Methods of treating and diagnosing disease using biomarkers for bcg therapy

Abstract

The invention provides methods of treating disease, such as hypercholesterolemia (e.g., by modulating serum lipids, such as cholesterol, low-density lipoproteins, high-density lipoproteins, and triglycerides) and hyperglycemia by administering Bacillus Calmette-Guerin (BCG). Methods of the invention also encompass the use of genomic, proteomic, and metabolomic analyses for determining the likelihood that a patient has disease or will respond to treatment (e.g., with BCG therapy), as well as for determining whether a patient previously administered BCG would benefit from BCG redosing.

1 . A method of reducing the level of cholesterol, low-density lipoprotein (LDL), or triglycerides in a subject in need thereof comprising administering  Bacillus  Calmette-Guerin (BCG) to said subject. 
     
     
         2 . A method of increasing the level of high-density lipoprotein (HDL) in a subject in need thereof comprising administering BCG to said subject. 
     
     
         3 . The method of  claim 1  or  2 , whereby said administering lowers the level of total cholesterol in said subject by 5% or more. 
     
     
         4 . The method of  claim 3 , wherein said subject has a total cholesterol level of about 100 mg/dL or greater, preferably wherein said subject has a total cholesterol level of about 129 mg/dL or greater. 
     
     
         5 . The method of any one of  claims 1 - 4 , whereby said administering lowers the level of LDLs in said subject by 5% or more. 
     
     
         6 . The method of  claim 5 , wherein said subject has a LDL level of about 80 mg/dL or greater. 
     
     
         7 . The method of any one of  claims 1 - 6 , whereby said administering elevates the level of high-density lipoproteins (HDLs) in said subject by 5% or more. 
     
     
         8 . The method of  claim 7 , wherein said subject has a HDL level of about 40 mg/dL or below. 
     
     
         9 . The method of any one of  claims 1 - 8 , wherein said subject has a triglyceride level of about 100 mg/dL or greater. 
     
     
         10 . The method of  claim 9 , wherein said subject has a triglyceride level of between about 100 mg/dL and about 500 mg/dL. 
     
     
         11 . The method of any one of  claims 1 - 10 , wherein said subject has a ratio of total cholesterol level to HDL level of about 5 or greater. 
     
     
         12 . The method of any one of  claims 1 - 10 , wherein said subject has a ratio of total cholesterol level to HDL level of between about 3 and about 10. 
     
     
         13 . The method of any one of  claims 1 - 3 , wherein said subject has a total cholesterol, LDL and/or triglyceride level that is higher than that which has previously been observed for said subject. 
     
     
         14 . The method of  claim 13 , wherein said subject has previously been observed as having a total cholesterol level less than about 180 mg/dL. 
     
     
         15 . The method of  claim 13  or  14 , wherein said subject has previously been observed as having a LDL level of less than about 100 mg/dL. 
     
     
         16 . The method of any one of  claims 13 - 15 , wherein said subject has previously been observed as having a triglyceride level of less than about 150 mg/dL. 
     
     
         17 . The method of any one of  claims 1 - 16 , wherein said subject is suffering from a disease associated with an elevated level of cholesterol. 
     
     
         18 . The method of  claim 17 , wherein said disease is selected from the group consisting of hypercholesterolemia, hyperlipidemia, coronary heart disease, peripheral arterial disease (PAD), peripheral vascular disease, hypertension, stroke, diabetes, metabolic syndrome, obesity, and insulin resistance. 
     
     
         19 . The method of  claim 17  or  18 , wherein said BCG is administered to said subject in an amount sufficient to alleviate or reduce a symptom associated with said disease. 
     
     
         20 . The method of  claim 19 , wherein said symptom is an elevated level of a substance selected from the group consisting of lactate dehydrogenase (LDH), LDL, and triglycerides. 
     
     
         21 . The method of  claim 20 , wherein said method results in a reduction in the level of said substance. 
     
     
         22 . The method of  claim 19 , wherein said symptom is selected from the group consisting of angina, arrhythmia, and heart failure. 
     
     
         23 . The method of  claim 22 , wherein said method alleviates or reduces said angina, arrhythmia, or heart failure. 
     
     
         24 . The method of any one of  claims 1 - 23 , wherein said method further comprises administering to said subject a hypolipidemic agent. 
     
     
         25 . The method of  claim 24 , wherein said hypolipidemic agent is selected from the group consisting of a HMG-CoA reductase inhibitor, niacin, a fibric acid derivative, a cholesterol absorption inhibitor, and a lipolytic agent. 
     
     
         26 . The method of  claim 25 , wherein said HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and combinations thereof. 
     
     
         27 . The method of  claim 25 , wherein said fibric acid derivative is selected from the group consisting of fenofibrate and gemfibrozil. 
     
     
         28 . The method of  claim 25 , wherein said cholesterol absorption inhibitor is ezetimibe. 
     
     
         29 . The method of  claim 25 , wherein said lipolytic agent is selected from the group consisting of norepinephrine, isoproterenol, forskolin, bucladesine, and theophylline. 
     
     
         30 . A method of treating a subject that has previously been diagnosed as having a disease selected from the group consisting of an autoimmune disease and a neurological condition, wherein said subject has been previously diagnosed by:
 a) determining a quantity of methylated cytosine residues in a sample of nuclear DNA isolated from said subject; and   b) comparing said quantity to a quantity of methylated cytosine residues in a reference sample,   wherein a determination that the quantity of methylated cytosine residues in said sample of nuclear DNA isolated from said subject is greater than or less than the quantity of methylated cytosine residues in said reference sample indicates that the subject has said disease, said method comprising administering BCG to said subject.   
     
     
         31 . A method of treating a subject that has previously been diagnosed as having a disease selected from the group consisting of an autoimmune disease and a neurological condition, wherein said subject has been previously diagnosed by:
 a) i) determining a level of one or more substances selected from the group consisting of an mRNA molecule encoding a cytokine or lipolytic protein, a protein selected from the group consisting of a cytokine and a lipolytic protein, an acetylated amino acid selected from the group consisting of N-acetylalanine, N-acetylaspartic acid, N-acetylserine, N-acetylthreonine, N-acetylhistidine, N-acetyl-3-methylhistidine, N-acetylvaline, and N-α-acetyllysine, and N-acetylmethionine, or a methylated metabolite selected from the group consisting of N-α-acetyl-3-methylhistidine, 3-methylglutaconic acid, 3-methylglutarylcarnitine, and N-ε-trimethyllysine in a sample from said subject; and
 (ii) comparing the level of the one or more substances to the level of the one or more substances in a reference sample, wherein a determination that the level of said one or more substances in the sample from the subject having said disease is less than the level of said one or more substances in the reference sample indicates that the subject has said disease; or 
   b) (i) determining a level of one or more substances selected from the group consisting of an mRNA molecule encoding a lipogenic protein, an adiponectin receptor, a lysine acetyltransferase, a histone acetyltransferase, a histone deacetylase, or a histone, a protein selected form the group consisting of a lipogenic protein, an adiponectin receptor, a lysine acetyltransferase, a histone acetyltransferase, a histone deacetylase, and a histone, or a methylated metabolite selected from the group consisting of 4-methyl-2-oxopentanoic acid and 3-methyl-2-oxobutyric acid in a sample from said subject; and
 (ii) comparing the level of the one or more substances to the level of the one or more substances in a reference sample, wherein a determination that the level of said one or more substances in the sample from the subject having said disease is greater than the level of said one or more substances in the reference sample indicates that the subject has said disease, 
   said method comprising administering BCG to said subject.   
     
     
         32 . The method of  claim 30  or  31 , wherein said autoimmune disease is selected from the group consisting of type I diabetes, Alopecia Areata, Ankylosing Spondylitis, Antiphospholipid Syndrome, Autoimmune Addison's Disease, Autoimmune Hemolytic Anemia, Autoimmune Hepatitis, Behcet's Disease, Bullous Pemphigoid, Cardiomyopathy, Celiac Sprue-Dermatitis, Chronic Fatigue Immune Dysfunction Syndrome (CFIDS), Chronic Inflammatory Demyelinating Polyneuropathy, Churg-Strauss Syndrome, Cicatricial Pemphigoid, CREST Syndrome, Cold Agglutinin Disease, Crohn's Disease, Essential Mixed Cryoglobulinemia, Fibromyalgia-Fibromyositis, Graves' Disease, Guillain-Barré, Hashimoto's Thyroiditis, Hypothyroidism, Idiopathic Pulmonary Fibrosis, Idiopathic Thrombocytopenia Purpura (ITP), IgA Nephropathy, Juvenile Arthritis, Lichen Planus, Lupus, Ménière's Disease, Mixed Connective Tissue Disease, Multiple Sclerosis, Myasthenia Gravis, Pemphigus Vulgaris, Pernicious Anemia, Polyarteritis Nodosa, Polychondritis, Polyglandular Syndromes, Polymyalgia Rheumatica, Polymyositis and Dermatomyositis, Primary Agammaglobulinemia, Primary Biliary Cirrhosis, Psoriasis, Raynaud's Phenomenon, Reiter's Syndrome, Rheumatic Fever, Rheumatoid Arthritis, Sarcoidosis, Scleroderma, Sjögren's Syndrome, Stiff-Man Syndrome, Takayasu Arteritis, Temporal Arteritis/Giant Cell Arteritis, Ulcerative Colitis, Uveitis, Vasculitis, Vitiligo, and Wegener's Granulomatosis. 
     
