INVITED REVIEW
Phosphorylated inositol compounds in beta -cell stimulus-response coupling

Christopher J. Barker, Ingo B. Leibiger, Barbara Leibiger, and Per-Olof Berggren

Department of Molecular Medicine, The Rolf Luft Center for Diabetes Research, Karolinska Institutet, S-171 76 Stockholm, Sweden


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
NEW ROLES FOR INOSITOL...
NEW INSIGHTS INTO ESTABLISHED...
A NEW ROLE FOR...
NEW ROLES FOR NOVEL...
ROLE OF PHOSPHORYLATED INOSITOL...
TWO DIFFERENT INSULIN RECEPTOR...
INSULIN-STIMULATED INSULIN...
CONCLUDING REMARKS
REFERENCES

Pancreatic beta -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 beta -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 beta -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 beta -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 beta -cell


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
NEW ROLES FOR INOSITOL...
NEW INSIGHTS INTO ESTABLISHED...
A NEW ROLE FOR...
NEW ROLES FOR NOVEL...
ROLE OF PHOSPHORYLATED INOSITOL...
TWO DIFFERENT INSULIN RECEPTOR...
INSULIN-STIMULATED INSULIN...
CONCLUDING REMARKS
REFERENCES

PANCREATIC beta -CELL stimulus-response coupling plays an essential role in the regulation of blood glucose concentration because of the beta -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 beta -cell stimulus-secretion coupling. The resting membrane potential of the beta -cell is thought to be set by the ATP-sensitive K+ (KATP) channel (reviewed in Ref. 4). Incubation of pancreatic beta -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 beta -cell high-Km/low-affinity glucose transporter GLUT2 and proceeds with the conversion into glucose 6-phosphate by the beta -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 beta -cell stimulus-response coupling.


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Fig. 1.   The structure of myo-inositol and its phosphorylated derivatives. H groupings are omitted for clarity; OH groups are represented by short lines attached to the ring structure and are substituted with monoester phosphate groups to form the phosphorylated inositol structures. The numbering system of the ring denotes the D-nomenclature adopted since the mid-1980s and centered around the phosphate position that links inositol to the diacylglycerol lipid backbone. Also shown is the finding that high-energy diphosphate groups (PP) can occur. In mammalian cells, the final positioning for at least one of these pyrophosphate substitutions still awaits confirmation; this uncertainty is reflected with a question mark (38).

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 beta -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.


    NEW ROLES FOR INOSITOL PHOSPHATES AND LIPIDS IN INSULIN STIMULUS-SECRETION COUPLING
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ABSTRACT
INTRODUCTION
NEW ROLES FOR INOSITOL...
NEW INSIGHTS INTO ESTABLISHED...
A NEW ROLE FOR...
NEW ROLES FOR NOVEL...
ROLE OF PHOSPHORYLATED INOSITOL...
TWO DIFFERENT INSULIN RECEPTOR...
INSULIN-STIMULATED INSULIN...
CONCLUDING REMARKS
REFERENCES

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 beta -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 beta -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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Fig. 2.   Role of phosphorylated inositol compounds in pathways leading to insulin secretion. GLUT2, glucose transporter 2; GPCR/PLC, G protein-coupled receptor/phospholipase C system; KATP channel, ATP-sensitive K+ channel; L-type VDCC, L-type voltage-dependent Ca2+ channel; IP3R, inositol trisphosphate (InsP3) receptor; ER, endoplasmic reticulum; PIP2, PtdIns(4,5)P2; IP3, Ins(1,4,5)P3; IP6, inositol hexakisphosphate; IP7, diphosphoinositol pentakisphosphate; PIP2, phosphatidylinositol-4,5-bisphosphate; [Ca2+]i, cytosolic Ca2+ concentration.


    NEW INSIGHTS INTO ESTABLISHED INOSITIDE PATHWAYS
TOP
ABSTRACT
INTRODUCTION
NEW ROLES FOR INOSITOL...
NEW INSIGHTS INTO ESTABLISHED...
A NEW ROLE FOR...
NEW ROLES FOR NOVEL...
ROLE OF PHOSPHORYLATED INOSITOL...
TWO DIFFERENT INSULIN RECEPTOR...
INSULIN-STIMULATED INSULIN...
CONCLUDING REMARKS
REFERENCES

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 beta -cells. At least two different types of Ca2+ oscillations occur in pancreatic beta -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, beta -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-gamma in a tyrosine kinase-dependent manner, whereas the former is mediated by PLC-beta 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-gamma -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-beta -cells mediated by PLC-gamma 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-gamma 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-gamma 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 beta -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.


    A NEW ROLE FOR INOSITOL LIPIDS IN KATP CHANNEL REGULATION?
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ABSTRACT
INTRODUCTION
NEW ROLES FOR INOSITOL...
NEW INSIGHTS INTO ESTABLISHED...
A NEW ROLE FOR...
NEW ROLES FOR NOVEL...
ROLE OF PHOSPHORYLATED INOSITOL...
TWO DIFFERENT INSULIN RECEPTOR...
INSULIN-STIMULATED INSULIN...
CONCLUDING REMARKS
REFERENCES

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 beta -cells, PtdIns(4,5)P2 has now been established to be a key regulator in its own right. In the beta -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 beta -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 beta -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.


