Abstract: Various embodiments relate to a compound (represented by Formula I) or a pharmaceutically acceptable salt or tautomer thereof. The compound may selectively inhibit a Forkhead Box O1 (FOXO1) transcription factor. Various embodiments relate to methods comprising administering to a mammal having a disease or disorder associated with impaired pancreatic endocrine function, a therapeutically effective amount of the compound or a pharmaceutically acceptable salt or tautomer thereof. Various embodiments relate to methods for producing enteroendocrine cells that make and secrete insulin in a mammal, comprising administering to the mammal an effective amount of the compound or a pharmaceutically acceptable salt or tautomer thereof.

Abstract: Methods are described for producing enteroendocrine cells that make and secrete insulin in a subject by co-administering a Foxo1 inhibitor in combination with a Notch inhibitor or ROCK inhibitor, or both. Also described are pharmaceutical compositions comprising a combination of a Foxo1 inhibitor with a Notch inhibitor or ROCK inhibitor, or both. The described methods and compositions may be used to treat a disorder associated with impaired pancreatic function such as diabetes.

Abstract: Disclosed herein are methods involving the targeting of 5HT biosynthesis in gut insulin-negative cells to convert them into insulin-positive cells. Also, disclosed are methods for treating a disease or disorder in a mammal, preferably a human, associated with impaired pancreatic endocrine function, by administering a therapeutically effective amount of an enumerated active agent that reduces the expression, biosynthesis, signaling or biological activity of serotonin or increases its degradation, wherein administering comprises delivering the agent to Gut Ins? cells in the mammal. Other embodiments of the method are directed to therapy wherein an agent that significantly reduces FOXO1 expression, biosynthesis, signaling or biological activity or increases its degradation is administered in addition to the agent that reduces serotonin, or alternatively an agent that reduces FOXO1 expression is targeted to serotonin-positive gut enteroendocrine cells.

Abstract: Methods are provided for obtaining a sample of ? cells from an isolated donor pancreas or isolated pancreatic islets and analyzing the sample using flow cytometry to determine the percentage of ? cells in the sample that express detectable levels of ALDH1 A3. If the percentage of ALDH1 A3-expressing ? cells in the sample is about 3% or lower, then it is possible to determine that the pancreas or islets are healthy enough for implantation into a subject, and implanting the pancreas or islets. If the percentage of ALDH1 A3-expressing cells is above about 5%, then it is determined that the pancreas or islets are not suitable for implantation into the subject and discarding the pancreas or islets. Isolated non-insulin-producing or low-insulin-producing pancreatic beta cells are also provided.

Abstract: Methods are described for producing enteroendocrine cells that make and secrete insulin in a mammal by blocking the expression or biological activity of one or more forkhead box O (Foxo) proteins or biologically active fragments or variants thereof.

Abstract: Disclosed herein are methods involving the targeting of 5HT biosynthesis in gut insulin-negative cells to convert them into insulin-positive cells. Also, disclosed are methods for treating a disease or disorder in a mammal, preferably a human, associated with impaired pancreatic endocrine function, by administering a therapeutically effective amount of an enumerated active agent that reduces the expression, biosynthesis, signaling or biological activity of serotonin or increases its degradation, wherein administering comprises delivering the agent to Gut Ins? cells in the mammal. Other embodiments of the method are directed to therapy wherein an agent that significantly reduces FOXO1 expression, biosynthesis, signaling or biological activity or increases its degradation is administered in addition to the agent that reduces serotonin, or alternatively an agent that reduces FOXO1 expression is targeted to serotonin-positive gut enteroendocrine cells.

Abstract: Methods are described for producing enteroendocrine cells that make and secrete insulin in a mammal by blocking the expression or biological activity of one or more forkhead box O (Foxo) proteins or biologically active fragments or variants thereof.

Abstract: Disclosed herein are methods involving the targeting of 5HT biosynthesis in gut insulin-negative cells to convert them into insulin-positive cells. Also disclosed are methods for treating a disease or disorder in a mammal, preferably a human, associated with impaired pancreatic endocrine function, by administering a therapeutically effective amount of an enumerated active agent that reduces the expression, biosynthesis, signaling or biological activity of serotonin or increases its degradation, wherein administering comprises delivering the agent to Gut Ins? cells in the mammal. Other embodiments of the method are directed to therapy wherein an agent that significantly reduces FOXO1 expression, biosynthesis, signaling or biological activity or increases its degradation is administered in addition to the agent that reduces serotonin, or alternatively an agent that reduces FOXO1 expression is targeted to serotonin-positive gut enteroendocrine cells.

