title: Chronic Glucose Exposure Systematically Shifts the Oscillatory Threshold of Mouse Islets: Experimental Evidence for an Early Intrinsic Mechanism of Compensation for Hyperglycemia.
abstract: Mouse islets exhibit glucose-dependent oscillations in electrical activity, intracellular Ca(2+) and insulin secretion. We developed a mathematical model in which a left shift in glucose threshold helps compensate for insulin resistance. To test this experimentally, we exposed isolated mouse islets to varying glucose concentrations overnight and monitored their glucose sensitivity the next day by measuring intracellular Ca(2+), electrical activity, and insulin secretion. Glucose sensitivity of all oscillation modes was increased when overnight glucose was greater than 2.8mM. To determine whether threshold shifts were a direct effect of glucose or involved secreted insulin, the KATP opener diazoxide (Dz) was coapplied with glucose to inhibit insulin secretion. The addition of Dz or the insulin receptor antagonist s961 increased islet glucose sensitivity, whereas the KATP blocker tolbutamide tended to reduce it. This suggests insulin and glucose have opposing actions on the islet glucose threshold. To test the hypothesis that the threshold shifts were due to changes in plasma membrane KATP channels, we measured cell KATP conductance, which was confirmed to be reduced by high glucose pretreatment and further reduced by Dz. Finally, treatment of INS-1 cells with glucose and Dz overnight reduced high affinity sulfonylurea receptor (SUR1) trafficking to the plasma membrane vs glucose alone, consistent with insulin increasing KATP conductance by altering channel number. The results support a role for metabolically regulated KATP channels in the maintenance of glucose homeostasis.
authors.affiliation: Department of Pharmacology and Brehm Diabetes Research Center (E.G., B.T., S.V., L.S.S.) and Department of Chemistry (S.L., R.T.K.), University of Michigan, Ann Arbor, Michigan 48105; and Laboratory of Biological Modeling (J.H., A.S.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Eric
authors.initials: E
authors.lastname: Glynn
authors.affiliation: Department of Pharmacology and Brehm Diabetes Research Center (E.G., B.T., S.V., L.S.S.) and Department of Chemistry (S.L., R.T.K.), University of Michigan, Ann Arbor, Michigan 48105; and Laboratory of Biological Modeling (J.H., A.S.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Thompson
authors.affiliation: Department of Pharmacology and Brehm Diabetes Research Center (E.G., B.T., S.V., L.S.S.) and Department of Chemistry (S.L., R.T.K.), University of Michigan, Ann Arbor, Michigan 48105; and Laboratory of Biological Modeling (J.H., A.S.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Suryakiran
authors.initials: S
authors.lastname: Vadrevu
authors.affiliation: Department of Pharmacology and Brehm Diabetes Research Center (E.G., B.T., S.V., L.S.S.) and Department of Chemistry (S.L., R.T.K.), University of Michigan, Ann Arbor, Michigan 48105; and Laboratory of Biological Modeling (J.H., A.S.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Shusheng
authors.initials: S
authors.lastname: Lu
authors.affiliation: Department of Pharmacology and Brehm Diabetes Research Center (E.G., B.T., S.V., L.S.S.) and Department of Chemistry (S.L., R.T.K.), University of Michigan, Ann Arbor, Michigan 48105; and Laboratory of Biological Modeling (J.H., A.S.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Kennedy
authors.affiliation: Department of Pharmacology and Brehm Diabetes Research Center (E.G., B.T., S.V., L.S.S.) and Department of Chemistry (S.L., R.T.K.), University of Michigan, Ann Arbor, Michigan 48105; and Laboratory of Biological Modeling (J.H., A.S.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Joon
authors.initials: J
authors.lastname: Ha
authors.affiliation: Department of Pharmacology and Brehm Diabetes Research Center (E.G., B.T., S.V., L.S.S.) and Department of Chemistry (S.L., R.T.K.), University of Michigan, Ann Arbor, Michigan 48105; and Laboratory of Biological Modeling (J.H., A.S.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Arthur
authors.initials: A
authors.lastname: Sherman
authors.affiliation: Department of Pharmacology and Brehm Diabetes Research Center (E.G., B.T., S.V., L.S.S.) and Department of Chemistry (S.L., R.T.K.), University of Michigan, Ann Arbor, Michigan 48105; and Laboratory of Biological Modeling (J.H., A.S.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Satin
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects*; D002478:Cells, Cultured; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology*; D018149:Glucose Intolerance / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism*; D006946:Hyperinsulinism / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008962:Models, Theoretical; D013997:Time Factors
chemical_list: D007328:Insulin; D005947:Glucose