the hormones , glucosedependent insulinotropic polypeptide ( gip ) and glucagonlike peptide1 ( glp1 ) , are released from the intestine in response to nutrient ingestion and stimulate insulin secretion in a glucosedependent manner , as a result of which they have been classified as 
incretins. additionally , both hormones play regulatory roles in the maintenance , growth and survival of pancreatic islets , as well as acting in an integrative manner on processes involved in nutrient metabolism , including events underlying the passage of chyme through the gastrointestinal tract , and nutrient digestion , absorption and storage . the biological actions of gip and glp1 are terminated by the prolyl endopeptidase , dipeptidyl peptidase4 ( dpp4 ) .
dpp4 resistant analogs of glp1 and dpp4 inhibitors are two recently introduced classes of type  2 diabetes therapeutics that mimic or potentiate , respectively , actions of the incretins .
although these agents have proven to be extremely effective in improving glucose tolerance , it is unlikely that their therapeutic potential has been fully realized , and it is important to elucidate the mechanistic basis underlying incretin actions . in the present review , we focus on the current understanding of the signaling events involved in gip actions on cell function and the adipocyte , with an emphasis on studies carried out in the authors laboratory .
the gip receptor ( gipr ) is a member of the class  b g  proteincoupled receptor family that has now been identified in chordates ranging from fish to mammals , although little is known about cellular signaling events in lower species .
there is extensive literature on the mode of action of glp1 on the cell that has been expertly reviewed , and information that is relevant to gip action will be integrated into the current review .
uptake and metabolism of glucose in the cell increases the intracellular adenosine triphosphate ( atp)/adenosine diphosphate ( adp ) ratio , resulting in closure of atpsensitive k ( katp ) channels and membrane depolarization , with consequent activation of voltagedependent ca channels ( vdcc ) , increases in intracellular ca ( ica ) and triggering of insulin granule exocytosis .
membrane repolarization is mediated by voltagedependent k ( kv ) channels and casensitive k ( kca ) channels .
both gip and glp1 have been shown to stimulate adenylyl cyclase ( ac ) through a stimulatory g  protein ( gs ) coupled process resulting in increased cyclic adenosine monophosphate ( camp ) , and this is considered to be the major signaling pathway involved in their potentiation of glucoseinduced insulin secretion . although gipstimulated insulin secretion is glucosedependent , camp production and subsequent activation of downstream signaling modules are not .
as discussed further below , synergistic interaction between glucose and incretin action occurs when ca fluxes are increased through modulation of katp channels and vdcc , as well as through release from the endoplasmic reticulum ( figure  1 ) .
type  viii ac has been proposed to act as a  coincidence detector of signals from glucose and camp , as it is activated by both cacalmodulin and gs .
cacalmodulin also modulates the activity of phosphodiesterase ( pde ) 1c , and synergistic interactions between gs and cacalmodulin have been suggested to drive synchronous , inphase oscillations of camp and ca .  signaling pathways proposed to be involved in proximal events in glucosedependent insulinotropic polypeptide ( gip)mediated potentiation of glucoseinduced insulin secretion .
( a ) evidence has been presented supporting roles for both protein kinase  a ( pka ) and cyclic adenosine monophosphate ( camp)activated guanine nucleotide exchange factor ( campgef)/exchange protein directly activated by camp ( epac ) in the modulation of adenosine triphosphate ( atp)sensitive k ( katp ) channels .
dissociation of campepac2 from sulfonulurea receptor  1 ( sur1 ) binding has been proposed to activate phospholipase c ( plc ) through rasrelated protein  1 ( rap1 ) , resulting in phosphatidylinositol 4,5 bisphosphate ( pip2 ) metabolism and inhibition of adenosine triphosphatesensitive channel subunit , kir6.2 , membrane depolarization and activation of voltagedependent ca channels ( vdcc ) .
