I am doing this blog post to show the complexity of figuring health issues out. With these notes I am trying to figure out how to correct health issues causing people to be hyperinsulinemic and hypoglycemic. These ones also have inhibited oxidative phosphorylation and inhibited beta oxidation which can lead to obesity. If this is not corrected it starts damaging the pancreas and causes beta cell loss leading to type two diabetes. It will seem like the notes are sporadic but each person has a different cause but often times I find one root cause that has effected each person differently but brought about the same results. Finding the most common causes and things that help will usually help narrow down a protocol that will help the most people safely. That being said this is not medical advice I just want to show the complexity of figuring these things out so I am going to post my notes I put together and I slowly work through them until I narrow down the best solution. Do not try to correct these things yourself if you are ill seek the aid of a qualified and experienced naturopathic practitioner.
Things that may correct hyperinsulinemia, hypoglycemia and inhibited fat burning.
Increasing progesterone helps increase fat buring. Wild yam and organic soy bean increases progesterone.
Reducing IL-1b helps
Increasing acetylcholesterase prevents excess salt retention and increases fat burning.
Increasing TGF-B helps
Reduce overexpression of P53, Bax/BC12, Caspace 3 and 9 they cause excess reactive oxygen species which causes insulin resistance, endothelial dysfunction and mitochondrial dysfunction.
Increase sepiateron reducaste. A deficiency causes low BH4 exnzymes which can cause sensitivity to catecholamines, adrenal issues, and cause issues with HPA axis. Valproic acid increases sepiateron.
Improve liver clearance of insulin.
EPAC2 overexpression causes hyperinsulinemia and decreased cardiovascular function.
Increasing EPAC1 activates SOC3 which prevents chronic pain.
Improve adrenal function if not functioning properly fat burning becomes inhibited.
Close K+ATP channels which regulate ATP and ADP. Excess extra cellular ATP causes K+ATP channels to open which increases insulin secretion , inflammation, nerve sensitivity, and inhibits fat burning. This can be causes by infection, microbial dysbiosis in the bladder or gut or infection.
Increase magnesium it stabilizes NBF1 and SUR1 which is needed to produce ADP. Magnesium helps prevent K+ATP from being stuck open causing excess insulin secretion. It prevents SUR1 from being inhibited. When SUR1 is inhibited it causes MGADRS Ability to limit insulin release.
Things that inhibit glycolysis my helps such as gingko, milk thistle, berries, and many spices. Phytonutrients fisetin, myricetin, quercetin, apigenin, genistein, cyanidin, diadzen, hesperetin, nariginen and catechin inhibit glycolysis.
Reducing HIF-1 may help. Vitamin D3, resveratrol, , berberin, and butyrate inhibits HIF-1.
Increasing glucagon helps to increase fat burning and improve glucose levels. Protein, complex carbohydrates increase glucagon. This would also reduce insulin levels.
Increase exonuclease 7(EXO7). Many have been injured by fluoroquinolone and it is needed to repair damage to DNA from fluoroquinolones.
Heme oxygenase 1- is overexpressed when endotoxins , inflammation or oxidative stress levels are high. Inhibiting HO-1 prevent the damage they would normally cause. When HO-1 and NRF2 are both overexpressed it causes atherosclerosis.
NOX4- when inhibited activating NRF2 will increase oxidative stress NRF2 is the master regulator of the antioxidant system and it’s activation has many benefits but a person must make sure HO-1 isn’t over expressed and NOX4 is not inhibited before activating NRF2. This is because NOX4 inhibition cause glutathione to become depleted and causes BCL-2 expression to be inhibited which causes cellular apoptosis. Loss of NOX4 decreases NRF2 expression, decreases mitochondrial potential and increases kidney cell death which can cause hyperinsulinemia and hypoglycemia. NOX4 is an NADPH oxidase.
XBP1 upregulates UPR which stabilizes NRF2.
Transcription factor EB (TFEB)- reduces inflammation, excess hydrogen peroxide, SELE, MCP1, VCAM1, IL-1B, inflammatory IL-6, and IL-8 which are over expressed in hyperinsulinemia and hyproglycemia. TFEB activates lipid catabolism pathways and represses biosyntetic pathways, it upregulates PGC1a which helps maintain glucose and insulin homeostasis. For proper TFEB signaling PPARa needs to be functioning. TFEB is over expressed in Huntingtons diseases. PBC1a/RXR are involved in the effects of TFEB. For TFEB to function calcineurin is needed for the release of calcium from lysosome.
