly inositol hexakisphosphate (InsP6), have been shown in the activation of the L-type Ca2+ channel (52) and both insulin exocytosis (22) and endocytosis (37).
The role of the below discussed phosphorylated inositol compounds in
pathways that lead to insulin secretion is schematically illustrated
and summarized in Fig. 2.
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NEW INSIGHTS INTO ESTABLISHED INOSITIDE PATHWAYS |
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The role of Ca2+ released from
Ins(1,4,5)P3-sensitive stores in
the insulin secretory process has often been seen to be secondary in
importance to Ca2+ entry via voltage-gated L-type
Ca2+ channels. It is nonetheless possible that these stores
play a role in modulating [Ca2+]i
oscillations in -cells. At least two different types of
Ca2+ oscillations occur in pancreatic
-cells, and they
can be distinguished by their frequency. It is interesting to note that
slow oscillations in [Ca2+]i (period
100-400 s; see Refs. 12 and 29) accompany similar oscillations in Ins(1,4,5)P3
concentrations (8), but the cause and effect still have to
be demonstrated. Although overexpression of PLC isoforms and their
respective G proteins show only a minimal impact on insulin secretion
(26) or are even inhibitory (39) and thus may
seem to negate the importance of this
Ins(1,4,5)P3-triggered system, such
an experimental approach may actually disrupt delicate feedback loops
associated with the generation of oscillations, for example by
chronically raising Ins(1,4,5)P3
rather than allowing it to oscillate. In the current review, we will
not focus on Ins(1,4,5)P3 in
detail, and the reader is referred to the reviews of Zawalich and
Zawalich (101), Hagar and Ehrlich (31), and
Gilon and Henquin (28) to examine these issues in more detail.
The simple mechanics of GPCR initiation of phospholipid breakdown may
be considered an established area with little novel to offer. However,
-cell biology is still full of interesting surprises. Recent studies
(65) have demonstrated that carbachol via muscarinic
receptors can instigate the breakdown not only of
PtdIns(4,5)P2 but also of PtdIns
and that these two actions are mechanistically distinct. The latter is
mediated by PLC-
in a tyrosine kinase-dependent manner, whereas the
former is mediated by PLC-
and is independent of tyrosine
phosphorylation. This discovery is important, as it represents a
divergence between PtdIns and
PtdIns(4,5)P2 pathways that has
significance in cellular signaling in all cells with muscarinic
receptors. The question is: does this bifurcation serve any purpose?
Mitchell et al. (65) noted that there is an obvious
difference in output as PLC breakdown of
PtdIns(4,5)P2 leads to two second
messengers, Ins(1,4,5)P3 and DAG,
whereas PtdIns breakdown only leads to one, namely DAG, the inositol
monophosphate having no known messenger function. This
diversification enables the cell to activate the PKC pathway without
triggering Ca2+ release. However, carbachol-stimulated
breakdown of PtdIns can generate an additional acid-labile putative
"second messenger," cyclic inositol monophosphate
[cIns(1:2)P; see Ref. 21], usually destroyed
and thus not detected by conventional inositol phosphate extraction
protocols. cIns(1:2)P is a major product of the PLC breakdown of PtdIns (21, 46, 63), whereas cyclic
Ins(1,4,5)P3 is only a minor
product of PtdIns(4,5)P2 breakdown
(46, 91). This would then represent an additional reason
for a bifurcation in the pathways. The precise function of
cIns(1:2)P still remains undefined, but in 3T3 fibroblasts,
overexpression of the enzyme that degrades it inhibits DNA synthesis
(77). The PLC-
-mediated induction of DNA synthesis has
previously been ascribed to the breakdown of
PtdIns(4,5)P2 in the initiation of
mitogenic responses (42). Clearly these observations merit
further investigation, since some of the mitogenic pathways in
non-
-cells mediated by PLC-
may have been wrongly attributed to
the breakdown of PtdIns(4,5)P2 and
the formation of Ins(1,4,5)P3.
However, such investigations will require some caution, since the
mitogenic effect of PLC-
in some cell systems is partially
(82) or wholly (99) independent of its lipase
activity. It is interesting to note that the exact mechanism whereby
carbachol/ACh activates PLC-
is unresolved. However, the fact that
both tyrosine- and PtdIns 3-kinase-dependent mechanisms are involved
does leave the possibility open that some PtdIns breakdown could be
secondary to insulin secretion.
Although important new aspects of established inositide signaling
pathways, like the breakdown of PtdIns above, have been revealed, other
more novel areas of phosphoinositol-based signaling have emerged
recently and have had a profound impact on our understanding of
-cell stimulus-secretion coupling. In particular, new roles have
been established for both phospholipids,
PtdIns(4,5)P2 and PtdIns(3,4,5)P3, and highly
phosphorylated inositol polyphosphates. We will now examine these new
areas in more detail.
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A NEW ROLE FOR INOSITOL LIPIDS IN KATP CHANNEL REGULATION? |
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Although historically
PtdIns(4,5)P2 is thought of in
terms of a precursor to more important second messengers such as
InsP3 (13) and
PtdIns(3,4,5)P3 (72),
in many cell types, including -cells,
PtdIns(4,5)P2 has now been
established to be a key regulator in its own right. In the
-cell,
PtdIns(4,5)P2 has been proposed to
have a role in the direct regulation of the KATP channel.
PtdIns(4,5)P2 serves to decrease
the sensitivity of the channel to ATP (reviewed in Refs.
