title: Enhanced GLP-1- and sulfonylurea-induced insulin secretion in islets lacking leptin signaling.
abstract: We have previously reported that the absence of leptin signaling in β-cells enhances glucose-stimulated insulin secretion and improves glucose tolerance in vivo. To investigate the relevance of β-cell leptin signaling in the context of postprandial or therapeutic insulin secretion, we examined the cross talk between leptin and glucagon-like peptide (GLP)-1 and sulfonylurea actions. Single and size-matched islets isolated from control or pancreas-specific leptin receptor knockout (pancreas-ObR-KO) mice were treated either with GLP-1 or with glibenclamide. Leptin suppressed GLP-1-stimulated intracellular Ca(2+) concentrations ([Ca(2+)](i)) increase that paralleled the decrease in insulin secretion in controls. In contrast, and as expected, the ObR-KO islets were nonresponsive to leptin, and instead, showed a 2.8-fold greater GLP-1-stimulated [Ca(2+)](i) increase and a 1.7-fold greater insulin secretion. Phosphorylation of cAMP-responsive element binding protein was enhanced, and phosphodiesterase enzymatic activity was suppressed in MIN6 β-cells with ObR knockdown compared with controls. The ObR-KO islets also showed significantly higher glibenclamide-induced insulin secretion compared with control islets, whereas [Ca(2+)](i) was similar to the controls. These data support enhanced insulinotropic effects of glucose, GLP-1, and sulfonylureas in the islets lacking leptin signaling with potential therapeutic implications.
authors.affiliation: Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Morioka
authors.forename: John F
authors.initials: JF
authors.lastname: Dishinger
authors.forename: Kendra R
authors.initials: KR
authors.lastname: Reid
authors.forename: Chong Wee
authors.initials: CW
authors.lastname: Liew
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Masaaki
authors.initials: M
authors.lastname: Inaba
authors.forename: Robert T
authors.initials: RT
authors.lastname: Kennedy
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D002460:Cell Line; D055785:Gene Knockdown Techniques; D052216:Glucagon-Like Peptide 1 / Q000502:physiology*; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000502:physiology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034622:RNA Interference; D018027:Receptors, Glucagon / Q000378:metabolism; D054411:Receptors, Leptin / Q000172:deficiency* / Q000235:genetics; D013453:Sulfonylurea Compounds / Q000494:pharmacology*
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007328:Insulin; D020738:Leptin; D018027:Receptors, Glucagon; D054411:Receptors, Leptin; D013453:Sulfonylurea Compounds; C515447:leptin receptor, mouse; D052216:Glucagon-Like Peptide 1; D005947:Glucose