( b ) diacylglycerolactivated pkc potentiates calciuminduced calcium release through ryanodine receptors and phosphatidylinositol trisphosphate ( ip3 ) stimulates ca release from ip3 sensitive endoplasmic reticulum ( er ) ca stores .
pka might act to sensitize the ca release channels ( based on references 15 , 20 , 31 , 36 ) .
ac , adenylyl cyclase ; cam , calmodulin ; gs , stimulatory g protein subunit , ip3r , inositol trisphosphate receptor ; p , phosphate ; ryr , ryanodine receptor ; serca , sarco(endo)plasmic reticulum caatpase .
incretininduced increases in cell camp result in the activation of both protein kinase  a ( pka ) and campactivated guanine nucleotide exchange factor ( campgef)/exchange protein directly activated by camp ( epac ) ( figure  1 ) .
epac2a has been identified as the major splicevariant involved in cell incretin signaling , but there are multiple pka isoforms present in cells and it is unclear as to which contribute to the modulation of insulin secretion . there is also uncertainty over the relative roles played by epac2 and pka in events leading to increases in insulin secretion , with katp channel closure , ca influx and intracellular mobilization , and processes underlying granule movement and exocytosis , all being potential targets .
a number of investigators have carried out sophisticated electrophysiological and imaging studies to identify the pathways targeted by glp1 and/or gip and , as these studies have been comprehensively reviewed , only a summary of the main findings will be presented .
glp1 was first suggested to modulate cell katp channel activity through a pkamediated pathway , and it was later reported that phosphorylation of the cell sulfonylurea  1 ( sur1 ) subunit resulted in katp channel closure ( figure  1a ) .
there is now controversy over the contribution of pka to katp channel regulation , as compelling evidence points to epac2 as the major factor linking camp to katp channel closure and increasing ca influx . under nonstimulated conditions , epac2 interacts with the nucleotidebinding fold1 of sur1 ( figure  1a ) . on binding camp , epac2 dissociates from sur1 , and activates the gtpase , rasrelated protein  1 ( rap1 ) .
have proposed that rap1 stimulates phospholipase c ( plc ) , resulting in localized metabolism of plasma membrane phosphatidylinositol 4,5 bisphosphate ( pip2 ) to phosphatidylinositol trisphosphate ( ip3 ) and diacylglycerol ( dag ; figure  1 ) .
as earlier studies showed that pip2 reduces the sensitivity of katp channels to atp , its depletion would be expected to result in potentiated atpdependent channel closure and membrane depolarization .
cell stimulation by both glp1 and gip in the presence of elevated glucose has been shown to result in increased ca uptake through vdcc and nonselective ion channels , as well as stimulation of ca release from intracellular stores that , in the case of glp1 , has been shown to involve epac2 activation .
gip probably activates identical pathways ( figure  1b ) , although studies on katp channeldeficient mice showed that gip actions on insulin secretion showed a greater dependency on katp channels than glp1 .
phospholipase c has been proposed to link epac and ica fluxes through the activation of endoplasmic reticulum ( er ) inositol trisphosphate ( ip3 ) channels and protein kinase c ( pkc)mediated potentiation of calciuminduced calcium release ( cicr ) through ryanodine receptors ( figure  1b ) , possibly through activation of calciumcalmodulin kinase  ii .
in addition , pka is capable of sensitizing the intracellular ca release channels to the effects of ip3 and ca .
gip also activates an islet group via caindependent phospholipase a2 ( ipla2 ) , resulting in increased arachidonic acid ( aa ) production from membrane lipids , and aa has been shown to increase release of ca from intracellular stores , suggesting that it might be coupled to insulin secretion .
cell repolarization involves closure of vdcc , as well as opening of delayed rectifier and atype kv channels .
gip and glp1 both reduce kv channel currents , prolonging cell action potentials and potentiating ca signals .
kv2.1 is the major delayed rectifier channel in rodent cells , playing a dominant role in glp1 , and probably gip , action .
posttranslational modification of kv2.1 in response to gip and glp1 can modulate channel gating , promote inactivation and increase channel internalization through processes that involve phosphorylation by pka and pkc , and acetylation by campresponse element binding protein ( creb ) binding protein ( cbp ; see cell prosurvival effects of gip section ) .
as aa was also recently shown to increase the rate of inactivation of kv2.1 channels , gipactivation of ipla2 might also be linked to cell repolarization .
in addition to the  upstream events involved in insulin secretion , both incretins exert distal effects on secretory granule exocytosis through pka and epac dependent pathways .