     
         33 . The method of  claim 30  or  31 , wherein said neurological condition is selected from the group consisting of a brain tumor, a brain metastasis, a spinal cord injury, schizophrenia, epilepsy, Amyotrophic lateral sclerosis (ALS), Parkinson's disease, Autism, Alzheimer's disease, Huntington's disease, and stroke. 
     
     
         34 . A method of treating a subject having a disease selected from the group consisting of a brain tumor, a brain metastasis, schizophrenia, epilepsy, Autism, stroke, an allergy, allograft rejection, graft-versus-host disease, asthma, macular degeneration, muscular atrophy, a disease related to miscarriage, atherosclerosis, bone loss, a musculoskeletal disease, and obesity comprising administering BCG to said subject. 
     
     
         35 . The method of  claim 34 , wherein said allergy is selected from the group consisting of food allergy, seasonal allergy, pet allergy, hives, hay fever, allergic conjunctivitis, poison ivy allergy oak allergy, mold allergy, drug allergy, dust allergy, cosmetic allergy, and chemical allergy. 
     
     
         36 . The method of  claim 34 , wherein said allograft rejection is selected from the group consisting of skin graft rejection, bone graft rejection, vascular tissue graft rejection, ligament graft rejection, and organ graft rejection. 
     
     
         37 . The method of  claim 36 , wherein said ligament graft rejection is selected from the group consisting of cricothyroid ligament graft rejection, periodontal ligament graft rejection, suspensory ligament of the lens graft rejection, palmar radiocarpal ligament graft rejection, dorsal radiocarpal ligament graft rejection, ulnar collateral ligament graft rejection, radial collateral ligament graft rejection, suspensory ligament of the breast graft rejection, anterior sacroiliac ligament graft rejection, posterior sacroiliac ligament graft rejection, sacrotuberous ligament graft rejection, sacrospinous ligament graft rejection, inferior pubic ligament graft rejection, superior pubic ligament graft rejection, anterior cruciate ligament graft rejection, lateral collateral ligament graft rejection, posterior cruciate ligament graft rejection, medial collateral ligament graft rejection, cranial cruciate ligament graft rejection, caudal cruciate ligament graft rejection, and patellar ligament graft rejection. 
     
     
         38 . The method of  claim 36 , wherein said organ graft rejection is selected from the group consisting of heart graft rejection, lung graft rejection, kidney graft rejection, liver graft rejection, pancreas graft rejection, intestine graft rejection, and thymus graft rejection. 
     
     
         39 . The method of  claim 34 , wherein said graft-versus-host disease arises from a bone marrow transplant or transplant of one or more blood cells selected from the group consisting of hematopoietic stem cells, common myeloid progenitor cells, common lymphoid progenitor cells, megakaryocytes, monocytes, basophils, eosinophils, neutrophils, macrophages, T-cells, B-cells, natural killer cells, and dendritic cells. 
     
     
         40 . The method of any one of  claims 1 - 39 , wherein said method further comprises administering to said subject an additional therapeutic agent. 
     
     
         41 . The method of  claim 40 , wherein said additional therapeutic agent is selected from the group consisting of tumor necrosis factor-alpha (TNFα), a tumor necrosis factor receptor 2 (TNFR2) agonist, an immunotherapy agent, and combinations thereof. 
     
     
         42 . The method of  claim 41 , wherein said immunotherapy agent is selected from the group consisting of an anti-CTLA-4 agent, an anti-PD-1 agent, an anti-PD-L1 agent, an anti-PD-L2 agent, a TNFα cross-linking agent, a TRAIL cross-linking agent, a CD27 agent, a CD30 agent, a CD40 agent, a 4-1 BB agent, a GITR agent, an OX40 agent, a TRAILR1 agent, a TRAILR2 agent, and a TWEAKR agent. 
     
     
         43 . The method of any one of  claims 1 - 42 , wherein said BCG is administered in a unit dosage form comprising between about 5×10 5  and about 1×10 7  colony forming units (cfu) per 0.1 milligrams of BCG. 
     
     
         44 . The method of  claim 43 , wherein said unit dosage form comprises between about 1×10 6  and about 6×10 6  cfu per 0.1 milligrams of BCG. 
     
     
         45 . The method of  claim 44 , wherein said unit dosage form comprises between about 1.8×10 6  and about 3.9×10 6  cfu per 0.1 milligrams of BCG. 
     
     
         46 . The method of any one of  claims 1 - 45 , whereby said administering modulates a methylation state of one or more deoxyribonucleotides in said subject. 
     
     
         47 . The method of  claim 46 , whereby said administering promotes methylation of one or more deoxyribonucleotides in said subject. 
     
     
         48 . The method of  claim 46 , whereby said administering promotes demethylation of one or more deoxyribonucleotides in said subject. 
     
     
         49 . The method of  claim 48 , wherein said one or more deoxyribonucleotides are located within a gene that encodes a transcription factor. 
     
     
         50 . The method of  claim 49 , wherein said transcription factor is FoxP3. 
     
     
         51 . The method of  claim 48 , wherein said one or more deoxyribonucleotides are located within a gene that encodes a protein that is expressed on the surface of a T-cell. 
     
     
         52 . The method of  claim 51 , wherein said protein is CD45. 
     
     
         53 . The method of any one of  claims 46 - 52 , wherein said one or more deoxyribonucleotides comprise cytosine. 
     
     
         54 . The method of any one of  claims 1 - 53 , whereby said administering promotes an increase in the level of one or more mRNA molecules that encode one or more proteins in said subject. 
     
     
         55 . The method of any one of  claims 1 - 53 , whereby said administering promotes an increase in the level of one or more proteins in said subject. 
     
     
         56 . The method of  claim 54  or  55 , wherein said one or more proteins comprise a cytokine. 
     
     
         57 . The method of  claim 56 , wherein said cytokine is selected from the group consisting of interleukin-6 (IL-6), tumor necrosis factor (TNFα), and interferon-gamma (IFNγ). 
     
     
         58 . The method of  claim 54  or  55 , wherein said one or more proteins comprise a lipolytic protein. 
     
     
         59 . The method of  claim 58 , wherein said lipolytic protein is selected from the group consisting of acyl co-enzyme A oxidase, carnitine palmitoyltransferase, lipase, and uncoupling protein. 
     
     
         60 . The method of any one of  claims 1 - 53 , whereby said administering promotes a decrease in the level of one or more mRNA molecules that encode one or more proteins in said subject. 
     
     
         61 . The method of any one of  claims 1 - 53 , whereby said administering promotes a decrease in the level of one or more proteins in said subject. 
     
     
         62 . The method of  claim 60  or  61 , wherein said one or more proteins comprise a lipogenic protein. 
     
     
         63 . The method of  claim 62 , wherein said lipogenic protein is selected from the group consisting of acetyl co-enzyme A carboxylase α, acetyl co-enzyme A carboxylase β, fatty acid synthase, glyceraldehydes-6-phosphate dehydrogenase, stearoyl-CoA saturase, malic enzyme, and glucose-6-phosphate dehydrogenase. 
     
     
         64 . The method of  claim 60  or  61 , wherein said one or more proteins comprise an adiponectin receptor. 
     
     
         65 . The method of  claim 64 , wherein said adiponectin receptor is selected from the group consisting of adiponectin receptor 1 and adiponectin receptor 2. 
     
     
         66 . The method of any one of  claims 1 - 65 , whereby said administering promotes acetylation of one or more amino acids in said subject. 
     
     
         67 . The method of  claim 66 , wherein said amino acid is selected from the group consisting of alanine, aspartic acid, serine, threonine, histidine, 3-methylhistidine, valine, lysine, and methionine. 
     
     
         68 . The method of any one of  claims 1 - 67 , whereby said administering promotes methylation of one or more metabolites in said subject. 
     
     
         69 . The method of  claim 68 , wherein said metabolite is selected from the group consisting of N-α-acetylhistidine, glutaconic acid, glutarylcarnitine, lysine, and cysteine. 
     
     
         70 . The method of any one of  claims 1 - 69 , whereby said administering promotes demethylation of one or more metabolites in said subject. 
     
     
         71 . The method of  claim 70 , wherein said metabolite is selected from the group consisting of 4-methyl-2-oxopentanoic acid and 3-methyl-2-oxobutyric acid. 
     
     
         72 . The method of any one of  claims 1 - 71 , whereby said administering promotes a decrease in the level of one or more lysine acetyltransferases (KATs). 
     
     
         73 . The method of  claim 72 , wherein said one or more lysine acetyltransferases are selected from the group consisting of KAT2A, KAT2B, KAT5, KAT6A, KAT6B, KAT7, and KAT8. 
     
     
         74 . The method of any one of  claims 1 - 73 , whereby said administering promotes a decrease in the level of one or more histone acetyltransferases. 
     
     
         75 . The method of any one of  claims 1 - 74 , whereby said administering promotes a decrease in the level of one or more histone deacetylases (HDACs). 
     
     
         76 . The method of  claim 75 , wherein said one or more histone deacetylases are selected form the group consisting of HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9, HDAC10, HDAC11, HDAC1P1, HDAC1P2, SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, and SIRT7. 
     
     
         77 . The method of any one of  claims 1 - 76 , whereby said administering promotes a decrease in the level of one or more histones. 
     
     
         78 . The method of  claim 77 , wherein said one or more histones belong to a family selected from the group consisting of H2A, H2B, H3, and H4. 
     
