the endocrine pancreas tightly regulates hormone secretion to maintain normoglycemia . under conditions of stress and increased demand , such as the inflammation and insulin resistance observed in obesity , adaptation of the pancreatic islet this compensatory adaptation could include cell proliferation and enhanced cell survival , and can allow increased insulin production to maintain euglycemia . failure to maintain adequate functional cell mass results in diabetes . therefore , understanding the pathways that control compensatory adaptation of the islet in nondiabetic obesity can provide insight into cell mass regulation . drug development targeting these pathways could provide important new therapies for diabetes , as none of the current diabetes medications directly target cell mass in humans . the cell does not exist in isolation , but is intimately associated with a host of other cell types in the pancreatic islet , including : cells , cells , ppcells , endothelial cells ( from the islet capillaries ) , and neurons . although less well understood , communication between these various cell types in the form of paracrine signaling is integral to the function of the islet as a microorgan that can respond both acutely and chronically to stress and increased demand . the importance of cell  cell communication on inflammatory stress response in the human islet was recently implicated by work showing that the islet as a whole responds differently to cytokineinduced stress than transformed cells in isolation1 . this suggests that perturbations in paracrine signaling could impair the adaptive response to obesity , and contribute to the pathophysiology of diabetes in humans . we and others have recently discovered that classic gutderived peptide hormones , including glucagonlike peptide1 ( glp1 ) and cholecystokinin ( cck ) , are produced in and secreted from islet cells under various stress conditions , including obesity2 , 3 , 4 , 5 . the production of incretin hormones in the pancreatic islet might be an adaptive mechanism to improve cell function and survival under conditions of stress . both glp1 and cck have positive effects on the cell , as they can stimulate insulin secretion , and might promote cell proliferation or protection from apoptosis6 , 7 . in the present review , we discuss the production of glp1 and cck , and how they might regulate one another in the pancreatic islet . it is not well understood how the production of these peptides is regulated in the islet , but identification of these regulatory pathways might allow us to find ways to enhance this beneficial adaptive response . glp1 is a peptide hormone , well studied as a product of neuroendocrine cells in the intestine and brain . it functions as an incretin to stimulate insulin secretion , but also has important roles in stimulating satiety and delaying gastric emptying8 . glp1 is cleaved from the precursor protein proglucagon by prohormone convertase  1/3 ( pc1/3 ) . the enzyme dipeptidyl peptidase4 degrades circulating glp1 within minutes9 , 10 , making it unlikely that postprandial glp1 secretion from the intestine can provide a sustained endocrine signal directly to the islet . a recent study suggests that the effects of glp1 on the cell are not as a result of gutderived hormone , but perhaps neuronal or even paracrine action8 . in the pancreatic islet however , pc1/3 and glp1 are expressed in cells under conditions of islet stress including pregnancy , the prediabetic nonobese diabetic mouse , and the ob / ob and db / db models of obesity and diabetes2 . neither diabetes nor obesity is associated with a significant change in serum glp1 levels in humans11 . however , we have shown that glp1 is secreted from human islets , with enhanced secretion from islets from obese donors5 . this suggests that intraislet paracrine function of glp1 might be one of the adaptive responses to stress that improves islet function and survival . cck is also a peptide hormone , and is best known for its role in digestion and satiety . cck is posttranslationally processed into a variety of isoforms , with the most bioactive form being sulfated cck8 . it is secreted by intestinal cells to stimulate gallbladder contraction and pancreatic exocrine secretion , and is found in the brain to modulate satiety , anxiety and memory12 . at supraphysiological levels , cck can act as an insulin secretagogue13 . cck is also expressed in the pancreatic cell14 , and is the most highly upregulated islet gene in response to obesity3 . the upregulation of islet cck occurs in multiple models of insulin resistance , including ob / ob , agouti and highfat diet ( hfd)fed mice . therefore , cck production might be part of a general adaptive islet response to insulin resistance or cell stress . however , until recently , the mechanisms that underlie endogenous cck regulation and function in the cell were unknown . there is evidence that the cck promoter is regulated by cyclic adenosine monophosphate ( camp ) signaling in other cell types . this transcriptional activation is mediated by camp response element binding protein ( creb ) that binds to the cck promoter in intestinal l  cells and cells of neuronal origin15 , 16 , 17 . transient creb overexpression in teratocarcinoma cells can increase cck promoter activity and conversely , deletion of a camp response element in the cck promoter or treatment with a dominant negative creb dramatically reduces forskolinmediated cck transcription15 . based on these data , we hypothesized that a similar mechanism of regulation might occur in the cell to stimulate cck transcription during obesity . indeed , we observe recruitment of creb to the cck promoter in cultured cells treated with camp5 . the glp1 receptor is coupled to gs proteins , and can stimulate adenylate cyclase and camp production in response to glp1 binding . in support of this , we find that islets from ob / ob mice