3, 51, and 36), and the proposal
that PtdIns(4,5)P2 regulates the
channel is an attractive one, since it could resolve a long-standing
paradox in KATP channel regulation. ATP in the micromolar
range can block the KATP channel; however, the cellular concentration of ATP is 3-5 mM. The desensitization of the
KATP channel by
PtdIns(4,5)P2 brings the regulation
of the channel into the physiological range of ATP concentrations found
in the cytosol (9, 35, 81). It is also appealing in that
one could envisage that the breakdown of
PtdIns(4,5)P2 by GPCR would lead to
increased sensitivity of the KATP channel to ATP. The
KATP channel then becomes the key integration point between
glucose metabolism and agonists working through GPCRs, the combination of the two having a synergistic effect on membrane depolarization and
thus stimulus-secretion coupling. However, there are a number of
caveats that need to be placed on these ideas. First, before the advent
of PtdIns(4,5)P2, there were other
explanations for resolving the discrepancy between high intracellular
ATP concentrations and the much lower concentrations of this
nucleotide required to effectively block the channel. One example was
the "spare channel" effect, which suggested that >99% of the
KATP channels need to be closed for the cell to depolarize
(16); thus, the high ATP caused most of the channels to be
inactivated, but a few were still open and thus small changes in ATP
could mediate this final complete closure. ADP has been suggested to
antagonize the effect of ATP, thus emphasizing the importance of the
ATP-to-ADP ratio over ATP concentration per se (41). It is
interesting, however, to note that some of the proponents of the latter
hypothesis have now incorporated it into a more comprehensive scheme
that also includes PtdIns(4,5)P2
(58). The main problem with the
PtdIns(4,5)P2 hypothesis, as
pointed out by us (51), is that many of the studies have
used unphysiological conditions to draw their conclusions. Our main
concern here is the physical state in which
PtdIns(4,5)P2 is presented in
electrophysiological experiments. In many studies, a patch of membrane
is excised from the cell membrane, and a preparation of
PtdIns(4,5)P2 is applied. There are
two concerns here. First, the lipid is added directly to the aqueous
buffer used in the experiment and sonicated, leading to the possibility
of insoluble aggregates (51). Second, even if the lipid is
prepared using the sonication of a dried lipid film, thus eliminating
the formation of aggregates, another danger lurks. In contrast to the
addition of a water-soluble chemical, the addition of a lipid of a
given concentration to a small membrane patch or even a cell is likely to lead to supraphysiological concentrations in the membrane. Other
studies rely on the overexpression of key phosphoinositide metabolizing
enzymes, an approach we suggest is problematic (see NEW INSIGHTS INTO ESTABLISHED INOSITIDE
PATHWAYS and Ref. 51) because of the possible
distortion of receptor-linked pools of PtdIns(4,5)P2 (27).
For example, studies in which the stimulation of PLC-linked GPCRs
appeared to increase channel sensitivity to ATP by the enhanced
degradation of PtdIns(4,5)P2 were
based on the overexpression of the receptors in model systems (9,
93). Another issue is the possibility that other inositol lipids
besides PtdIns(4,5)P2 are
candidates for this regulatory role. A series of studies, including the
original reports (34, 45, 51, 81), have suggested that
PtdIns(3,4,5)P3, the product of
PtdIns 3-kinase-dependent
PtdIns(4,5)P2 phosphorylation, may
serve the same function as
PtdIns(4,5)P2. This may be
particularly important when considering insulin-mediated feedback on
the
-cell and will be discussed in this context below. In
conclusion, the PtdIns(4,5)P2 KATP channel hypothesis is attractive, but until the
definitive experiments have been done in
-cells, linking muscarinic
or other PLC-linked receptors to
PtdIns(4,5)P2 breakdown and the
activation of the KATP channel in situ, we must be cautious.
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NEW ROLES FOR NOVEL INOSITOL PHOSPHATES |
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Although the precise role of the second messenger
Ins(1,4,5)P3 in -cell
stimulus-secretion coupling is still unclear, another inositol
polyphosphate, only distantly related to
Ins(1,4,5)P3, has now emerged as a
potential major player in this process. InsP6 has been demonstrated to both directly stimulate secretion
(22) and enhance the current through the L-type
voltage-dependent Ca2+ channel (52). The more
direct effect of InsP6 on exocytosis is also
mimicked by the main inositol pentakisphosphate in cells, inositol
1,3,4,5,6-pentakisphosphate (22), and appears to be dependent on PKC. This effect may be considered to be an "inositol polyphosphate effect" similar to that seen with synaptotagmin (25). The effect on the L-type Ca2+ channel is
apparently more specific for InsP6 and is
mediated at least in part by the inhibition of serine/threonine protein phosphatase activity (52). A recent study in neuronal
cells (98) has confirmed that the effect of
InsP6 specifically relates to L-type
Ca2+ channels and has also introduced the additional
observation that InsP6 can activate adenylate
cyclase, a key player in
-cell stimulus-secretion coupling
(67, 90). The fact that data indicate that both protein kinase A (18) and serine/threonine protein phosphatase 2A
(19) are associated with the channel via specific
protein-protein interactions and that InsP6 can
be tightly associated with membrane structures suggests that a specific
pool of InsP6 may regulate the L-type Ca2+ channel. Our studies in
-cells (52)
indicate that a small but consistent transient elevation in
InsP6 concentration follows glucose stimulation
and that the temporal changes in InsP6 correlate well with the initial rise in intracellular Ca2+ mediated
by the channels. The small changes in InsP6
concentration suggest that only a small pool of
InsP6 is mediating these effects. The membrane
association of InsP6 (70) does give
some credence to the idea that a small, metabolically active but
physically distinct pool of this inositol phosphate might exist. More
recent studies on neuronal cells lend further support to the idea that there may be discrete functionally distinct pools of
InsP6 within cells. This is because type II and
type III InsP6 kinases are specifically
localized in the nucleus and the cytosol, respectively (79). In addition, older data have indicated that a
considerable amount of InsP6 may be associated
with specific proteins, even within the cytosol (25).
As we have discussed previously (7), the metal chelating
property of InsP6, specifically because of its
binding of intracellular iron and the subsequent blockade of free
radical cascades, may represent an important oxidant defense mechanism
for the -cell, which otherwise is poorly protected against free
radical-mediated cell death because of the dearth of protective enzymes
(2). It is interesting to note that in other cells the
nuclear type II InsP6 kinase mentioned above
mediates interferon-
-induced apoptosis (66).
The mechanism is not known, but obviously the kinase could cause the
specific local depletion of InsP6, a protective molecule, in the nucleus, thus increasing the possibility of
apoptosis resulting from free radical production. Further
support for the protective effect of InsP6 comes
again from other cell systems, suggesting that
InsP6 can both specifically block DNA damage
(64) and activate DNA-dependent kinase (32).
Because the players in these studies are universal in all cells, these
data have important implications for the
-cell as well. The products
of the InsP6 kinase are high-energy
pyrophosphate derivatives and represent an important new field of
inositide research. Their role in the
-cell still remains to be
assessed, but preliminary data suggest that at least one isoform is at
an unusually high concentration in a
-cell line [C. J. Barker,
J. Yu, and P. O. Berggren, unpublished observations, and Larsson
et al. (52), Fig. 1]. Again, a recent study on
neurons has demonstrated that another InsP6
kinase, i.e., type I, is connected to membrane trafficking and
exocytotic events via interactions with GRAB and Rab3A
(59). Thus InsP6 and its pyrophosphate derivatives are likely to be involved in three key processes in the pancreatic
-cell, namely, regulation of the voltage-dependent L-type Ca2+ channel (52,
98), vesicle trafficking/exocytosis/endocytosis (22, 37,
59), and apoptosis (52). We believe that
highly phosphorylated inositol phosphates represent an important new direction for
-cell research.