     
         79 . The method of any one of  claims 1 - 78 , wherein said subject exhibits a reduction in total cholesterol of between about 5% and about 40% relative to a control subject not treated with said BCG. 
     
     
         80 . The method of  claim 79 , wherein said subject exhibits said reduction in total cholesterol within about 3 months to about 7 years after being treated with said BCG. 
     
     
         81 . The method of any one of  claims 1 - 80 , wherein said subject exhibits a reduction in LDL of between about 5% and about 60%. 
     
     
         82 . The method of  claim 81 , wherein said subject exhibits said reduction in LDL within about 3 months to about 7 years after being treated with said BCG. 
     
     
         83 . The method of any one of  claims 1 - 82 , wherein said subject exhibits a reduction in glycated hemoglobin of between about 5% and about 30%. 
     
     
         84 . The method of  claim 83 , wherein said subject exhibits said reduction in glycated hemoglobin within about 2 weeks to about 7 years after being treated with said BCG. 
     
     
         85 . The method of any one of  claims 79 - 84 , wherein said reduction is maintained for between about 1 year and about 8 years. 
     
     
         86 . A method of diagnosing a subject as having a disease, said method comprising:
 a) determining a quantity of methylated cytosine residues in a sample of nuclear DNA isolated from said subject; and   b) comparing said quantity to a quantity of methylated cytosine residues in a reference sample,   wherein a determination that the quantity of methylated cytosine residues in said sample of nuclear DNA isolated from said subject is greater than or less than the quantity of methylated cytosine residues in said reference sample indicates that the subject has said disease.   
     
     
         87 . The method of  claim 86 , said method further comprising determining whether the subject is likely to respond to treatment with a therapeutic agent for said disease, wherein a determination that the quantity of methylated cytosine residues in said sample of nuclear DNA isolated from said subject is greater than or less than the quantity of methylated cytosine residues in said reference sample indicates that said subject is likely to respond to said treatment. 
     
     
         88 . The method of  claim 86  or  67 , wherein said quantity of methylated cytosine residues in said sample of nuclear DNA isolated from said subject is greater than said quantity of methylated cytosine residues in said reference sample by 1% or more. 
     
     
         89 . The method of  claim 88 , wherein said quantity of methylated cytosine residues in said sample of nuclear DNA isolated from said subject is greater than said quantity of methylated cytosine residues in said reference sample by 5% or more. 
     
     
         90 . The method of  claim 89 , wherein said quantity of methylated cytosine residues in said sample of nuclear DNA isolated from said subject is greater than said quantity of methylated cytosine residues in said reference sample by 10% or more. 
     
     
         91 . The method of  claim 86  or  87 , wherein said quantity of methylated cytosine residues in said sample of nuclear DNA isolated from said subject is less than said quantity of methylated cytosine residues in said reference sample by 1% or more. 
     
     
         92 . The method of  claim 91 , wherein said quantity of methylated cytosine residues in said sample of nuclear DNA isolated from said subject is less than said quantity of methylated cytosine residues in said reference sample by 5% or more. 
     
     
         93 . The method of  claim 92 , wherein said quantity of methylated cytosine residues in said sample of nuclear DNA isolated from said subject is less than said quantity of methylated cytosine residues in said reference sample by 10% or more. 
     
     
         94 . A method of determining whether a subject previously administered a therapeutic agent for the treatment of a disease would benefit from receiving one or more additional doses of said therapeutic agent, said method comprising:
 a) determining a quantity of methylated cytosine residues in a sample of nuclear DNA isolated from said subject; and   b) comparing said quantity to a quantity of methylated cytosine residues in a reference sample,   wherein a determination that the quantity of methylated cytosine residues in said sample of nuclear DNA isolated from said subject is within 10% of the quantity of methylated cytosine residues in said reference sample indicates that the subject would benefit from one or more additional doses of said therapeutic agent.   
     
     
         95 . The method of  claim 94 , wherein a determination that the quantity of methylated cytosine residues in said sample of nuclear DNA isolated from said subject is within 5% of the quantity of methylated cytosine residues in said reference sample indicates that the subject would benefit from one or more additional doses of said therapeutic agent. 
     
     
         96 . The method of  claim 95 , wherein a determination that the quantity of methylated cytosine residues in said sample of nuclear DNA isolated from said subject is within 1% of the quantity of methylated cytosine residues in said reference sample indicates that the subject would benefit from one or more additional doses of said therapeutic agent. 
     
     
         97 . The method of  claim 96 , wherein a determination that the quantity of methylated cytosine residues in said sample of nuclear DNA isolated from said subject is the same as the quantity of methylated cytosine residues in said reference sample indicates that the subject would benefit from one or more additional doses of said therapeutic agent. 
     
     
         98 . The method of any one of  claims 86 - 90  and  94 - 97 , wherein said methylated cytosine residues are located within a gene that encodes a transcription factor. 
     
     
         99 . The method of  claim 98 , wherein said transcription factor is FoxP3. 
     
     
         100 . The method of any one of  claims 86 - 90  and  94 - 97 , wherein said methylated cytosine residues are located within a gene that encodes a protein that is expressed on the surface of a T-cell. 
     
     
         101 . The method of  claim 100 , wherein said protein is CD45. 
     
     
         102 . The method of any one of  claims 86 - 101 , said method comprising isolating a polynucleotide comprising one or more cytosine residues and treating said polynucleotide with bisulfite. 
     
     
         103 . The method of  claim 102 , said method further comprising amplifying said polynucleotide using a polymerase chain reaction (PCR). 
     
     
         104 . A method of diagnosing a subject as having a disease, said method comprising:
 a) i) determining a level of one or more substances selected from the group consisting of an mRNA molecule encoding a cytokine or lipolytic protein, a protein selected from the group consisting of a cytokine and a lipolytic protein, an acetylated amino acid selected from the group consisting of N-acetylalanine, N-acetylaspartic acid, N-acetylserine, N-acetylthreonine, N-acetylhistidine, N-acetyl-3-methylhistidine, N-acetylvaline, and N-α-acetyllysine, and N-acetylmethionine, or a methylated metabolite selected from the group consisting of N-α-acetyl-3-methylhistidine, 3-methylglutaconic acid, 3-methylglutarylcarnitine, and N-ε-trimethyllysine in a sample from said subject; and
 (ii) comparing the level of the one or more substances to the level of the one or more substances in a reference sample, wherein a determination that the level of said one or more substances in the sample from the subject having said disease is less than the level of said one or more substances in the reference sample indicates that the subject has said disease; or 
   b) (i) determining a level of one or more substances selected from the group consisting of an mRNA molecule encoding a lipogenic protein, an adiponectin receptor, a lysine acetyltransferase, a histone acetyltransferase, a histone deacetylase, or a histone, a protein selected form the group consisting of a lipogenic protein, an adiponectin receptor, a lysine acetyltransferase, a histone acetyltransferase, a histone deacetylase, and a histone, or a methylated metabolite selected from the group consisting of 4-methyl-2-oxopentanoic acid and 3-methyl-2-oxobutyric acid in a sample from said subject; and
 (ii) comparing the level of the one or more substances to the level of the one or more substances in a reference sample, wherein a determination that the level of said one or more substances in the sample from the subject having said disease is greater than the level of said one or more substances in the reference sample indicates that the subject has said disease. 
   
     
     
         105 . The method of  claim 104 , said method further comprising determining whether the subject is likely to respond to treatment with a therapeutic agent for said disease, wherein a determination that the level of the one or more substances listed in (a) in the sample from the subject having said disease is less than the level of said one or more substances in the reference sample indicates that the subject is likely to respond to said treatment, or wherein a determination that the level of the one or more substances listed in (b) in the sample from the subject having said disease is greater than the level of said one or more substances in the reference sample indicates that the subject is likely to respond to said treatment. 
     
     
         106 . A method of determining whether a subject previously administered a therapeutic agent for the treatment of a disease would benefit from receiving one or more additional doses of said therapeutic agent, said method comprising:
 a) (i) determining a level of one or more substances selected from the group consisting of a an mRNA molecule encoding a cytokine or lipolytic protein, a protein selected from the group consisting of a cytokine and a lipolytic protein, an acetylated amino acid selected from the group consisting of N-acetylalanine, N-acetylaspartic acid, N-acetylserine, N-acetylthreonine, N-acetylhistidine, N-acetyl-3-methylhistidine, N-acetylvaline, and N-α-acetyllysine, and N-acetylmethionine, or a methylated metabolite selected from the group consisting of N-α-acetyl-3-methylhistidine, 3-methylglutaconic acid, 3-methylglutarylcarnitine, and N-ε-trimethyllysine in a sample from said subject; and
 (ii) comparing the level of the one or more substances to the level of the one or more substances in a reference sample, wherein a determination that the level of said one or more substances in the sample from the subject is the same as or less than the level of said one or more substances in said reference sample indicates that said subject would benefit from additional doses of said therapeutic agent, or 
   b) (i) determining a level of one or more substances selected from the group consisting of an mRNA molecule encoding a lipogenic protein, an adiponectin receptor, a lysine acetyltransferase, a histone acetyltransferase, a histone deacetylase, or a histone, a protein selected form the group consisting of a lipogenic protein, an adiponectin receptor, a lysine acetyltransferase, a histone acetyltransferase, a histone deacetylase, and a histone, or a methylated metabolite selected from the group consisting of 4-methyl-2-oxopentanoic acid and 3-methyl-2-oxobutyric acid in a sample from said subject; and
 (ii) comparing the level of the one or more substances to the level of the one or more substances in a reference sample, wherein a determination that the level of said one or more substances in the sample from the subject is the same as or greater than the level of said one or more substances in said reference sample indicates that said subject would benefit from additional doses of said therapeutic agent. 
   
