INTESTINAL FXR AGONISM ENHANCES GLP-1 SIGNALING TO RESTORE PANCREATIC BETA CELL FUNCTIONS

Disclosed are embodiments of a method of treating or preventing latent autoimmune diabetes of adults (LADA) in a subject. Such embodiments include administering to a subject (e.g., via the gastrointestinal tract) a therapeutically effective amount of one or farnesoid X receptor (FXR) agonist compounds, thereby activating FXR receptors in the intestines, and treating or preventing latent autoimmune diabetes of adults (LADA) in the subject. 1. A method of treating or preventing latent autoimmune diabetes of adults (LADA) in a subject , comprising administering to a gastrointestinal tract of the subject a therapeutically effective amount of one or more farnesoid X receptor (FXR) agonists , thereby activating FXR receptors in the intestine of the subject and treating or preventing LADA in the subject.2. The method of claim 1 , wherein the one or more FXR agonists is minimally absorbed systemically.3. The method of claim 1 , wherein the method substantially restores pancreatic beta cell function in the subject claim 1 , increases glucose-stimulated insulin secretion (GSIS) claim 1 , increases glucagon-like peptide 1 (GLP1) secretion in enteroendrocrine L cells of the subject claim 1 , increases expression of glucagon-like peptide-1 receptor (GLP-1R) in pancreatic beta cells of the subject claim 1 , or combinations thereof claim 1 , relative to no administration of the one or more FXR agonists.4. The method of claim 1 , wherein the method improves glucose homeostasis in the subject.5. The method of claim 1 , further comprising detecting one or more markers of pancreatic beta cell damage in the subject.6. The method of claim 5 , wherein the one or more markers of pancreatic beta cell damage comprises thioredoxin-interacting protein (Txnip).8. The method of claim 1 , wherein the one or more FXR agonists is deuterated.10. The method of claim 1 , wherein the subject has a body mass index (BMI) of 25 of higher claim 1 , is hyperglycemic claim 1 , produces no insulin or is ...

ERR ALPHA AND ERR GAMMA ARE ESSENTIAL COORDINATORS OF CARDIAC METABOLISM AND FUNCTION

Provided herein are methods and kits for increasing cardiac contraction, increasing mitochondrial activity, and/or increasing oxphos activity. Such methods include use of therapeutically effective amounts of one or more agents that increases estrogen-related receptor (ERR) α activity and one or more agents that increases ERRγ activity. In some examples, the method further includes administering a therapeutically effective amount of one or more agents that increases mitofusin 1 (Mfn1) activity. 1. A method of increasing cardiac contraction , increasing mitochondrial activity , and/or increasing oxphos activity , comprising:administering a therapeutically effective amount of one or more agents that increases estrogen-related receptor (ERR) α activity to a mammal needing increased cardiac contraction, increased mitochondrial activity, and/or increased oxphos activity; andadministering a therapeutically effective amount of one or more agents that increases ERRγ activity to a mammal needing increased cardiac contraction, increased mitochondrial activity, and/or increased oxphos activity.2. The method of claim 1 , wherein the method further comprises not exercising the mammal.3. The method of claim 1 , wherein the method further comprises:selecting a mammal in need of increased cardiac contraction, increased mitochondrial activity, and/or increased oxphos activity or a mammal at risk for developing a disorder that can benefit from increased cardiac contraction, increased mitochondrial activity, and/or increased oxphos activity.4. The method of claim 1 , wherein the mammal has or is at risk for heart failure claim 1 , bradycardia and/or cardiomyopathy.5. The method of claim 1 , wherein the method further comprises administering to the mammal a therapeutically effective amount of an agent that balances electrolytes claim 1 , an agent that prevents arrhythmias claim 1 , an agent that lowers blood pressure claim 1 , an agent that prevents blood clots from forming claim 1 , an ...

Fibroblast growth factor 1 (fgf1) mutant proteins that selectively activate fgfr1b to reduce blood glucose

The present disclosure provides FGF1 mutant proteins, which selectively bind to/activate FGFR1b. Also provided are nucleic acid molecules that encode such proteins, and vectors and cells that include such nucleic acids. Methods of using the disclosed FGF1 mutants to reduce blood glucose in a mammal and treat a metabolic disorder are provided.

FIBROBLAST GROWTH FACTOR (FGF) 1 WITH MUTATION IN THE HEPARIN BINDING DOMAIN AND METHODS OF USE TO REDUCE BLOOD GLUCOSE

The present disclosure provides FGF1 mutant proteins having one or more mutations in the heparin binding domain. Such mutants may also have an N-terminal deletion, point mutation(s), or combinations thereof. In some examples, the mutant FGF1 proteins have reduced mitogenic activity. Also provided are nucleic acid molecules that encode such proteins, and vectors and cells that include such nucleic acids. The disclosed FGF1 mutants can reduce blood glucose in a mammal, and in some examples are used to treat a metabolic disorder. 1. A method of reducing blood glucose in a mammal , comprising:administering to the mammal a therapeutically effective amount of an isolated mutated mature fibroblast growth factor (FGF) 1 protein comprising:an S116 mutation; andat least one point mutation at one or more of K9, K10, K12, L14, Y15, C16, H21, R35, Q40, L44, L46, S47, E49, Y55, M67, L73, C83, L86, E87, H93, Y94, N95, H102, A103, E104, K105, N106, F108, V109, L111, K112, K113, C117, K118, R119, G120, P121, R122, F132, L133, P134, and L135, wherein the numbering refers to the amino acid sequence shown in SEQ ID NO: 5,wherein the mutated mature FGF1 protein comprises at least 90% sequence identity to SEQ ID NO: 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24,thereby reducing blood glucose in the mammal.2. The method of claim 1 , wherein the S116 mutation is S116R.3. The method of claim 1 , further comprising a methionine added to the N-terminus of the protein.4. The method of claim 1 , wherein the mutated mature FGF1 protein further comprises a portion of FGF19 claim 1 , a portion of FGF21 claim 1 , a β-Klotho binding protein claim 1 , an FGFR1c binding protein claim 1 , or combinations thereof.5. The method of claim 1 , wherein the mutated mature FGF1 protein comprises a deletion of at least 9 contiguous N-terminal amino acids claim 1 , wherein the mutated FGF1 protein has reduced mitogenic activity as compared to a wild-type mature FGF1 protein of SEQ ID NO: 5.6. The method of ...

REPROGRAMMING PROGENITOR COMPOSITIONS AND METHODS OF USE THEREFORE

The invention generally features compositions comprising induced pluripotent stem cell progenitors (also termed reprogramming progenitor cells) and methods of isolating such cells. The invention also provides compositions comprising induced pluripotent stem cells (iPSCs) derived from such progenitor cells. Induced pluripotent stem cell progenitors generate iPSCs at high efficiency. In particular embodiments the invention is predicated upon increased expression of an estrogen related receptor and changes in the oxidative and glycolytic pathways. 1. (canceled)2. A method for selecting a mammalian induced pluripotent stem cell progenitor , the method comprising isolating an induced pluripotent stem cell progenitor expressing one or more of Oct4 , Sox2 , Klf4 and cMyc , having increased expression of an estrogen related receptor and having reduced expression of stem cell antigen 1 (Sca1) and CD34 relative to a reference cell , thereby selecting an induced pluripotent stem cell progenitor.37-. (canceled)8. A method of obtaining a murine induced pluripotent stem cell progenitor , the method comprising expressing Oct4 , Sox2 , Klf4 and cMyc in a murine cell in culture , isolating from the culture a cell having reduced expression of Sca1 and CD34 and having increased expression of ERRγ relative to a reference cell , and culturing the cell to obtain an induced pluripotent stem cell progenitor.9. The method of claim 8 , wherein the murine cell is a mouse embryonic fibroblast.10. The method of claim 8 , wherein the cell further expresses an increased level of PGC-1β and/or IDH3 relative to a reference cell.11. A method of obtaining a human induced pluripotent stem cell progenitor claim 8 , the method comprising expressing Oct4 claim 8 , Sox2 claim 8 , Klf4 and cMyc in a human cell in culture claim 8 , isolating from the culture a cell that expresses Sca1 and/or CD34 or a human ortholog or functional equivalent thereof claim 8 , wherein the cell has increased expression of ERRγ ...

