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OwnerPer-Olof Berggren, Barbara Leibiger +1inventors
InventorsPer-Olof Berggren, Barbara Leibiger, Ingo Leibiger
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Insulin resistance is a central feature of type II diabetes and other diseases, and may affect every tissue of the body, including the pancreatic beta cell. Insulin signaling is mediated by a complex network of diverging and converging pathways, with alternative proteins and isoforms at almost every step in the process. We have previously shown that insulin activates the transcription of its own gene by signaling through Insulin Receptor A type (Ex11−), PI3 kinase and p70 s6 kinase. When studying the mechanisms underlying the glucose-stimulated activation of the glucokinase gene in pancreatic beta cells, we now demonstrate that also here secreted insulin is a key-factor. In contrast to the insulin gene, transcription of the glucokinase gene is promoted by signaling via Insulin Receptor B type (Ex11+) and protein kinase B (c-Akt). These data provide the first evidence for selectivity in insulin action via the two isoforms of the Insulin Receptor, A type (Ex11−) and B type (Ex11+), and reinforce the concept of the beta cell being an important target of insulin action.
An Insulin Receptor isoform-specific readout system comprising:
An Insulin Receptor isoform-specific readout system according to any of the previous claims, wherein measurement of reporter gene expression is performed by measurement of fluorescence.
An Insulin Receptor isoform-specific readout system according to any of the previous claims, wherein the measurement of insulin promoter activation is performed by measurement of DsRed fluorescence.
An Insulin Receptor isoform-specific readout system according to any of the previous claims, wherein the measurement of βGK promoter activation is performed by measurement of GFP fluorescence.
A plasmid selected from the group consisting of prIns1.DsRed and prβGK.GFP.
An isolated transfected cell expressing the gene product of at least one genetical element comprising a suitable reporter gene under control of
An isolated transfected cell, expressing the gene product of a plasmid selected from the group consisting of prIns1.DsRed and prβGK.GFP, said cell being selected from the group consisting of transfected isolated pancreatic islets cells or insulin-producing HIT-T15 cells.
A stable transfected pancreatic beta cell line expressing the gene product of at least one genetical element comprising a suitable reporter gene under control of either an insulin promoter or a βGK promoter.
A stable transfected pancreatic beta cell line expressing the gene product of a plasmid selected from the group consisting of prIns1.DsRed and prβGK.GFP.
A transfected primary pancreatic beta cell culture expressing the gene product of at east one genetical element comprising a suitable reporter gene under control of either an insulin promoter or a βGK promoter.
A transfected primary pancreatic beta cell culture expressing the gene product of a plasmid selected from the group consisting of prIns1.DsRed and prβGK.GFP.
A method for determining the selectivity of a drug, chemical substance and/or a chemical composition for Insulin Receptor isoform A versus Insulin Receptor isoform B, comprising measuring the ratio between insulin promoter activation and βGK promoter activation that is induced by providing said drug, chemical substance and/or a chemical composition.
A method for determining the selectivity of a drug, chemical substance and/or a chemical composition for Insulin Receptor isoform A versus Insulin Receptor isoform B, comprising measuring the ratio between insulin promoter activation and βGK promoter activation that is induced by providing said drug, chemical substance and/or chemical composition, characterised by
A method of treatment of Type II Diabetes comprising administering a drug selective for Insulin Receptor isoform B to a patient in need thereof.
A method of treatment of Type II Diabetes comprising administering a drug selective for Insulin Receptor isoform A to a patient in need thereof.
A method for identifying a drug capable of stimulating βGK transcription comprising the steps of testing whether it activates cellular signalling through
A method for identifying a drug capable of stimulating insulin transcription comprising the steps of testing whether it activates cellular signalling through
A method of treatment of Type II Diabetes comprising administering a drug capable of stimulating βGK transcription in pancreatic beta cells to a patient in need thereof.
A method of treatment of Type II Diabetes comprising administering a drug capable of stimulating insulin transcription in pancreatic beta cells to a patient in need thereof.
Use of a plasmid selected from the group consisting of prIns1.DsRed and prβGK.GFP for measuring Insulin Receptor isoform-specific activation.
A pharmaceutical composition comprising a compound, the compound being selective for Insulin Receptor isoform B and a market authorisation, the market authorisation being based on an application for market authorisation comprising data showing selectivity for Insulin Receptor isoform B.
Dependencies are inferred from the claim text.