     
     
         107 . The method of any one of  claims 104 - 06 , said method comprising determining the level of an mRNA molecule encoding a cytokine or lipolytic protein. 
     
     
         108 . The method of any one of  claims 104 - 106 , said method comprising determining the level of a protein selected from the group consisting of a cytokine and a lipolytic protein. 
     
     
         109 . The method of  claim 107  or  108 , wherein said cytokine is selected from the group consisting of IL-6, TNFα, and IFNγ. 
     
     
         110 . The method of  claim 107  or  108 , wherein said lipolytic protein is selected from the group consisting of acyl co-enzyme A oxidase, carnitine palmitoyltransferase, lipase, and uncoupling protein. 
     
     
         111 . The method of any one of  claims 104 - 106 , said method comprising determining the level of an acetylated amino acid selected from the group consisting of N-acetylalanine, N-acetylaspartic acid, N-acetylserine, N-acetylthreonine, N-acetylhistidine, N-acetyl-3-methylhistidine, N-acetylvaline, and N-α-acetyllysine, and N-acetylmethionine. 
     
     
         112 . The method of any one of  claims 104 - 106 , said method comprising determining the level of a methylated metabolite selected from the group consisting of N-α-acetyl-3-methylhistidine, 3-methylglutaconic acid, 3-methylglutarylcarnitine, and N-ε-trimethyllysine. 
     
     
         113 . The method of any one of  claims 104 - 106 , said method comprising determining the level of an mRNA molecule encoding a lipogenic protein, an adiponectin receptor, a lysine acetyltransferase, a histone acetyltransferase, a histone deacetylase, or a histone. 
     
     
         114 . The method of any one of  claims 104 - 106 , said method comprising determining the level of a protein selected from the group consisting of a lipogenic protein, an adiponectin receptor, a lysine acetyltransferase, a histone acetyltransferase, a histone deacetylase, and a histone. 
     
     
         115 . The method of  claim 113  or  114 , wherein said lipogenic protein is selected from the group consisting of acetyl co-enzyme A carboxylase α, acetyl co-enzyme A carboxylase β, fatty acid synthase, glyceraldehydes-6-phosphate dehydrogenase, stearoyl-CoA saturase, malic enzyme, and glucose-6-phosphate dehydrogenase. 
     
     
         116 . The method of  claim 113  or  114 , wherein said adiponectin receptor is selected from the group consisting of adiponectin receptor 1 and adiponectin receptor 2. 
     
     
         117 . The method of  claim 113  or  114 , wherein said lysine acetyltransferase is selected from the group consisting of KAT2A, KAT2B, KAT5, KAT6A, KAT6B, KAT7, and KAT8. 
     
     
         118 . The method of  claim 113  or  114 , wherein said histone deacetylase is selected from the group consisting of HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9, HDAC10, HDAC11, HDAC1P1, HDAC1P2, SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, and SIRT7. 
     
     
         119 . The method of  claim 113  or  114 , wherein said histone is selected from the group consisting of H2A, H2B, H3, and H4. 
     
     
         120 . The method of any one of  claims 104 - 106 , said method comprising determining the level of a methylated metabolite selected from the group consisting of 4-methyl-2-oxopentanoic acid and 3-methyl-2-oxobutyric acid. 
     
     
         121 . The method of any one of  claims 104 - 106 ,  107 ,  109 ,  110 ,  113 , and  115 - 119 , wherein the level of said mRNA molecule is determined by performing an assay selected from the group consisting of reverse transcription PCR (RT-PCR) and a Northern blot. 
     
     
         122 . The method of any one of  claims 104 - 106 ,  108 - 110 , and  114 - 119 , wherein the level of said protein is determined by performing an assay selected from the group consisting of an immunoblot and an enzyme-linked immunosorbant assay (ELISA). 
     
     
         123 . The method of any one of  claims 104 - 106 ,  111 ,  112 , and  120 , wherein the level of said acetylated amino acid or said methylated metabolite is determined by nuclear magnetic resonance (NMR) spectroscopy. 
     
     
         124 . The method of any one of  claims 30 ,  31 ,  86 - 93 ,  104 , and  105 , wherein said reference sample is a sample isolated from a control subject not having said disease. 
     
     
         125 . The method of  claim 124 , wherein said control subject is a subject of the same age and/or gender of said subject having said disease. 
     
     
         126 . The method of any one of  94 - 97  and  106 , wherein said reference sample is a prior sample that has been previously isolated from said subject. 
     
     
         127 . The method of  claim 126 , wherein said prior sample was isolated between about 24 hours and about 5 years before making said determination. 
     
     
         128 . The method of  claim 127 , wherein said prior sample was isolated between about 1 month and about 1 year prior to making said determination. 
     
     
         129 . The method of any one of  claims 126 - 128 , wherein said prior sample was isolated prior to said subject being administered said therapeutic agent. 
     
     
         130 . The method of any one of  claims 86 - 129 , wherein said disease is a condition associated with elevated levels of cholesterol. 
     
     
         131 . The method of  130 , wherein said condition is selected from the group consisting of hypercholesterolemia, hyperlipidemia, coronary heart disease, peripheral arterial disease (PAD), peripheral vascular disease, hypertension, stroke, diabetes, metabolic syndrome, obesity, and insulin resistance. 
     
     
         132 . The method of any one of  claims 86 - 129 , wherein said disease is selected from the group consisting of an autoimmune disease, a neurological condition, an allergy, allograft rejection, graft-versus-host disease, asthma, macular degeneration, muscular atrophy, a disease related to miscarriage, atherosclerosis, bone loss, a musculoskeletal disease, and obesity. 
     
     
         133 . The method of  claim 132 , wherein said disease associated with elevated levels of cholesterol is selected from the group consisting of hypercholesterolemia, coronary heart disease, peripheral vascular disease, hypertension, and stroke. 
     
     
         134 . The method of  claim 132 , wherein said autoimmune disease is selected from the group consisting of type I diabetes, Alopecia Areata, Ankylosing Spondylitis, Antiphospholipid Syndrome, Autoimmune Addison's Disease, Autoimmune Hemolytic Anemia, Autoimmune Hepatitis, Behcet's Disease, Bullous Pemphigoid, Cardiomyopathy, Celiac Sprue-Dermatitis, Chronic Fatigue Immune Dysfunction Syndrome (CFIDS), Chronic Inflammatory Demyelinating Polyneuropathy, Churg-Strauss Syndrome, Cicatricial Pemphigoid, CREST Syndrome, Cold Agglutinin Disease, Crohn's Disease, Essential Mixed Cryoglobulinemia, Fibromyalgia-Fibromyositis, Graves' Disease, Guillain-Barré, Hashimoto's Thyroiditis, Hypothyroidism, Idiopathic Pulmonary Fibrosis, Idiopathic Thrombocytopenia Purpura (ITP), IgA Nephropathy, Juvenile Arthritis, Lichen Planus, Lupus, Ménière's Disease, Mixed Connective Tissue Disease, Multiple Sclerosis, Myasthenia Gravis, Pemphigus Vulgaris, Pernicious Anemia, Polyarteritis Nodosa, Polychondritis, Polyglandular Syndromes, Polymyalgia Rheumatica, Polymyositis and Dermatomyositis, Primary Agammaglobulinemia, Primary Biliary Cirrhosis, Psoriasis, Raynaud's Phenomenon, Reiter's Syndrome, Rheumatic Fever, Rheumatoid Arthritis, Sarcoidosis, Scleroderma, Sjögren's Syndrome, Stiff-Man Syndrome, Takayasu Arteritis, Temporal Arteritis/Giant Cell Arteritis, Ulcerative Colitis, Uveitis, Vasculitis, Vitiligo, and Wegener's Granulomatosis. 
     
     
         135 . The method of  claim 132 , wherein said neurological condition is selected from the group consisting of a brain tumor, a brain metastasis, a spinal cord injury, schizophrenia, epilepsy, Amyotrophic lateral sclerosis (ALS), Parkinson's disease, Autism, Alzheimer's disease, Huntington's disease, and stroke. 
     
     
         136 . The method of  claim 132 , wherein said allergy is selected from the group consisting of food allergy, seasonal allergy, pet allergy, hives, hay fever, allergic conjunctivitis, poison ivy allergy oak allergy, mold allergy, drug allergy, dust allergy, cosmetic allergy, and chemical allergy. 
     
     
         137 . The method of  claim 132 , wherein said allograft rejection is selected from the group consisting of skin graft rejection, bone graft rejection, vascular tissue graft rejection, ligament graft rejection, and organ graft rejection. 
     
     
         138 . The method of  claim 137 , wherein said ligament graft rejection is selected from the group consisting of cricothyroid ligament graft rejection, periodontal ligament graft rejection, suspensory ligament of the lens graft rejection, palmar radiocarpal ligament graft rejection, dorsal radiocarpal ligament graft rejection, ulnar collateral ligament graft rejection, radial collateral ligament graft rejection, suspensory ligament of the breast graft rejection, anterior sacroiliac ligament graft rejection, posterior sacroiliac ligament graft rejection, sacrotuberous ligament graft rejection, sacrospinous ligament graft rejection, inferior pubic ligament graft rejection, superior pubic ligament graft rejection, anterior cruciate ligament graft rejection, lateral collateral ligament graft rejection, posterior cruciate ligament graft rejection, medial collateral ligament graft rejection, cranial cruciate ligament graft rejection, caudal cruciate ligament graft rejection, and patellar ligament graft rejection. 
     