FIBROBLAST GROWTH FACTOR (FGF) 1 MUTANTS AND METHODS OF USE TO REDUCE BLOOD GLUCOSE

The present disclosure provides FGF1 mutant proteins, which include an N-terminal deletion, point mutation(s), or combinations thereof. In some examples, the mutant FGF1 proteins have reduced mitogenic activity. Also provided are nucleic acid molecules that encode such proteins, and vectors and cells that include such nucleic acids. The disclosed FGF1 mutants can reduce blood glucose in a mammal, and in some examples are used to treat a metabolic disorder. 1. A method of reducing blood glucose in a mammal , comprising:administering a therapeutically effective amount of a mutated mature fibroblast growth factor (FGF) 1 protein to the mammal, or a nucleic acid molecule encoding the mutated FGF1 protein or a vector comprising the nucleic acid molecule, thereby reducing the blood glucose,wherein the mutated mature FGF1 protein comprises at least 90% sequence identity to any one of SEQ ID NOS: 11-258.2. A method of treating a metabolic disease in a mammal , comprising:administering a therapeutically effective amount of a mutated mature fibroblast growth factor (FGF) 1 protein to the mammal, or a nucleic acid molecule encoding the mutated FGF1 protein or a vector comprising the nucleic acid molecule, thereby treating the metabolic disease,wherein the mutated mature FGF1 protein comprises at least 90% sequence identity to any one of SEQ ID NOS: 11-258.3. The method of claim 2 , wherein the metabolic disease is type 2 diabetes claim 2 , non-type 2 diabetes claim 2 , type 1 diabetes claim 2 , polycystic ovary syndrome (PCOS) claim 2 , metabolic syndrome (MetS) claim 2 , obesity claim 2 , non-alcoholic steatohepatitis (NASH) claim 2 , non-alcoholic fatty liver disease (NAFLD) claim 2 , hyperlipidemia claim 2 , hypertension claim 2 , latent autoimmune diabetes (LAD) claim 2 , or maturity onset diabetes of the young (MODY).4. A method of reducing fed and fasting blood glucose claim 2 , improving insulin sensitivity and glucose tolerance claim 2 , reducing systemic chronic ...

ANALOGS OF FEXARAMINE AND METHODS OF MAKING AND USING

Novel compounds having a formula 3. The compound of claim 1 , wherein Ris deuterium.4. The compound of claim 2 , wherein Ror Ror both are halogen.5. The compound of claim 4 , wherein Ror Ror both are F.8. The compound of claim 1 , wherein RC comprises a nitrogen-containing heteroaryl ring.9. The compound of claim 8 , wherein RC is selected from pyridine claim 8 , pyrazole claim 8 , pyrrole claim 8 , imidazole claim 8 , oxazole claim 8 , isoxazole claim 8 , thiazole claim 8 , isothiazole claim 8 , triazole claim 8 , pyrimidine claim 8 , pyrazine claim 8 , triazine claim 8 , benzopyrazole claim 8 , benzimidazole claim 8 , indole claim 8 , quinoline claim 8 , indazole claim 8 , purine claim 8 , quinoxaline claim 8 , or acridine.11. The compound of claim 10 , wherein Z is N; R claim 10 , R claim 10 , Rand Rare all H; Ris methyl; or a combination thereof.13. The compound of claim 12 , wherein Rand Rare both methyl.17. A compound claim 12 , selected frommethyl (E)-3-(3-(N-(4-(1-methyl-1H-indazol-5-yl)benzyl)cyclohexanecarboxamido)phenyl)acrylate;methyl (E)-3-(3-((1R,2S,4S)—N-(4-(1-methyl-1H-indazol-5-yl)benzyl)bicyclo[2.2.1]heptane-2-carboxamido)phenyl)acrylate;methyl (E)-3-(3-(1-methyl-N-(4-(1-methyl-1H-indazol-5-yl)benzyl)piperidine-4-carboxamido)phenyl)acrylate;methyl (E)-3-(5-(N-((1-methyl-1H-benzo[f]indazol-8-yl)methyl)cyclohexanecarboxamido)pyridin-3-yl)acrylate;methyl (E)-3-(3-fluoro-5-((1S,2R,4R)—N-((1-methyl-1H-benzo[1]indazol-8-yl)methyl)bicyclo[2.2.1]heptane-2-carboxamido)phenyl)acrylate;methyl (E)-3-(3-(N-((9-fluoro-1-methyl-1H-benzo[f]indazol-8-yl)methyl)cyclohexanecarboxamido)phenyl)acrylate;methyl (E)-3-(3-((1R,4S)—N-((9-fluoro-1-methyl-1H-benzo[f]indazol-8-yl)methyl)bicyclo[2.2.1]heptane-2-carboxamido)phenyl)acrylate;methyl (E)-3-(3-(N-((9-fluoro-1-methyl-1H-benzo[f]indazol-8-yl)methyl)-1-methylpiperidine-4-carboxamido)phenyl)acrylate;methyl (E)-3-(5-(N-((9-fluoro-1-methyl-1H-benzo[f]indazol-8-yl)methyl)cyclohexanecarboxamido)pyridin-3-yl)acrylate;methyl ( ...

Analogs of fexaramine and methods of making and using

embodiments of a method of making the same, and of a composition comprising them are disclosed herein. Also disclosed are embodiments of a method of treating or preventing a metabolic disorder in a subject, comprising administering to a subject (e.g., via the gastrointestinal tract) a therapeutically effective amount of one or more of the disclosed compounds, thereby activating FXR receptors in the intestines, and treating or preventing a metabolic disorder in the subject. Additionally disclosed are embodiments of a method of treating or preventing inflammation in an intestinal region of a subject, comprising administering to the subject (e.g., via the gastrointestinal tract) a therapeutically effective amount of one or more of the disclosed compounds, thereby activating FXR receptors in the intestines, and thereby treating or preventing inflammation in the intestinal region of the subject.

COMPOSITIONS AND METHODS FOR TREATING TYPE 1 AND TYPE 2 DIABETES AND RELATED DISORDERS

The invention features compositions comprising in vitro generated beta cells capable of glucose-stimulated insulin secretion, methods of inducing beta cell maturation from embryonic or induced pluripotent stem cell-derived beta-like cells, and methods of using in vitro generated beta cells for the treatment of type 1 diabetes, type 2 diabetes, or a related disorder. 1. A method of ameliorating hyperglycemia in a mammalian subject in need thereof , the method comprising:administering to the subject an effective amount of mature pancreatic β-cells that have been differentiated from pancreatic β-cell progenitor cells by contacting pancreatic β-cell progenitor cells which express PDX1 and insulin with a viral vector encoding estrogen-related captor γ (ERR γ) in an amount sufficient to overexpress ERR γ in the cells, wherein said contacting matures the pancreatic β-cell progenitor cells into functional β-cells which are capable of glucose-stimulated insulin secretion;wherein said administration of the mature β-cells reduces or normalizes blood glucose levels in the mammalian subject, thereby ameliorating the subject's hyperglycemia.2. The method of claim 1 , wherein the pancreatic β cell progenitor expresses one or more β cell transcription factors selected from the group consisting of Nkx2.2 claim 1 , NeuroD1 claim 1 , Foxa2 claim 1 , Pax6 HNF4a MafA and Nkx6-1.3. The method of claim 1 , wherein the pancreatic β cell progenitor expresses one or more β cell markers selected from the group consisting of glucagon and somatostatin.4. The method of claim 1 , wherein the mature pancreatic β cell expresses one or more mRNA selected from the group consisting of Mafa claim 1 , Pax6 claim 1 , NeuroD claim 1 , GCK claim 1 , CHGA claim 1 , VAMP2 claim 1 , PC1/3 claim 1 , Glut2 claim 1 , Nkx6.1 claim 1 , GCG claim 1 , SST claim 1 , and U36B4.5. The method of claim 1 , wherein the pancreatic β-cell progenitor cells are derived from the subject.6. The method of claim 1 , wherein the ...