secrete active glp1 and also transcribe the cck gene5 . in cultured cells , glp1 can stimulate cck transcription through direct targeting by creb . in  vivo , creb occupancy at the mouse islet cck promoter increases as a function of obesity . as cell glp1 secretion and cell cck transcription are both increased in obesity , locally produced glp1 might be responsible for creb activation of cell cck in  vivo ( figure  1 ) . our recent data suggest that in obesity , glp1 produced from the cell rapidly stimulates production and secretion of cck through direct targeting in the cell . we hypothesize that cell cck mediates survival through autocrine / paracrine signaling and could also further stimulate cell production of glp1 to create a positive feedback loop . camp , cyclic adenosine monophosphate ; creb , cyclic adenosine monophosphate response element binding protein . notably , the stimulation of cck by glp1 or camp does not depend on insulin production , and occurs equally well in low glucose , suggesting a direct effect ( unpublished observations and linnemann et  al.5 ) . this also suggests that cck secretion from the cell is regulated by a mechanism that is distinct from that of insulin , and cck is not packaged in the insulin secretory granule . as intestinal cells show regulated secretion of cck18 , 19 , we suspect that cck secretion from the islet is also regulated . it still remains to be determined whether the hyperglycemic conditions observed in diabetes affect islet secretion of cck . glp1 and cck might also regulate one another in a feedforward mechanism to maximize their production in a stressful environment , such as obesity . in rat islets , glp1 treatment increases pc1/3 and glp1 production through a positive feedback mechanism20 . treatment with a stable cck analog can also increase cell glp1 and pc1/3 expression in obese mice21 . reinforcement of a glp1/cck islet signaling axis in  vivo through a positive feedback loop could amplify the signals leading to compensatory adaptation to obesity . despite compelling evidence that glp1 plays a role in apoptosis protection in rodent islet and cell lines22 , 23 , there have been a relatively small number of studies suggesting that glp1 can directly protect human islets from cell apoptosis . human islets in culture have reduced basal rates of cell death when cultured in the presence of glp124 . cytokines are elevated in obesity , and contribute to cell apoptosis in both type  1 and type  2 diabetes25 . human islets treated ex  vivo with glp1 have reduced cell apoptosis in response to cytokine treatment26 . however , another group found that combination treatment with both the glp1 receptor agonist , exendin4 , and the growth factor , betacellulin , was required to protect human islets from cytokinemediated apoptosis27 . this combined treatment resulted in increased / preserved expression of active akt ( protein kinase  b ) , active creb and the prosurvival protein , bcl2 ( bcell lymphoma2 ) . the antiapoptotic effects of glp1 are dependent on creb , as they were reduced when a dominant negative version of creb was expressed27 . many studies using rodent islets or cultured cells have also shown that glp1 has antiapoptotic effects , including when produced locally in the islet28 . loss of cck in ob / ob mice causes a reduction in islet size , decreased cell mass and increased cell death leading to hyperglycemia3 . overexpression of cck in these obese knockout islets or in a cell line can rescue from apoptosis3 , 29 . additionally , transgenic overexpression of cck in the cell confers protection from streptozotocin ( stz)induced apoptosis29 . considering our observation that glp1 stimulates cell production and secretion of cck5 , we hypothesize that glp1stimulated production of cck in the islet is important for cell survival in obesity . this adaptive response might also contribute to diabetes prevention through increased cell numbers , and thus increased capabilities for insulin production . the mechanism by which cck signals to protect cells from apoptosis is not well understood . cck can signal through two gprotein coupled receptors , the cck a  receptor ( cckar or cck  1 receptor ) and cck b  receptor ( cckbr or cck  2 receptor ) to activate a number of different signal transduction pathways30 . the expression pattern of the cck receptors within the islet is not clear in the literature , partly because of problems with quality and specificity of antibodies against these gprotein coupled receptors proteins30 , 31 , 32 , 33 . receptor expression in models of obesity and diabetes has not been studied , and these states might alter receptor levels . we used a nonselective cck receptor antagonist to show that autocrine cck signaling in the cell is required for glp1mediated apoptosis protection5 . however , specific blockade of the cckar inhibited downstream cck signaling pathways in a cell line and mouse islets34 , supporting an important role for cckar in the cell . we propose a model wherein glp1 secreted from obese islets acts in a paracrine manner to stimulate cell cck production ( figure  1 ) . the isletderived cck can act locally to protect the cell from apoptosis through autocrine regulation . in light of evidence that exogenous cck treatment enhances cell glp1 production under hfd feeding21 , there might also be a positive feedback loop that amplifies this pathway in  vivo . disruptions in glp1 and cck signaling could contribute to the pathophysiology of type  2 diabetes . a reduction in glp1 levels could be a factor in the clinical presentation of diabetes , although evidence is mixed and collectively there appears to be no difference in plasma glp1 levels in patients with diabetes11 . therefore , glp1 production or signaling might be perturbed in other ways that contribute to diabetes pathogenesis , including at the level of the islet . interestingly , islets from donors with a history of