     
         139 . The method of  claim 137 , wherein said organ graft rejection is selected from the group consisting of heart graft rejection, lung graft rejection, kidney graft rejection, liver graft rejection, pancreas graft rejection, intestine graft rejection, and thymus graft rejection. 
     
     
         140 . The method of  claim 132 , wherein said graft-versus-host disease arises from a bone marrow transplant or transplant of one or more blood cells selected from the group consisting of hematopoietic stem cells, common myeloid progenitor cells, common lymphoid progenitor cells, megakaryocytes, monocytes, basophils, eosinophils, neutrophils, macrophages, T-cells, B-cells, natural killer cells, and dendritic cells. 
     
     
         141 . The method of any one of  claims 87 - 103  and  104 - 140 , wherein said therapeutic agent is BCG. 
     
     
         142 . The method of any one of  claims 86 - 141 , said method further comprising administering BCG to said subject. 
     
     
         143 . The method of  claim 142 , wherein said BCG is administered in a unit dosage form comprising between about 5×10 5  and about 1×10 7  colony forming units (cfu) per 0.1 milligrams of BCG. 
     
     
         144 . The method of  claim 143 , wherein said unit dosage form comprises between about 1×10 6  and about 6×10 6  cfu per 0.1 milligrams of BCG. 
     
     
         145 . The method of  claim 144 , wherein said unit dosage form comprises between about 1.8×10 6  and about 3.9×10 6  cfu per 0.1 milligrams of BCG. 
     
     
         146 . The method of any one of  claims 142 - 145 , wherein said BCG is administered to said subject about once every 1-20 years. 
     
     
         147 . The method of  claim 146 , wherein said BCG is administered to said subject about once every 1-10 years. 
     
     
         148 . The method of  claim 147 , wherein said BCG is administered to said subject about once every 5 years. 
     
     
         149 . The method of any one of  claims 146 - 148 , wherein said subject is administered a total of 1-20 doses of said BCG. 
     
     
         150 . The method of  claim 149 , wherein said subject is administered a total of 2-5 doses of said BCG. 
     
     
         151 . The method of  claim 150 , wherein said subject is administered a total of 2 doses of said BCG. 
     
     
         152 . The method of any one of  claims 87 - 103  and  104 - 140 , wherein said therapeutic agent is a hypolipidemic agent selected from the group consisting of a HMG-CoA reductase inhibitor, niacin, a fibric acid derivative, a cholesterol absorption inhibitor, and a lipolytic agent. 
     
     
         153 . The method of  claim 152 , said method further comprising administering to said subject a hypolipidemic agent selected from the group consisting of a HMG-CoA reductase inhibitor, niacin, a fibric acid derivative, a cholesterol absorption inhibitor, and a lipolytic agent. 
     
     
         154 . The method of  claim 152  or  153 , wherein said hypolipidemic agent is selected from the group consisting of a HMG-CoA reductase inhibitor, niacin, a fibric acid derivative, a cholesterol absorption inhibitor, and a lipolytic agent. 
     
     
         155 . The method of  claim 154 , wherein said HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and combinations thereof. 
     
     
         156 . The method of  claim 155 , wherein said fibric acid derivative is selected from the group consisting of fenofibrate and gemfibrozil. 
     
     
         157 . The method of  claim 155 , wherein said cholesterol absorption inhibitor is ezetimibe. 
     
     
         158 . The method of  claim 155 , wherein said lipolytic agent is selected from the group consisting of norepinephrine, isoproterenol, forskolin, bucladesine, and theophylline. 
     
     
         159 . The method of any one of  claims 142 - 158 , said method further comprising administering an additional therapeutic agent to said subject. 
     
     
         160 . The method of  claim 159 , wherein said additional therapeutic agent is selected from the group consisting of TNFα, a TNFR2 agonist, and an immunotherapy agent. 
     
     
         161 . The method of  claim 160 , wherein said immunotherapy agent is selected from the group consisting of an anti-CTLA-4 agent, an anti-PD-1 agent, an anti-PD-L1 agent, an anti-PD-L2 agent, a TNFα cross-linking agent, a TRAIL cross-linking agent, a CD27 agent, a CD30 agent, a CD40 agent, a 4-1 BB agent, a GITR agent, an OX40 agent, a TRAILR1 agent, a TRAILR2 agent, and a TWEAKR agent. 
     
     
         162 . The method of any one of  claims 1 - 161 , wherein said subject is a mammal. 
     
     
         163 . The method of  claim 162 , wherein said mammal is a human. 
     
     
         164 . A kit comprising BCG and a package insert instructing a user of said kit to treat a subject according to the method of any one of  claims 1 - 85 . 
     
     
         165 . The kit of  claim 164 , wherein kit further comprises the additional therapeutic agent of any one of  claims 159 - 161 . 
     
     
         166 . A kit comprising an agent that can be used to determine the methylation state of one or more cytosine residues, wherein said kit further comprises a package insert instructing a user of said kit to perform the method of any one of  claims 86 - 103 . 
     
     
         167 . A kit comprising an agent that can be used to detect one or more mRNA molecules, wherein said kit further comprises a package insert instructing a user of said kit to perform the method of any one of  claims 104 - 106 ,  107 ,  109 ,  110 ,  113 , and  115 - 119 . 
     
     
         168 . A kit comprising an agent that can be used to detect one or more proteins, wherein said kit further comprises a package insert instructing a user of said kit to perform the method of any one of  claims 104 - 106 ,  108 - 110 , and  114 - 119 . 
     
     
         169 . A method of reducing the level of glucose in the blood of a subject in need thereof comprising administering BCG to said subject. 
     
     
         170 . The method of  claim 169 , whereby said administering lowers the level of glucose in the blood of said subject by about 0.1% or more relative to a measurement of blood glucose in said subject prior to administration of said BCG. 
     
     
         171 . The method of  claim 170 , whereby said administering lowers the level of glucose in the blood of said subject by from about 10% to about 40% relative to a measurement of blood glucose in said subject prior to administration of said BCG. 
     
     
         172 . The method of  claim 169 , whereby said administering lowers the level of glucose in the blood of said subject by about 5% or more relative to a control subject not treated with said BCG, preferably wherein said control subject has the same age and/or gender as said subject. 
     
     
         173 . The method of  claim 172 , whereby said administering lowers the level of glucose in the blood of said subject by from about 10% to about 40% relative to a control subject not treated with said BCG, preferably wherein said control subject has the same age and/or gender as said subject. 
     
     
         174 . The method of any one of  claims 169 - 173 , whereby said administering lowers the level of glucose in the blood of said subject within about 1 week to about 7 weeks after being treated with said BCG. 
     
     
         175 . The method of any one of  claims 169 - 174 , whereby said administering lowers the level of glycated hemoglobin in the blood of said subject. 
     
     
         176 . The method of  claim 175 , whereby said administering lowers the level of glycated hemoglobin in the blood of said subject by about 5% or more relative to a measurement of glycated hemoglobin in said subject prior to administration of said BCG. 
     
     
         177 . The method of  claim 176 , whereby said administering lowers the level of glycated hemoglobin in the blood of said subject by about 15% or more relative to a measurement of glycated hemoglobin in said subject prior to administration of said BCG. 
     
     
         178 . The method of  claim 175 , whereby said administering lowers the level of glycated hemoglobin in the blood of said subject by about 5% or more relative to a subject not treated with said BCG, preferably wherein said control subject has the same age and/or gender as said subject. 
     
     
         179 . The method of  claim 178 , whereby said administering lowers the level of glycated hemoglobin in the blood of said subject by about 15% or more relative to a subject not treated with said BCG, preferably wherein said control subject has the same age and/or gender as said subject. 
     
     
         180 . The method of any one of  claims 173 - 179 , whereby said administering lowers the level of glycated hemoglobin in the blood of said subject within about 2 weeks to about 8 years after being treated with said BCG. 
     
     
         181 . The method of any one of  claims 169 - 180 , whereby said administering causes an increase in the rate of glycolysis in said subject relative to the rate of glycolysis in the subject prior to administration of said BCG. 
     
     
         182 . The method of any one of  claims 169 - 181 , whereby said administering causes an increase in flux through the pentose phosphate shunt in said subject relative to flux through the pentose phosphate shunt in the subject prior to administration of said BCG. 
     
     
         183 . The method of any one of  claims 169 - 182 , whereby said administering causes a decrease in the rate of oxidative phosphorylation of adenosine diphosphate in said subject relative to the rate of oxidative phosphorylation of adenosine diphosphate in the subject prior to administration of said BCG. 
     
     
         184 . The method of any one of  claims 169 - 183 , whereby said administering increases the level of lactate in the blood of said subject relative to a measurement of lactate in the blood of the subject prior to administration of said BCG. 
     
     
         185 . The method of any one of  claims 169 - 184 , whereby said administering increases the level of 1,5-anhydroglucitol in the blood of said subject relative to a measurement of 1,5-anhydroglucitol in the blood of the subject prior to administration of said BCG. 
     
     
         186 . The method of any one of  claims 169 - 185 , whereby said administering lowers the level of α-ketobutyrate in the blood of said subject relative to a measurement of α-ketobutyrate in the blood of the subject prior to administration of said BCG. 
     