protein kinase  a phosphorylates proteins that are components of the exocytotic machinery , including soluble nethylmaleimidesensitive fusion proteinattachment protein ( snap ) and mammalian uncoordinated homology 131 ( munc 131 ) .
a number of models have been proposed to explain the role of epac2 in increasing the probability of granule exocytosis .
proposed that epac2 interacts with sur1 associated with both the secretory granule and the plasma membrane , resulting in activation of a secretory granule chloride channel cic3 , granule acidification and priming through a vtype hatpase . in a series of elegant experiments , seino et  al .
epac2a appears to be more important for regulating the readilyreleasable pool during the first phase of insulin secretion , whereas pka might be critical for second phase release .
in addition to sur1 and rap1 , epac2 also interacts with rasrelated in brain  3 ( rab3)interactive molecule  2 ( rim2 ) , piccolo and snap25 , and a camp  epac2rim2 complex was shown to play a central role in secretory granule dynamics .
although the mechanisms involved in complex formation are still being clarified , dissociation of camp 
epac2a from sur1 promotes cadependent heterodimerization of rim2 and piccolo , followed by interaction with rab3a and munc131 , core components of the exocytotic apparatus .
gipinduced insulin secretion was greatly impaired in rim2 knockout mice and their isolated islets , establishing its importance in the secretory pathway .
additionally , phosphorylation of snapin by pka has been shown to be essential for incretinstimulated assembly of collectrin , snap25 and epac2 .
finally , we recently found that a selective epac agonist was capable of activating protein kinase b ( pkb ; akt ) , emphasizing the importance of interaction between kinase pathways .
it is currently unclear as to whether this interaction is related to insulin secretion or restricted to cell mitogenic and prosurvival effects of gip ( see next section ) .
cell dysfunction and reduced cell mass are major factors in the etiology of type  1 diabetes and type  2 diabetes . whereas autoimmune reactions are responsible for apoptotic loss of cells in type  1 diabetes , chronic hyperglycemia and hyperlipidemia , elevated cytokines , amyloid deposits , er stress and other factors contribute to type  2 diabetes .
a number of procedures are being investigated for replenishing cell mass in diabetes patients , including the production of surrogate cells for transplantation and stimulation of residual cell proliferation .
however , it appears that human cell regenerative capacity is limited to around the first three decades of life .
therefore , prevention of cell loss by inhibiting apoptotic processes is an attractive alternative target .
a role for incretin hormones in maintaining the normal integrity of pancreatic islets was first shown by the observation that glp1r mice have elevated levels of cell apoptosis .
both gip and glp1 have been shown to exert strong prosurvival effects on cells in  vitro .
additionally , studies on a number of rodent models have shown that gipr or glp1r agonists exert marked antiapoptotic effects in  vivo .
our laboratory has focused on identifying mechanisms underlying the prosurvival actions of gip and the following overview summarizes recent findings .
gip shows protective effects on cells that have been subjected to a number of apoptosisinducing stressors , including high glucose    fatty acids ( glucolipotoxicity ) , serum depletion and a low glucose environment or treatment with agents that induce genotoxic , mitochondrial or er stress . in studies on staurosporineinduced apoptosis in insulinoma1 ( ins1 ) cells , gip was shown to exert effects at multiple levels in the apoptotic pathway , with reduced mitochondrial translocation of bcell lymphoma2 ( bcl2 ) associated death promoter ( bad ) and bcl2 interacting mediator of cell deathel ( bimel ) and oligomerization of bcl2associated x protein ( bax ) , release of cytochrome  c and caspase  3 activation .
ultimately , gip reduces the influence of mitochondriaassociated proapoptotic bcl2 family members , thus restraining the effects of stressors on the cell .
although the pathways linking incretininduced production of camp and activation of pka and epac2a with the stimulation of insulin secretion have been extensively studied , the role of camp in prosurvival pathways has not been clearly defined .