MUTATED FIBROBLAST GROWTH FACTOR (FGF) 1 AND METHODS OF USE

The present disclosure provides FGF1 mutant proteins, such as those having an N-terminal deletion, point mutation(s), or combinations thereof, which can reduce blood glucose in a mammal. Such mutant FGF1 proteins can be part of a chimeric protein that includes a β-Klotho-binding protein, an FGFR1c-binding protein, a β-Klotho-binding protein and a FGFR1c-binding protein, a C-terminal region from FGF19 or FGF21. In some examples, mutant FGF1 proteins have reduced mitogenic activity. Also provided are nucleic acid molecules that encode such proteins, and vectors and cells that include such nucleic acids. Methods of using the disclosed molecules to reduce blood glucose levels are also provided. 1. A method of reducing blood glucose in a mammal , comprising:(a) administering a therapeutically effective amount of a mutated mature fibroblast growth factor (FGF) 1 protein to the mammal, or a nucleic acid molecule encoding the mutated FGF1 protein or a vector comprising the nucleic acid molecule, thereby reducing the blood glucose, a deletion of at least six contiguous N-terminal amino acids;', 'at least one point mutation;', 'or combinations thereof;, 'wherein the mutated mature FGF1 protein comprises(b) administering a therapeutically effective amount of a fibroblast growth factor receptor (FGFR) 1c-binding protein to the mammal, or a nucleic acid molecule encoding the FGFR1c-binding protein or a vector comprising the nucleic acid molecule, thereby reducing the blood glucose, wherein the FGFR1c-binding protein comprises a multimer of FGFR1c-binding proteins; or(c) combinations of (a) and (b).2. A method of treating a metabolic disease in a mammal , comprising:(a) administering a therapeutically effective amount of a mutated mature fibroblast growth factor (FGF) 1 protein to the mammal, or a nucleic acid molecule encoding the mutated FGF1 protein or a vector comprising the nucleic acid molecule, thereby treating the metabolic disease, a deletion of at least six contiguous N ...

Analogs of fexaramine and methods of making and using

embodiments of a method of making the same, and of a composition comprising them are disclosed herein. Also disclosed are embodiments of a method of treating or preventing a metabolic disorder in a subject, comprising administering to a subject (e.g., via the gastrointestinal tract) a therapeutically effective amount of one or more of the disclosed compounds, thereby activating FXR receptors in the intestines, and treating or preventing a metabolic disorder in the subject. Additionally disclosed are embodiments of a method of treating or preventing inflammation in an intestinal region of a subject, comprising administering to the subject (e.g., via the gastrointestinal tract) a therapeutically effective amount of one or more of the disclosed compounds, thereby activating FXR receptors in the intestines, and thereby treating or preventing inflammation in the intestinal region of the subject.

USE OF BROMODOMAIN-CONTAINING PROTEIN 9 ANTAGONISTS IN COMBINATION WITH VITAMIN D RECEPTOR AGONISTS IN DIABETES TREATMENT

Methods are provided for reducing blood glucose, which utilize an agent that increases the biological activity of a vitamin D receptor (VDR) (e.g., a VDR agonist), in combination with an antagonist of bromodomain-containing protein 9 (BRD9). IN some examples, such methods treat type II diabetes. 1. A method of reducing blood glucose in a mammal , comprising:administering a therapeutically effective amount of one or more vitamin D receptor (VDR) agonists to the mammal, andadministering a therapeutically effective amount of one or more bromodomain-containing protein 9 (BRD9) antagonists to the mammal,thereby reducing blood glucose in the mammal.2. A method of treating type 2 diabetes in a mammal , comprising:administering a therapeutically effective amount of one or more vitamin D receptor (VDR) agonists to the mammal, andadministering a therapeutically effective amount of one or more bromodomain-containing protein 9 (BRD9) antagonists to the mammal,thereby treating type 2 diabetes in the mammal.3. A method , comprising:administering a therapeutically effective amount of one or more vitamin D receptor (VDR) agonists to a mammal, andadministering a therapeutically effective amount of one or more bromodomain-containing protein 9 (BRD9) antagonists to the mammal,wherein the method reduces fed and fasting blood glucose, increases insulin sensitivity, increases glucose tolerance, increases insulin secretion, increases beta cell function, increases the size of islets, reduced beta cell death, increases insulin granules, reduces fibrosis, treats an autoimmune disease, or combinations thereof, in the mammal.4. The method of claim 1 , wherein the therapeutically effective amount of the one or more VDR agonists is at least 0.01 mg/kg claim 1 , the therapeutically effective amount of the one or more BRD9 antagonists is at least 0.1 mg/kg claim 1 , or both.5. The method of claim 1 , wherein the administering is subcutaneous claim 1 , intraperitoneal claim 1 , intramuscular claim ...

Compositions and methods for treating age-related diabetes and related disorders

The invention features compositions and methods treating or preventing for age-related insulin resistance, type 2 diabetes and related disorders. The method involves depleting fTreg cells with an anti-ST2 antibody to decrease age-related fTreg accumulation and restore insulin sensitivity, thereby treating age-related insulin resistance, type 2 diabetes and related disorders.

FIBROBLAST GROWTH FACTOR (FGF) 1 PROTEINS WITH GLUCOSE LOWERING ABILITY AND REDUCED MITOGENICITY

The present disclosure provides FGF1 mutant proteins, which include an N-terminal deletion, point mutation(s), or combinations thereof. In some examples, the mutant FGF1 proteins have reduced mitogenic activity. Also provided are nucleic acid molecules that encode such proteins, and vectors and cells that include such nucleic acids. The disclosed FGF1 mutants can reduce blood glucose in a mammal, and in some examples are used to treat a metabolic disorder. 1. An isolated mutated mature fibroblast growth factor (FGF) 1 protein comprising at least 80% , at least 85% , at least 90% , at least 95% , at least 96% , at least 97% , at least 99% , or 100% sequence identity to any one of SEQ ID NOS: 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 or 25.2. The isolated mutated mature FGF1 protein of claim 1 , wherein the mutated mature FGF1 protein comprises a deletion of at least 9 claim 1 , at least 10 claim 1 , at least 11 claim 1 , at least 12 claim 1 , or at least 13 contiguous N-terminal amino acids from the native FGF1 protein claim 1 , wherein the mutated FGF1 protein has reduced mitogenic activity as compared to a wild-type mature FGF1 protein.3. The isolated mutated mature FGF1 protein of claim 1 , wherein the mutated mature FGF1 protein comprises at least one point mutation shown in Table 1.4. The isolated mutated mature FGF1 protein of claim 1 , wherein the mutated mature FGF1 protein comprises one or more point mutations selected from the group consisting of: K12V claim 1 , H21Y claim 1 , Q40K claim 1 , L44F claim 1 , S47A claim 1 , S47V claim 1 , S47I claim 1 , Y55F claim 1 , Y55V claim 1 , Y55S claim 1 , Y55A claim 1 , Y55W claim 1 , A66C claim 1 , C83T claim 1 , C83S claim 1 , C83A claim 1 , C83V claim 1 , E87Q claim 1 , E87D claim 1 , E87V claim 1 , E87A claim 1 , E87S claim 1 , E87T claim 1 , E87H claim 1 , H93G claim 1 , H93A claim 1 , N95V claim 1 , N95A claim 1 , N95S claim 1 , N95T claim 1 , S99A claim 1 , K101E claim 1 , H102Y ...