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ROLE OF PHOSPHORYLATED INOSITOL COMPOUNDS IN AUTOCRINE INSULIN
FEEDBACK ACTION IN PANCREATIC ![]() |
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Receptor-mediated events in -cells have taken an entirely new
direction with the growing evidence that insulin itself is a key player
in
-cell physiology. This includes processes such as the regulation
of gene transcription (11, 17, 53-57, 92, 97),
translation (95), ion flux (6, 94),
-cell
proliferation (49, 87, 88), cell survival
(50), and finally insulin secretion (5, 6, 45,
68). In this scenario, phosphorylated inositol compounds are
central to the autocrine insulin effect. Consequently, both the
disputed idea that insulin itself may trigger PLC-mediated breakdown of
PtdIns(4,5)P2 and the
well-documented activation of PtdIns 3-kinase by insulin become central
topics in understanding how inositol derivatives are involved in the complex regulation of
-cell function.
Data by Velloso et al. (86) and Harbeck et al.
(33) convincingly showed that pancreatic -cells express
insulin receptors. Moreover, it has been demonstrated that insulin,
secreted upon glucose stimulation, activates insulin receptors and the
downstream-located PtdIns 3-kinase, which generates
PtdIns(3,4,5)P3, and insulin receptor substrate proteins (33, 86). These studies
provide evidence for an autocrine feedback action of insulin at the
molecular level but do not yet resolve whether insulin is a negative,
positive, or complex (negative and positive) signal in
-cell
function. To date, at least two of these insulin-feedback responses
have been suggested to involve the activity of PtdIns 3-kinase, namely gene transcription (17, 53, 57, 60) and insulin
exocytosis, the latter in a controversial manner (5, 45).
This list is unlikely to be exhaustive, since established components of
insulin signal-transduction, characterized in other cell types, are
likely to be found also in the pancreatic
-cell. For example, the
insulin-mediated activation of PLC-
has been reported in several
cell types (42). In the
-cell, this may be of
particular interest given observations of Mitchell et al.
(65) that this enzyme can be coupled to PtdIns rather than
PtdIns(4,5)P2 breakdown, as
discussed above.
In the following two sections we will focus on insulin feedback
regulation of gene expression and KATP channel activity by the lipid products of PtdIns 3-kinase(s). The role of the
phosphorylated inositol compounds involved in the feedback action by
insulin (to be discussed) is schematically illustrated and summarized in Fig. 3.
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TWO DIFFERENT INSULIN RECEPTOR SUBTYPES CONTROL GENE REGULATION VIA DISTINCT PTDINS 3-KINASE ACTIVITIES |
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As mentioned briefly above, activation of PtdIns 3-kinase, and
thereby generation of
PtdIns(3,4,5)P3 in response to
glucose stimulation of pancreatic -cells and the subsequent
activation of insulin receptors by secreted insulin were already
reported in 1995 (78, 86). Recent work by others and us,
employing the pharmacological inhibitors wortmannin and LY-294002 of
PtdIns 3-kinase and the dominant-negative mutant of p85, e.g.,
p
85 (20), clearly demonstrates the involvement of
PtdIns 3-kinase class Ia in the autocrine insulin feedback in glucose-
and/or insulin-stimulated upregulation of insulin gene transcription
(17, 53, 57, 60). In other cell types, in addition to
class Ia, insulin has been shown to activate class II PtdIns 3-kinases,
such as PtdIns 3-kinase-C2
(1, 15) and
PtdIns 3-kinase-C2
(1), kinases that generate
preferentially phosphatidylinositol 3-monophosphate and
PtdIns(3,4)P2. We suggest the
involvement of class II PtdIns 3-kinase (reviewed in Ref.
24), most likely PtdIns 3-kinase-C2
, in the
activation of glucose- and/or insulin-dependent glucokinase gene
expression in pancreatic
-cells (53, 44). This
assumption is based on the observation that elevated concentrations of
the pharmacological inhibitors LY-294002 and wortmannin are needed to
inhibit the stimulatory effect of glucose/insulin on glucokinase gene
expression. Western blot analysis revealed the presence of PtdIns
3-kinase-C2
in insulin-producing cells, and
coimmunoprecipitation of PtdIns 3-kinase-C2
and insulin
receptors suggests a direct interaction (44). A novel and
fascinating aspect of the two alternative PtdIns 3-kinase pathways
regulating insulin and glucokinase gene transcription is our
observation that each pathway is mediated by a different subtype of the
insulin receptor (53). Although secreted insulin activates
the transcription of its own gene by signaling via the A-type insulin
receptor (Ex11
) and the activation of PtdIns 3-kinase class Ia, it
needs signaling via the B-type receptor (Ex11+) and probably the class
II PtdIns 3-kinase activity to upregulate glucokinase gene
transcription. This is the first time a differential output for these
receptors has been demonstrated, and this observation clearly has
important implications for areas of insulin regulation outside the
-cell.
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INSULIN-STIMULATED INSULIN SECRETION DEBATE: A ROLE FOR PTDINS(3,4,5)P3 IN INSULIN FEEDBACK VIA THE KATP CHANNEL? |
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In addition to a role in the stimulation of gene expression, the
insulin feedback mechanism in -cells has been proposed to be
involved in the regulation of insulin exocytosis. This idea is not a
new one; however, the area is controversial and is currently under
discussion. Historically, insulin secretion was suggested to be
inhibited by secreted insulin (23, 40,45, 100, 102). On the other hand, similar models used by others fail to support this
concept (61, 80, 84). An important impetus for the hypothesis that insulin stimulates its own secretion came from the
characterization of the
IRKO mouse, an animal model that lacks the
expression of insulin receptors in the pancreatic
-cell. At 8 wk,
these mice exhibit a selective loss of glucose-stimulated acute insulin
secretion (48). However, care must be exercised in linking
longer-term knockout effects with the acute regulation demonstrated in
the biochemical experiments discussed below. In some reports, feedback
via the insulin receptor has been suggested to be part of a
feed-forward mechanism by increasing [Ca2+]i
and thus exocytosis (5, 6, 94, 96). The key differences in
these studies are whether the [Ca2+]i rise is
dependent on PtdIns 3-kinase (5, 6) or not (96, 94) as well as the source of the
[Ca2+]i rise, i.e., blockade of the
(sarco)- endoplasmic reticulum (ER) Ca2+-ATPase (SERCA)
(94, 96), or by a more direct mobilization of
Ca2+ from the ER (6). In other studies,
insulin has been suggested to activate a negative feedback loop
(45, 100, 102). Another area of active debate is the
methodology employed to support the feed-forward mechanism of insulin
on insulin exocytosis (5, 6), in particular, the use of
5-hydroxytryptamine as a surrogate for insulin to enable easier
detection of secreted insulin. This is because of the inhibitory action
of serotonin loading on the stimulus-secretion coupling
(100). Nonetheless, it is important to note that the
original feed-forward findings, based on serotonin amperometry, were
confirmed with insulin-specific electrodes (5). Clearly,
it is important to resolve this discrepancy.
