METHODS FOR TREATMENT OF METABOLIC DISORDERS USING EPIMETABOLIC SHIFTERS, MULTIDIMENSIONAL INTRACELLULAR MOLECULES, OR ENVIRONMENTAL INFLUENCERS

1 . A method for treating, alleviating symptoms of, inhibiting progression of, or preventing a metabolic disorder in a mammal, the method comprising: administering to the mammal in need thereof a therapeutically effective amount of a pharmaceutical composition comprising at least one environmental influencer (env-influencer), wherein the environmental influencer selectively elicits, in a disease cell of the mammal, a cellular metabolic energy shift towards normalized mitochondrial oxidative phosphorylation.

2 . The method of claim 1 , wherein the environmental influencer does not substantially elicit, in normal cells of the mammal, the cellular metabolic energy shift towards mitochondrial oxidative phosphorylation.

3 . The method of claim 1 , wherein the mammal is human (or a non-human mammal).

4 . The method of claim 1 , wherein the metabolic disorder is responsive or sensitive to treatment by Coenzyme Q10 or its metabolites or analogs thereof.

5 . The method of claim 1 , wherein the metabolic disorder is characterized by a dysregulated mitochondrial oxidative phosphorylation function that leads to altered gene regulation and/or protein-protein interactions which contribute to or causally lead to the metabolic disease.

6 . The method of claim 1 , wherein the environmental influencer comprises:

(a) benzoquinone or at least one molecule that facilitates the biosynthesis of the benzoquinone ring, and

(b) at least one molecule that facilitates the synthesis of and/or attachment of isoprenoid units to the benzoquinone ring.

7 . The method of claim 6 , wherein said at least one molecule that facilitates the biosynthesis of the benzoquinone ring comprises: L-Phenylalanine, DL-Phenylalanine, D-Phenylalanine, L-Tyrosine, DL-Tyrosine, D-Tyrosine, 4-hydroxy-phenylpyruvate, 3-methoxy-4-hydroxymandelate (vanillylmandelate or VMA), vanillic acid, pyridoxine, or panthenol.

8 . The method of claim 6 , wherein said at least one molecule that facilitates the synthesis of and/or attachment of isoprenoid units to the benzoquinone ring comprises: phenylacetate, 4-hydroxy-benzoate, mevalonic acid, acetylglycine, acetyl-CoA, or farnesyl.

9 . The method of claim 1 , wherein the environmental influencer comprises:

(a) one or more of L-Phenylalanine, L-Tyrosine, and 4-hydroxyphenylpyruvate; and,

(b) one or more of 4-hydroxy benzoate, phenylacetate, and benzoquinone.

10 . The method of claim 1 , wherein the environmental influencer:

(a) inhibits Bcl-2 expression and/or promotes Caspase-3 expression; and/or,

(b) inhibits cell proliferation.

11 . The method of claim 1 , wherein the environmental influencer is a multidimensional intracellular molecule (MIM).

12 . The method of claim 11 , wherein the MIM is selected from: alpha ketoglutarate/alpha ketoglutaric acid, Malate/Malic acid, Succinate/Succinic acid, Glucosamine, Adenosine, Adenosine Diphosphate, Glucuronide/Glucuronic acid, Nicotinic Acid, Nicotinic Acid Dinucleotide, Alanine/Phenylalanine, Pyridoxine, Thiamine, or Flavin Adenine Dinucleotide.

13 . The method of claim 1 , wherein the environmental influencer is an epimetabolic shifter (epi-shifter).

14 . The method of claim 13 , wherein the epimetabolic shifter is selected from: Transaldolase, Transketolase, Succinyl CoA synthase, Pyruvate Carboxylase, or Riboflavin.

15 . The method of claim 13 , wherein the epimetabolic shifter is coenzyme Q10.

16 . The method of claim 1 , wherein the concentration of the environmental influencer in the tissues of the human being treated is different than that of a control standard of human tissue representative of a healthy or normal state.

