Insulin resistance and elevated levels of circulating branched-chain amino acids

Elevated circulating levels of branched-chain amino acids have been associated with insulin resistance where decreased degradation of branched-chain amino acids could be what is leading to elevated circulating levels of branched-chain amino acids.

Methylcrotonyl CoA carboxylase and propionyl-CoA carboxylase are two biotin-dependent enzymes in the branched-chain amino acid degradation pathway. Dysregulation of the sodium-dependent multivitamin transporter which transports biotin could dysregulate the branched-chain amino acid degradation pathway leading to high levels of circulating branched-chain amino acids and insulin resistance.

Insulin resistance is present in 52% of individuals with bipolar disorder. Insulin resistance develops is brains of individuals with Alzheimer’s disease. In China in individuals with schizophrenia the prevalence of insulin resistance is 37.2% Both disease processes and drugs used to treat these illnesses could increase insulin resistance in theses illnesses. A commonality among these illnesses could be dysregulation of the sodium-dependent multivitamin transporter both by disease processes and drugs used to treat these illnesses.

Biotin supplementation decreases hyperglycemia, normalizing glucose levels, in patients with non-insulin dependent diabetes. There is reduced hyperglycemia is diabetic patients taking biotin.

The sodium-dependent multivitamin transporter transports both biotin and pantothenate. Pantothenate is needed to synthesize coenzyme A which is closely tied to the actions of biotin-dependent enzymes. Biotinylation of the sodium-dependent transporter reduces transport by the sodium-dependent multivitamin transporter. High levels of biotin could decrease transport of pantothenate by the sodium-dependent multivitamin transporter. A combination of pantothenic acid and biotin where 500 mg. of pantothenic acid is taken once a day away from supplemental biotin and 5 mg of biotin is taken three times a day could word work better in controlling hyperglycemia than biotin alone.

Only the abundance of biotinylated 3-methylcrotonyl-CoA carboxylase (holo-MCC) and propionyl-CoA carboxylase (holo-PCC) can distinguish between biotin-deficient and biotin-sufficient individuals. Methylcrotonyl CoA carboxylase and propionyl-CoA carboxylase could be particularly sensitive to biotin deficiencies.

Deficiencies in vitamin D in schizophrenia, bipolar disorder, Alzheimer’s disease and Parkinson’s disease

Low levels of vitamin D are associated with schizophrenia, bipolar disorder Alzheimer’s disease and Parkinson’s disease. Vitamin D is a fat soluble vitamin. Bile acids are required for fat absorption. Taurocholic acid is a bile acid that is a conjugation of cholic acid with taurine. Taurochenodeoxycholic acid is a bile acid formed in the liver by conjugation of chenodeoxycholic acid with taurine. Taurine increases absorption of vitamin D.

There are low levels of vitamin D in schizophrenia, bipolar disorder, Alzheimer’s disease and Parkinson’s disease due to dysregulation of taurine synthesis in these illnesses attendant on dysregulation of the transsulfuration pathway which synthesizes L-cysteine from which taurine is synthesized.

Supplementation with vitamin D in these illnesses heretofore has not helped much as difficulties in fat absorption have not been addressed. Taurine, which regulates calcium homeostasis besides aiding in fat absorption, calcium hydroxyapatite and vitamin D are required to address low levels of vitamin D where there are also chronic illnesses.

Fatty acids synthesized from essential fatty acids in schizophrenia

Levels of arachidonic acid (AA), which is synthesized from linoleic acid and docosahexaenoic acid (DHA) which is synthesized from alpha linoelic acid are significantly lower (P < 0.001) in drug-naive patients with schizophrenia compared to controls. See also Reddy et al. Linoleic acid and alpha linoelic are the two essential fatty acids. Essential fatty acids must be obtained from the diet. Essential fatty acids must also be absorbed to be effective.

With difficulties in fat absorption due to low levels of taurine, which is required for synthesis of various taurine conjugated bile acids, absorption of essential fatty acids would be impaired which would lead to low levels of arachidonic acid and low levels of docosahexaenoic acid which is what is seen in schizophrenia.