A further possible mechanism for insulin to regulate its secretion is
to modulate the activity of the KATP channel. In neurons, it has been suggested that stimulation by insulin via the activation of
PtdIns 3-kinase and the production of
PtdIns(3,4,5)P3 can serve to open
the KATP channel (83). If this were to occur
in the -cell, the stimulus-secretion coupling should be switched
off. In parallel work on a rat insulinoma
-cell model (GRI-G1), the same group was unable to see similar effects on the KATP
channel, although
PtdIns(3,4,5)P3 levels were
increased significantly (34). However, a recent study on a
more physiologically relevant model, normal mouse
-cells, has now
produced concrete evidence that KATP channels can be opened
by insulin via PtdIns 3-kinase (45), the most likely
candidate being PtdIns(3,4,5)P3. As
mentioned above, PtdIns(4,5)P2 and
PtdIns(3,4,5)P3 have been suggested
to be physiological "openers" of KATP channels, thereby
shifting the ATP-dependent closure of the channel into the
physiological range of ATP concentrations (51). The
aforementioned studies of normal mouse
-cells have demonstrated a
PtdIns 3-kinase-dependent inactivation of insulin secretion by
hyperpolarization of the plasma membrane (45), the latter
providing the potential molecular basis for pulsatile insulin release
(69) via the probable production of
PtdIns(3,4,5)P3. The presence of
oscillatory insulin release and the therefore nonconstant exposure of
the insulin receptor to insulin would also facilitate the proper
functionality of the insulin receptor by preventing its desensitization.
![]() |
CONCLUDING REMARKS |
---|
The aim of this review was to highlight known and potential roles
of phosphorylated inositol compounds in -cell stimulus-response coupling. Besides the newly addressed roles for inositol phosphates and
lipids in insulin stimulus-response coupling, there are exciting possibilities for phosphorylated inositol compounds resulting from the
autocrine insulin feedback action in
-cell function (5, 6, 17,
45, 50, 53, 57, 60, 68, 95). Insulin, by feeding back through
its own and possibly the IGF-I receptor effectively initiates
-signal transduction cascades. Although general consensus exists on
the idea that insulin feedback action positively affects the regulation
of its own gene via the activation of PtdIns 3-kinase Ia (17, 53,
57, 60), the most controversially discussed topic is the effect
of secreted insulin on insulin secretion (5, 6, 45, 68, 100,
102). However, as contradictory as these reports might look at
first glance, perhaps the different experimental conditions used may offer the explanation of the reported results. One crucial aspect may
be the dynamics of events triggered by insulin. In fact, secreted insulin activates its own receptor and thereby PtdIns 3-kinase rapidly.
This may indeed form the basis for an influence on processes involved,
even in the first phase of insulin exocytosis, not to mention the
potential modulation of the second phase by promoting recruitment of
secretory granules to the plasma membrane. On the other hand,
continuous exposure of
-cells to high levels of insulin, as is the
case in insulin-clamp studies or as a result of long-term incubation of
-cells with insulin secretagogues, may indeed result in a lack of
response because of desensitization of the signaling cascade or even in
a negative feedback.
Besides insulin secretion, other -cell parameters, such as the
regulation of Ca2+ flux, protein biosynthesis, and
cytoprotective action, have been suggested to be dependent on
insulin-activated PtdIns 3-kinase (5, 6, 17, 45, 50, 53, 57, 60,
68, 95). Future research will not only have to clarify which
processes that have previously been described to be glucose dependent
are in fact insulin dependent but will also have to show to what extent maintenance of
-cell function is dependent on the autocrine insulin feedback action and signaling via phosphorylated inositol compounds.
![]() |
ACKNOWLEDGEMENTS |
---|
This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-58508, The Swedish Research Council, Juvenile Diabetes Research Foundation International, Novo Nordisk Foundation, and Funds of Karolinska Institutet.
![]() |
FOOTNOTES |
---|
Address for reprint requests and other correspondence: P.-O. Berggren, Dept. of Molecular Medicine, The Rolf Luft Center for Diabetes Research, Karolinska Hospital L3, Karolinska Institutet, S-171 76 Stockholm, Sweden (E-mail: Per-Olof.Berggren{at}molmed.ki.se).
10.1152/ajpendo.00088.2002
![]() |
REFERENCES |
---|
1.
Arcaro, A,
Zwelebil MJ,
Wallasch C,
Ullrich A,
Waterfield MD,
and
Domin J.
Class II phosphoinositide 3-kinases are downstream targets of activated polypeptide growth factor receptors.
Mol Cell Biol
20:
3817-3830,
2000
2.
Asayama, K,
and
Burr IM.
Rat superoxide dismutases. Purification, labeling, immunoassay, and tissue concentration.
J Biol Chem
260:
2212-2217,
1985[Abstract].
3.
Ashcroft, FM.
Exciting times for PIP2.
Science
282:
1059-1060,
1998
4.
Ashcroft, FM,
and
Rorsman P.
ATP-senstitive K+ channels: a link between B-cell metabolism and insulin secretion.
Biochem Soc Trans
18:
109-111,
1990[ISI][Medline].
5.
Aspinwall, CA,
Lakey JRT,
and
Kennedy RT.
Insulin-stimulated insulin secretion in single pancreatic -cells.
J Biol Chem
274:
6360-6365,
1999
6.
Aspinwall, CA,
Qian WJ,
Roper MG,
Kulkarni RN,
Kahn CR,
and
Kennedy RT.
Roles of insulin receptor substrate-1, phosphatidylinositol 3-kinase, and release of intracellular Ca2+ stores in insulin-stimulated insulin secretion in -cells.
J Biol Chem
275:
22331-22338,
2000
7.
Barker, CJ,
and
Berggren PO.
Inositol hexakisphosphate and beta-cell stimulus-secretion coupling.