17 . The method of claim 1 , wherein the form of the environmental influencer administered to the human is different than the predominant form found in systemic circulation in the human.

18 . The method of claim 1 , wherein the amount sufficient to treat the metabolic disorder in the human up-regulates or down-regulates mitochondrial oxidative phosphorylation.

19 . The method of claim 18 , wherein the amount sufficient to treat the metabolic disorder in the human modulates anaerobic use of glucose and/or lactate biosynthesis.

20 . The method of claim 1 , wherein the treatment occurs via an interaction of the env-influencer with HNF4alpha.

21 . The method of claim 1 , wherein the treatment occurs via an interaction of the env-influencer with transaldolase.

22 . The method of claim 1 , wherein the metabolic disorder is selected from the group consisting of diabetes, obesity, pre-diabetes, Metabolic Syndrome and any key elements of a metabolic disorder.

23 . The method of claim 22 , wherein the metabolic disorder is diabetes, and the env-influencer affects beta cell function, insulin metabolism, and/or glucagon deposition.

24 . The method of claim 22 , wherein the metabolic disorder is obesity, and the env-influencer affects beta cell oxidation in the mitochondria, decrease in adipocyte size, and/or control of cortisol levels.

25 . The method of claim 22 , wherein the metabolic disorder is a cardiovascular disease, and the env-influencer affects decrease in smooth muscle cell proliferation in the tunica media, lipid peroxidation, thromboxane-ax2 synthesis, TNFα, IL-1B, platelet aggregation, decrease in nitric oxide (NO) production, plaque deposition and/or normalized glycemic control.

26 . The method of claim 22 , wherein said key elements of a metabolic disorder is selected from the group consisting of impaired fasting glucose, impaired glucose tolerance, increased waist circumference, increased visceral fat content, increased fasting plasma glucose, increased fasting plasma triglycerides, decreased fasting high density lipoprotein level, increased blood pressure, insulin resistance, hyperinsulinemia, cardiovascular disease, arteriosclerosis, coronary artery disease, peripheral vascular disease, cerebrovascular disease, congestive heart failure, elevated plasma norepinephrine, elevated cardiovascular-related inflammatory factors, elevated plasma factors potentiating vascular endothelial dysfunction, hyperlipoproteinemia, arteriosclerosis or atherosclerosis, hyperphagia, hyperglycemia, hyperlipidemia, and hypertension or high blood pressure, increased plasma postprandial triglyceride or free fatty acid levels, increased cellular oxidative stress or plasma indicators thereof, increased circulating hypercoagulative state, hepatic steatosis, hetaptic steatosis, renal disease including renal failure and renal insufficiency.

27 . The method of claim 1 , further comprising administering an additional therapeutic agent.

28 . The method of claim 27 , wherein the additional therapeutic agent is selected from the group consisting of diabetes mellitus-treating agents, diabetic complication treating agents, anti-hyperlipemic agents, hypotensive or antihypertensive agents, anti-obesity agents, diuretics, chemotherapeutic agents, immunotherapeutic agents and immunosuppressive agents.

29 . A method for selectively augmenting mitochondrial oxidative phosphorylation, in a disease cell of a mammal in need of treatment for a metabolic disorder, the method comprising: administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising at least one env-influencer, thereby selectively augmenting mitochondrial oxidative phosphorylation in said disease cell of the mammal.

30 . The method of claim 29 , further comprising up-regulating the expression of one or more genes selected from the group consisting of the molecules listed in Tables 2-4 & 6-28 & 63-68 having a positive fold change; and/or down-regulating the expression of one or more genes selected from the group consisting of the molecules listed in Tables 2-4 and 6-28 & 63-68 having a negative fold change.

