TCF1 links GIPR signaling to the control of beta cell function and survival
The details of the GIP signaling pathway are murky, but new data identify a downstream pathway involving Tcf7 that regulates beta cell survival and activity. The glucagon-like peptide-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor transduce nutrient-stimulated...
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| Published in | Nature medicine Vol. 22; no. 1; pp. 84 - 90 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
New York
Nature Publishing Group US
01.01.2016
Nature Publishing Group |
| Subjects | |
| Online Access | Get full text |
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| Abstract | The details of the GIP signaling pathway are murky, but new data identify a downstream pathway involving Tcf7 that regulates beta cell survival and activity.
The glucagon-like peptide-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor transduce nutrient-stimulated signals to control beta cell function
1
. Although the GLP-1 receptor (GLP-1R) is a validated drug target for diabetes
1
, the importance of the GIP receptor (GIPR) for the function of beta cells remains uncertain
2
,
3
,
4
. We demonstrate that mice with selective ablation of GIPR in beta cells (
MIP-Cre:Gipr
Flox/Flox
; Gipr
−/−
β
Cell
) exhibit lower levels of meal-stimulated insulin secretion, decreased expansion of adipose tissue mass and preservation of insulin sensitivity when compared to
MIP-Cre
controls. Beta cells from
Gipr
−/−
β
Cell
mice display greater sensitivity to apoptosis and markedly lower islet expression of T cell–specific transcription factor-1 (TCF1, encoded by
Tcf7
), a protein not previously characterized in beta cells. GIP, but not GLP-1, promotes beta cell
Tcf7
expression via a cyclic adenosine monophosphate (cAMP)-independent and extracellular signal–regulated kinase (ERK)-dependent pathway.
Tcf7
(in mice) or
TCF7
(in humans) levels are lower in islets taken from diabetic mice and in humans with type 2 diabetes; knockdown of
TCF7
in human and mouse islets impairs the cytoprotective responsiveness to GIP and enhances the magnitude of apoptotic injury, whereas restoring TCF1 levels in beta cells from
Gipr
−/−
β
Cell
mice lowers the number of apoptotic cells compared to that seen in
MIP-Cre
controls.
Tcf7
−/−
mice show impaired insulin secretion, deterioration of glucose tolerance with either aging and/or high-fat feeding and increased sensitivity to beta cell injury relative to wild-type (WT) controls. Hence the GIPR-TCF1 axis represents a potential therapeutic target for preserving both the function and survival of vulnerable, diabetic beta cells. |
|---|---|
| AbstractList | The details of the GIP signaling pathway are murky, but new data identify a downstream pathway involving Tcf7 that regulates beta cell survival and activity.
The glucagon-like peptide-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor transduce nutrient-stimulated signals to control beta cell function
1
. Although the GLP-1 receptor (GLP-1R) is a validated drug target for diabetes
1
, the importance of the GIP receptor (GIPR) for the function of beta cells remains uncertain
2
,
3
,
4
. We demonstrate that mice with selective ablation of GIPR in beta cells (
MIP-Cre:Gipr
Flox/Flox
; Gipr
−/−
β
Cell
) exhibit lower levels of meal-stimulated insulin secretion, decreased expansion of adipose tissue mass and preservation of insulin sensitivity when compared to
MIP-Cre
controls. Beta cells from
Gipr
−/−
β
Cell
mice display greater sensitivity to apoptosis and markedly lower islet expression of T cell–specific transcription factor-1 (TCF1, encoded by
Tcf7
), a protein not previously characterized in beta cells. GIP, but not GLP-1, promotes beta cell
Tcf7
expression via a cyclic adenosine monophosphate (cAMP)-independent and extracellular signal–regulated kinase (ERK)-dependent pathway.
Tcf7
(in mice) or
TCF7
(in humans) levels are lower in islets taken from diabetic mice and in humans with type 2 diabetes; knockdown of
TCF7
in human and mouse islets impairs the cytoprotective responsiveness to GIP and enhances the magnitude of apoptotic injury, whereas restoring TCF1 levels in beta cells from
Gipr
−/−
β
Cell
mice lowers the number of apoptotic cells compared to that seen in
MIP-Cre
controls.