Anticancer Res
19:
3737-3741,
1999[ISI][Medline].
8.
Barker, CJ,
Nilsson T,
Kirk CJ,
Michell RH,
and
Berggren PO.
Simultaneous oscillations of cytoplasmic free Ca2+ concentration and Ins(1,4,5)P3 concentration in mouse pancreatic beta-cells.
Biochem J
297:
265-268,
1994[ISI][Medline].
9.
Baukrowitz, T,
Schulte U,
Oliver D,
Herlitze S,
Krauter T,
Tucker SJ,
Ruppersberg JP,
and
Fakler B.
PIP2 and PIP as determinants for ATP inhibition of KATP channels.
Science
282:
1141-1144,
1998
10.
Berggren, PO,
and
Larsson O.
Ca2+ and pancreatic B-cell function.
Biochem Soc Trans
22:
12-18,
1994[ISI][Medline].
11.
Berggren, PO,
Rorsman P,
Efendic S,
Östenson CG,
Flatt P,
Nilsson T,
Arkhammer P,
and
Juntti-Berggren L.
Mechanisms of action of entero-insular hormones and neural input on the insulin secretory process.
In: Nutrient Regulation of Insulin Secretion, edited by Flatt P.. Portland, OR: Portland Press, 1992, chapt. 14, p. 289-318.
12.
Bergsten, P.
Role of oscillations in membrane potential, cytoplasmic Ca2+, and metabolism for plasma insulin oscillations.
Diabetes
51, Suppl1:
S171-S176,
2002
13.
Berridge, MJ,
and
Irvine RF.
Inositol phosphates and cell signalling.
Nature
341:
197-205,
1989[ISI][Medline].
14.
Biden, TJ,
Peter-Riesch B,
Schlegel W,
and
Wollheim CB.
Ca2+-mediated generation of inositol 1,4,5-triphosphate and inositol 1,3,4,5-tetrakisphosphate in pancreatic islets. Studies with K+, glucose, and carbamylcholine.
J Biol Chem
262:
3567-3571,
1987
15.
Brown, RA,
Domin J,
Arcaro A,
Waterfield MD,
and
Shepherd PR.
Insulin activates the isoform of class II phosphoinositide 3-kinase.
J Biol Chem
274:
14529-14532,
1999
16.
Cook, DL,
Satin LS,
Ashford ML,
and
Hales CN.
ATP-sensitive K+ channels in pancreatic beta-cells. Spare-channel hypothesis.
Diabetes
37:
495-498,
1988[Abstract].
17.
Da Silva Xavier, G,
Varadi A,
Ainscow WK,
and
Rutter GA.
Regulation of gene expression by glucose in pancreatic -cells (MIN6) via insulin secretion and activation of phosphatidylinositol 3'-kinase.
J Biol Chem
275:
36269-36277,
2000
18.
Davare, MA,
Dong F,
Rubin CS,
and
Hell JW.
The A-kinase anchor protein MAP2B and cAMP-dependent protein kinase are associated with class C L-type calcium channels in neurons.
J Biol Chem
274:
30280-30287,
1999
19.
Davare, MA,
Horne MC,
and
Hell JW.
Protein phosphatase 2A is associated with class C L-type calcium channels (Cav1.2) and antagonizes channel phosphorylation by cAMP-dependent protein kinase.
J Biol Chem
275:
39710-39717,
2000
20.
Dhand, R,
Hara K,
Hiles I,
Bax B,
Gout I,
Pnayotou G,
Fry MJ,
Yonezawa K,
Kasuga M,
and
Waterfield MD.
PI 3-kinase: structural and functional analysis of intersubunit interactions.
EMBO J
13:
511-521,
1994[Abstract].
21.
Dixon, JF,
and
Hokin LE.
Kinetic analysis of the formation of inositol 1:2-cyclic phosphate in carbachol-stimulated pancreatic minilobules. Half is formed by direct phosphodiesteratic cleavage of phosphatidylinositol.
J Biol Chem
264:
11721-11724,
1989
22.
Efanov, AM,
Zaitsev SV,
and
Berggren PO.
Inositol hexakisphosphate stimulates non-Ca2+-mediated and primes Ca2+-mediated exocytosis of insulin by activation of protein kinase C.
Proc Natl Acad Sci USA
94:
4435-4439,
1997
23.
Elahi, D,
Nagulesparan M,
Hershcopf RJ,
Muller DC,
Tobin JD,
Blix PM,
Rubenstein AH,
Unger RH,
and
Andres R.
Feedback inhibition of insulin secretion by insulin: relation to the hyperinsulinemia of obesity.
N Engl J Med
306:
1196-1202,
1982[Abstract].
24.
Fruman, DA,
Myers RA,
and
Cantley LC.
Phosphoinositide kinases.
Annu Rev Biochem
67:
481-507,
1998[ISI][Medline].
25.
Fukuda, M,
and
Mikoshiba K.
The function of inositol high polyphosphate binding proteins.
Bioessays
19:
593-603,
1997[ISI][Medline].
26.
Gasa, R,
Trinh KY,
Yu K,
Wilkie TM,
and
Newgard CB.
Overexpression of G11alpha and isoforms of phospholipase C in islet beta-cells reveals a lack of correlation between inositol phosphate accumulation and insulin secretion.
Diabetes
48:
1035-1044,
1999[Abstract].
27.
Gershengorn, MC,
Heinflink M,
Nussenzveig DR,
Hinkle PM,
and
Falck-Pedersen E.
Thyrotropin-releasing hormone (TRH) receptor number determines the size of the TRH-responsive phosphoinositide pool Demonstration using controlled expression of TRH receptors by adenovirus mediated gene transfer.
J Biol Chem
269:
6779-6783,
1994
28.
Gilon, P,
and
Henquin JC.
Mechanisms and physiological significance of the cholinergic control of pancreatic beta-cell function.
Endocr Rev
22:
565-604,
2001
29.
Gilon, P,
Ravier MA,
Jonas JC,
and
Henquin JC.
Control mechanisms of the oscillations of insulin secretion in vitro and in vivo.
Diabetes
51, Suppl1:
S144-S151,
2002
30.
Gromada, J,
and
Dissing S.
Membrane potential and cytosolic free calcium levels modulate acetylcholine-induced inositol phosphate production in insulin-secreting TC3 cells.
Biochim Biophys Acta
1310:
145-148,
1996[ISI][Medline].
31.
Hagar, RE,
and
Ehrlich BE.
Regulation of the type III InsP3 receptor and its role in -cell function.
