title: Glucagon-Like Peptide-1 Regulates Cholecystokinin Production in β-Cells to Protect From Apoptosis.
abstract: Cholecystokinin (CCK) is a classic gut hormone that is also expressed in the pancreatic islet, where it is highly up-regulated with obesity. Loss of CCK results in increased β-cell apoptosis in obese mice. Similarly, islet α-cells produce increased amounts of another gut peptide, glucagon-like peptide 1 (GLP-1), in response to cytokine and nutrient stimulation. GLP-1 also protects β-cells from apoptosis via cAMP-mediated mechanisms. Therefore, we hypothesized that the activation of islet-derived CCK and GLP-1 may be linked. We show here that both human and mouse islets secrete active GLP-1 as a function of body mass index/obesity. Furthermore, GLP-1 can rapidly stimulate β-cell CCK production and secretion through direct targeting by the cAMP-modulated transcription factor, cAMP response element binding protein (CREB). We find that cAMP-mediated signaling is required for Cck expression, but CCK regulation by cAMP does not require stimulatory levels of glucose or insulin secretion. We also show that CREB directly targets the Cck promoter in islets from obese (Leptin(ob/ob)) mice. Finally, we demonstrate that the ability of GLP-1 to protect β-cells from cytokine-induced apoptosis is partially dependent on CCK receptor signaling. Taken together, our work suggests that in obesity, active GLP-1 produced in the islet stimulates CCK production and secretion in a paracrine manner via cAMP and CREB. This intraislet incretin loop may be one mechanism whereby GLP-1 protects β-cells from apoptosis.
authors.affiliation: Department of Medicine (A.K.L., T.J.B., J.A.W., M.E.K., D.B.D.), Division of Endocrinology, University of Wisconsin-Madison, Madison, Wisconsin 53705; Department of Nutritional Sciences (J.C.N.), University of Wisconsin-Madison, Madison, Wisconsin 53706; and William S. Middleton Memorial Veterans Hospital (D.B.D.), Madison, Wisconsin 53705.
authors.forename: Amelia K
authors.initials: AK
authors.lastname: Linnemann
authors.affiliation: Department of Medicine (A.K.L., T.J.B., J.A.W., M.E.K., D.B.D.), Division of Endocrinology, University of Wisconsin-Madison, Madison, Wisconsin 53705; Department of Nutritional Sciences (J.C.N.), University of Wisconsin-Madison, Madison, Wisconsin 53706; and William S. Middleton Memorial Veterans Hospital (D.B.D.), Madison, Wisconsin 53705.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Neuman
authors.affiliation: Department of Medicine (A.K.L., T.J.B., J.A.W., M.E.K., D.B.D.), Division of Endocrinology, University of Wisconsin-Madison, Madison, Wisconsin 53705; Department of Nutritional Sciences (J.C.N.), University of Wisconsin-Madison, Madison, Wisconsin 53706; and William S. Middleton Memorial Veterans Hospital (D.B.D.), Madison, Wisconsin 53705.
authors.forename: Therese J
authors.initials: TJ
authors.lastname: Battiola
authors.affiliation: Department of Medicine (A.K.L., T.J.B., J.A.W., M.E.K., D.B.D.), Division of Endocrinology, University of Wisconsin-Madison, Madison, Wisconsin 53705; Department of Nutritional Sciences (J.C.N.), University of Wisconsin-Madison, Madison, Wisconsin 53706; and William S. Middleton Memorial Veterans Hospital (D.B.D.), Madison, Wisconsin 53705.
authors.forename: Jaclyn A
authors.initials: JA
authors.lastname: Wisinski
authors.affiliation: Department of Medicine (A.K.L., T.J.B., J.A.W., M.E.K., D.B.D.), Division of Endocrinology, University of Wisconsin-Madison, Madison, Wisconsin 53705; Department of Nutritional Sciences (J.C.N.), University of Wisconsin-Madison, Madison, Wisconsin 53706; and William S. Middleton Memorial Veterans Hospital (D.B.D.), Madison, Wisconsin 53705.
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Kimple
authors.affiliation: Department of Medicine (A.K.L., T.J.B., J.A.W., M.E.K., D.B.D.), Division of Endocrinology, University of Wisconsin-Madison, Madison, Wisconsin 53705; Department of Nutritional Sciences (J.C.N.), University of Wisconsin-Madison, Madison, Wisconsin 53706; and William S. Middleton Memorial Veterans Hospital (D.B.D.), Madison, Wisconsin 53705.
authors.forename: Dawn Belt
authors.initials: DB
authors.lastname: Davis
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D015992:Body Mass Index; D045744:Cell Line, Tumor; D002766:Cholecystokinin / Q000096:biosynthesis* / Q000378:metabolism; D000242:Cyclic AMP; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D007328:Insulin; D011949:Receptors, Cholecystokinin; D052216:Glucagon-Like Peptide 1; D002766:Cholecystokinin; D000242:Cyclic AMP