gipmediated antiapoptotic signaling in ins1 cells appears to be strongly dependent on camp production , as low concentrations of the adenylyl cyclase inhibitor mdl12,300a ( santa cruz biotechnology , santa cruz , ca , usa ) ablated the protective effects of gip on staurosporineinduced cell death
. one major pathway by which gipr and glp1rmediated increases in camp production promote survival is by increasing expression of antiapoptotic genes through pka phosphorylation of creb at serine ( ser)133 . in the case of gip , bcl2 gene expression in ins1 cells was also found to involve pkastimulated dephosphorylation of amp activated protein kinase ( ampk ) and increased nuclear entry of campresponsive creb coactivator  2 ( torc2 ) .
incretins activate a number of other genes involved in prosurvival pathways ; for example , expression of insulin receptor substrate  2 ( irs2 ) is stimulated by glp1activated pka phosphorylation of creb .
recently , creb was reported to be responsible for an acute phase of campdependent gene expression in cells , whereas a delayed phase involved induction of irs2/pkb pathways , activation of mammalian target of rapamycin ( mtor ) and increasing hypoxiainducible factor ( hif ) activity .
this increase was shown to be associated with altered ins1 cell metabolic activity and improved cell viability .
an additional effect of sustained cell stimulation by gipinduced activation of pkb is the phosphorylation and nuclear exclusion of forkhead box protein  o1 ( foxo1 ) , that also promotes cell survival as a result of the requirement of nuclear foxo1 for expression of proapoptotic proteins , such as bax .
it remains to be determined whether the hif pathway also modulates expression of prosurvival bcl2 family proteins .
pkb phosphorylation on threonine ( thr)308 and ser473 has been shown to be essential for enzyme activation in many cell types . however , in cells , gip was found to produce rapid increases in pkb activity through a nonpi3kinaseactivated pathway in the absence of detectable thr308 phosphorylation .
as 8(4chlorophenylthio)2omethyl camp ( 8cpt camp ) , an epacselective agonist , mimicked the effects of gip , activation appears to be mediated by epac2 , although it is currently unclear as to whether rap1 is involved .
apoptosis signalregulating kinase 1 ( ask1 ) has been shown to operate as a redox sensor that , on exposure to excessive levels of reactive oxygen species ( ros ) , initiates the mitochondriamediated apoptotic pathway through activation of p38 mitogenactivated protein kinase ( p38 mapk ) and jun nterminal kinase ( jnk ) . among the stressors shown to activate ask1 are oxidative and er stress , ca overload and receptor mediated inflammatory signals
exposure of ins1 cells transfected with human ask1 to thapsigargin was found to increase phosphorylation of thr845 and reduce phosphorylation of ser83 in ask1 , changes that increase its enzyme activity , resulting in phosphorylation and activation of p38 mapk and jnk , through mapk / extracellular signalregulated kinase ( erk ) kinase ( mek ) 3/6 and mek 4/7 , respectively .
activation of pkb with gip treatment prevented these changes in ask1 phosphorylation and downstream targets . suppressing ask1 activation with gip treatment inhibited apoptosis induced by all apoptosisinducing agents tested . as a result of the complexity of the system ,
the mechanism of gip action is currently only open to speculation . in nonstressed cells , ask1 forms a high molecular weight complex that has been termed the  ask1 signalosome , and , in nonstressed cells when ask1 activity is inhibited ,
the antioxidative protein , thioredoxin ( trx ) , is a component of the signalosome .
if the oxidative state of the cell is greatly increased , the oxidized form of trx dissociates from ask1 and tumor necrosis factor ( tnf ) receptorassociated factor  2 ( traf2 ) and traf6 binding activates ask1 signaling . although gipstimulated phosphorylation of ser83 by akt was clearly involved in inhibiting ask1 activity , it is also possible that the binding of thioredoxin and/or traf2/6 to ask1 were impacted on .
additional gene regulatory actions of gip and glp1 involve modification of chromatin structure , thus altering the accessibility of transcription factors to target genes .
a number of different posttranslational modifications of histone ntermini have been identified , and we showed that both incretin hormones modulate cell chromatin structure by increasing acetylation and phosphorylation of core h3 histones , with both elevated histone h3 acetyltransferase and reduced histone deacetylase activities contributing to the former .
responses to both incretins involved activation of pka , and downstream erk1/2 ( p44/42 mapk ) and p38 mapk signaling modules , ultimately resulting in the activation of mitogen and stressactivated kinase1 ( msk1 ) and creb .