Taurine is synthesized from L-cysteine. L-cysteine is synthesized by the transsulfuration pathway. With dysregulation of the transsulfuration pathway in schizophrenia there will be low levels of L-cysteine and low levels of taurine which will lead to low levels of various omega-6 and omega-3 fatty acids in schizophrenia.

In schizophrenia all paths lead to the transsulfuration pathway

With a dysregulation of the transsulfuration pathway (homocysteine to L-cysteine) sufficient L-cysteine for iron-sulfur cluster formation is not synthesized. Sulfur for iron-sulfur cluster biogenesis is derived from L-cysteine. Supplemental iron increases levels of iron-sulfur proteins. Supplemental iron can partly compensate for dysregulation of the transsulfuration pathway in schizophrenia. Selenomethionine, the food form of selenium is metabolized by enzymes in the transsulfuration pathway. Metabolism off Se-methylselenocysteine by-passes the transsulfuration pathway whereby Se-methylselenocysteine can provide bioavailable selenium for individuals with schizophrenia. Taurine is synthesized from L-cysteine. With L-cysteine not synthesized appropriately taurine will not be synthesized at appropriate levels. Taurine is needed to form various bile acids, With low levels of taurine there will not be sufficient taurine conjugated bile acids. Fat absorption requires bile acids. With low levels of taurine due to low levels of L-cysteine fat absorption will be impaired. Supplemental taurine and supplemental essential fatty acids will compensate for low levels of taurine due to low levels of L-cysteine which are in turn due to dysregulation of the transsulfuration pathway. Taurine by sparing L-cysteine will also increase levels of L-cysteine.

An Important Warning: No supplements that contain L-cysteine or L-methionine should be supplemented. And no supplements that reduce cystine to L-cysteine, such as lipoic acid, should be supplemented. See the Treatment page for supplements that can be of assistance in the treatment of schizophrenia.

Inflammation, alpha-linoleic acid and taurine in schizophrenia, Parkinson’s disease and Alzheimer’s disease

Inflammation is associated with schizophrenia, Parkinson’s disease and Alzheimer’s disease. A point I have strongly stressed is that the transsulfuration pathway is dysregulated in many neurological illnesses. With the transsulfuration pathway dysregulated there will de decreased levels of L-cysteine which is synthesized via the transsulfuration pathway. Decreased levels of l-cysteine will lead to decreased levels of taurine. Taurine is synthesized from L-cysteine. The bile acid, taurocholate, is synthesized from taurine. With low levels of taurocholate fatty acids will not be absorbed sufficiently. Alpha–linoleic acid is an essential fatty acid that must be obtained from diets. Diets high in alpha-linoleic acid are protective against inflammation. With low levels of taurocholate sufficient alpha-linoleic acid will not be absorbed which will lead to inflammation. . Inflammation in schizophrenia, Parkinson’s disease and Alsheimer’s disease could be due to low levels of taurine which leads to failures to absorb sufficient alpha-linoleic acid which is protective against inflammation.

Coffee and homocysteine

Filtered or unfiltered coffee increases homocysteine levels in healthy individuals whereas caffeine has a much weaker effect on homocysteine levels. Stopping drinking coffee reduces homocysteine levels.

Increased homocysteine levels point to decreased levels of L-cysteine which is synthesized from homocysteine. With decreased synthesis of L-cysteine iron-sulfur cluster formation could be dysregulated which could upset many biological processes. Increased homocysteine levels could could affect DNA methylation. In schizophrenia there is a positive association between plasma homocysteine and DNA methylation. Difficulties due to coffee could take years to develop due to hypermethylation of genes taking years to develop.

The Major Histocompatibility Complex, HFE and schizophrenia

The Major Histocompatibility Complex (MHC) has been associated with schizophrenia. The hemochromatosis gene, HFE, which regulates iron levels is linked to the MHC on chromosome 6. In cells that express HFE IRP1 and IRP2 binding increases as the labile iron pool decreases with increased HFE expression. IRP1 and IRP2 are regulated by iron levels. Genetic studies that have associated the MHC region with schizophrenia frequently conclude that this is evidence for an infectious etiology to schizophrenia as the MHC is involved in immunity. What genetic associations of the MHC to schizophrenia could be picking up is associations of HFE with schizophrenia where such associations arise due to dysregulations in iron metabolism.