Abstract: Methods are provided for obtaining a sample of ? cells from an isolated donor pancreas or isolated pancreatic islets and analyzing the sample using flow cytometry to determine the percentage of ? cells in the sample that express detectable levels of ALDH1 A3. If the percentage of ALDH1 A3-expressing ? cells in the sample is about 3% or lower, then it is possible to determine that the pancreas or islets are healthy enough for implantation into a subject, and implanting the pancreas or islets. If the percentage of ALDH1 A3-expressing cells is above about 5%, then it is determined that the pancreas or islets are not suitable for implantation into the subject and discarding the pancreas or islets. Isolated non-insulin-producing or low-insulin-producing pancreatic beta cells are also provided.

Abstract: Provided herein are insulin-negative cells that have been genetically modified to report expression of one or more target genes. Exemplified are reporter cell lines that provide a readout of Ngn3, Foxo1 or Tph2 expression. Reporter cells are used to screen for agents that affect expression of one or more of these genes to identify agents capable of converting gut progenitor cells to insulin-positive cells.

Abstract: Disclosed herein are methods involving the targeting of 5HT biosynthesis in gut insulin-negative cells to convert them into insulin-positive cells. Also disclosed are methods for treating a disease or disorder in a mammal, preferably a human, associated with impaired pancreatic endocrine function, by administering a therapeutically effective amount of an enumerated active agent that reduces the expression, biosynthesis, signaling or biological activity of serotonin or increases its degradation, wherein administering comprises delivering the agent to Gut Ins? cells in the mammal. Other embodiments of the method are directed to therapy wherein an agent that significantly reduces FOXO1 expression, biosynthesis, signaling or biological activity or increases its degradation is administered in addition to the agent that reduces serotonin, or alternatively an agent that reduces FOXO1 expression is targeted to serotonin-positive gut enteroendocrine cells.

Abstract: Methods are described for producing enteroendocrine cells that make and secrete insulin in a mammal by blocking the expression or biological activity of one or more Foxo proteins or biologically active fragments or variants thereof.

Abstract: Methods are described for producing enteroendocrine cells that make and secrete insulin in a mammal by blocking the expression or biological activity of one or more Foxo proteins or biologically active fragments or variants thereof.

Abstract: G protein-coupled receptor (GPCR) Gpr17 expressed in hypothalamic Agouti-related peptide-expressing (AgRP) neurons increases appetite and glucose tolerance and insulin sensitivity. By contrast, increasing Gpr17 reduced glucose tolerance and increased appetite. Gpr17-agonists had no effect on FoxO1-deficient mice, indicating, together with other data, that Gpr17 is a FoxO1 target. Certain embodiments are directed to methods for reducing appetite, increasing glucose tolerance and insulin sensitivity and treating diabetes by administering Gpr17 antagonists or inhibitory oligonucleotides. Appetite can be increased by administering Gpr17 agonists.

Abstract: G protein-coupled receptor (GPCR) Gpr17 expressed in hypothalamic Agouti-related peptide-expressing (AgRP) neurons increases appetite and glucose tolerance and insulin sensitivity. By contrast, increasing Gpr17 reduced glucose tolerance and increased appetite. Gpr17-agonists had no effect on FoxO1-deficient mice, indicating, together with other data, that Gpr17 is a Fox-O1 target. Certain embodiments are directed to methods for reducing appetite, increasing glucose tolerance and insulin sensitivity and treating diabetes by administering Gpr17 antagonists or inhibitory oligonucleotides. Appetite can be increased by administering Gpr17 agonists.

Abstract: Methods are described for producing enteroendocrine cells that make and secrete insulin in a mammal by blocking the expression or biological activity of one or more Foxo proteins or biologically active fragments or variants thereof.

Abstract: The invention is directed to spontaneously immortalized pancreatic duct cells and methods for generating pancreatic endocrine cells from spontaneously immortalized pancreatic duct cells that express the transcription factors Pdx1 and FoxO1. The invention also provides for methods for treating beta cell failure, the method comprising administering to a subject an effective amount of spontaneously immortalized pancreatic duct cells expressing a mutated version FoxO1.