MTORC1 inhibition causes an accumulation of TFEB.
TFEB activators are genistein, curcumin and PI3K inhibition.
TFEB is inhibited in Alzheimers and Parkinson’s.
MIR-128 inhibition rescues TFEB function.
TFEB is the master regulator of lysosome autophagy pathway.
Trehalose activates TFEB but sacharromyces boulardii is needed to produce the metabolites for the transcription of TFEB. There are also enzymes in the gut that help to break down trehalose that are needed so inflammation in the gut could inhibit the benefits of trehalose. Trehalose is found in mushrooms, algae, but the highest levels are found in shiitake mushrooms, maitake mushrooms, nameko and judas ear mushrooms. Thiamine is needed to produce the beneficial metabolites from trehalose. Chlorella, bakers yeast, asparagus racemosus root and liverwort also contain trehalose.
If a person has C Diff they should not consume trehalose unless they consume lactoferrin with it to prevent feeding C Diff.
TREH is the human trehalose gene which is a stress response gene.
Low leptin levels and leptin resistance inhibits fatty acid burning, and causes hyperinsulinemia and hypoglycemia. This creates a positive feedback loop that is difficult to break because hyperinsulinemia and hypoglycemia reduces plasma leptin levels.Reducing inflammation , oxidative stress, increasing fiber intake helps to prevent leptin resistance. Reducing bad testosterone and stress hormones improves leptin sensitivity. MSB added to food for flavor and excess fructose consumption can cause leptin resistance. Leptin deficiency causes obesity. Leptin prevents high triglycerides, fat accumulation in organs. It is needed to prevent damage to the pancreas and other organs from excess free plasma fatty acids. Leptin deficiency or leptin resistance causes high A1C levels.
Ghrelin inhibits inulin secretion, prevents muscular atrophy by inducing muscle cell differentiation and fusion. Ghrelin helps to prevent obesity, insulin resistance and helps normalize glucose levels. Ghrelin prevents hyperinsulinemia and hypoglycemia. Ghrelin prevents B-cell apoptosis. Pancreatic B-cell death leads to type 2 diabetes. Ghrelin is produced in pancreatic E-cells. Remember inflammation and excess oxidative stress caused by FFAs inhibit pancreatic function. Ghrelin prevents muscle atrophy and excess insulin secretion.
Intramuscular adipose tissue (IMAT) causes insulin resistance , loss of strength, and mobility dysfunction. High IMAT levels can cause COPD and localized inflammation in muscle. Endurance exercise increases Type 1 muscle cells which reduces IMAT.
Biogenesis occurs in the endoplasmic reticulum. It prevents protein aggregation, cholesterol accumulation and prevents lysosome related diseases. If lipid biogenesis is impraired oxidative capacity of the mitochondrial is reduced which causes muscle stem cells to differentiate towards an adipogenic lineage. Increased myogenesis and decreased biogenesis leads to IMAT formation which decreases cell formation and growth. BSCL2 (seipin) is needed for early lipid droplet biogenesis.
PGC1a and coactivator PPARy control mitochoncrial biogenesis. Coactivators are NRF2, PPARs, RARs, and thyroid hormone receptors, myorcyte enhancer factor 2 (MEF2) which induces PGC1a expression. Over expression of PGC1a stimulates production of slow oxidative muscle. This can be caused by excess type 2 muscle fibers which increase from lifting heavy weight.
Impaired blood flow increases lipolysis within muscle cells which can cause insulin resistance.
Myostatin (GDF8) produced and released by myocytes in cardiac muscle smooth muscle and muscle throughout the body inhibits muscle cell growth. It causes inhibits myogenesis and increases adipogenesis which reduces muscle growth and increases fat retention. Inhibiting myostatin prevents obesity. PPARy over expression inhibits the negative effects of myostatin. Ketones reduces myostatin. During calorie restriciton myostatin is reduced to preserve muscle mass but those with hypyerinsulemia can go into cardiac arrest or coma from they hyper glycemia so this would not be an option for them.
There are two types of IL-6 one is inflammatory one is anti-inflammatory. Excess consumption of saturated fatty acids, excess production of short chain fatty acids in the gut can increase inflammatory IL-6, and endotoxins increase IL-6.
The IL-6 normally produced in the body promotes lypolysis and fatty acid oxidation and helps maintain glucose and insulin homeostasis.