Tcf7
−/−
mice show impaired insulin secretion, deterioration of glucose tolerance with either aging and/or high-fat feeding and increased sensitivity to beta cell injury relative to wild-type (WT) controls. Hence the GIPR-TCF1 axis represents a potential therapeutic target for preserving both the function and survival of vulnerable, diabetic beta cells. The glucagon-like peptide-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor transduce nutrient-stimulated signals to control beta cell function. Although the GLP-1 receptor (GLP-1R) is a validated drug target for diabetes, the importance of the GIP receptor (GIPR) for the function of beta cells remains uncertain. We demonstrate that mice with selective ablation of GIPR in beta cells (MIP-Cre:Gipr(Flox/Flox); Gipr(-/-βCell)) exhibit lower levels of meal-stimulated insulin secretion, decreased expansion of adipose tissue mass and preservation of insulin sensitivity when compared to MIP-Cre controls. Beta cells from Gipr(-/-βCell) mice display greater sensitivity to apoptosis and markedly lower islet expression of T cell-specific transcription factor-1 (TCF1, encoded by Tcf7), a protein not previously characterized in beta cells. GIP, but not GLP-1, promotes beta cell Tcf7 expression via a cyclic adenosine monophosphate (cAMP)-independent and extracellular signal-regulated kinase (ERK)-dependent pathway. Tcf7 (in mice) or TCF7 (in humans) levels are lower in islets taken from diabetic mice and in humans with type 2 diabetes; knockdown of TCF7 in human and mouse islets impairs the cytoprotective responsiveness to GIP and enhances the magnitude of apoptotic injury, whereas restoring TCF1 levels in beta cells from Gipr(-/-βCell) mice lowers the number of apoptotic cells compared to that seen in MIP-Cre controls. Tcf7(-/-) mice show impaired insulin secretion, deterioration of glucose tolerance with either aging and/or high-fat feeding and increased sensitivity to beta cell injury relative to wild-type (WT) controls. Hence the GIPR-TCF1 axis represents a potential therapeutic target for preserving both the function and survival of vulnerable, diabetic beta cells. The glucagon-like peptide-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor transduce nutrient-stimulated signals to control beta cell function. Although the GLP-1 receptor (GLP-1R) is a validated drug target for diabetes, the importance of the GIP receptor (GIPR) for the function of beta cells remains uncertain. We demonstrate that mice with selective ablation of GIPR in beta cells (MIP-Cre:Gipr(Flox/Flox); Gipr(-/-βCell)) exhibit lower levels of meal-stimulated insulin secretion, decreased expansion of adipose tissue mass and preservation of insulin sensitivity when compared to MIP-Cre controls. Beta cells from Gipr(-/-βCell) mice display greater sensitivity to apoptosis and markedly lower islet expression of T cell-specific transcription factor-1 (TCF1, encoded by Tcf7), a protein not previously characterized in beta cells. GIP, but not GLP-1, promotes beta cell Tcf7 expression via a cyclic adenosine monophosphate (cAMP)-independent and extracellular signal-regulated kinase (ERK)-dependent pathway. Tcf7 (in mice) or TCF7 (in humans) levels are lower in islets taken from diabetic mice and in humans with type 2 diabetes; knockdown of TCF7 in human and mouse islets impairs the cytoprotective responsiveness to GIP and enhances the magnitude of apoptotic injury, whereas restoring TCF1 levels in beta cells from Gipr(-/-βCell) mice lowers the number of apoptotic cells compared to that seen in MIP-Cre controls. Tcf7(-/-) mice show impaired insulin secretion, deterioration of glucose tolerance with either aging and/or high-fat feeding and increased sensitivity to beta cell injury relative to wild-type (WT) controls. Hence the GIPR-TCF1 axis represents a potential therapeutic target for preserving both the function and survival of vulnerable, diabetic beta cells.The glucagon-like peptide-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor transduce nutrient-stimulated signals to control beta cell function. Although the GLP-1 receptor (GLP-1R) is a validated drug target for diabetes, the importance of the GIP receptor (GIPR) for the function of beta cells remains uncertain. We demonstrate that mice with selective ablation of GIPR in beta cells (MIP-Cre:Gipr(Flox/Flox); Gipr(-/-βCell)) exhibit lower levels of meal-stimulated insulin secretion, decreased expansion of adipose tissue mass and preservation of insulin sensitivity when compared to MIP-Cre controls. Beta cells from Gipr(-/-βCell) mice display greater sensitivity to apoptosis and markedly lower islet expression of T cell-specific transcription factor-1 (TCF1, encoded by Tcf7), a protein not previously