Mutated fibroblast growth factor (fgf) 1 and methods of use

The present disclosure provides FGF1 mutant proteins, such as those having an N-terminal deletion, point mutation(s), or combinations thereof, which can reduce blood glucose in a mammal. Such mutant FGF1 proteins can be part of a chimeric protein that includes a β-Klotho-binding protein, an FGFR1c-binding protein, a β-Klotho-binding protein and a FGFR1c-binding protein, a C-terminal region from FGF19 or FGF21. In some examples, mutant FGF1 proteins have reduced mitogenic activity. Also provided are nucleic acid molecules that encode such proteins, and vectors and cells that include such nucleic acids. Methods of using the disclosed molecules to reduce blood glucose levels are also provided.

MUTATED FIBROBLAST GROWTH FACTOR (FGF) 1 AND METHODS OF USE

The present disclosure provides FGF1 mutant proteins, such as those having an N-terminal deletion, point mutation(s), or combinations thereof, which can reduce blood glucose in a mammal. Such mutant FGF1 proteins can be part of a chimeric protein that includes a β-Klotho-binding protein, an FGFR1c-binding protein, a β-Klotho-binding protein and a FGFR1c-binding protein, a C-terminal region from FGF19 or FGF21. In some examples, mutant FGF1 proteins have reduced mitogenic activity. Also provided are nucleic acid molecules that encode such proteins, and vectors and cells that include such nucleic acids. Methods of using the disclosed molecules to reduce blood glucose levels are also provided. 1. An isolated mutated mature fibroblast growth factor (FGF) 1 protein comprising:at least 90% sequence identity to the protein sequence of SEQ ID NO: 213, and comprising a C117V and K118V mutation.2. The isolated mutated mature FGF1 protein of claim 1 , wherein the protein comprises at least 95% sequence identity to the protein sequence of SEQ ID NO: 213 claim 1 , and comprises a C117V and K118V mutation.3. The isolated mutated mature FGF1 protein of claim 1 , wherein the protein comprises at least 96% sequence identity to the protein sequence of SEQ ID NO: 213 claim 1 , and comprises a C117V and K118V mutation.4. The isolated mutated mature FGF1 protein of claim 1 , wherein the protein comprises at least 97% sequence identity to the protein sequence of SEQ ID NO: 213 claim 1 , and comprises a C117V and K118V mutation.5. The isolated mutated mature FGF1 protein of claim 1 , wherein the protein comprises at least 98% sequence identity to the protein sequence of SEQ ID NO: 213 claim 1 , and comprises a C117V and K118V mutation.6. The isolated mutated mature FGF1 protein of claim 1 , wherein the protein comprises at least 99% sequence identity to the protein sequence of SEQ ID NO: 213 claim 1 , and comprises a C117V and K118V mutation.7. The isolated mutated mature FGF1 protein of ...

CHIMERIC FIBROBLAST GROWTH FACTOR (FGF) 2/FGF1 PEPTIDES AND METHODS OF USE

The present disclosure provides chimeric proteins having an N-terminus coupled to a C-terminus, wherein the N-terminus comprises an N-terminal portion of fibroblast growth factor (FGF) 2 and the C-terminus comprises a portion of an FGF1 protein, wherein the chimeric protein comprises at least 95% sequence identity to SEQ ID NO: 9, 10, 11, 12 or 13. Also provided are nucleic acid molecules that encode such proteins, and vectors and cells that include such nucleic acids. Methods of using the disclosed molecules to reduce blood glucose levels are also provided. 1. A chimeric protein comprising:an N-terminus coupled to a C-terminus, wherein the N-terminus comprises an N-terminal portion of fibroblast growth factor (FGF) 2 and the C-terminus comprises a portion of an FGF1 protein, wherein the chimeric protein comprises at least 95% sequence identity to SEQ ID NO: 9, 10, 11, 12 or 13.2. The chimeric protein of claim 1 , wherein the chimeric protein comprises at least 96% sequence identity to SEQ ID NO: 9 claim 1 , 10 claim 1 , 11 claim 1 , 12 or 13.3. The chimeric protein of claim 1 , wherein the chimeric protein comprises at least 97% sequence identity to SEQ ID NO: 9 claim 1 , 10 claim 1 , 11 claim 1 , 12 or 13.4. The chimeric protein of claim 1 , wherein the chimeric protein comprises at least 98% sequence identity to SEQ ID NO: 9 claim 1 , 10 claim 1 , 11 claim 1 , 12 or 13.5. The chimeric protein of claim 1 , wherein the chimeric protein comprises at least 99% sequence identity to SEQ ID NO: 9 claim 1 , 10 claim 1 , 11 claim 1 , 12 or 13.6. The chimeric protein of claim 1 , wherein the chimeric protein comprises SEQ ID NO: 9 claim 1 , 10 claim 1 , 11 claim 1 , 12 or 13.7. The chimeric protein of claim 1 , wherein the chimeric protein consists of SEQ ID NO: 9 claim 1 , 10 claim 1 , 11 claim 1 , 12 or 13.8. The chimeric protein of claim 1 , wherein the chimeric protein comprises 1 to 8 conservative amino acid substitutions.9. An isolated nucleic acid molecule encoding ...

ESTROGEN RELATED RECEPTOR GAMMA (ERRgamma) ENHANCES AND MAINTAINS BROWN FAT THERMOGENIC CAPACITY

Brown adipose tissue (BAT) plays a role in keeping an organism warm in response to a cold environment. In response to cold, transcription factors, including peroxisome proliferator receptor alpha (PGC1α), mediate the adaptive changes in the expression of oxidative and thermogenic genes in BAT. However, even without cold, BAT exhibits high expression of these genes relative to white adipose tissue (WAT). It is shown herein that estrogen related receptor gamma (ERRγ) is a critical factor that controls the expression of key metabolic genes in BAT under basal conditions. ERRγ is highly expressed in BAT versus WAT, yet is not transcriptionally induced by cold, suggesting it plays an important role in innate basal BAT function rather than in the adaptive response to cold. Based on these observations, methods of increasing thermogenesis in a subject by administering a therapeutically effective amount of one or more agents that increase ERRγ activity are provided.

COMPOSITIONS AND METHODS FOR ORGANOID GENERATION AND DISEASE MODELING

The invention features pancreatic islet and pancreatic organoids, and cell cultures and methods that are useful for the rapid and reliable generation of pancreatic islet and pancreatic islet organoids. The invention also features methods of treating pancreatic diseases and methods of identifying agents that are useful for treatment of pancreatic diseases, such as type 2 diabetes and pancreatic cancer, using the pancreatic islet and pancreatic organoids of the invention. 1. A method of generating a pancreatic islet organoid , the method comprising culturing an induced pluripotent stem cell (iPSC)-derived beta-like cell in a 3-dimensional matrix comprising gellan gum , thereby generating a pancreatic islet organoid.2. The method of claim 1 , further comprising culturing the iPSC-derived beta-like cell with an adipose-derived stem cell and/or an endothelial cell.3. The method of claim 1 , further comprising culturing the iPSC-derived beta-like cell with an iPSC-derived alpha-like cell claim 1 , an iPSC-derived delta-like cell claim 1 , or an iPSC-derived duct-like cell.46-. (canceled)7. A cell culture comprising an organoid generated according to the method of or an iPSC-derived beta-like cell in a three-dimensional matrix comprising gellan gum.8. The cell culture of claim 7 , further comprising an adipose-derived stem cell and/or an endothelial cell.911-. (canceled)12. A cell culture comprising an organoid generated according to the method of or a human iPSC-derived beta-like cell claim 1 , a human adipose-derived stem cell (hADSC) claim 1 , and a human umbilical vein endothelial cell (HUVEC) in a three-dimensional matrix comprising gellan gum.13. A pancreatic islet organoid generated according to the method of claim 1 , comprising an iPSC-derived beta-like cell claim 1 , wherein the organoid is vascularized and exhibits glucose-stimulated insulin secretion (GSIS).14. The pancreatic islet organoid of claim 13 , further comprising an iPSC-derived alpha-like cell claim ...