Cell Mol Life Sci
57:
1938-1949,
2000[ISI][Medline].
32.
Hanakahi, LA,
Bartlet-Jones M,
Chappell C,
Pappin D,
and
West SC.
Binding of inositol phosphate to DNA-PK and stimulation of double-strand break repair.
Cell
102:
721-729,
2000[ISI][Medline].
33.
Harbeck, MC,
Louie DC,
Howland J,
Wolf BA,
and
Rothenberg PL.
Expression of insulin receptor mRNA and insulin receptor substrate 1 in pancreatic islet -cells.
Diabetes
45:
711-717,
1996[Abstract].
34.
Harvey, J,
McKay NG,
Walker KS,
Van der KJ,
Downes CP,
and
Ashford ML.
Essential role of phosphoinositide 3-kinase in leptin-induced K(ATP) channel activation in the rat CRI-G1 insulinoma cell line.
J Biol Chem
275:
4660-4669,
2000
35.
Hilgemann, DW,
and
Ball R.
Regulation of cardiac Na+, Ca2+ exchange and KATP potassium channels by PIP2.
Science
273:
956-959,
1996[Abstract].
36.
Hilgemann DW, Feng S, and Nasuhoglu C. The complex and intriguing
lives of PIP2 with ion channels and transporters. Sci
STKE: RE19, 2001. (http://www.stke.org/cgi/content/full/oc_sigtrans; 2001/111/rel9)
37.
Hoy, M,
Efanov AM,
Bertorello AM,
Zaitsev SV,
Olsen HL,
Bokvist K,
Leibiger B,
Leibiger IB,
Zwiller J,
Berggren PO,
and
Gromada J.
Inositol hexakisphosphate promotes dynamin I-mediated endocytosis.
Proc Natl Acad Sci USA
99:
6773-6777,
2002
38.
Irvine, RF,
and
Schell MJ.
Back in the water: the return of the inositol phosphates.
Nat Rev Mol Cell Biol
2:
327-338,
2001[ISI][Medline].
39.
Ishihara, H,
Wada T,
Kizuki N,
Asano T,
Yazaki Y,
Kikuchi M,
and
Oka Y.
Enhanced phosphoinositide hydrolysis via overexpression of phospholipase C beta1 or delta1 inhibits stimulus-induced insulin release in insulinoma MIN6 cells.
Biochem Biophys Res Commun
254:
77-82,
1999[ISI][Medline].
40.
Iversen, J,
and
Miles DW.
Evidence for a feedback inhibition of insulin on insulin secretion in the isolated, perfused canine pancreas.
Diabetes
20:
1-9,
1971[ISI][Medline].
41.
Kakei, M,
Kelly RP,
Ashcroft SJ,
and
Ashcroft FM.
The ATP-sensitivity of K+ channels in rat pancreatic B-cells is modulated by ADP.
FEBS Lett
208:
63-66,
1986[ISI][Medline].
42.
Kamat, A,
and
Carpenter G.
Phospholipase C-gamma1: regulation of enzyme function and role in growth factor-dependent signal transduction.
Cytokine Growth Factor Rev
8:
109-117,
1997[Medline].
43.
Katz, LEL,
Bhala A,
Camron E,
Nunn SE,
Hintz RL,
and
Cohen P.
IGF-II, IGF-binding proteins and IGF receptors in pancreatic -cell lines.
J Endocrinol
152:
455-464,
1997[Abstract].
44.
Kemper, S,
Leibiger B,
Moede T,
Domin J,
Berggren PO,
and
Leibiger IB.
Selective signaling via A- and B-type insulin receptors in pancreatic -cells involves different PI3K (Abstract).
Diabetologia
44, Suppl 1:
497,
2001.
45.
Khan, FA,
Goforth PB,
Zhang M,
and
Satin LS.
Insulin activates ATP-sensitive K+ channels in pancreatic -cells through a phosphatidylinositol 3-kinase-dependent pathway.
Diabetes
50:
2192-2198,
2001
46.
Kim, JW,
Ryu SH,
and
Rhee SG.
Cyclic and noncyclic inositol phosphates are formed at different ratios by phospholipase C isozymes.
Biochem Biophys Res Commun
163:
177-182,
1989[ISI][Medline].
47.
Koranyi, L,
James DE,
Kraegen EW,
and
Permutt MA.
Feedback inhibition of insulin gene expression by insulin.
J Clin Invest
89:
432-436,
1992[ISI][Medline].
48.
Kulkarni, RN,
Bruning JC,
Winnay JN,
Postic C,
Magnuson MA,
and
Kahn CR.
Tissue-specific knockout of the insulin receptor in pancreatic -cells creates an insulin secretory defect similar to that in type 2 diabetes.
Cell
96:
329-339,
1999[ISI][Medline].
49.
Kulkarni, RN,
Winnay JN,
Daniels M,
Bruning JC,
Flier SN,
Hanahan D,
and
Kahn CR.
Altered function of insulin receptor substrate-1-deficient mouse islets and cultured -cell lines.
J Clin Invest
104:
R69-R75,
1999[ISI][Medline].
50.
Kwon, G,
Xu G,
Marshall CA,
and
McDaniel ML.
Tumor necrosis factor -induced pancreatic
-cell insulin resistance is mediated by nitric oxide and prevented by 15-deoxy-
12,14-prostaglandin J2 and aminoguanidine. A role for peroxisome proliferator-activated receptor
activation and iNOS expression.
J Biol Chem
274:
18702-18707,
1999
51.
Larsson, O,
Barker CJ,
and
Berggren PO.
Phosphatidylinositol 4,5-bisphosphate and ATP-sensitive potassium channel regulation: a word of caution.
Diabetes
49:
1409-1412,
2000[Abstract].
52.
Larsson, O,
Barker CJ,
Sjoholm A,
Carlqvist H,
Michell RH,
Bertorello A,
Nilsson T,
Honkanen RE,
Mayr GW,
Zwiller J,
and
Berggren PO.
Inhibition of phosphatases and increased Ca2+ channel activity by inositol hexakisphosphate.
Science
278:
471-474,
1997
53.
Leibiger, B,
Leibiger IB,
Moede T,
Kemper S,
Kulkarni RN,
Kahn CR,
de Vargas LM,
and
Berggren PO.
Selective signaling through A and B insulin receptors regulates transcription of insulin and glucokinase genes in pancreatic cells.
Mol Cell
7:
559-570,
2001[ISI][Medline].
54.
Leibiger, B,
Moede T,
Schwarz T,
Brown GR,
Köhler M,
Leibiger IB,
and
Berggren PO.