histone acetyltransferase ( hat ) inhibition resulted in significant reductions in incretinstimulated , crebactivated , bcl2 gene transcription , showing that histone h3 modification plays an important role in the regulation of apoptosisrelated proteins .
both gip and glp1 also inhibit er stressinduced apoptosis through complex mechanisms that involve both reductions in the apoptotic pathway , leading to caspase activation , and altered expression or activity of a number of proteins involved in the unfolded protein response ( upr ) , including activating transcription factor  4 ( atf4 ) , binding immunoglobin protein ( bip ) , ccaatenhancerbinding protein homologous protein ( chop ) and growth arrest and deoxyribonucleic acid damageinducible protein  34 ( gadd34 ) . in recent studies
, we identified an interesting link between incretinstimulated posttranslational modification of kv channels and apoptosis ( figure  2 ) .
cell shrinkage ( apoptotic volume decrease ; avd ) occurs early in the apoptotic process , before dna fragmentation , cytochrome  c release and caspase  3 activation , and it is a prerequisite for completion of programmed cell death .
efflux of k is a critical component of the avd and , as activities of a number of caspases and endonucleases are suppressed at normal intracellular k concentrations , decreases in its intracellular concentration result in their activation . in different cell types ,
we decided to examine a possible role for the most prevalent rodent cell family member , kv2.1 , in the development of apoptosis , and determine whether regulation of this process by gip and glp1 contributes to their prosurvival effects .
ins1 cells , in which kv2.1 was overexpressed , showed potentiated apoptotic responses to mitochondrial and er stress , whereas gip or glp1 reduced the potentiation . in studies designed to identify their mode of action ,
both gip and glp1 promoted phosphorylation and acetylation of kv2.1 through pathways involving pka , and/or msk1 and hat ( figure  2 ) .
we subsequently found that gip and glp1 promoted nuclear / cytoplasmic shuttling of cbp , resulting in its interaction with kv2.1 ( figure  2 ) .
downregulation of cbp ablated incretininduced acetylation of kv2.1 , suggesting that this hat is primarily responsible for the acetylation . as ask1 has been shown to play a key role in the proapoptotic modulation of kv channels , it is likely that the gipactivated pathway leading to phosphorylation of serine 83 in ask1 interacts with events leading to kv protein modification . 
proposed signaling pathways by which glucosedependent insulinotropic polypeptide ( gip ) regulates endocytosis of voltagedependent k ( kv)2.1 .
binding of gip to its receptor ( gipr ) activates protein kinase  a ( pka ) and , potentially , mitogen and stressactivated kinase1 ( msk1 ) , resulting in phosphorylation of kv2.1 . through an unknown mechanism
, cyclic adenosine monophosphateresponse element binding protein binding protein ( cbp ) is translocated from the nucleus to the plasma membrane , where it acetylates kv2.1 .
ac , adenylyl cyclase ; ac , acetylated ; creb , campresponse element binding protein ; gs , stimulatory g  protein subunit ; p , phosphorylated ; torc2 , transducer of regulated cyclic adenosine monophosphate response element binding protein activity .
fat ingestion is a major stimulus for gip secretion in humans , dogs and rodents , and there is increasing evidence supporting a physiological role for gip in promoting fat storage .
there are two pathways by which gip impacts on adipocyte metabolism : directly through interaction with gip receptors on the adipocyte and through stimulation of insulin secretion .
gip infusion has been shown to promote the clearance of chylomicronassociated triglyceride ( tg ) in dogs , and to lower plasma tg responses to intraduodenal fat in rats . however , gip had no major effect on the rate of removal of intravenously administered tg , suggesting that gip stimulates release of tg from chylomicrons and uptake into adipose tissue .
support for a role for gip in regulating adipose tissue mass came from rodent studies .
mice that were treated with gipr peptide antagonists , vaccinated against gip or subjected to selective kcell ablation all showed increased resistance to highfat feedinginduced obesity , showing that gip normally promotes lipid storage .
early studies on direct adipocyte actions of gip showed stimulatory effects on fatty acid ( fa ) synthesis from acetate in adipose tissue explants , increased uptake and incorporation of glucose into lipids , as well as enhanced free fa ( ffa ) incorporation into adipose tissue .