characterized in beta cells. GIP, but not GLP-1, promotes beta cell Tcf7 expression via a cyclic adenosine monophosphate (cAMP)-independent and extracellular signal-regulated kinase (ERK)-dependent pathway. Tcf7 (in mice) or TCF7 (in humans) levels are lower in islets taken from diabetic mice and in humans with type 2 diabetes; knockdown of TCF7 in human and mouse islets impairs the cytoprotective responsiveness to GIP and enhances the magnitude of apoptotic injury, whereas restoring TCF1 levels in beta cells from Gipr(-/-βCell) mice lowers the number of apoptotic cells compared to that seen in MIP-Cre controls. Tcf7(-/-) mice show impaired insulin secretion, deterioration of glucose tolerance with either aging and/or high-fat feeding and increased sensitivity to beta cell injury relative to wild-type (WT) controls. Hence the GIPR-TCF1 axis represents a potential therapeutic target for preserving both the function and survival of vulnerable, diabetic beta cells. The glucagon-like peptide-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor transduce nutrient-stimulated signals to control beta cell function (1). Although the GLP-1 receptor (GLP-1R) is a validated drug target for diabetes (1), the importance of the GIP receptor (GIPR) for the function of beta cells remains uncertain (2-4). We demonstrate that mice with selective ablation of GIPR in beta cells ([MIP-Cre:Gipr.sup.Flox/Flox]; [Gipr-/-.sup.βCell]) exhibit lower levels of meal-stimulated insulin secretion, decreased expansion of adipose tissue mass and preservation of insulin sensitivity when compared to M/P-Cre controls. Beta cells from [Gipr-/-.sup.βCell] mice display greater sensitivity to apoptosis and markedly lower islet expression of T cell-specific transcription factor-1 (TCF1, encoded by Tcf7), a protein not previously characterized in beta cells. GIP, but not GLP-1, promotes beta cell Tcf7 expression via a cyclic adenosine monophosphate (cAMP)-independent and extracellular signal-regulated kinase (ERK)-dependent pathway. Tcf7 (in mice) or TCF7 (in humans) levels are lower in islets taken from diabetic mice and in humans with type 2 diabetes; knockdown of TCF7 in human and mouse islets impairs the cytoprotective responsiveness to GIP and enhances the magnitude of apoptotic injury, whereas restoring TCF1 levels in beta cells from [Gipr-/-.sup.βCell] mice lowers the number of apoptotic cells compared to that seen in MIP-Cre controls. [Tcf7.sup.-/-] mice show impaired insulin secretion, deterioration of glucose tolerance with either aging and/or high-fat feeding and increased sensitivity to beta cell injury relative to wild-type (WT) controls. Hence the GIPR-TCF1 axis represents a potential therapeutic target for preserving both the function and survival of vulnerable, diabetic beta cells. The details of the GIP signaling pathway are murky, but new data identify a downstream pathway involving Tcf7 that regulates beta cell survival and activity. Our current data establish that TCF1, acting through PTTG1, links GIPR signaling to the control of insulin secretion, the survival of beta cells and the adaptation of these cells to metabolic stress. Given that GIPR, but not GLP-1R, signaling controlled the TCF1-PTTG1 axis in beta cells, and that GIP responsiveness was rapidly restored after a brief period of improved glucose control in human subjects with T2D13, our findings highlight the potential of targeting GIPR-TCF1-PTTG1 signaling for the preservation of beta cell mass and the treatment of diabetes. Collectively, our data imply that the development of GIP-based therapies may target novel pathways, independently of GLP-1R signaling, thus linking nutrient-activated signals to the control of beta cell function and survival. |
| Audience | Academic |
| Author | Campbell, Jonathan E Kolic, Jelena Liu, Yu Wrana, Jeffrey L Ussher, John R Baggio, Laurie L MacDonald, Patrick E Mulvihill, Erin E Tamarina, Natalia Drucker, Daniel J Cao, Xiemen Morii, Tsukasa Streutker, Catherine J Lamont, Benjamin J Philipson, Louis H |