Chimeric fibroblast growth factor (fgf) 2/fgf1 peptides and methods of use

The present disclosure provides chimeric proteins having an N-terminus coupled to a C-terminus, wherein the N-terminus comprises an N-terminal portion of fibroblast growth factor (FGF) 2 and the C-terminus comprises a portion of an FGF1 protein. Such FGF2/FGF1 chimeras can further include a fibroblast growth factor receptor (FGFR) 1c-binding protein, a β-Klotho-binding protein, or both. Also provided are nucleic acid molecules that encode such proteins, and vectors and cells that include such nucleic acids. Methods of using the disclosed molecules to reduce blood glucose levels are also provided.

TREATMENT OF STEROID-INDUCED HYPERGLYCEMIA WITH FIBROBLAST GROWTH FACTOR (FGF) 1 ANALOGS

Methods of using FGF1 analogs, such as FGF1 mutant proteins having an N-terminal deletion, point mutation(s), or combinations thereof, to reduce blood glucose levels in subjects with steroid-induced diabetes, hypercortisolemia, or diabetes due to treatment with an antipsychotic agent, are provided. Such mutant FGF1 proteins can be part of a chimeric protein that includes a β-Klotho-binding protein, an FGFR1-binding protein, a β-Klotho-binding protein and a FGFR1-binding protein, a C-terminal region from FGF19 or FGF21. 1. A method of reducing blood glucose in a mammal with steroid-induced diabetes , hypercortisolemia , or diabetes due to treatment with an antipsychotic agent comprising:(a) administering a therapeutically effective amount of a mutated mature fibroblast growth factor (FGF) 1 protein to the mammal, or a nucleic acid molecule encoding the mutated FGF1 protein or a vector comprising the nucleic acid molecule, thereby reducing the blood glucose, a deletion of at least six contiguous N-terminal amino acids;', 'at least one point mutation;', 'or combinations thereof;, 'wherein the mutated mature FGF1 protein comprises(b) administering a therapeutically effective amount of a fibroblast growth factor receptor (FGFR) 1c-binding protein to the mammal, or a nucleic acid molecule encoding the FGFR1-binding protein or a vector comprising the nucleic acid molecule, thereby reducing the blood glucose, wherein the FGFR1-binding protein comprises a multimer of FGFR1-binding proteins; or(c) combinations of (a) and (b), thereby reducing blood glucose in the mammal with steroid-induced diabetes, hypercortisolemia, or diabetes due to treatment with an antipsychotic agent.2. A method of treating steroid-induced diabetes , hypercortisolemia , or diabetes due to treatment with an antipsychotic agent , in a mammal , comprising:(a) administering a therapeutically effective amount of a mutated mature fibroblast growth factor (FGF) 1 protein to the mammal, or a nucleic acid ...

METHODS OF USING FEXARAMINE AND AGENTS THAT INCREASE SYMPATHETIC NERVOUS SYSTEM ACTIVITY TO PROMOTE BROWNING OF WHITE ADIPOSE TISSUE

Provided are methods of promoting browning of white adipose tissue (WAT) in a subject. Such methods can include administering to a subject (e.g., via the gastrointestinal tract) a therapeutically effective amount of fexaramine in combination with a therapeutically effective amount of a compound that mimics or increases sympathetic nervous system activity (e.g., one or more beta-adrenergic agonists and/or compounds that increase epinephrine secretion). 1. A method of promoting browning of white adipose tissue (WAT) , comprising:administering a therapeutically effective amount of fexaramine to a gastrointestinal tract of a subject; andadministering a therapeutically effective amount of one or more compounds that mimic or increase sympathetic nervous system activity, thereby promoting browning of white adipose tissue (WAT).2. The method of claim 1 , wherein the one or more compounds that mimic or increase sympathetic nervous system activity comprise one or more beta-adrenergic agonists.3. The method of claim 2 , wherein the one or more beta-adrenergic agonists comprise one or more beta-2 agonists claim 2 , one or more beta-3 agonists claim 2 , or combinations thereof.4. The method of claim 3 , wherein the one or more beta-2 agonists comprise a short acting β2 agonist claim 3 , a long-acting β2 agonist claim 3 , a ultra-long-acting β2 agonist claim 3 , or combinations thereof.5. The method of claim 4 , wherein the short acting β2 agonist comprises one or more of: salbutamol claim 4 , levosalbutamol claim 4 , terbutaline claim 4 , pirbuterol claim 4 , procaterol claim 4 , clenbuterol claim 4 , metaproterenol claim 4 , fenoterol claim 4 , bitolterol mesylate claim 4 , ritodrine claim 4 , and isoprenaline.6. The method of claim 4 , wherein the long acting β2 agonist comprises one or more of: salmeterol claim 4 , formoterol claim 4 , bambuterol claim 4 , clenbuterol claim 4 , and olodaterol.7. The method of claim 4 , wherein the ultra-long-acting β2 agonist comprises ...

Compositions and methods for treating age-related diabetes and related disorders

The invention features compositions and methods treating or preventing for age-related insulin resistance, type 2 diabetes and related disorders. The method involves depleting fTreg cells with an anti-ST2 antibody to decrease age-related fTreg accumulation and restore insulin sensitivity, thereby treating age-related insulin resistance, type 2 diabetes and related disorders.

Use of fibroblast growth factor 1 (fgf1)-vagus nerve targeting chimeric proteins to treat hyperglycemia

The present disclosure provides FGF1 mutant proteins, which include an N-terminal deletion, point mutation(s), or combinations thereof, as well as FGF1-vagus targeting chimeric proteins which include an FGF1 portion (e.g., native FGF1 or mutant FGF1) and a portion that targets the chimera to the vagus nerve (e.g., GLP or exendin-4). Also provided are nucleic acid molecules that encode such proteins, and vectors and cells that include such nucleic acids. The disclosed FGF1 mutants and FGF1-vagus targeting chimeric proteins can reduce blood glucose in a mammal, and in some examples are used to treat a metabolic disorder.

FGF2 TRUNCATIONS AND MUTANTS AND USES THEREOF

The present disclosure provides FGF2 mutant proteins, such as those having an N-terminal deletion, point mutation(s), or combinations thereof, which can reduce blood glucose in a mammal. Thus, the disclosed mutant FGF2 proteins can be used to treat one or more metabolic diseases. In some examples, mutant FGF2 proteins have reduced mitogenic activity. Also provided are nucleic acid molecules that encode such proteins, and vectors and cells that include such nucleic acids. Methods of using the disclosed molecules to reduce blood glucose levels, for example to treat a metabolic disorder are also provided. 1. A method of reducing blood glucose in a mammal , comprising:administering a therapeutically effective amount of a mutated mature fibroblast growth factor (FGF) 2 protein to the mammal, or a nucleic acid molecule encoding the mutated mature FGF2 protein or a vector comprising the nucleic acid molecule, thereby reducing the blood glucose, at least one point mutation, wherein the at least one point mutation comprises a mutation at one or more of G19, H25, F26, K30, Y33, R53, Q65, C96, E105, N111, Y112, N113, T121, K128, R129, Q132, K134, and S137, wherein the numbering refers to the sequence shown SEQ ID NO: 3; and', 'optionally a deletion of at least six contiguous N-terminal amino acids., 'wherein the mutated mature FGF2 protein comprises2. A method of reducing fed and fasting blood glucose , improving insulin sensitivity and glucose tolerance , reducing systemic chronic inflammation , ameliorating hepatic steatosis , or combinations thereof , in a mammal , comprising:administering a therapeutically effective amount of a mutated mature FGF2 protein to the mammal, or a nucleic acid molecule encoding the mutated FGF2 protein or a vector comprising the nucleic acid molecule, thereby reducing fed and fasting blood glucose, improving insulin sensitivity and glucose tolerance, reducing systemic chronic inflammation, ameliorating hepatic steatosis in a mammal, or ...