adipocyte lipoprotein lipase ( lpl ) is responsible for the hydrolysis of tg in circulating chylomicrons , tgrich lipoproteins and very lowdensity lipoproteins , resulting in adipocyte uptake of ffa and monoacylglycerol , and the promotion of lipogenesis .
gip was shown to increase lpl enzyme activity , in an insulindependent manner , in cultured 3t3l1 adipocytes , rodent adipocytes and subcutaneous human adipocytes . in view of the close correlation between human gip responses and plasma postheparin lpl levels
, it has been suggested that gip acts on adipocyte storage by matching adipose tissue uptake of fa with the triglyceride load .
suboptimal levels of circulating ffa result in greatly reduced cell responsiveness to subsequent glucose stimulation . in  vitro studies
showed that , in the absence of insulin , gip stimulates adipocyte tg hydrolysis through pka activation , and we suggested that gip primes cells during fasting by releasing adipocyte ffa into the circulation .
. showed that gipstimulated increases in glycerol production were accompanied by decreased ffa in perifused adipocytes .
a similar response was recently reported in humans , with gip infusion resulting in small increases in adipose tissue ffa reesterification .
gip might also have longterm effects on lipid metabolism , as synthesis of pancreatic lipase and colipase were both stimulated by gip , an effect that should increase efficiency of lipid uptake . in the presence of insulin ,
gip signaling appears to play important roles in both the differentiation of preadipocytes and lipogenesis .
a complex set of events is involved in preadipocyte to adipocyte development , including growth arrest , increased transcription factor and lipogenic enzyme expression , accumulation of lipid , and the development of sensitivity to regulatory hormones .
expression of the gipr is extremely low in preadipocytes , but both messenger ribonucleic acid ( mrna ) and protein expression increase during differentiation of 3t3l1 cell and human preadipocytes .
gip acted synergistically with insulin to increase neutral lipid accumulation during progression of 3t3l1 preadipocytes to the adipocyte phenotype .
however , it was unclear as to whether synergistic effects of gip and insulin on gipr mrna levels were a result of direct effects on gene transcription or secondary to the progression of differentiation .
3t3l1 cell differentiation was associated with upregulation of nuclear levels of peroxisome proliferatoractivated receptor ( ppar). treatment with the ppar receptor agonists , ly171883 and rosiglitazone , increased gipr expression in fully differentiated 3t3l1 adipocytes , whereas the antagonist , gw9662 , ablated expression .
acetylation of histone h3/h4 was also increased during differentiation , and both ppar and acetylated histone h3/h4 bound to a region of the gipr promoter containing the peroxisome proliferator response element ( ppre ) . as rna interference ( rnai )
knockdown of ppar in differentiated 3t3l1 adipocytes greatly reduced gipr levels , ppar appears to be a critical transcription factor in regulating adipocyte receptor expression , but it is unclear as to the role played by insulin .
evidence has been presented for the involvement of both ppar and ppar in the regulation of rodent cell gipr expression , and further studies are required to clarify whether there are cellselective differences in regulation .
additionally , in earlier studies , it was shown that the gipr is downregulated in cells of obese rodent models of diabetes , but in studies on vancouver diabetic fatty ( vdf ) zucker rats , we recently found that , compared with lean controls , gipr and ppar protein levels were increased in epididymal and retroperitoneal fat pads , decreased in the perirenal fat depot and unchanged in other fat deposits ( figure  3 ) .
in contrast , gipr expression in subcutaneous adipose tissue from human obese females was reported to be lower than in lean control subjects . however , these results are difficult to compare , because of the different fat depots studied . additionally , the sensitivity of gipr expression to the prevailing insulin concentration , the level of adipose tissue insulin resistance and the glycemic status of the subjects / animals could all contribute significantly to the level of gipr expression . 
glucosedependent insulinotropic polypeptide receptor ( gipr ) and peroxisome proliferatoractivated receptor ( ppar) protein expression levels in adipose tissue depots from lean and obese vancouver diabetic fatty ( vdf ) zucker rats .
tissue was collected from 18weekold rats and western blot analyses were carried out , with quantification by densitometry ( n  =  46 rats ) .