GEFT – Rho specific GEFT is needed during skeletal muscle regeneration, it inhibits insulin induced adipogenisis by increasing Rho kinase.
Macropage clean up and remove dead and damaged cells. They are stimulated by inflammation , macrophage levels are high in obesity and type 2 diabetes. Both are known to have systemic inflammation.
IGE1 inhibition inhibits energy metabolism.
Excess thymidine can cause fat build up in muscle. Urindine corrects this but is not very bioavailable. Consuming alcohol with uridine increases it’s absorption and bioavailability. Beer is high in uridine. Foods high in uridine are raw goat and sheep milk, sugar cane extract, tomatoes, brewers yeast, broccoli, organ meats, and walnuts. Before eating these a person must address uric acid levels and make sure they are not high. Those foods increase ruines such as adenine and guanosine which are needed for DNA but can increase uric acid. Urindine is needed for glycolysis pathway of galactose and udp-glucose metabolism.
PPARg inhibition causes lipodystrophy, type 2 diabetes, obesity , hypertension, PCOS, cirrhosis of the liver, insulin resistance, elevated triglycerides, hypertension and low PPARy levels.
PPARy activation improves insulin sensitivity.
BSCL2 upregulation increases SEIPEN which helps maintain lipid homeostasis, BSCL2 gene is regulated by the HPA axis.
MFN2 increases mitochondrial fusion which increases oxphos.
Mitochondrial transcription factor ACTFAM stabilizes mtDNA transcription. Reduced levels causes lypodystrophy, reduced mitochondrial biogenesis, reduced glucose metablolism, decreased heart function, increased inflammation and NAFLD.
CR6 interacting factor 1 (CRIF1) is essential for intramitochondrial translation of mtDNA encoded oxphos. A deficiencyin CRIF1 reduces oxphos.
Galactose increases oxphos. Glalactose is increase by lactose consumption.
RAR and RXR need to be functioning in order for the body to metabolize fats properly.
PPARa binds both saturated and unsaturated fatty acids. It inhibits fatty acid synthesis and increases fatty acid catabolism.
PPARa is involved in lipid transport and beta oxidation of fatty acids. Activation of PPARa prevents high triglyceride levels and in creases HDL levels. It is widely expressed in the digestive tract where it is anti-inflammatory.
PPARa is stimulated by phosphorylation, mitogen activated kinase (MAPK), protein kinase C (pkc) and Amp-activated protein kinase (AMPK) which phosphorylates PPARa.
Magnolia bark, licorice root, and false indigo activates both PPARa and RXR. Magnolia bark is the most potent activator. Lavender, citrus peel extract, contain ligands for PPARa and increase fatty acid oxidation. Coryophyllene found in clove, rosemary, hopes, black caraway, basil, orgegano oil, and cinnamon increases PPARa through the CB2 receptor.
Farnesol found in citronella, nerol, cyclamen, lemon grass, tuberosa, rose, musk balsam and tolu increases PPARa expression by increasing carnitine palmitoyl transferase which increases acyl carnitine which is needed for beta oxidation of long chain fatty acids and to provide energy for muscles.
Pine bark extract contains phytochemicals that increase PPARa and PPARb expression.
Chlorophyll contains phytol which increasesw expression of PPARa, PPARy and RXR.
Oleanolic acid found in olive oil increases PPARa expression.
Hops contains isohulene and isohumulone which activates PPARa and PPARy which reduces dyslipodemia and tryiglycerides and plasma free fatty acid levels. It also upregulates enzymes involved in fatty acid oxidation.
Buckthorn, pholomus spp, figwort spp, bacopa, mullein, Buddleja araucana, buddleja globosa, boddeia cordata, broomrape spp, cristanche spp, plantain herb, vervian, aloysia, citrodora latona cammara, read sage and olives contain verbascoside which reduces gut inflammation and increases PPARa expression.
Carrot, corriander, angelica spp, mouse eared hawk weed, big leaf hydrangea, and water willow contains umbelliferone that reverses fatty liver by increasing fatty acid oxidation gene expression including PPARa expression and beta oxidation. Angelica spp, cridium monnier contains osthol which has similar effects as viagra. It activates PPARa and PPARy through AMPK pathway. It helps to heal penis injury and vaginal atrophy. It heals skin related diseases. Osthol is also antibacterial , anti-allergic, antifungal, anti-ostioporotic and improves hippocampus function.
Sesame seed contains sesamin which down regulates LXRa reducing fatty liver disease and it increases PPARa expression.