FGF2 TRUNCATIONS AND MUTANTS AND USES THEREOF

The present disclosure provides FGF2 mutant proteins, such as those having an N-terminal deletion, point mutation(s), or combinations thereof, which can reduce blood glucose in a mammal. Thus, the disclosed mutant FGF2 proteins can be used to treat one or more metabolic diseases. In some examples, mutant FGF2 proteins have reduced mitogenic activity. Also provided are nucleic acid molecules that encode such proteins, and vectors and cells that include such nucleic acids. Methods of using the disclosed molecules to reduce blood glucose levels, for example to treat a metabolic disorder are also provided. 1. A method of reducing blood glucose in a mammal , comprising:administering a therapeutically effective amount of a mutated mature fibroblast growth factor (FGF) 2 protein to the mammal, or a nucleic acid molecule encoding the mutated mature FGF2 protein or a vector comprising the nucleic acid molecule, thereby reducing the blood glucose, a deletion of at least six contiguous N-terminal amino acids;', 'at least one point mutation;', 'or combinations thereof., 'wherein the mutated mature FGF2 protein comprises2. A method of reducing fed and fasting blood glucose , improving insulin sensitivity and glucose tolerance , reducing systemic chronic inflammation , ameliorating hepatic steatosis , or combinations thereof , in a mammal , comprising:administering a therapeutically effective amount of a mutated mature FGF2 protein to the mammal, or a nucleic acid molecule encoding the mutated FGF2 protein or a vector comprising the nucleic acid molecule, thereby reducing fed and fasting blood glucose, improving insulin sensitivity and glucose tolerance, reducing systemic chronic inflammation, ameliorating hepatic steatosis in a mammal, or combinations thereof, in a mammal, a deletion of at least six contiguous N-terminal amino acids;', 'at least one point mutation;', 'or combinations thereof., 'wherein the mutated mature FGF2 protein comprises3. A method of treating one or more ...

FIBROBLAST GROWTH FACTOR (FGF) 1 WITH MUTATION IN THE HEPARIN BINDING DOMAIN AND METHODS OF USE TO REDUCE BLOOD GLUCOSE

The present disclosure provides FGF1 mutant proteins having one or more mutations in the heparin binding domain. Such mutants may also have an N-terminal deletion, point mutation(s), or combinations thereof. In some examples, the mutant FGF1 proteins have reduced mitogenic activity. Also provided are nucleic acid molecules that encode such proteins, and vectors and cells that include such nucleic acids. The disclosed FGF1 mutants can reduce blood glucose in a mammal, and in some examples are used to treat a metabolic disorder. 1. An isolated mutated mature fibroblast growth factor (FGF) 1 protein comprising:an S116 mutation; andat least one point mutation at one or more of K9, K10, K12, L14, Y15, C16, H21, R35, Q40, L44, L46, S47, E49, Y55, M67, L73, C83, L86, E87, H93, Y94, N95, H102, A103, E104, K105, N106, F108, V109, L111, K112, K113, C117, K118, R119, G120, P121, R122, F132, L133, P134, L135, wherein the numbering refers to the amino acid sequence shown SEQ ID NO: 5,wherein the mutated mature FGF1 protein comprises at least 90% sequence identity to SEQ ID NO: 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24.2. The isolated protein of claim 1 , wherein the S116 mutation is S116R.3. The isolated protein of claim 1 , wherein the N-terminal amino acid is a methionine.4. The isolated protein of claim 1 , wherein the mutated mature FGF1 protein further comprises a portion of FGF19 claim 1 , a portion of FGF21 claim 1 , a β-Klotho binding protein claim 1 , an FGFR1c binding protein claim 1 , or combinations thereof.5. The isolated protein of claim 1 , wherein the mutated mature FGF1 protein comprises a deletion of at least 9 claim 1 , at least 10 claim 1 , at least 11 claim 1 , at least 12 or at least 13 contiguous N-terminal amino acids claim 1 , wherein the mutated FGF1 protein has reduced mitogenic activity as compared to a wild-type mature FGF1 protein.6. The isolated protein of claim 1 , wherein the at least one point mutation comprises one or more of the ...

METHODS OF USING FIBROBLAST GROWTH FACTOR (FGF) 1 WITH MUTATION IN THE HEPARIN BINDING DOMAIN AND METHODS TO REDUCE BLOOD GLUCOSE

The present disclosure provides FGF1 mutant proteins having one or more mutations in the heparin binding domain. Such mutants may also have an N-terminal deletion, point mutation(s), or combinations thereof. In some examples, the mutant FGF1 proteins have reduced mitogenic activity. Also provided are nucleic acid molecules that encode such proteins, and vectors and cells that include such nucleic acids. The disclosed FGF1 mutants can reduce blood glucose in a mammal, and in some examples are used to treat a metabolic disorder. 1. A method of reducing blood glucose in a mammal , comprising:administering a therapeutically effective amount of a mutated mature fibroblast growth factor (FGF) 1 protein to the mammal, or a nucleic acid molecule encoding the mutated FGF1 protein or a vector comprising the nucleic acid molecule, thereby reducing the blood glucose, an S116 mutation;', 'optionally a deletion of at least six contiguous N-terminal amino acids;', 'optionally at least one additional point mutation;', 'or combinations thereof., 'wherein the mutated mature FGF1 protein comprises2. A method of treating a metabolic disease in a mammal , comprising:administering a therapeutically effective amount of a mutated mature fibroblast growth factor (FGF) 1 protein to the mammal, or a nucleic acid molecule encoding the mutated FGF1 protein or a vector comprising the nucleic acid molecule, thereby treating the metabolic disease, an S116 mutation;', 'optionally a deletion of at least six contiguous N-terminal amino acids;', 'optionally at least one additional point mutation;', 'or combinations thereof., 'wherein the mutated mature FGF1 protein comprises3. The method of claim 2 , wherein the metabolic disease is type 2 diabetes claim 2 , non-type 2 diabetes claim 2 , type 1 diabetes claim 2 , polycystic ovary syndrome (PCOS) claim 2 , metabolic syndrome (MetS) claim 2 , obesity claim 2 , non-alcoholic steatohepatitis (NASH) claim 2 , non-alcoholic fatty liver disease (NAFLD) claim ...

COMPOSITIONS AND METHODS FOR TREATING TYPE 1 AND TYPE 2 DIABETES AND RELATED DISORDERS

The invention features compositions comprising in vitro generated beta cells capable of glucose-stimulated insulin secretion, methods of inducing beta cell maturation from embryonic or induced pluripotent stem cell-derived beta-like cells, and methods of using in vitro generated beta cells for the treatment of type 1 diabetes, type 2 diabetes, or a related disorder. 1. A method for reprogramming a beta-like cell to a functional beta cell or generating a cell capable of glucose-stimulated insulin secretion , the method comprising expressing recombinant estrogen-related receptor (ERR) gamma in a beta-like cell , thereby reprogramming the beta-like cell to a functional beta cell or generating a cell capable of glucose-stimulated insulin secretion.2. The method of claim 1 , wherein the beta-like cell expresses one or more cell transcription factors selected from the group consisting of Nkx2.2 claim 1 , NeuroD1 claim 1 , Foxa2 claim 1 , Pax6 HNF4a claim 1 , Pdx1 claim 1 , MafA and Nkx6-1 mRNA expression.3. The method of claim 1 , wherein the beta-like cell expresses one or more cell markers selected from the group consisting of Insulin 1 claim 1 , Insulin 2 claim 1 , glucagon and somatostatin.4. The method of claim 1 , wherein the beta-like cell is an embryonic stem cell claim 1 , induced pluripotent stem cell claim 1 , adipocyte-derived stem cell claim 1 , human umbilical vein endothelial cell (Huvec) claim 1 , or a progenitor or stem cell thereof.5. The method of claim 1 , wherein the beta-like cell is modified to express ERRgamma in vitro or in vivo.6. The method of claim 1 , wherein the reprogrammed cell expresses insulin and/or secretes insulin in response to glucose stimulation.7. The method of claim 1 , wherein the beta-like cell is obtained by contacting an embryonic stem cell or induced pluripotent stem cell in culture with one or more of activin A claim 1 , wingless-type MMTV integration site family member 3A (Wnt3a) claim 1 , insulin growth factor (IGF)-2 ...