 keuls posthoc test . * * p  <  0.05 vs lean control group .
the pathways involved in gipstimulated lipogenesis are proving difficult to define , as a result of interactions between gip , insulin and adipokine signaling .
gip stimulation of glucose uptake was shown to involve increasing plasma membrane glucose transporter4 ( glut4 ) levels through a pkbmediated pathway .
human lpl gene expression is also stimulated by gip activation of pkb , resulting in downstream reductions in lkb1 and ampk phosphorylation , and increased translocation of torc2 ( campresponsive creb coactivator  2 [ crtc2 ] ) into the nucleus .
regulation of the phosphorylation state of torc2 is complex and other members of the ampk family ( saltinducible kinases [ sik ] and mark2 ) are also capable of torc2 phosphorylation , whereas calcineurin and a campactivated pathway induce dephosphorylation .
gip also enhances lpl enzyme activity in cultured 3t3l1 cells and subcutaneous human adipocytes by nontranscriptional mechanisms . in the 3t3l1 cell line ,
gip induces transient activation of p38 mapk and sustained activation of stressactivated protein kinase ( sapk)/jnk , resulting in the release of resistin that , in turn activates pkb .
somewhat surprisingly , subsequent events mimic those downstream of gip in the human adipocyte , with decreases in lkb1 and ampk phosphorylation linked to increased lpl secretion .
human resistin ( fizz3 ) shares only moderate sequence homology ( 53% ) with the mouse peptide .
additionally , fizz3/resistin is only weakly expressed in human adipocytes , and monocytes / macrophages are the major sites of fizz3/resistin production in adipose tissue .
it is currently unknown whether fizz3/resistin serves a paracrine function in adipocyte regulation or whether there is an entero  adipokine axis involving gip and fizz3/resistin in humans .
however , fizz3/resistin has been reported to increase ffa reesterification . in the majority of in vitro studies to date ,
the effects of gip on adipogenesis and lipogenesis have been shown to involve synergistic actions with insulin , and there has been significant interest in gipr antagonists as potential therapies for obesity .
however , adipose tissue expansion has been suggested to be an important adaptive response to increased food intake , as it protects against excess fat deposition in other sites , such as liver and muscle .
gip could be an important contributor to this response and reducing its effect might not result in the anticipated benefits .
additionally , studies on both transgenic mice and pigs expressing a dominantnegative gipr showed greatly reduced cell mass , with the mice becoming severely diabetic , supporting a critical role for gip signaling in cell development and proliferation .
 abstractglucosedependent insulinotropic polypeptide ( gip ) was the first incretin to be identified . 
 in addition to stimulating insulin secretion , gip plays regulatory roles in the maintenance , growth and survival of pancreatic islets , as well as impacting on adipocyte function . 
 the current review focuses on the intracellular signaling pathways by which gip contributes to the regulation of cell secretion and survival , and adipocyte differentiation and lipogenesis . 
 studies on signaling underlying the insulinotropic actions of the incretin hormones have largely been carried out with glucagonlike peptide1 . 
 they have provided evidence for contributions by both protein kinase  a ( pka ) and exchange protein directly activated by cyclic adenosine monophosphate ( epac2 ) , and their probable role in gip signaling is discussed . 
 recent studies have shown that inhibition of the kinase apoptosis signalregulating kinase  1 ( ask1 ) by gip plays a key role in reducing mitochondriainduced apoptosis in cells through protein kinase b ( pkb)mediated pathways , and that gipinduced posttranslational modification of voltage dependent k+ ( kv ) channels also contributes to its prosurvival role . through regulation of gene expression , 
 gip tips the balance between pro and antiapoptotic members of the bcell lymphoma2 ( bcl2 ) protein family towards cell survival . 
 gip also plays important roles in the differentiation of preadipocytes to adipocytes , and in the regulation of lipoprotein lipase expression and lipogenesis . 
 these events involve interactions between gip , insulin and resistin signaling pathways . 
 ( j diabetes invest , doi : 10.1111/j.20401124.2012.00196.x , 2012 ) 
Introduction
GIP Stimulation of Insulin Secretion
Cell Prosurvival Effects of GIP
Effects of GIP on Adipose Tissue