Pomegranate and terminalia bellirica contain phytochemicals that enhance PPARy signaling. They also inhibit TGF-B1 which prevents and reverses fibrenogenesis which would prevent excess blood clotting and diseases that involved excess fibrin build up in organs. It prevents MRSA infection and increases PPARa and PPARy.
Reveratrol found in grape skins, grape seed extract, japanese knotweed root, and malberries activates PPARa and PPARy. Sulfation and glucuronidation is needed for proper metabolism of resveratrol.
Boesenbergia pandurata root contains panduratin A which stimulates AMPK which activates PPARa and PPARb.
Gumweed, cricket vine, artemisia spp, sage spp, crossostephium chinense, and rosemary contain hispdulin that activates PPARa and fatty acid buring genes increasing beta oxidation.
Scutellaria, and oroxylum indicum contain wogonin which activates PPARa and down regulates osteopontin. High levels of osteopontin causes allergies, leukemia and cardiovascular disease. Wogonin also decreases TGF-B1.
Horny goatweed contains Icarin which upregulates PPARa and PPARy, it inhibits NfxkB expression which is neuroprotective and anti-inflammatory.
Green tea contains Epigallocatechin-3-gallate which increases PPARa and suppresses HO-1 expression . Ho-1 over expression causes delirium and high bilirubin levels increasing risk of mortality.
Red clover , alfalfa sprouts, chick pea, and other legumes contain biochin A. Biochin A is a phytoestrogen that inhibits fatty acid amide hydrolase (FAAH) which reduces anxiety, pain and increases endogenous cannabinoid anadamide. It also increases PPARa expression.
Kudzu contains tectoridin which increases PPAra expression and prevents fatty liver but can kill a mans sperm if taken in excess.
Gingko biloba contains bilobetin which prevents hyperlipdemia, lipotoxicity and insulin resistance through PKA activation. Bilobetin also increases phosphorylation. Has potent antifungal and antiviral properties. It can damage the liver if taken in extremely high doses but many vitamins can do that. I t should be taken with food because it can decrease glucose levels.
Quassia contains Picrasidin C which is selective PPARa agonist only and activates PPARa only.
Berberas spp, Barberry, coptis, tree tumeric , phellodendron, amur cork tree bark, tinospora, prickly poppy, and california poppy contain berberine which activates AMPK, inhibits CypwD6, and CYP3A4 which are invovled in the metabolism of xenobiotics and carcinogenic hormones. It is very effective against herpes viruses. It restores reverese cholesterol homeostasis through PPARa activation.
Sophora root contains oxymatrine which prevents fibrosis in organs, decreases ischemia in organs, prevents myocardial injury, heart arrythmia and improves heart function. It inhibits SMAD3 binding to TGF-B , it down regulates SREBF1. SREBF1 over expression causes insulin resistance and NAFLD and increase risk of cancer. Oxymatrine also increases PPARa expression.
PPAr inhbition can cause obesity, hyperinsulinemia, hypoglycemia, and organ fibrosis.
White birch, indian plum , self heal, persimon, inhibits CB1 and activates CB2 which can inhibit PPARy which could help type 1 diabetes. It inhibits melanoma, reduces inflammation, fights malaria and retroviruses and prevents fatty liver, insulin resistance from PPARy over activation. PPARy expression is high in type 1 diabetes and low in Type 2 diabetes. Akkermansia mciniphila decreases PPARy expression. Roseburia intestinalis, Roseburia hominis, Fusobacterium naviforme, Prevotella copri, Atopobium paruvlum, Enterococcus faecalis and Lactobacillus casei increases PPARy expression.
These microbes may help with type 1 diabetes because they inhibit PPARy. Proprionibacterium shermanii, Akkermansia munciniphila, Faecalibacterium prausnitzii, and streptococcus slivarius.
PPARy over activation can cause oxidative stress, and inflammation, it can inhibit glucose uptake into cells and prevent osteogenesis.
PPARy responds to unsaturated FFAs. It regulates the uptake and storage of FFAs and glucose homeostasis. It is involved in the regulation of inflammation. PPARy activation reduces inflammation.
PPARy inhibition reduces glucose uptake into cells which causes adipocytes to expand until they die releasing toxic lipids.
PPARy upregulation prevents intestinal infection and gut inflammation and increases beta oxidation. Lactobacillus paracasei increases PPARy expression.