Compositions and methods for treating age-related diabetes and related disorders

The invention features compositions and methods treating or preventing for age-related insulin resistance, type 2 diabetes and related disorders. The method involves depleting fTreg cells with an anti-ST2 antibody to decrease age-related fTreg accumulation and restore insulin sensitivity, thereby treating age-related insulin resistance, type 2 diabetes and related disorders.

Compositions and methods for treating type 1 and type 2 diabetes and related disorders

The invention features compositions comprising in vitro generated beta cells capable of glucose-stimulated insulin secretion, methods of inducing beta cell maturation from embryonic or induced pluripotent stem cell-derived beta-like cells, and methods of using in vitro generated beta cells for treatment of type 1 diabetes, type 2 diabetes, or a related disorder.

Use of bromodomain-containing protein 9 antagonists in combination with vitamin D receptor agonists in diabetes treatment

Methods are provided for reducing blood glucose, which utilize an agent that increases the biological activity of a vitamin D receptor (VDR) (e.g., a VDR agonist), in combination with an antagonist of bromodomain-containing protein 9 (BRD9). IN some examples, such methods treat type II diabetes.

Compositions and methods for treating type 1 and type 2 diabetes and related disorders

The invention features compositions comprising in vitro generated beta cells capable of glucose-stimulated insulin secretion, methods of inducing beta cell maturation from embryonic or induced pluripotent stem cell-derived beta-like cells, and methods of using in vitro generated beta cells for treatment of type 1 diabetes, type 2 diabetes, or a related disorder.

A method for the preparation of alumina

Abstract A method for the preparation of alumina, the method comprising the steps of: treating aluminous material to increase the alumina content to over about 30 %; treating the aluminous material to provide particle size less than about 0.5 mm; calcining the aluminous material at about 400 - 700 °C; treating the aluminous material to provide particle sizes less than about 500 pm; leaching the aluminous material with a mineral acid to provide a pregnant liquor; conducting a plurality of steps of precipitating aluminium chloride hexahydrate; conducting a plurality of ion exchange steps; and calcining aluminium chloride hexahydrate to provide alumina.

Reprogramming progenitor compositions and methods of use therefore

The invention generally features compositions comprising induced pluripotent stem cell progenitors (also termed reprogramming progenitor cells) and methods of isolating such cells. The invention also provides compositions comprising induced pluripotent stem cells (iPSCs) derived from such progenitor cells. Induced pluripotent stem cell progenitors generate iPSCs at high efficiency. In particular embodiments the invention is predicated upon increased expression of an estrogen related receptor and changes in the oxidative and glycolytic pathways.

Reprogramming progenitor compositions and methods of use therefore

The invention generally features compositions comprising induced pluripotent stem cell progenitors (also termed reprogramming progenitor cells) and methods of isolating such cells. The invention also provides compositions comprising induced pluripotent stem cells (iPSCs) derived from such progenitor cells. Induced pluripotent stem cell progenitors generate iPSCs at high efficiency. In particular embodiments the invention is predicated upon increased expression of an estrogen related receptor and changes in the oxidative and glycolytic pathways.

Treatment of steroid-induced hyperglycemia with fibroblast growth factor (fgf) 1 analogs

Methods of using FGF1 analogs, such as FGF1 mutant proteins having an N-terminal deletion, point mutation(s), or combinations thereof, to reduce blood glucose levels in subjects with steroid-induced diabetes, hypercortisolemia, or diabetes due to treatment with an antipsychotic agent, are provided. Such mutant FGF1 proteins can be part of a chimeric protein that includes a β- Klotho-binding protein, an FGFR1 -binding protein, a β-Klotho-binding protein and a FGFR1 - binding protein, a C-terminal region from FGF19 or FGF21.

Compositions and methods for organoid generation and disease modeling

The invention features pancreatic islet and pancreatic organoids, and cell cultures and methods that are useful for the rapid and reliable generation of pancreatic islet and pancreatic islet organoids. The invention also features methods of treating pancreatic diseases and methods of identifying agents that are useful for treatment of pancreatic diseases, such as type 2 diabetes and pancreatic cancer, using the pancreatic islet and pancreatic organoids of the invention.

Analogs of fexaramine and methods of making and using

Novel compounds having a formula embodiments of a method of making the same, and of a composition comprising them are disclosed herein. Also disclosed are embodiments of a method of treating or preventing a metabolic disorder in a subject, comprising administering to a subject ( e.g. , via the gastrointestinal tract) a therapeutically effective amount of one or more of the disclosed compounds, thereby activating FXR receptors in the intestines, and treating or preventing a metabolic disorder in the subject. Additionally disclosed are embodiments of a method of treating or preventing inflammation in an intestinal region of a subject, comprising administering to the subject ( e.g. , via the gastrointestinal tract) a therapeutically effective amount of one or more of the disclosed compounds, thereby activating FXR receptors in the intestines, and thereby treating or preventing inflammation in the intestinal region of the subject.

A method for the preparation of alumina

Abstract A method for the preparation of alumina, the method comprising the steps of: treating aluminous material to increase the alumina content to over about 30 %; treating the aluminous material to provide particle size less than about 0.5 mm; calcining the aluminous material at about 400 - 700 0C; treating the aluminous material to provide particle sizes less than about 500 [tm; leaching the aluminous material with a mineral acid to provide a pregnant liquor; conducting a plurality of steps of precipitating aluminium chloride hexahydrate; conducting a plurality of ion exchange steps; and calcining aluminium chloride hexahydrate to provide alumina.

A Method For The Preparation Of Alumina

A method for the preparation of alumina, the method comprising the steps of: treating aluminous material to increase the alumina content to over about 30 %; treating the aluminous material to provide particle size less than about 0.5 mm; calcining the aluminous material at about 400 - 700 °C; treating the aluminous material to provide particle sizes less than about 500 pm; leaching the aluminous material with a mineral acid to provide a pregnant liquor; conducting a plurality of steps of precipitating aluminium chloride hexahydrate; conducting a plurality of ion exchange steps; and calcining aluminium chloride hexahydrate to provide alumina.

Reprogramming progenitor compositions and methods of use therefore

of the Disclosure As described below, the invention generally features compositions comprising induced pluripotent stem cell progenitors (also termed reprogramming progenitor cells) and methods of 5 isolating such cells. The invention also provides compositions comprising induced pluripotent stem cells (iPSCs) derived from such progenitor cells. Induced pluripotent stem cell progenitors generate iPSCs at high efficiency.

Mutated fibroblast growth factor (fgf) 1 and methods of use

The present disclosure provides FGF1 mutant proteins, such as those having an N-terminal deletion, point mutation(s), or combinations thereof, which can reduce blood glucose in a mammal. Such mutant FGF1 proteins can be part of a chimeric protein that includes a ß-Klotho-binding protein, an FGFRlc-binding protein, a ß-Klotho-binding protein and a FGFRlc- binding protein, a C-terminal region from FGF 19 or FGF21. In some examples, mutant FGF1 proteins have reduced mitogenic activity. Also provided are nucleic acid molecules that encode such proteins, and vectors and cells that include such nucleic acids. Methods of using the disclosed molecules to reduce blood glucose levels are also provided.

Analogs of fexaramine and methods of making and using

embodiments of a method of making the same, and of a composition comprising them are disclosed herein. Also disclosed are embodiments of a method of treating or preventing a metabolic disorder in a subject, comprising administering to a subject (e.g., via the gastrointestinal tract) a therapeutically effective amount of one or more of the disclosed compounds, thereby activating FXR receptors in the intestines, and treating or preventing a metabolic disorder in the subject. Additionally disclosed are embodiments of a method of treating or preventing inflammation in an intestinal region of a subject, comprising administering to the subject (e.g., via the gastrointestinal tract) a therapeutically effective amount of one or more of the disclosed compounds, thereby activating FXR receptors in the intestines, and thereby treating or preventing inflammation in the intestinal region of the subject.