Short-term regulation of insulin gene transcription by glucose.
Proc Natl Acad Sci USA
95:
9307-9312,
1998
55.
Leibiger, B,
Moede T,
Uhles S,
Berggren PO,
and
Leibiger IB.
Short-term regulation of insulin gene transcription.
Biochem Soc Trans
30:
312-317,
2002[ISI][Medline].
56.
Leibiger, B,
Wåhlander K,
Berggren PO,
and
Leibiger IB.
Glucose-stimulated insulin biosynthesis depends on insulin-stimulated insulin gene transcription.
J Biol Chem
275:
30153-30156,
2000
57.
Leibiger, IB,
Leibiger B,
Moede T,
and
Berggren PO.
Exocytosis of insulin promotes insulin gene transcription via the insulin receptor/PI-3 kinase/p70 s6 kinase and CaM kinase pathways.
Mol Cell
1:
933-938,
1998[ISI][Medline].
58.
Loussouarn, G,
Pike LJ,
Ashcroft FM,
Makhina EN,
and
Nichols CG.
Dynamic sensitivity of ATP-sensitive K(+) channels to ATP.
J Biol Chem
276:
29098-29103,
2001
59.
Luo, HR,
Saiardi A,
Nagata E,
Ye K,
Yu H,
Jung TS,
Luo X,
Jain S,
Sawa A,
and
Snyder SH.
GRAB: a physiologic guanine nucleotide exchange factor for Rab3a, which interacts with inositol hexakisphosphate kinase.
Neuron
31:
439-451,
2001[ISI][Medline].
60.
Macfarlane, WM,
Smith SB,
James RFL,
Clifton AD,
Doza YN,
Cohen P,
and
Docherty K.
The p38/reactivating kinase mitogen-activated protein kinase cascade mediates the activation of the transcription factor insulin upstream factor 1 and insulin gene transcription by high glucose in pancreatic -cells.
J Biol Chem
272:
20936-20944,
1997
61.
Malaisse, WJ,
Malaisse-Lagae F,
Lacy PE,
and
Wright PH.
Insulin secretion by isolated islets in presence of glucose, insulin and anti-insulin serum.
Proc Soc Exp Biol Med
124:
497-500,
1967.
62.
Matschinsky, FM.
A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm.
Diabetes
45:
223-241,
1996[Abstract].
63.
Michell, RH,
and
Lapetina EG.
Production of cyclic inositol phosphate in stimulated tissues.
Nat New Biol
240:
258-260,
1972[ISI][Medline].
64.
Midorikawa, K,
Murata M,
Oikawa S,
Hiraku Y,
and
Kawanishi S.
Protective effect of phytic acid on oxidative DNA damage with reference to cancer chemoprevention.
Biochem Biophys Res Commun
288:
552-557,
2001[ISI][Medline].
65.
Mitchell, CJ,
Kelly MM,
Blewitt M,
Wilson JR,
and
Biden TJ.
Phospholipase C-gamma mediates the hydrolysis of phosphatidylinositol, but not of phosphatidylinositol 4,5-bisphoshate, in carbamylcholine-stimulated islets of langerhans.
J Biol Chem
276:
19072-19077,
2001
66.
Morrison, BH,
Bauer JA,
Kalvakolanu DV,
and
Lindner DJ.
Inositol hexakisphosphate kinase 2 mediates growth suppressive and apoptotic effects of interferon--in ovarian carcinoma cells.
J Biol Chem
276:
24965-24970,
2001
67.
Nesher, R,
Anteby E,
Yedovizky M,
Warwar N,
Kaiser N,
and
Cerasi E.
-Cell protein kinases and the dynamics of the insulin response to glucose.
Diabetes
51, Suppl1:
S68-S73,
2002
68.
Persaud, SJ,
Asare-Anane H,
and
Jones PM.
Insulin receptor activation inhibits secretion from human islets of Langerhans.
FEBS Lett
510:
225-228,
2002[ISI][Medline].
69.
Porksen, N.
The in vivo regulation of pulsatile insulin secretion.
Diabetologia
45:
3-20,
2002[ISI][Medline].
70.
Poyner, DR,
Cooke F,
Hanley MR,
Reynolds DJ,
and
Hawkins PT.
Characterization of metal ion-induced [3H]inositol hexakisphosphate binding to rat cerebellar membranes.
J Biol Chem
268:
1032-1038,
1993
71.
Prentki, M,
Biden TJ,
Janjic D,
Irvine RF,
Berridge MJ,
and
Wollheim CB.
Rapid mobilization of Ca2+ from rat insulinoma microsomes by inositol-1,4,5-trisphosphate.
Nature
309:
562-564,
1984[ISI][Medline].
72.
Rameh, LE,
and
Cantley LC.
The role of phosphoinositide 3-kinase lipid products in cell function.
J Biol Chem
274:
8347-8350,
1999
73.
Rana, RS,
Sekar MC,
Hokin LE,
and
MacDonald MJ.
A possible role for glucose metabolites in the regulation of inositol-1,4,5-trisphosphate 5-phosphomonoesterase activity in pancreatic islets.
J Biol Chem
261:
5237-5240,
1986
74.
Rana, RS,
Sekar MC,
Mertz RJ,
Hokins LE,
and
MacDonald MJ.
Potentiation by glucose metabolites of inositol trisphosphate-induced calcium mobilization in permeabilized rat pancreatic islets.
J Biol Chem
262:
13567-13570,
1987
75.
Randel, PJ.
Glucokinase and candidate genes for type 2 (non-insulin-dependent) diabetes mellitus.
Diabetologia
36:
269-275,
1993[ISI][Medline].
76.
Roe, MW,
Lancaster ME,
Mertz RJ,
Worley JF, III,
and
Dukes ID.
Voltage-dependent intracellular calcium release from mouse islets stimulated by glucose.
J Biol Chem
268:
9953-9956,
1993
77.
Ross, TS,
Whiteley B,
Graham RA,
and
Majerus PW.
Cyclic hydrolase-transfected 3T3 cells have low levels of inositol 1,2-cyclic phosphate and reach confluence at low density.
J Biol Chem
266:
9086-9092,
1991
78.
Rothenberg, PL,
Willison LD,
Simon J,
and
Wolf BA.
Glucose-induced insulin receptor tyrosine phosphorylation in insulin-secreting -cells.
Diabetes
44:
802-809,
1995[Abstract].
79.
Saiardi, A,
Nagata E,
Luo HR,
Snowman AM,
and
Snyder SH.