type  2 diabetes secrete more glp1 than nondiabetic islets ( marchetti35 and unpublished observations ) and mice with stzinduced diabetes similarly have increased pancreatic cell production of glp136 . thus , it is likely that an intraislet defect in glp1 signaling exists downstream of cell glp1 production . indeed , human type  2 diabetic islets have decreased glp1 receptor ( glp1r ) expression37 . induction of diabetes with lowdose stz in glp1r knockout mice also leads to a more severe phenotype with increased levels of islet apoptosis36 . furthermore , glp1r null mice show abnormalities in islet adenylate cyclase activity and increased sensitivity to cell injury38 , 39 . we find that glp1 can stimulate cell cck production and prevent cell apoptosis in  vitro , and this protection is at least partially dependent on cck receptor signaling5 . in line with this , we find that cck is both necessary and sufficient to protect cells from apoptosis in  vivo 
 3 , 29 . while specific downstream signaling pathways are implicated in glp1mediated protection40 , 41 , cck production and signaling through the cck receptors can provide an alternate explanation for activation of these same signaling molecules . it is plausible that in  vivo cell protection mediated by glp1 depends on cck production and paracrine signaling . therefore , we propose that the increased susceptibility to cell apoptosis with glp1r loss might be at least partially as a result of the inability to upregulate cck production . it is intriguing to consider that glp1 and cck signaling pathways overlap in the islet such that when one pathway is perturbed , they might compensate for one another . for example , islets from glp1 receptor / glucagon receptor double knockout mice have significantly increased expression of cckar transcript and sensitivity to cck42 , and this enhanced cck signaling could minimize the impact of the genotype on blood glucose homeostasis . further support for the importance of cck signaling in maintenance of cell mass comes from the otsuka longevans tokushima fatty ( oletf ) rat . this rat has a naturally occurring mutation in the cckar , and develops obesity and diabetes . there is also some evidence that cckbr signaling might be relevant in protection from cell apoptosis . gastrin , which predominantly signals through the cckbr , can reduce cell apoptosis after partial pancreatectomy43 . combined therapy with gastrin and glp1 can also reduce cell apoptosis44 , 45 , but these studies are confounded by the fact that treated animals have improved glycemia and therefore less cell stress . regardless of the receptor involved in cck signaling , evidence suggests that glp1 and cck signaling are both clearly important for cell survival . although the mechanism is still unclear in  vivo , it is likely that glp1 regulation of cell cck in the intact islet is a major contributor to stress adaptation and enhanced cell survival . the use of glp1 mimetics and dipeptidyl peptidase4 inhibitors for the treatment of type  2 diabetes is increasing rapidly , and several recent clinical trials have also examined their efficacy in the treatment of type  1 diabetes46 , 47 . although glp1based therapy seems to reduce dependence on insulin in type  1 diabetics , it remains to be seen whether longterm use in either type  1 or type  2 diabetes can directly impact cell mass to prevent further decline . it is clear that higherpowered and longerterm studies will be required , and examination of ongoing registered clinical trials suggests that we will see more of these types of studies in the near future . we have described a novel mechanism whereby glp1directed therapies might exert protective effects on the cell through activation of cck production . we also provide evidence that activation of intraislet glp1 signaling is a natural physiological response , or adaptation , to obesity5 . future work will be necessary to determine the factor(s ) responsible and the mechanism by which they activate an antiapoptotic adaptation to obesity . many questions remain regarding if or how glp1 mimetics could contribute to cell mass preservation in individuals with diabetes . it was recently shown that acute treatment of mice on a hfd with either a combination of cck and glp1 or a novel cck / glp1 hybrid peptide can lower blood glucose and improve glucose tolerance48 , 49 . synergy between cck / gastrin and glp1 has also been shown elsewhere in hfd and ob / ob mouse models50 . given what we now know regarding the ability of both glp1 and cck to regulate one another and prevent cell death , we propose that longterm treatment with these hormones might impact islet peptide production to allow maintenance of cell mass . examination of how glp1 and cck specifically signal in the islet might also provide new therapeutic targets that could minimize nonislet side effects . importantly , putting this work into the context of disrupted signaling events in diabetes will provide critical mechanistic insight for future development of targeted receptor agonists as potential therapies .
abstractprecise control of blood glucose is dependent on adequate cell mass and function . 
 thus , reductions in cell mass and function lead to insufficient insulin production to meet demand , and result in diabetes . 
 recent evidence suggests that paracrine signaling in the islet might be important in obesity , and disruption of this signaling could play a role in the pathogenesis of diabetes . 
 for example , we recently discovered a novel islet incretin axis where glucagonlike peptide1 regulates cell production of another classic gut hormone , cholecystokinin . 
 this axis is stimulated by obesity , and plays a role in enhancing cell survival . in the present review 
 , we place our observations in the wider context of the literature on incretin regulation in the islet , and discuss the potential for therapeutic targeting of these pathways .