     
         187 . The method of any one of  claims 169 - 186 , whereby said administering lowers the level of 2-hydroxybutyrate in the blood of said subject relative to a measurement of 2-hydroxybutyrate in the blood of the subject prior to administration of said BCG. 
     
     
         188 . The method of any one of  claims 169 - 187 , whereby said administering increases the expression of hypoxia-inducible factor 1-α (HIF1-α) in the blood of said subject relative to a measurement of HIF1-α in the blood of the subject prior to administration of said BCG. 
     
     
         189 . The method of  claim 188 , whereby said administering increases the expression of HIF1-α in a lymphocyte in said subject. 
     
     
         190 . The method of  claim 189 , wherein said lymphocyte is a peripheral blood lymphocyte. 
     
     
         191 . The method of  claim 188 , whereby said administering increases the expression of HIF1-α in a monocyte in said subject. 
     
     
         192 . The method of any one of  claims 188 - 191 , wherein said expression of HIF1-α is assessed by monitoring HIF1-α mRNA in a sample isolated from said subject. 
     
     
         193 . The method of any one of  claims 188 - 192 , whereby said administering increases expression of HIF-1α mRNA by from about 3-fold to about 6-fold. 
     
     
         194 . The method of any one of  claims 169 - 193 , whereby said administering increases the expression of a glucose transporter in the blood of said subject relative to a measurement of said glucose transporter in the blood of the subject prior to administration of said BCG. 
     
     
         195 . The method of  claim 194 , wherein said glucose transporter is solute carrier family 2 member 6 (SLC2A6). 
     
     
         196 . The method of  claim 194  or  195 , wherein said expression of said glucose transporter is assessed by monitoring mRNA encoding said glucose transporter in a sample isolated from said subject. 
     
     
         197 . The method of any one of  claims 169 - 196 , whereby said administering increases the expression of a glycolytic enzyme in the blood of said subject relative to a measurement of said glycolytic enzyme in the blood of the subject prior to administration of said BCG. 
     
     
         198 . The method of  claim 197 , wherein said glycolytic enzyme is selected from the group consisting of hexokinase 2 (HK2), glucose-6-phosphate isomerase (G6PI), triosephosphate isomerase 1 (TPI1), galactokinase 1 (GALK1), and galactose mutarotase (GALM). 
     
     
         199 . The method of  claim 197  or  198 , wherein said expression of said glycolytic enzyme is assessed by monitoring mRNA encoding said glycolytic enzyme in a sample isolated from said subject. 
     
     
         200 . The method of any one of  claims 169 - 199 , whereby said administering reduces the expression of an enzyme that promotes flux through the Krebs cycle in the blood of said subject relative to a measurement of said enzyme that promotes flux through the Krebs cycle in the blood of the subject prior to administration of said BCG. 
     
     
         201 . The method of  claim 200 , wherein said enzyme that promotes flux through the Krebs cycle is selected from the group consisting of adenosine triphosphate citrate lyase (ACLY), aconitase 2 (ACO2), citrate synthase (CS), dihydrolipoamide dehydrogenase (DLD), oxoglutarate dehydrogenase (OGDH), succinate dehydrogenase iron-sulfur complex subunit B (SDHB), and succinate-CoA ligase subunit α (SUCLG1). 
     
     
         202 . The method of  claim 200  or  201 , wherein said expression of said enzyme that promotes flux through the Krebs cycle is assessed by monitoring mRNA encoding said glycolytic enzyme in a sample isolated from said subject. 
     
     
         203 . The method of any one of  claims 169 - 202 , wherein said subject has a blood glucose level of about 100 mg/dL or greater, preferably wherein said subject has a blood glucose level of about 126 mg/dL or greater. 
     
     
         204 . The method of  claim 203 , wherein said subject has a blood glucose level of about 200 mg/dL or greater. 
     
     
         205 . The method of any one of  claims 169 - 204 , wherein said subject has a blood glucose level that is higher than that which has previously been observed for said subject. 
     
     
         206 . The method of  claim 205 , wherein said subject has previously been observed as having a blood glucose level of less than about 200 mg/dL. 
     
     
         207 . The method of  claim 206 , wherein said subject has previously been observed as having a blood glucose level of less than about 126 mg/dL. 
     
     
         208 . The method of  claim 207 , wherein said subject has previously been observed as having a blood glucose level of about 100 mg/dL or less. 
     
     
         209 . The method of any one of  claims 169 - 208 , wherein said subject is suffering from a disease associated with an elevated blood glucose level. 
     
     
         210 . The method of  claim 209 , wherein said disease is selected from the group consisting of type 2 diabetes, noninsulin-dependent diabetes mellitus (NIDDM), nonalcoholic steatohepatitis (NASH), metabolic syndrome, cystic fibrosis, drug induced hyperglycemia, insulin resistance syndromes, diseases caused by genetic mutations in the pancreas, cancer, infection, Leprechaunism, Rabson Mandenhall syndrome, lipoatrophic diabetes, pancreatitis, trauma, hemochromatoisis, fibrocalculous pancreatopathy, acromegaly, Cushings syndrome, glucagonoma, pheochromocytoma, hyperthyroism, somatostatinoma, aldosteroma, infections associated with beta cell destruction, Rubella, coxsachie virus B, mumps, cytomegatolovirus infection, adenovirus infection, a genetic syndrome, stiff person syndrome, anti-insulin receptor abnormalities, liver disease, and renal failure. 
     
     
         211 . The method of  claim 210 , wherein said drug induced hyperglycemia is induced by one or more agents selected from the group consisting of steroids, cortisol, thiazides, diazocide, calcineurin inhibitors, oral contraceptives, beta adrenergic agonists, nicotinic acid, pentamidine, alpha interferon, anti-psychotic agents, anti-retroviral agents, and rodenticides. 
     
     
         212 . The method of  claim 211 , wherein said rodenticide is pyrinuron. 
     
     
         213 . The method of  claim 210 , wherein said cancer is pancreatic cancer. 
     
     
         214 . The method of  claim 210 , wherein said genetic syndrome is selected from the group consisting of Down's syndrome, Klinefelter's syndrome, Turner syndrome, Woldfram syndrome, and Friendreich ataxia. 
     
     
         215 . The method of any one of  claims 169 - 214 , wherein said subject has undergone a pancreatectomy. 
     
     
         216 . The method of any one of  claims 169 - 215 , wherein said subject exhibits one or more mutations in a mitochondrial gene. 
     
     
         217 . The method of any one of  claims 169 - 216 , wherein said subject exhibits one or more mutations in a gene selected from the group consisting of hepatic nuclear factor 1 (MODY3), glucokinase (MODY2), and hepatocyte nuclear factor 4-α (MODY1). 
     
     
         218 . The method of any one of  claims 169 - 217 , wherein said BCG is administered to said subject in an amount sufficient to alleviate or reduce a symptom associated with said disease. 
     
     
         219 . The method of  claim 218 , wherein said symptom is polyphagia, polydipsia, polyuria, blurred vision, fatigue, cardiac arrhythmia, stupor, dry mouth, and poor wound healing. 
     
     
         220 . The method of any one of  claims 169 - 219 , wherein said BCG is administered in a unit dosage form comprising between about 5×10 5  and about 1×10 7  cfu per 0.1 milligrams of BCG. 
     
     
         221 . The method of  claim 220 , wherein said unit dosage form comprises between about 1×10 6  and about 6×10 6  cfu per 0.1 milligrams of BCG. 
     
     
         222 . The method of  claim 221 , wherein said unit dosage form comprises between about 1.8×10 6  and about 3.9×10 6  cfu per 0.1 milligrams of BCG. 
     
     
         223 . The method of any one of  claims 169 - 222 , wherein said BCG is administered to said subject about once every 1-20 years. 
     
     
         224 . The method of  claim 223 , wherein said BCG is administered to said subject about once every 1-10 years. 
     
     
         225 . The method of  claim 224 , wherein said BCG is administered to said subject about once every 5 years. 
     
     
         226 . The method of any one of  claims 169 - 225 , wherein said subject is administered a total of 1-20 doses of said BCG. 
     
     
         227 . The method of  claim 226 , wherein said subject is administered a total of 2-5 doses of said BCG. 
     
     
         228 . The method of  claim 227 , wherein said subject is administered a total of 2 doses of said BCG. 
     
     
         229 . The method of  claim 228 , wherein said subject is administered a first dose of BCG followed by a second dose of BCG from about 2 weeks to about 8 weeks after administration of said first dose. 
     
     
         230 . The method of  claim 229 , wherein said subject is administered a first dose of BCG followed by a second dose of BCG about 4 weeks after administration of said first dose. 
     
     
         231 . The method of any one of  claims 1 - 85 ,  142 - 151 ,  159 - 163 , and  169 - 230 , wherein administration of said BCG increases the expression of nuclear receptor subfamily 1 group H member 3 (NR1H3). 
     
     
         232 . The method of  claim 231 , wherein said expression of NR1H3 is assessed by monitoring NR1H3 mRNA. 
     
     
         233 . The method of any one of  claims 1 - 85 ,  142 - 151 ,  159 - 163 , and  169 - 232 , wherein administration of said BCG increases the expression of a gene selected from the group consisting of adenosine triphosphate binding cassette subfamily A member 1 (ABCA1), adenosine triphosphate binding cassette subfamily G (ABCG), apolipoprotein E(APOE), Fas cell surface death receptor (FAS), and stearoyl-CoA desaturase (SCD1) relative to a measurement of the expression of said gene in said subject prior to administration of said BCG. 
     