    NEW ROLES FOR NOVEL INOSITOL PHOSPHATES
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ABSTRACT
INTRODUCTION
NEW ROLES FOR INOSITOL...
NEW INSIGHTS INTO ESTABLISHED...
A NEW ROLE FOR...
NEW ROLES FOR NOVEL...
ROLE OF PHOSPHORYLATED INOSITOL...
TWO DIFFERENT INSULIN RECEPTOR...
INSULIN-STIMULATED INSULIN...
CONCLUDING REMARKS
REFERENCES

Although the precise role of the second messenger Ins(1,4,5)P3 in beta -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 beta -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 beta -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 beta -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-beta -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 beta -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 beta -cell still remains to be assessed, but preliminary data suggest that at least one isoform is at an unusually high concentration in a beta -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 beta -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 beta -cell research.


    ROLE OF PHOSPHORYLATED INOSITOL COMPOUNDS IN AUTOCRINE INSULIN FEEDBACK ACTION IN PANCREATIC beta -CELLS
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ABSTRACT
INTRODUCTION
NEW ROLES FOR INOSITOL...
NEW INSIGHTS INTO ESTABLISHED...
A NEW ROLE FOR...
NEW ROLES FOR NOVEL...
ROLE OF PHOSPHORYLATED INOSITOL...
TWO DIFFERENT INSULIN RECEPTOR...
INSULIN-STIMULATED INSULIN...
CONCLUDING REMARKS
REFERENCES

Receptor-mediated events in beta -cells have taken an entirely new direction with the growing evidence that insulin itself is a key player in beta -cell physiology. This includes processes such as the regulation of gene transcription (11, 17, 53-57, 92, 97), translation (95), ion flux (6, 94), beta -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 beta -cell function.

Data by Velloso et al. (86) and Harbeck et al. (33) convincingly showed that pancreatic beta -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 beta -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 beta -cell. For example, the insulin-mediated activation of PLC-gamma has been reported in several cell types (42). In the beta -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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Fig. 3.   Role of phosphorylated inositol compounds in pathways resulting from the autocrine feedback action of insulin. PLC, phospholipase C; IP3R, inositol trisphosphate receptor; SERCA, (sarco)endoplasmic reticulum Ca2+ ATPase; IR/IGFIR, insulin receptor or IGF-I receptor; IRS, insulin receptor substrate protein; PI3K, phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate.


    TWO DIFFERENT INSULIN RECEPTOR SUBTYPES CONTROL GENE REGULATION VIA DISTINCT PTDINS 3-KINASE ACTIVITIES
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ABSTRACT
INTRODUCTION
NEW ROLES FOR INOSITOL...
NEW INSIGHTS INTO ESTABLISHED...
A NEW ROLE FOR...
NEW ROLES FOR NOVEL...
ROLE OF PHOSPHORYLATED INOSITOL...
TWO DIFFERENT INSULIN RECEPTOR...
INSULIN-STIMULATED INSULIN...
CONCLUDING REMARKS
REFERENCES

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 beta -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., pDelta 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-C2alpha (1, 15) and PtdIns 3-kinase-C2beta (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-C2alpha , in the activation of glucose- and/or insulin-dependent glucokinase gene expression in pancreatic beta -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-C2alpha in insulin-producing cells, and coimmunoprecipitation of PtdIns 3-kinase-C2alpha 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 beta -cell.


    INSULIN-STIMULATED INSULIN SECRETION DEBATE: A ROLE FOR PTDINS(3,4,5)P3 IN INSULIN FEEDBACK VIA THE KATP CHANNEL?
TOP
ABSTRACT
INTRODUCTION
NEW ROLES FOR INOSITOL...
NEW INSIGHTS INTO ESTABLISHED...
A NEW ROLE FOR...
NEW ROLES FOR NOVEL...
ROLE OF PHOSPHORYLATED INOSITOL...
TWO DIFFERENT INSULIN RECEPTOR...
INSULIN-STIMULATED INSULIN...
CONCLUDING REMARKS
REFERENCES

In addition to a role in the stimulation of gene expression, the insulin feedback mechanism in beta -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 beta IRKO mouse, an animal model that lacks the expression of insulin receptors in the pancreatic beta -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 beta -cell, the stimulus-secretion coupling should be switched off. In parallel work on a rat insulinoma beta -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 beta -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 beta -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
TOP
ABSTRACT
INTRODUCTION
NEW ROLES FOR INOSITOL...
NEW INSIGHTS INTO ESTABLISHED...
A NEW ROLE FOR...
NEW ROLES FOR NOVEL...
ROLE OF PHOSPHORYLATED INOSITOL...
TWO DIFFERENT INSULIN RECEPTOR...
INSULIN-STIMULATED INSULIN...
CONCLUDING REMARKS
REFERENCES

The aim of this review was to highlight known and potential roles of phosphorylated inositol compounds in beta -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 beta -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 beta -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 beta -cells to high levels of insulin, as is the case in insulin-clamp studies or as a result of long-term incubation of beta -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 beta -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 beta -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
TOP
ABSTRACT
INTRODUCTION
NEW ROLES FOR INOSITOL...
NEW INSIGHTS INTO ESTABLISHED...
A NEW ROLE FOR...
NEW ROLES FOR NOVEL...
ROLE OF PHOSPHORYLATED INOSITOL...
TWO DIFFERENT INSULIN RECEPTOR...
INSULIN-STIMULATED INSULIN...
CONCLUDING REMARKS
REFERENCES

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Am J Physiol Endocrinol Metab 283(6):E1113-E1122
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