Nuts, avocado, saw palmetto, stinging nettles and many vegetables contain B-sitosterol which reduces bad testosterone in the body which can cause sterility and vaginal atrophy in women. B-sitosterol inhibits aromatase and 5-alpha reductase and improves urinary function and reduces prostate inflammation. It activates the insulin receptors helping to prevent insulin resistance. It activates Glut4 transporter which is inhibited in type 2 diabetes. B-sitosterol decreases SREBP, TNF-a and inflammatory IL-6, it inhibits NfxkB and improves insulin signaling by improving PPARy function and preventing it’s over activation.
Excess blood clotting, ischemia, low oxygen levels, and low erthrocyte levels can inhibit fatty acid oxidation. Proteins from organ meats, legumes, beans, and eggs can help to increase erthrocyte levels. Dark leafy greans, copper, iron, vitamin C, vitamin B6 and vitamin E are needed for the production of erthrocytes. Nattokinase, grape seed extract and gingko help to prevent excess blood clotting.
Improving mitochondrial function will improve insulin sensitivity and help restore metabolic homeostasis.
Avoiding carbs before exercise and eating them afterwards improves mitochondrial function. Beet root juice, Omega 3 oils, nitrate or nitrite improves mitochondrial function. When mitochondrial function is inhibited the electron transport chain gets inhibited.
Exposure to cold increases UCP1 expression in brown fat which increase fat buring without the need for phosphorylation. UCP1 increases fat burning and is inhibited buy urine nucleosides diphosphate and triphosphate. Omega 3 fatty acids overcome this inhibition by competing with diphosphates and triphosphates this activates lipolysis.
Superoxide, HNE and lipid peroxidation products activates UCP1.
To increases superoxide eat seed sprouts, melon, Vitamin E, N-acetylcysteine (NAC) curcumine, zinc, inron, manganese, squash or melon seeds especially pumpkin seeds, hazel nuts, and black choke berry increases SOD. Chlorella, dunaliella salina, haematococcus porphyridium cruetum, arthrospira platensis contain bioavailable SOD.
Type 1 muscle fibers increases UCP1. It increases UCP3 which increases biogenesis. Vitamin D3 also increases biogenesis. Type 1 muscle fibers are increased by endurance training.
UCPs regulate glucose and insulin homeostasis. Ketones increases UCPs. UCP2 prevents insulin resistance. Olive oil upregulates UCP protein expression. UCP3 prevents the negative effects of excess salt consumption. Leptin increases UCPs. Thyroid hormones increases UCP1. Bile acids increases UCP1 which increases brown fat. Brown fat prevents obesity.
Beta blockers increase weight gain because they inhibit UCP1.
Increasing irisin increases UCP1. Omega 3 oils, cold exposure, leptin, CoQ10, holy basil and devices that vibrate the body increases irisin.
Things that can cause low irisin are low AMPK levels, fasting, bad sleep habits, high TGF-B levels.
L-dopa in velvet bean increases UCP1. Ursolic acid found in apple peels, cran berries, holy basil, oregano, rosemary, thyme and grape skins increases UCP1.
Kaemprferol found in cruciferous vegetables, capers, arugula, fresh deal, garden kress, endive, fennel leaves and swiss chard increases UCP1.
If you increase UCP levels with low nitric oxide levels it will cause excess weight loss and frailty.
Oxidative phosphorylation is needed to produce energy for cells from fats which increases endurance and exercise tolerance. Some things needed for oxphos are nicotinamide, L-carnitine, Thiamine, biotin, riboflavin, folinic acid. Folate is also needed for other B vitamins to function properly.
Things that increase exercise endurance are nitric oxide, L-arginine, creatine, CoQ10, alpha-lipoic acid, monosaturated fatty which are high in pumpkin seed oil, pistachios, almonds, olive oil and avocados. Mufas also improves insulin and glucose status.
If PPAR levels are low and oxphos is increases it will cause excess oxidative stress. If ATP is low or AMPK is inhibited it will also cause excess oxidative stress if oxphos is increases. They prevent oxphos from causing oxidative stress.
IGF1 over expression can cause hypoglycemia but it prevents atherosclerosis, cardiovascular diseases and has antidepressant effects.
IGF1 is involved in the metabolism of almost all energy sources including fats and carbohydrates. They are regulated by IGF1 binding proteins (IGFBPs). IFG1 promotes glucose uptake into neurons through GLUT4 production. IGF1 and IGF receptor activation increases glucose utilization. IGF1 can be manipulated without effecting glucose levels.