     
         234 . The method of any one of  claims 1 - 85 ,  142 - 151 ,  159 - 163 , and  169 - 233 , wherein administration of said BCG reduces the expression of a gene selected from the group consisting of fructose-bisphosphatase 1 (FBP1), glucose-6-phosphate dehydrogenase (G6PD), and muscle pyruvate kinase (PKM) relative to a measurement of the expression of said gene in said subject prior to administration of said BCG. 
     
     
         235 . The method of any one of  claims 169 - 234 , wherein said subject is not suffering from a disease or condition selected from the group consisting of an autoimmune disease, a neurological condition, an allergy, allograft rejection, graft-versus-host disease, asthma, macular degeneration, muscular atrophy, a disease related to miscarriage, atherosclerosis, bone loss, a musculoskeletal disease, and obesity. 
     
     
         236 . The method of any one of  claims 169 - 234 , wherein said subject is not suffering from an autoimmune disease. 
     
     
         237 . The method of any one of  claims 169 - 234 , wherein said subject is not suffering from an autoimmune disease selected from the group consisting of type I diabetes, Alopecia Areata, Ankylosing Spondylitis, Antiphospholipid Syndrome, Autoimmune Addison's Disease, Autoimmune Hemolytic Anemia, Autoimmune Hepatitis, Behcet's Disease, Bullous Pemphigoid, Cardiomyopathy, Celiac Sprue-Dermatitis, Chronic Fatigue Immune Dysfunction Syndrome (CFIDS), Chronic Inflammatory Demyelinating Polyneuropathy, Churg-Strauss Syndrome, Cicatricial Pemphigoid, CREST Syndrome, Cold Agglutinin Disease, Crohn's Disease, Essential Mixed Cryoglobulinemia, Fibromyalgia-Fibromyositis, Graves' Disease, Guillain-Barré, Hashimoto's Thyroiditis, Hypothyroidism, Idiopathic Pulmonary Fibrosis, Idiopathic Thrombocytopenia Purpura (ITP), IgA Nephropathy, Juvenile Arthritis, Lichen Planus, Lupus, Ménière's Disease, Mixed Connective Tissue Disease, Multiple Sclerosis, Myasthenia Gravis, Pemphigus Vulgaris, Pernicious Anemia, Polyarteritis Nodosa, Polychondritis, Polyglandular Syndromes, Polymyalgia Rheumatica, Polymyositis and Dermatomyositis, Primary Agammaglobulinemia, Primary Biliary Cirrhosis, Psoriasis, Raynaud's Phenomenon, Reiter's Syndrome, Rheumatic Fever, Rheumatoid Arthritis, Sarcoidosis, Scleroderma, Sjögren's Syndrome, Stiff-Man Syndrome, Takayasu Arteritis, Temporal Arteritis/Giant Cell Arteritis, Ulcerative Colitis, Uveitis, Vasculitis, Vitiligo, and Wegener's Granulomatosis. 
     
     
         238 . The method of any one of  claims 169 - 234 , wherein said subject is not suffering from a neurological condition. 
     
     
         239 . The method of any one of  claims 169 - 234 , wherein said subject is not suffering from a neurological condition selected from the group consisting of a brain tumor, a brain metastasis, a spinal cord injury, schizophrenia, epilepsy, Amyotrophic lateral sclerosis (ALS), Parkinson's disease, Autism, Alzheimer's disease, Huntington's disease, and stroke. 
     
     
         240 . The method of any one of  claims 169 - 234 , wherein said subject is not suffering from an allergy. 
     
     
         241 . The method of any one of  claims 169 - 234 , wherein said subject is not suffering from an allergy selected from the group consisting of food allergy, seasonal allergy, pet allergy, hives, hay fever, allergic conjunctivitis, poison ivy allergy oak allergy, mold allergy, drug allergy, dust allergy, cosmetic allergy, and chemical allergy. 
     
     
         242 . A method of diagnosing a subject as having hyperglycemia or a disease associated therewith, said method comprising:
 a) i) determining a level of one or more substances selected from the group consisting of glucose, cholesterol, LDL, a triglyceride, glycated hemoglobin, an mRNA molecule encoding a protein selected from the group consisting of FBP1, G6PD, and PKM, a protein selected from the group consisting of FBP1, G6PD, and PKM, an mRNA molecule encoding an enzyme that promotes flux through the Krebs cycle, an enzyme that promotes flux through the Krebs cycle, α-ketobutyrate, and 2-hydroxybutyrate in a sample from said subject; and
 (ii) comparing the level of the one or more substances to the level of the one or more substances in a reference sample, wherein a determination that the level of said one or more substances in the sample from the subject is greater than the level of said one or more substances in the reference sample indicates that the subject has said disease; or 
   b) (i) determining a level of one or more substances selected from the group consisting of an mRNA molecule encoding a glycolytic enzyme, a glycolytic enzyme, an mRNA molecule encoding a glucose transporter, a glucose transporter, an mRNA molecule encoding HIF1-α, HIF1-α, an mRNA molecule encoding NR1H3, NR1H3, lactate, and 1,5-anhydroglucitol in a sample from said subject; and
 (ii) comparing the level of the one or more substances to the level of the one or more substances in a reference sample, wherein a determination that the level of said one or more substances in the sample from the subject is less than the level of said one or more substances in the reference sample indicates that the subject has said disease. 
   
     
     
         243 . The method of  claim 242 , said method further comprising determining whether the subject is likely to respond to treatment with a therapeutic agent for said disease, wherein a determination that the level of the one or more substances listed in (a) in the sample from the subject having said hyperglycemia or disease associated therewith is greater than the level of said one or more substances in the reference sample indicates that the subject is likely to respond to said treatment, or wherein a determination that the level of the one or more substances listed in (b) in the sample from the subject having said disease is less than the level of said one or more substances in the reference sample indicates that the subject is likely to respond to said treatment. 
     
     
         244 . A method of determining whether a subject previously administered a therapeutic agent for the treatment of a disease would benefit from receiving one or more additional doses of said therapeutic agent, said method comprising:
 a) (i) determining a level of one or more substances selected from the group consisting of glucose, cholesterol, LDL, a triglyceride, glycated hemoglobin, an mRNA molecule encoding a protein selected from the group consisting of FBP1, G6PD, and PKM, a protein selected from the group consisting of FBP1, G6PD, and PKM, an mRNA molecule encoding an enzyme that promotes flux through the Krebs cycle, an enzyme that promotes flux through the Krebs cycle, α-ketobutyrate, and 2-hydroxybutyrate in a sample from said subject; and
 (ii) comparing the level of the one or more substances to the level of the one or more substances in a reference sample, wherein a determination that the level of said one or more substances in the sample from the subject is the same as or greater than the level of said one or more substances in said reference sample indicates that said subject would benefit from one or more additional doses of said therapeutic agent, or 
   b) (i) determining a level of one or more substances selected from the group consisting of an mRNA molecule encoding a glycolytic enzyme, a glycolytic enzyme, an mRNA molecule encoding a glucose transporter, a glucose transporter, an mRNA molecule encoding HIF1-α, HIF1-α, an mRNA molecule encoding NR1H3, NR1H3, lactate, and 1,5-anhydroglucitol in a sample from said subject; and
 (ii) comparing the level of the one or more substances to the level of the one or more substances in a reference sample, wherein a determination that the level of said one or more substances in the sample from the subject is the same as or less than the level of said one or more substances in said reference sample indicates that said subject would benefit from one or more additional doses of said therapeutic agent. 
   
     
     
         245 . The method of any one of  claims 242 - 244 , wherein said enzyme that promotes flux through the Krebs cycle is selected from the group consisting of ACLY, ACO2, CS, DLD, OGDH, SDHB, and SUCLG1. 
     
     
         246 . The method of any one of  claims 242 - 244 , wherein said glycolytic enzyme is selected from the group consisting of HK2, G6PI, TPI1, GALK1, and GALM. 
     
     
         247 . The method of any one of  claims 242 - 244 , wherein said glucose transporter is SLC2A6. 
     
     
         248 . The method of any one of  claims 242 - 247 , wherein the level of said mRNA molecule is determined by performing an assay selected from the group consisting of reverse transcription PCR (RT-PCR) and a Northern blot. 
     
     
         249 . The method of any one of  claims 242 - 247 , wherein the level of said enzyme that promotes flux through the Krebs cycle, glycolytic enzyme, glucose transporter, HIF-1a, NR1H3, FBP1, G6PD, or PKM is determined by performing an assay selected from the group consisting of an immunoblot and an enzyme-linked immunosorbant assay (ELISA). 
     
     
         250 . The method of any one of  claims 242 - 247 , wherein the level of said α-ketobutyrate, 2-hydroxybutyrate, lactate, or 1,5-anhydroglucitol is determined by nuclear magnetic resonance (NMR) spectroscopy. 
     
     
         251 . The method of  claim 242  or  243 , wherein said reference sample is a sample isolated from a control subject not having said disease. 
     
     
         252 . The method of  claim 251 , wherein said control subject is a subject of the same age and/or gender of said subject having said disease. 
     
     
         253 . The method of  claim 244 , wherein said reference sample is a prior sample that has been previously isolated from said subject. 
     
     
         254 . The method of  claim 253 , wherein said prior sample was isolated between about 24 hours and about 5 years before making said determination. 
     
     
         255 . The method of  claim 254 , wherein said prior sample was isolated between about 1 month and about 1 year prior to making said determination. 
     