Fibroblast growth factor (fgf) 1 mutants and methods of use to reduce blood glucose

The present disclosure provides FGF1 mutant proteins, which include an N-terminal deletion, point mutation(s), or combinations thereof. In some examples, the mutant FGF1 proteins have reduced mitogenic activity. Also provided are nucleic acid molecules that encode such proteins, and vectors and cells that include such nucleic acids. The disclosed FGF1 mutants can reduce blood glucose in a mammal, and in some examples are used to treat a metabolic disorder.

Reprogramming progenitor compositions and methods of use thereof

The invention generally features compositions comprising induced pluripotent stem cell progenitors (also termed reprogramming progenitor cells) and methods of isolating such cells. The invention also provides compositions comprising induced pluripotent stem cells (iPSCs) derived from such progenitor cells. Induced pluripotent stem cell progenitors generate iPSCs at high efficiency.

Cells, islets, and organoids that evade immune detection and autoimmunity, methods of production and use thereof

The invention features cells, islet-like cells, pancreatic islets and organoids (e.g., human islet-like organoids or HILOs), as well as cell cultures and methods that are useful for the rapid and reliable generation of cells and organoids, such as pancreatic islets and organoids, that are sustainable in vivo and that evade immune detection, rejection and autoimmunity. The invention also features methods of treating pancreatic diseases, such as type 2 diabetes, and pancreatic cancer, using the cells, islet-like cells, pancreatic islets and organoids (e.g., HILOs) that are designed to modulate the activity of immune cells that would otherwise react against them.

Cells, islets, and organoids that evade immune detection and autoimmunity, methods of production and use thereof

The invention features cells, islet-like cells, pancreatic islets and organoids (e.g., human islet-like organoids or HILOs), as well as cell cultures and methods that are useful for the rapid and reliable generation of cells and organoids, such as pancreatic islets and organoids, that are sustainable in vivo and that evade immune detection, rejection and autoimmunity. The invention also features methods of treating pancreatic diseases, such as type 2 diabetes, and pancreatic cancer, using the cells, islet-like cells, pancreatic islets and organoids (e.g., HILOs) that are designed to modulate the activity of immune cells that would otherwise react against them.

Cells, islets and organoids that evade immune detection and autoimmunityy, methods of production and use thereof

The invention features cells, islet-like cells, pancreatic islets and organoids (e.g., human islet-like organoids or HILOs), as well as cell cultures and methods that are useful for the rapid and reliable generation of cells and organoids, such as pancreatic islets and organoids, that are sustainable in vivo and that evade immune detection, rejection and autoimmunity. The invention also features methods of treating pancreatic diseases, such as type 2 diabetes, and pancreatic cancer, using the cells, islet-like cells, pancreatic islets and organoids (e.g., HILOs) that are designed to modulate the activity of immune cells that would otherwise react against them.

Cells, islets, and organoids that evade immune detection and autoimmunity, methods of production and use thereof

The invention features cells, islet-like cells, pancreatic islets and organoids (e.g., human islet-like organoids or HILOs), as well as cell cultures and methods that are useful for the rapid and reliable generation of cells and organoids, such as pancreatic islets and organoids, that are sustainable in vivo and that evade immune detection, rejection and autoimmunity. The invention also features methods of treating pancreatic diseases, such as type 2 diabetes, and pancreatic cancer, using the cells, islet-like cells, pancreatic islets and organoids (e.g., HILOs) that are designed to modulate the activity of immune cells that would otherwise react against them.

Methods of lowering blood glucose and treating type 2 diabetes by activation of pde4d3

Methods of lowering blood glucose and treating Type 2 diabetes in a subject by increasing expression or activity of phosphodiesterase 4D isoform 3 (PDE4D3) in adipocytes of the subject are described. In some instances, expression of PDE4D3 in adipocytes is increased by administering a vector that expresses PDE4D3 specifically in adipocytes, or via gene editing by introduction of a PDE4D3-encoding nucleic acid into adipocytes. Use of small molecule activators of PDE4D3 that are targeted to adipocytes is also described.

Analogs of fexaramine and methods of making and using

Novel compounds having a formula embodiments of a method of making the same, and of a composition comprising them are disclosed herein. Also disclosed are embodiments of a method of treating or preventing a metabolic disorder in a subject, comprising administering to a subject ( e.g. , via the gastrointestinal tract) a therapeutically effective amount of one or more of the disclosed compounds, thereby activating FXR receptors in the intestines, and treating or preventing a metabolic disorder in the subject. Additionally disclosed are embodiments of a method of treating or preventing inflammation in an intestinal region of a subject, comprising administering to the subject ( e.g. , via the gastrointestinal tract) a therapeutically effective amount of one or more of the disclosed compounds, thereby activating FXR receptors in the intestines, and thereby treating or preventing inflammation in the intestinal region of the subject.

Fibroblast growth factor (fgf) 1 with mutation in the heparin binding domain and methods of use to reduce blood glucose

The present disclosure provides FGF1 mutant proteins having one or more mutations in the heparin binding domain. Such mutants may also have an N-terminal deletion, point mutation(s), or combinations thereof. In some examples, the mutant FGF1 proteins have reduced mitogenic activity. Also provided are nucleic acid molecules that encode such proteins, and vectors and cells that include such nucleic acids. The disclosed FGF1 mutants can reduce blood glucose in a mammal, and in some examples are used to treat a metabolic disorder.

Compositions and methods for organoid generation and disease modeling

The invention features pancreatic islet and pancreatic organoids, and cell cultures and methods that are useful for the rapid and reliable generation of pancreatic islet and pancreatic islet organoids. The invention also features methods of treating pancreatic diseases and methods of identifying agents that are useful for treatment of pancreatic diseases, such as type 2 diabetes and pancreatic cancer, using the pancreatic islet and pancreatic organoids of the invention.

A method for the treatment of aluminous material

A method for the treatment of aluminous material

A method for the treatment of aluminous material

Chimeric fibroblast growth factor (FGF) 2/FGF1 peptides and methods of use

The present disclosure provides chimeric proteins having an N-terminus coupled to a C-terminus, wherein the N-terminus comprises an N-terminal portion of fibroblast growth factor (FGF) 2 and the C-terminus comprises a portion of an FGF1 protein, wherein the chimeric protein comprises at least 95% sequence identity to SEQ ID NO: 9, 10, 11, 12 or 13. Also provided are nucleic acid molecules that encode such proteins, and vectors and cells that include such nucleic acids. Methods of using the disclosed molecules to reduce blood glucose levels are also provided.

Mutated fibroblast growth factor (FGF) 1 and methods of use

The present disclosure provides FGF1 mutant proteins, such as those having an N-terminal deletion, point mutation(s), or combinations thereof, which can reduce blood glucose in a mammal. Such mutant FGF1 proteins can be part of a chimeric protein that includes a β-Klotho-binding protein, an FGFR1c-binding protein, a β-Klotho-binding protein and a FGFR1c-binding protein, a C-terminal region from FGF19 or FGF21. In some examples, mutant FGF1 proteins have reduced mitogenic activity. Also provided are nucleic acid molecules that encode such proteins, and vectors and cells that include such nucleic acids. Methods of using the disclosed molecules to reduce blood glucose levels are also provided.

Compositions and methods for treating type 1 and type 2 diabetes and related disorders

The invention features compositions comprising in vitro generated beta cells capable of glucose-stimulated insulin secretion, methods of inducing beta cell maturation from embryonic or induced pluripotent stem cell-derived beta-like cells, and methods of using in vitro generated beta cells for the treatment of type 1 diabetes, type 2 diabetes, or a related disorder.