Identification and characterization of a novel inositol hexakisphosphate kinase.
J Biol Chem
276:
39179-39185,
2001
80.
Schatz, H,
and
Pfeiffer EF.
Release of immunoreactive and radioactively prelabelled endogenous (pro)-insulin from isolated islets of rat pancreas in the presence of exogenous insulin.
J Endocrinol
74:
243-249,
1977[Abstract].
81.
Shyng, SL,
and
Nichols CG.
Membrane phospholipid control of nucleotide sensitivity of KATP channels.
Science
282:
1138-1141,
1998
82.
Smith, MR,
Liu YL,
Matthews NT,
Rhee SG,
Sung WK,
and
Kung HF.
Phospholipase C-gamma 1 can induce DNA synthesis by a mechanism independent of its lipase activity.
Proc Natl Acad Sci USA
91:
6554-6558,
1994[Abstract].
83.
Spanswick, D,
Smith MA,
Mirshamsi S,
Routh VH,
and
Ashford ML.
Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats.
Nat Neurosci
8:
757-758,
2000.
84.
Stagner, J,
Samols E,
Polonsky K,
and
Pugh W.
Lack of direct inhibition of insulin secretion by exogenous insulin in the canine pancreas.
J Clin Invest
78:
1193-1198,
1986[ISI][Medline].
85.
Takenawa, T,
and
Itoh T.
Phosphoinositides, key molecules for regulation of actin cytoskeletal organization and membrane traffic from the plasma membrane.
Biochim Biophys Acta
1533:
190-206,
2001[ISI][Medline].
86.
Velloso, LA,
Carneiro EM,
Crepaldi SC,
Boschero AC,
and
Saad MJA
Glucose- and insulin-induced phosphorylation of the insulin receptor and its primary substrates IRS-1 and IRS-2 in rat pancreatic islets.
FEBS Lett
377:
353-357,
1995[ISI][Medline].
87.
Welsh, M,
Anneren C,
Lindholm C,
Kriz V,
and
Öberg-Welsh C.
Role of tyrosine kinase signaling for -cell replication and survival.
Ups J Med Sci
105:
7-15,
2000[ISI][Medline].
88.
Withers, DJ,
Gutierrez JS,
Towery H,
Burks DJ,
Ren JM,
Previs S,
Zhang Y,
Bernal D,
Pons S,
Shulman GI,
Bonner-Weir S,
and
White MF.
Disruption of IRS-2 causes type 2 diabetes in mice.
Nature
391:
900-904,
1998[ISI][Medline].
89.
Wollheim, CB,
and
Biden TJ.
Signal transduction in insulin secretion: comparison between fuel stimuli and receptor agonists.
Ann NY Acad Sci
488:
317-333,
1986[Abstract].
90.
Wollheim, CB,
and
Maechler P.
-Cell mitochondria and insulin secretion: messenger role of nucleotides and metabolites.
Diabetes
51, Suppl1:
S37-S42,
2002
91.
Wong, NS,
Barker CJ,
Shears SB,
Kirk CJ,
and
Michell RH.
Inositol 1:2(cyclic),4,5-trisphosphate is not a major product of inositol phospholipid metabolism in vasopressin-stimulated WRK1 cells.
Biochem J
252:
1-5,
1988[ISI][Medline].
92.
Wu, H,
Macfarlane WM,
Tadayyon M,
Arch JRS,
James RFL,
and
Docherty K.
Insulin stimulates pancreatic-duodenal homeobox factor-1 (PDX1) DNA-binding activity and insulin promoter activity in pancreatic cells.
Biochem J
344:
813-818,
1999[ISI][Medline].
93.
Xie, LH,
Horie M,
and
Takano M.
Phospholipase C-linked receptors regulate the ATP-sensitive potassium channel by means of phosphatidylinositol 4,5-bisphosphate metabolism.
Proc Natl Acad Sci USA
96:
15292-15297,
1999
94.
Xu, G,
Gao Z,
Borge PD, Jr,
Jegier PA,
Young RA,
and
Wolf BA.
Insulin regulation of -cell function involves a feedback loop on SERCA gene expression, Ca2+ homeostasis, and insulin expression and secretion.
Biochemistry
39:
14912-14919,
2000[ISI][Medline].
95.
Xu, G,
Kwon G,
Marshall CA,
Lin TA,
Lawrence JC, Jr,
and
McDaniel ML.
Branched-chain amino acids are essential in the regulation of PHAS-I and p70 s6 kinase by pancreatic -cells. A possible role in protein translation and mitogenic signaling.
J Biol Chem
273:
28178-28184,
1998
96.
Xu, GG,
Gao ZY,
Borge PD, Jr,
and
Wolf BA.
Insulin receptor substrate 1-induced inhibition of endoplasmic reticulum Ca2+ uptake in beta-cells. Autocrine regulation of intracellular Ca2+ homeostasis and insulin secretion.
J Biol Chem
274:
18067-18074,
1999
97.
Xu, GG,
and
Rothenberg PL.
Insulin receptor signaling in the -cell influences insulin gene expression and insulin content. Evidence for autocrine
-cell regulation.
Diabetes
47:
1243-1252,
1998[Abstract].
98.
Yang, SN,
Yu J,
Mayr GW,
Hofmann F,
Larsson O,
and
Berggren PO.
Inositol hexakisphosphate increases L-type Ca2+ channel activity by stimulation of adenylyl cyclase.
FASEB J
15:
1753-1763,
2001
99.
Ye, K,
Aghdasi B,
Luo HR,
Moriarity JL,
Wu FY,
Hong JJ,
Hurt KJ,
Bae SS,
Suh PG,
and
Snyder SH.
Phospholipase C gamma 1 is a physiological guanine nucleotide exchange factor for the nuclear GTPase PIKE.
Nature
415:
541-544,
2002[ISI][Medline].
100.
Zawalich, WS,
Tesz GJ,
and
Zawalich KC.
Are 5-hydroxytryptamine-preloaded -cells an appropriate physiologic model system for establishing that insulin stimulates insulin secretion?
J Biol Chem
276:
37120-37123,
2001
101.
Zawalich, WS,
and
Zawalich KC.
Regulation of insulin secretion by phospholipase C.
Am J Physiol Endocrinol Metab
271:
E409-E416,
1996
102.
Zawalich, WS,
and
Zawalich KC.
A link between insulin resistance and hyperinsulinemia: inhibitors of phosphatidylinositol 3-kinase augment glucose-induced insulin secretion from islets of lean, but not obese, rats.
Endocrinology
141:
3287-3295,
2000