     
         256 . The method of any one of  claims 253 - 255 , wherein said prior sample was isolated prior to said subject being administered said therapeutic agent. 
     
     
         257 . The method of any one of  claims 242 - 256 , wherein said disease associated with hyperglycemia is selected from the group consisting of type 2 diabetes, noninsulin-dependent diabetes mellitus (NIDDM), nonalcoholic steatohepatitis (NASH), metabolic syndrome, cystic fibrosis, drug induced hyperglycemia, insulin resistance syndromes, diseases caused by genetic mutations in the pancreas, cancer, infection, Leprechaunism, Rabson Mandenhall syndrome, lipoatrophic diabetes, pancreatitis, trauma, hemochromatoisis, fibrocalculous pancreatopathy, acromegaly, Cushings syndrome, glucagonoma, pheochromocytoma, hyperthyroism, somatostatinoma, aldosteroma, infections associated with beta cell destruction, Rubella, coxsachie virus B, mumps, cytomegatolovirus infection, adenovirus infection, a genetic syndrome, stiff person syndrome, anti-insulin receptor abnormalities, liver disease, and renal failure. 
     
     
         258 . The method of  claim 257 , wherein said drug induced hyperglycemia is induced by one or more agents selected from the group consisting of steroids, cortisol, thiazides, diazocide, calcineurin inhibitors, oral contraceptives, beta adrenergic agonists, nicotinic acid, pentamidine, alpha interferon, anti-psychotic agents, anti-retroviral agents, and rodenticides. 
     
     
         259 . The method of  claim 258 , wherein said rodenticide is pyrinuron. 
     
     
         260 . The method of  claim 257 , wherein said cancer is pancreatic cancer. 
     
     
         261 . The method of  claim 257 , wherein said genetic syndrome is selected from the group consisting of Down's syndrome, Klinefelter's syndrome, Turner syndrome, Woldfram syndrome, and Friendreich ataxia. 
     
     
         262 . The method of any one of  claims 244 - 250  and  253 - 261 , said method comprising administering said therapeutic agent to said subject identified as a subject that would benefit from one or more additional doses of said therapeutic agent. 
     
     
         263 . The method of any one of  claims 244 - 250  and  253 - 262 , wherein said therapeutic agent is BCG. 
     
     
         264 . The method of any one of  claims 242 - 252  and  257 - 261 , said method comprising administering BCG to said subject identified as having hyperglycemia or a disease associated therewith. 
     
     
         265 . The method of any one of  claims 169 - 241  and  262 - 264 , wherein BCG is the only therapeutic agent administered to said subject. 
     
     
         266 . The method of any one of  claims 169 - 241  and  262 - 264 , wherein said subject is not administered an agent that promotes the expression of IL-2. 
     
     
         267 . The method of any one of  claims 169 - 241  and  262 - 264 , wherein said subject is not administered lymphotoxin. 
     
     
         268 . The method of any one of  claims 169 - 241  and  262 - 264 , wherein said subject is not administered Lentinan. 
     
     
         269 . The method of any one of  claims 169 - 241  and  262 - 264 , wherein said subject is not administered an agent that promotes the expression of TNF-α other than BCG. 
     
     
         270 . The method of any one of  claims 169 - 268 , wherein said subject is a mammal. 
     
     
         271 . The method of  claim 269 , wherein said mammal is a human. 
     
     
         272 . A kit comprising BCG and a package insert instructing a user of said kit to perform the method of any one of  claims 169 - 270 . 
     
     
         273 . The method of  claim 169 , wherein said disease is selected from the group consisting of type 2 diabetes, noninsulin-dependent diabetes mellitus (NIDDM), nonalcoholic steatohepatitis (NASH), metabolic syndrome, cystic fibrosis, drug induced hyperglycemia, insulin resistance syndromes, diseases caused by genetic mutations in the pancreas, cancer, infection, Leprechaunism, Rabson Mandenhall syndrome, lipoatrophic diabetes, pancreatitis, trauma, hemochromatoisis, fibrocalculous pancreatopathy, acromegaly, Cushings syndrome, glucagonoma, pheochromocytoma, hyperthyroism, somatostatinoma, aldosteroma, infections associated with beta cell destruction, Rubella, coxsachie virus B, mumps, cytomegatolovirus infection, adenovirus infection, a genetic syndrome, stiff person syndrome, anti-insulin receptor abnormalities, liver disease, and renal failure. 
     
     
         274 . The method of  claim 169 , wherein said BCG is administered in a unit dosage form comprising between about 5×10 5  and about 1×10 7  cfu per 0.1 milligrams of BCG. 
     
     
         275 . The method of  claim 274 , wherein said unit dosage form comprises between about 1×10 6  and about 6×10 6  cfu per 0.1 milligrams of BCG. 
     
     
         276 . The method of  claim 169 , wherein said subject is not suffering from a disease or condition selected from the group consisting of an autoimmune disease, a neurological condition, an allergy, allograft rejection, graft-versus-host disease, asthma, macular degeneration, muscular atrophy, a disease related to miscarriage, atherosclerosis, bone loss, a musculoskeletal disease, and obesity. 
     
     
         277 . The method of  claim 169 , wherein said subject is not suffering from an autoimmune disease. 
     
     
         278 . The method of  claim 169 , wherein said subject is not suffering from an autoimmune disease selected from the group consisting of type I diabetes, Alopecia Areata, Ankylosing Spondylitis, Antiphospholipid Syndrome, Autoimmune Addison's Disease, Autoimmune Hemolytic Anemia, Autoimmune Hepatitis, Behcet's Disease, Bullous Pemphigoid, Cardiomyopathy, Celiac Sprue-Dermatitis, Chronic Fatigue Immune Dysfunction Syndrome (CFIDS), Chronic Inflammatory Demyelinating Polyneuropathy, Churg-Strauss Syndrome, Cicatricial Pemphigoid, CREST Syndrome, Cold Agglutinin Disease, Crohn's Disease, Essential Mixed Cryoglobulinemia, Fibromyalgia-Fibromyositis, Graves' Disease, Guillain-Barré, Hashimoto's Thyroiditis, Hypothyroidism, Idiopathic Pulmonary Fibrosis, Idiopathic Thrombocytopenia Purpura (ITP), IgA Nephropathy, Juvenile Arthritis, Lichen Planus, Lupus, Ménière's Disease, Mixed Connective Tissue Disease, Multiple Sclerosis, Myasthenia Gravis, Pemphigus Vulgaris, Pernicious Anemia, Polyarteritis Nodosa, Polychondritis, Polyglandular Syndromes, Polymyalgia Rheumatica, Polymyositis and Dermatomyositis, Primary Agammaglobulinemia, Primary Biliary Cirrhosis, Psoriasis, Raynaud's Phenomenon, Reiter's Syndrome, Rheumatic Fever, Rheumatoid Arthritis, Sarcoidosis, Scleroderma, Sjögren's Syndrome, Stiff-Man Syndrome, Takayasu Arteritis, Temporal Arteritis/Giant Cell Arteritis, Ulcerative Colitis, Uveitis, Vasculitis, Vitiligo, and Wegener's Granulomatosis. 
     
     
         279 . The method of  claim 169 , wherein said subject is not suffering from type I diabetes. 
     
     
         280 . The method of  claim 169 , wherein said subject is a human. 
     
     
         281 . A method of inducing an increase in the rate of aerobic glycolysis in a mammalian subject, said method comprising administering to said subject BCG. 
     
     
         282 . The method of  claim 281 , wherein the rate of aerobic glycolysis is increased relative to a measurement of aerobic glycolysis in said subject prior to administration of said BCG. 
     
     
         283 . The method of  claim 281 , whereby said administering reduces the rate of oxidative phosphorylation of adenosine diphosphate in said subject relative to a measurement of oxidative phosphorylation of adenosine diphosphate in said subject prior to administration of said BCG. 
     
     
         284 . The method of  claim 281 , whereby said administering reduces the level of one or more substances selected from the group consisting of glucose, cholesterol, LDL, a triglyceride, glycated hemoglobin, an mRNA molecule encoding a protein selected from the group consisting of FBP1, G6PD, and PKM, a protein selected from the group consisting of FBP1, G6PD, and PKM, an mRNA molecule encoding an enzyme that promotes flux through the Krebs cycle, an enzyme that promotes flux through the Krebs cycle, α-ketobutyrate, and 2-hydroxybutyrate in said subject relative to a measure of said substance in said subject prior to administration of said BCG. 
     
     
         285 . The method of  claim 281 , whereby said administering increases the level of one or more substances selected from the group consisting of an mRNA molecule encoding a glycolytic enzyme, a glycolytic enzyme, an mRNA molecule encoding a glucose transporter, a glucose transporter, an mRNA molecule encoding HIF1-α, HIF1-α, an mRNA molecule encoding NR1H3, NR1H3, lactate, and 1,5-anhydroglucitol in said subject relative to a measure of said substance in said subject prior to administration of said BCG. 
     
     
         286 . The method of  claim 284 , wherein said enzyme that promotes flux through the Krebs cycle is selected from the group consisting of ACLY, ACO2, CS, DLD, OGDH, SDHB, and SUCLG1. 
     
     
         287 . The method of  claim 285 , wherein said glycolytic enzyme is selected from the group consisting of HK2, G6PI, TPI1, GALK1, and GALM. 
     
     
         288 . The method of  claim 285 , wherein said glucose transporter is SLC2A6. 
     
     
         289 . The method of  claim 281 , wherein said mammalian subject is a human.