31 . The method of claim 29 , further comprising modulating the expression of one or more genes selected from the group consisting of HNF4-alpha, Bcl-xl, Bcl-xS, BNIP-2, Bcl-2, Birc6, Bcl-2-L11, XIAP, 20 BRAF, Bax, c-Jun, Bmf, PUMA, cMyc, transaldolase 1, COQ1, COQ3, COQ6, prenyltransferase, 4-hydrobenzoate, neutrophil cytosolic factor 2, nitric oxide synthase 2A, superoxide dismutase 2, VDAC, Bax channel, ANT, Cytochrome c, complex 1, complex II, complex III, complex IV, Foxo 3a, DJ-1, IDH-1, Cpt1C and Cam Kinase II.

32 . The method of anyone of claims 29 - 31 , wherein the metabolic disorder is selected from the group consisting of diabetes, obesity, pre-diabetes, Metabolic Syndrome and any key elements of a metabolic disorder.

33 . The method of anyone of claims 29 - 31 , wherein said key elements of a metabolic disorder is selected from the group consisting of impaired fasting glucose, impaired glucose tolerance, increased waist circumference, increased visceral fat content, increased fasting plasma glucose, increased fasting plasma triglycerides, decreased fasting high density lipoprotein level, increased blood pressure, insulin resistance, hyperinsulinemia, cardiovascular disease, arteriosclerosis, coronary artery disease, peripheral vascular disease, cerebrovascular disease, congestive heart failure, elevated plasma norepinephrine, elevated cardiovascular-related inflammatory factors, elevated plasma factors potentiating vascular endothelial dysfunction, hyperlipoproteinemia, arteriosclerosis or atherosclerosis, hyperphagia, hyperglycemia, hyperlipidemia, and hypertension or high blood pressure, increased plasma postprandial triglyceride or free fatty acid levels, increased cellular oxidative stress or plasma indicators thereof, increased circulating hypercoagulative state, hepatic steatosis, hetaptic steatosis, renal disease including renal failure and renal insufficiency.

34 . The method of claim 29 , further comprising administering an additional therapeutic agent.

35 . The method of claim 34 , wherein the additional therapeutic agent is selected from the group consisting of diabetes mellitus-treating agents, diabetic complication treating agents, antihyperlipemic agents, hypotensive or antihypertensive agents, antiobesity agents, diuretics, chemotherapeutic agents, immunotherapeutic agents and immunosuppressive agents.

36 . A method of identifying an agent that is effective in treating a metabolic disorder, the method comprising:

(1) selecting an environmental influencer;

(2) identifying an environmental influencer capable of shifting the metabolic state of a cell; and

(3) determining whether the environmental influencer is effective in treating the metabolic disorder;

thereby identifying an agent that is effective in treating a metabolic disorder.

37 . The method of claim 36 , wherein an environmental influencer is identified as capable of shifting the metabolic state of a cell by measuring changes in any one or more of mRNA expression, protein expression, lipid or metabolite concentration, levels of bioenergetic molecules, cellular energetics, mitochondrial function and mitochondrial number.

38 . The method of claim 36 , wherein an environmental influencer effective in treating a metabolic disorder is capable of reducing glucose levels or lipid levels in a patient.

39 . A composition comprising an agent identified according to the method of any one of claims 36 - 38 .

40 . A kit comprising the composition of claim 39 .

41 . A method of reducing glucose levels in a patient comprising administering to the patient an effective amount of the composition of claim 39 .

42 . A method of reducing lipid levels in a patient comprising administering to the patient an effective amount of the composition of claim 39 .

43 . A method for treating, alleviating symptoms of, inhibiting progression of, or preventing a Coenzyme Q10 responsive disorder in a mammal, the method comprising: administering to the mammal in need thereof a therapeutically effective amount of pharmaceutical composition comprising at least one environmental influencer (env-influencer), wherein the environmental influencer selectively elicits, in a disease cell of the mammal, a cellular metabolic energy shift towards levels of glycolysis and mitochondrial oxidative phosphorylation observed in a normal cell of the mammal under normal physiological conditions.

44 . The method of claim 43 , wherein the Coenzyme Q10 responsive disorder is a metabolic disorder.