Reducing Daf2/IFG1 signaling increases life span.
IGF1 increases hippocampal neurogenesis. BDNF is IGF1 dependent. IGF1 is needed for neural plasticity and is protective during ischemic injury.
Arginine decreases with age which reduces IFG1. IGF1 deficiency causes Alzheimer and parkinson’s. IGF1 is needed for glucose uptake into the brain.
IGF1 inhibits growth hormone production.
IGF1 is needed for full function of brown adipose tissue.
Growth hormone (GH) activates stat which increases lipolysis and decreases lipogenesis but reduces IGF1.
GH hormone deficiency increases insulin sensitivity and increases longevity.
Insulin reduces IGFBP1 concentration which causes glucose intolerance, type 2 diabetes. Increasing ghrelin or Akt prevents insulin inhibition of IGFBP1.
IGFBP2 is decreased in obesity, and insulin resistance.
IGFBP3 interacts with PPARy. IGFBP3 over expression increases weight gain, causes NAFLD and increases blood glucose levels.
GH is low in those who have high levels of abdominal fat, and loss of muscle mass.
IGF1 is high and IGFBP1 is low in lipodystrophy.
IGF2 excess causes insulin resistance.
Excess free fatty acids (FFAs) reduces ghrelin and impairs GHRH stimulation of growth hormones. Increasing GHRH prevents this from occurring. IGFBP1 is inhibited by insulin secretion. Increasing ghrelin prevents insulin inhibition of IGFBP1
Increasing IGF1 and IGFBP3 improves glucose metabolism and reduces total body fat, with no effect on viscerol adiposity in lypodystrophy.
FFAs are the primary fuel for the heart and skeletal muscle and are precursors to hormones.
Serum albumin is the most important FFA transporter. Albumin also prevents the degredation of folate.
Liver disease, malnutrition, gut inflammation, thyroid disease, and dehydration can cause low serum albumin.
Serum albumin is also a major zinc transporter in plasma. High FFA levels especially palmitic acideffects albumins ability to bind to zinc which results in the dysregulation of zinc handling and disturbs zinc transportation. Zince is needed to prevent excess blood clotting. The impaired zinc transport causes a zinc type deficient state. Zinc is needed for proper B-cell function. This is why those with diabetes shows symptoms of being deficient in zinc. Until the palmitic acid levels are reduce supplementing with zinc will most likely have no benefits.
Glucagen like-peptide 1 (GLP-1) found in the gut stimulates insulin secretion by pancreatic B-cells.
GLP-1 is regulated by GPR41 and GPR43 which are regulated by the microbiome and effect metabolic health. Gut bacteria are one of the major sources of free fatty acids.
Excess FFAs overwhelm the body which means the conversion to TAGS does not occur resulting in inhibited beta oxidation. This is mainly the result of high palmitic acid levels. These toxic lipids cause endoplasmic reticulum stress, mitochondrial dysfunction and causes the generation of excess reactive oxygen species. This results in insulin resistance, cellular apotosis, instability in adipocytexs, B-cells and skeletal muscle cells.
PUFAs counter acts free fatty acid toxicity because it they promote the TAG formation and Beta oxidation.
The inflammation caused by FFAs interfere with insulin signaling.
Omega 6 fatty acids increase inflammation.
Omega 3 fatty acids are precursors to resolvins that are anti-inflammatory.
Saturated fatty acids activate the same inflammatory receptors and cytokines as endotoxins. Omega 3 suppresses receptors and cytokines activated by Omega 6 and endotoxins.
Excess inflammation and oxidative stress causes loss of pancreatic B-cells leading to type 2 diabetes.
Excess saturated free fatty acids change the composition of cellular membranes fluidity and permeability to ions and molecules as well as incorporation of insulin receptors into membranes. The increased fatty acid cause insulin resistance from impaired insulin signaling which can lead to type 2 diabetes. This causes reduced conversation of FFAs to TAGS which results in increased inflammation and increased oxidative stress. This also increases food intake. High levels of saturated free fatty acids damage the hypothalamus-pituitary adrenal axis. It increases cortisol release. If this continues for an extended period of time the adrenals , hypothalamus and pituitary start losing the ability to function. Alpha lipoic acid and oleyethanolamide regulate satiety and beta oxidation and help to prevent the effects of SFFAs.
Insulin reduces the activity of hormone-sensitive-lipase a protein required for lipolysis which results in excess FFA production which farther increases insulin resistance and glucose intolerance. This causes the accumulation of fatty acids in the organs.
