title: cAMP-secretion coupling is impaired in diabetic GK/Par rat β-cells: a defect counteracted by GLP-1.
abstract: cAMP-raising agents with glucagon-like peptide-1 (GLP-1) as the first in class, exhibit multiple actions that are beneficial for the treatment of type 2 diabetic (T2D) patients, including improvement of glucose-induced insulin secretion (GIIS). To gain additional insight into the role of cAMP in the disturbed stimulus-secretion coupling within the diabetic β-cell, we examined more thoroughly the relationship between changes in islet cAMP concentration and insulin release in the GK/Par rat model of T2D. Basal cAMP content in GK/Par islets was significantly higher, whereas their basal insulin release was not significantly different from that of Wistar (W) islets. Even in the presence of IBMX or GLP-1, their insulin release did not significantly change despite further enhanced cAMP accumulation in both cases. The high basal cAMP level most likely reflects an increased cAMP generation in GK/Par compared with W islets since 1) forskolin dose-dependently induced an exaggerated cAMP accumulation; 2) adenylyl cyclase (AC)2, AC3, and G(s)α proteins were overexpressed; 3) IBMX-activated cAMP accumulation was less efficient and PDE-3B and PDE-1C mRNA were decreased. Moreover, the GK/Par insulin release apparatus appears less sensitive to cAMP, since GK/Par islets released less insulin at submaximal cAMP levels and required five times more cAMP to reach a maximal secretion rate no longer different from W. GLP-1 was able to reactivate GK/Par insulin secretion so that GIIS became indistinguishable from that of W. The exaggerated cAMP production is instrumental, since GLP-1-induced GIIS reactivation was lost in the presence the AC blocker 2',5'-dideoxyadenosine. This GLP-1 effect takes place in the absence of any improvement of the [Ca(2+)](i) response and correlates with activation of the cAMP-dependent PKA-dependent pathway.
authors.affiliation: Université Paris-Diderot, Sorbonne-Paris-Cité, Laboratoire B2PE (Biologie et Pathologie du Pancreas Endocrine), Unité Biologie Fonctionnelle et Adaptive, EAC 4413, Centre National de Recherche Scientifique, Paris, France.
authors.forename: Manuel
authors.initials: M
authors.lastname: Dolz
authors.forename: Jamileh
authors.initials: J
authors.lastname: Movassat
authors.forename: Danielle
authors.initials: D
authors.lastname: Bailbé
authors.forename: Hervé
authors.initials: H
authors.lastname: Le Stunff
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Giroix
authors.forename: Magali
authors.initials: M
authors.lastname: Fradet
authors.forename: Micheline
authors.initials: M
authors.lastname: Kergoat
authors.forename: Bernard
authors.initials: B
authors.lastname: Portha
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D055571:Secretory Pathway / Q000187:drug effects / Q000502:physiology; D013311:Streptozocin
chemical_list: D007328:Insulin; D013311:Streptozocin; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP; D005947:Glucose