title: Elevated Basal Insulin Secretion in Type 2 Diabetes Caused by Reduced Plasma Membrane Cholesterol.
abstract: Elevated basal insulin secretion under fasting conditions together with insufficient stimulated insulin release is an important hallmark of type 2 diabetes, but the mechanisms controlling basal insulin secretion remain unclear. Membrane rafts exist in pancreatic islet cells and spatially organize membrane ion channels and proteins controlling exocytosis, which may contribute to the regulation of insulin secretion. Membrane rafts (cholesterol and sphingolipid containing microdomains) were dramatically reduced in human type 2 diabetic and diabetic Goto-Kakizaki (GK) rat islets when compared with healthy islets. Oxidation of membrane cholesterol markedly reduced microdomain staining intensity in healthy human islets, but was without effect in type 2 diabetic islets. Intriguingly, oxidation of cholesterol affected glucose-stimulated insulin secretion only modestly, whereas basal insulin release was elevated. This was accompanied by increased intracellular Ca2+spike frequency and Ca2+influx and explained by enhanced single Ca2+channel activity. These results suggest that the reduced presence of membrane rafts could contribute to the elevated basal insulin secretion seen in type 2 diabetes.
authors.affiliation: Department of Clinical Sciences Malmö (V.N., A.S.K., J.H., C.L., S.B., P.B., T.M.R., E.Z., E.R.), Lund University Diabetes Centre, Lund University, SE-20502 Malmö, Sweden; and Science for Life Laboratory (S.W.), KTH Royal Institute of Technology, SE-171 77 Stockholm, Sweden.
authors.forename: Vini
authors.initials: V
authors.lastname: Nagaraj
authors.affiliation: Department of Clinical Sciences Malmö (V.N., A.S.K., J.H., C.L., S.B., P.B., T.M.R., E.Z., E.R.), Lund University Diabetes Centre, Lund University, SE-20502 Malmö, Sweden; and Science for Life Laboratory (S.W.), KTH Royal Institute of Technology, SE-171 77 Stockholm, Sweden.
authors.forename: Abdulla S
authors.initials: AS
authors.lastname: Kazim
authors.affiliation: Department of Clinical Sciences Malmö (V.N., A.S.K., J.H., C.L., S.B., P.B., T.M.R., E.Z., E.R.), Lund University Diabetes Centre, Lund University, SE-20502 Malmö, Sweden; and Science for Life Laboratory (S.W.), KTH Royal Institute of Technology, SE-171 77 Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Helgeson
authors.affiliation: Department of Clinical Sciences Malmö (V.N., A.S.K., J.H., C.L., S.B., P.B., T.M.R., E.Z., E.R.), Lund University Diabetes Centre, Lund University, SE-20502 Malmö, Sweden; and Science for Life Laboratory (S.W.), KTH Royal Institute of Technology, SE-171 77 Stockholm, Sweden.
authors.forename: Clemens
authors.initials: C
authors.lastname: Lewold
authors.affiliation: Department of Clinical Sciences Malmö (V.N., A.S.K., J.H., C.L., S.B., P.B., T.M.R., E.Z., E.R.), Lund University Diabetes Centre, Lund University, SE-20502 Malmö, Sweden; and Science for Life Laboratory (S.W.), KTH Royal Institute of Technology, SE-171 77 Stockholm, Sweden.
authors.forename: Satadal
authors.initials: S
authors.lastname: Barik
authors.affiliation: Department of Clinical Sciences Malmö (V.N., A.S.K., J.H., C.L., S.B., P.B., T.M.R., E.Z., E.R.), Lund University Diabetes Centre, Lund University, SE-20502 Malmö, Sweden; and Science for Life Laboratory (S.W.), KTH Royal Institute of Technology, SE-171 77 Stockholm, Sweden.
authors.forename: Pawel
authors.initials: P
authors.lastname: Buda
authors.affiliation: Department of Clinical Sciences Malmö (V.N., A.S.K., J.H., C.L., S.B., P.B., T.M.R., E.Z., E.R.), Lund University Diabetes Centre, Lund University, SE-20502 Malmö, Sweden; and Science for Life Laboratory (S.W.), KTH Royal Institute of Technology, SE-171 77 Stockholm, Sweden.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Reinbothe
authors.affiliation: Department of Clinical Sciences Malmö (V.N., A.S.K., J.H., C.L., S.B., P.B., T.M.R., E.Z., E.R.), Lund University Diabetes Centre, Lund University, SE-20502 Malmö, Sweden; and Science for Life Laboratory (S.W.), KTH Royal Institute of Technology, SE-171 77 Stockholm, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wennmalm
authors.affiliation: Department of Clinical Sciences Malmö (V.N., A.S.K., J.H., C.L., S.B., P.B., T.M.R., E.Z., E.R.), Lund University Diabetes Centre, Lund University, SE-20502 Malmö, Sweden; and Science for Life Laboratory (S.W.), KTH Royal Institute of Technology, SE-171 77 Stockholm, Sweden.
authors.forename: Enming
authors.initials: E
authors.lastname: Zhang
authors.affiliation: Department of Clinical Sciences Malmö (V.N., A.S.K., J.H., C.L., S.B., P.B., T.M.R., E.Z., E.R.), Lund University Diabetes Centre, Lund University, SE-20502 Malmö, Sweden; and Science for Life Laboratory (S.W.), KTH Royal Institute of Technology, SE-171 77 Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Renström
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005089:Exocytosis / Q000502:physiology; D005260:Female; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar
chemical_list: D015220:Calcium Channels; D007328:Insulin; D002784:Cholesterol; D005947:Glucose; D002118:Calcium