The liver is the hub for fatty acid metabolism and energy production. Fatty acids can be synthesized from carbohydrates and through gluconeogenesis which is glucose production from fatty acids. Inhibiting gluconeogenesis in the liver improves insulin sensitivity and decreases intestinal absorption of glucose.
When FFA levels are high some of the excess gets taken into the liver this can result in NAFLD the liver loses it’s ability to suppress glucose production or may go the other way and lose the ability to produce glucose from the loss of glucagen.
Excess FFAs cause ischemia in a number of ways. The excess inflammation and oxidative stress can cause damage to red blood cells, excess blood clotting, blood vessel damage, endothelial dysfunction, restricted blood flow through the blood vessels from the inflammation in which all cause reduce blood flow to tissue and organs. This can farther add to the inflammation and damage in the body. Eventually if not corrected a person may start developing heart disease, obesity, and type 2 diabetes and many other health problems. The insulin signaling becomes reduces, nitric oxide levels are decreased farther adding to the health issues. The excess FFAs start adhering to arterial walls causing atherosclerosis farther restricting blood flow. Excess FFAs causes blood clotting and thrombosis farther adding to ischemic damage in the body.
Excess FFAs overwhelm the Krebbs cycle and the electron transport chain which results in incomplete fatty acid oxidation and excess oxidative stress which results in mitochondrial dysfunction farther adding to the inability to properly metabolize FFAs.
AMPK activation increases B-oxidation and inhibits lipogenesis.
HMG-Coa upregulation increases expression of LDL receptors on cell surface increasing cellular uptake of serum LDL which reducing serum levels of LDL.
Nicotinamde reduces plasma FFA levels and increases beta oxidation.
Fiber prevents bile acid reabsorption which reduces FFA levels.
Omega 3s activate PPARa and PPARy which reduces inflammation and FFA levels.
Reducing plasma palmitic acid levels, inflammation and oxidative stress improves insulin signaling and reduces FFA levels.
Improving adrenal health improves hormone levels, improves the metabolism of FFAs and improves insulin signaling.
Carnitine Palmitoyltransferase helps get fat into cells, a deficiency causes hyperinsulinemia and hypoglycemia.
Citrin deficiency causes hyperinsulinemia and hypoglycemia and high ammonia levels. This requires a low protein diet and increased carbohydrate intake, increased arginine intake, sodium benzoate can also help reduce ammonia levelws. A deficiency in citrin is called citrullinemia. Citrin helps to regulate NAD+/NADh ratio.
FOXA2 increased expression increases citrin and HDL. Valproic acid increases citrin. Choline also increases FOXA2 expression. Excess vitamin E and excess vitamin C inhibits FOXA2 expression. FXR activation increases FOXA2 expression.
CES1 – increased expression reduces FFA levels by increasing beta oxidation and decreasing SREBP processing which reduces lipogenesis and increases insulin sensitivity. CES1 deficiency increases acetaldehyde and ROS. Excess acetaldehyde makes a person very sensitive to their environment. FXR activation increases CES1.
FXR activation prevents fatty liver disease, improves insulin sensitivity, reduces fat in accumulation in the liver, increases glycogen production and reduces gluconeogenesis. FXR activation increases PPARa expression, enhances reverse cholesterol transport, reduces bile acid pool size and reduces cholesterol absorption in the intestine.
Ursodeoxycholic acid (UCDA) produced by certain microbes in the microbiome activates FXR. Phenylalanine, tyrosine, and leucine also activate FXR receptor. But those who have mitochondrial issues may not be able to properly metabolize them or if a person has too many microbes involved in protein proteolysis they may react to those proteins. Bifidobacterium animalis, Ruminococcus gnavus, Clostridium absonium, and Clostridium buratii produce UCDA.
Reducing Tauro-B-muricholic acid (taurocholic acid) would increase FXR expression. Most Blautia spp of microbes reduces taurocholic acid. Blautia ovata, Blautia luti, Blautia wexlerae, and Blautia odeum reduces taurocholic acid. Bacteroides ovata and bacteriodes theatoiomicron reduces taurocholic acid. Most Blautia species prevents insulin resistance espceially Blautia misseliensis, and Blautia marsielle, Blautia producta. Blautia producta and Bacteriodes theataiotamicron also helps to prevent insulin resistance by preventing overgrowth of Candida. Polyphenols are toxic to the body until broken down by our gut bacteria. Blautia spp break down polyphenols for the body. Reducing animal fat consumption especially from pork fat increases Blautia spp. Soil based bacillus species increases Blautia spp especially Bacillus subtillus.