| Author_xml | – sequence: 1 givenname: Jonathan E surname: Campbell fullname: Campbell, Jonathan E organization: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital – sequence: 2 givenname: John R surname: Ussher fullname: Ussher, John R organization: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Present addresses: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada (J.R.U.); Department of Medicine, University of Melbourne, Melbourne, Australia (B.J.L.); Akita University Graduate School of Medicine, Akita, Japan (T.M.) – sequence: 3 givenname: Erin E surname: Mulvihill fullname: Mulvihill, Erin E organization: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital – sequence: 4 givenname: Jelena surname: Kolic fullname: Kolic, Jelena organization: Department of Pharmacology, University of Alberta, Alberta Diabetes Institute, University of Alberta – sequence: 5 givenname: Laurie L surname: Baggio fullname: Baggio, Laurie L organization: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital – sequence: 6 givenname: Xiemen surname: Cao fullname: Cao, Xiemen organization: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital – sequence: 7 givenname: Yu surname: Liu fullname: Liu, Yu organization: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital – sequence: 8 givenname: Benjamin J surname: Lamont fullname: Lamont, Benjamin J organization: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Present addresses: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada (J.R.U.); Department of Medicine, University of Melbourne, Melbourne, Australia (B.J.L.); Akita University Graduate School of Medicine, Akita, Japan (T.M.) – sequence: 9 givenname: Tsukasa surname: Morii fullname: Morii, Tsukasa organization: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Present addresses: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada (J.R.U.); Department of Medicine, University of Melbourne, Melbourne, Australia (B.J.L.); Akita University Graduate School of Medicine, Akita, Japan (T.M.) – sequence: 10 givenname: Catherine J surname: Streutker fullname: Streutker, Catherine J organization: St. Michael's Hospital, University of Toronto – sequence: 11 givenname: Natalia surname: Tamarina fullname: Tamarina, Natalia organization: Department of Medicine, Kovler Diabetes Center, University of Chicago – sequence: 12 givenname: Louis H surname: Philipson fullname: Philipson, Louis H organization: Department of Medicine, Kovler Diabetes Center, University of Chicago – sequence: 13 givenname: Jeffrey L surname: Wrana fullname: Wrana, Jeffrey L organization: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital – sequence: 14 givenname: Patrick E surname: MacDonald fullname: MacDonald, Patrick E organization: Department of Pharmacology, University of Alberta, Alberta Diabetes Institute, University of Alberta – sequence: 15 givenname: Daniel J surname: Drucker fullname: Drucker, Daniel J email: drucker@lunenfeld.ca organization: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Department of Medicine, University of Toronto |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26642437$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | Springer Nature America, Inc. 2015 COPYRIGHT 2016 Nature Publishing Group Copyright Nature Publishing Group Jan 2016 |
| Copyright_xml | – notice: Springer Nature America, Inc. 2015 – notice: COPYRIGHT 2016 Nature Publishing Group – notice: Copyright Nature Publishing Group Jan 2016 |
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| DOI | 10.1038/nm.3997 |
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| Snippet | The details of the GIP signaling pathway are murky, but new data identify a downstream pathway involving Tcf7 that regulates beta cell survival and activity.... The glucagon-like peptide-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor transduce nutrient-stimulated signals to... |
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| SubjectTerms | 631/443/319/1642 64 64/110 692/163/2743/137/773 Adipose tissue Animals Apoptosis - genetics Biomedicine Blotting, Western Cancer Research Cell receptors Cellular biology Comparative analysis Diabetes Diabetes Mellitus, Experimental - genetics Diabetes Mellitus, Experimental - metabolism Diabetes Mellitus, Type 2 - genetics Diabetes Mellitus, Type 2 - metabolism Gene Knockout Techniques Genetic aspects Glucose Glucose Tolerance Test Hepatocyte Nuclear Factor 1-alpha - genetics Hepatocyte Nuclear Factor 1-alpha - metabolism Humans Infectious Diseases Insulin - metabolism Insulin Resistance - genetics Insulin Secretion Insulin-Secreting Cells - metabolism Islets of Langerhans - metabolism letter Male Metabolic Diseases Mice Molecular Medicine Neurosciences Nutrients Pancreatic beta cells Physiological aspects Real-Time Polymerase Chain Reaction Receptors, Gastrointestinal Hormone - genetics Receptors, Gastrointestinal Hormone - metabolism RNA, Messenger - metabolism Sequence Analysis, RNA Signal Transduction Survival T Cell Transcription Factor 1 - genetics T Cell Transcription Factor 1 - metabolism Transcription factors |
| Title | TCF1 links GIPR signaling to the control of beta cell function and survival |
| URI | https://link.springer.com/article/10.1038/nm.3997 https://www.ncbi.nlm.nih.gov/pubmed/26642437 https://www.proquest.com/docview/1754094729 https://www.proquest.com/docview/1760880801 |
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