Foods fermented with the fungus Aspergillus oryzae produces glycoceramide which increases Blautia spp. Aspergillus oryze also produces amylase which is reduced in times of stress during aging. Amylase helps to maintain pancreatic health. Low amylase levels can cause type 2 diabetes. Amylase improves digestion. It can also be found in raw fruits, vegetables, royal jelly, seeds, nuts and legumes.
Blautia is overgrown in type 1 diabetes especially Blautia coccoides.
Reducing Eubacterium Lenta, Ruminococcus Pickettii and Escericha albertii improves glucose levels and insulin sensitivity.
Dorea overgrowth causes insulin resistance.
Vitamin E, silymarin, phosphatidylcholine, S-adenoxyl-L-methionine (SAMe) help to prevent liver fibrosis and improve liver function which can help reduce FFA levels.
Fat from free range organic animals decreases risk of insulin resistance and glucose intolerance.
Fat from pork increases risk of insulin resistance and glucose intolerance.
Lactobacillus salivarius, Lactobaccillus gasseri, Lactobacillus acidophilus, Lactobacillus Johnsii produce 10-hydroxy-cis-12-octadecenoic acid (HYA) which prevents the inflammatory effects caused by Omega 6 fatty acids.
Coconut oil increases Bifidobacterium and Lactobacillus levels.
Phytates can be antinutrients if we do not have the microbes in our guts to convert them to inositol. Inositol has too many health benefits to list. It takes a variety of microbes to fully convert phytates to inositol. These are the microbes needed. Bifidobacterium longhum, Bifidobacterium infantis, Bifidobacterium pseudocatenulatum, Bacteroides thetaiotaomicron, Bifidobacterium Breve, and the Commensal E coli such as E Coli nissle 1917.
Barnesiella intestinihominis promotes a lean body type and increases exercise endurance.
Increasing adiponectin increases fat burning.
Urease is produced by the body to prevent cavities and help maintain proper PH. Our microbiome break down urease in the gut and produce nitric oxide for the body. Urease and arginine is used by the body to prevent the mouth from becoming too acidic which causes cavities. Without nitric oxide this can not occur. High urease levels can damage the gut and pancrease which causes diabetes and obesity. There are good and bad microbes in the gut when it comes to urease. The good microbes convert the urease to beneficial metabolites needed in the body and the bad will cause high ammonia levels when they break down urease. The high ammonia levels causes the gut and bladder PH to become too high making a person more prone to infection and cause inflammation. There are also urease producing microbes in the gut that can cause high ammonia levels these can increase if we consume too many alkalizing foods, from antibiotics or toxins in our food like glyphosate. The high ammonia levels causes brain swelling, inhibits the immune system making one prone to infection, it can lead to hepatic coma, digestion becomes inhibited because the ammonia produced neutralizes stomach acid, the high ammonia causes struvite, apitite and carbonite crystals to form which damage the renal system. The high ammonia levels also causes urithiosis or pyelonephritis.
These microbes reduce urease producing nitric oxide and other metabolites the body needs. Streptococcus salivarius, Actinomyces naestundii, Bifidobacterium infantis, Lactobacillus reuteri, streptococcus vestibularis.
These microbes produce urease and increase ammonia levels in the gut and bladder. Clostridium perforingens, H pylori overgrowth, Proteus mirabulis, Salmonella spp, Staphylococcus saprophyticus, ureiaplasma urealyticum yersinia, Eterocolitica, Cryptococcus neoformis, and Coccoides posadii. Many fungal infections can cause increase urease or ammonia levels. Keep in mind that eating too many processed foods, toxins in our foods, metabolic or gene issues can cause high ammonia levels causing the overgrowth of these microbes.
Excess extracellular ATP causes increases purinergic receptor activation which increast sensitivity to pain and causes inflammation especially in the bladder , gut and brain. This also causes endothelial dysfunction which can cause inhibited blood flow and excess blood clotting. This can be caused by inflammation, excess oxidative stress, infection or microbial imbalance. Sophora root, kudzu root and resveratrol can help to reduce purinergic signaling.
HIF1a not to be mistaken for HIF1, decreases purinergic signaling, reduces ER stress and reduces palmitic acid levels.
Autophagy reduces palmitic acid levels.
Leptin reduces palmitic acid levels.
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