Autoimmune Thyroid Disease

An Unfortunate and Lengthy Adventure in Misdiagnosis

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ACE and weight gain

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Thanks to a yahoo group called TaubesTalk for the following news article and abstract:

SYDNEY (AFP) – Australian scientists may have discovered how to help people lose weight without cutting back on food, a breakthrough that could pave the way for fat-burning drugs.

Researchers in Melbourne found that by manipulating fat cells in mice they were able to speed up the animals’ metabolisms.

They found that when a particular enzyme, known as angiotensin converting enzyme (ACE), was removed, mice were able to eat the same amount as other mice but burn more calories and therefore gain less weight.

Animals without the enzyme were on average 20 percent lighter than normal mice and had 50 to 60 percent less body fat, senior researcher at the Howard Florey Institute Michael Mathai said.

“It is very clear that they do have less body fat,” he told AFP.

Mathai, who is also a lecturer in nutrition at Victoria University, said the slimmer mice also appeared to have less chance of developing diabetes because they processed sugar faster than normal mice.

He said the research, to be published Tuesday in the US-based Proceedings of the National Academy of Sciences, could be used to develop drugs to assist weight loss.

Drugs which impair the action of ACE already exist and are mostly used to combat high blood pressure.

“The drugs are out there because they are used for hypertension,” he said.

“So we know their safety and their tolerability. What we don’t know is whether or not they will work in humans. And we don’t know whether it will work in all obese humans.”

Mathai said it could be a question of finding the right dosage of hypertension medication, or developing a new type of drug of the same class, to be used as weight-loss pills.

“This might be one way in which you can increase metabolic rate in combination with managing nutrition to limit the intake of calories,” he said.

Mathai said the research, conducted at the Howard Florey Institute, Victoria University, La Trobe University, Deakin University, the Baker Institute and the University of Melbourne, was yet to pinpoint why the genetic manipulation led to weight loss.

“Because we deleted the gene, the gene is gone from the whole body, that means that it is gone from all tissues including the brain,” he said.

“And so we don’t know whether it’s a direct effect of the deficiency in the tissue or whether it’s something coming from the brain.” Australian scientists report weight loss breakthrough

And the abstract:

Angiotensin II (AII), acting via its G-protein linked receptor, is an important regulator of cardiac, vascular, and renal function. Following injection of AII into rats, we find that there is also a rapid tyrosine phosphorylation of the major insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) in the heart. This phenomenon appears to involve JAK2 tyrosine kinase, which associates with the AT1 receptor and IRS-1/IRS-2 after AII stimulation. AII-induced phosphorylation leads to binding of phosphatidylinositol 3-kinase (PI 3-kinase) to IRS-1 and IRS-2; however, in contrast to other ligands, AII injection results in an acute inhibition of both basal and insulin-stimulated PI 3-kinase activity. The latter occurs without any reduction in insulin receptor or IRS phosphorylation or in the interaction of the p85 and p110 subunits of PI 3-kinase with each other or with IRS-1/IRS-2. These effects of AII are inhibited by AT1 receptor antagonists. Thus, there is direct cross-talk between insulin and AII signaling pathways at the level of both tyrosine phosphorylation and PI 3-kinase activation. These interactions may play an important role in the association of insulin resistance, hypertension, and cardiovascular disease. Cross-talk between the insulin and angiotensin signaling systems

I think this may be why low carbohydrate diets help so many people with food chemical intolerance. Lower your insulin levels, and I bet you lower your ACE output.


Written by alienrobotgirl

1 May, 2008 at 6:24 pm

Posted in The Genetics of FCI?

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ACE and premenstrual tension

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ACE – it stands for angiotensin converting enzyme. People with a common deletion in their ACE gene secrete more angiotensin II and aldosterone than people with the common insertion variant.

Emotional upsets related to changes in ovarian hormones are highly prevalent and are responsible for psychiatric morbidity and mortality. Significant increases in acute psychiatric hospitalizations, suicidal activity, and other psychopathology occur during the premenstruum and during menstruation.

This paper reviews evidence indicating that menstrual cycle psychopathology may be mediated by the effects of estrogen, progesterone, and possibly the renin—angiotensin—aldosterone system on the brain monoamines, norepinephrine, dopamine, and serotonin.

During the menstrual cycle, psychopathology often begins with the onset of luteal estrogen—progesterone—angiotensin—aldosterone secretion and intensifies as these hormone levels later fall, prior to and during menstruation. Aldosterone is reported elevated in cases of premenstrual tension syndrome.

There are numerous reports of affective upsets occurring with the use of estrogen—progestin oral contraceptives and following their withdrawal. Contraceptives stimulate the renin—angiotensin—aldosterone system and are reported useful in alleviating premenstrual—menstrual emotional upsets and postpartum depressive episodes.

What a counter-intuitive conclusion – aldosterone increases PMT, but if you increase aldosterone even further whilst nuking the menstrual cycle, it ‘alleviates’ the problem. It certainly didn’t work that way for me. When I was on the pill my ‘premenstrual’ tension went away – I just had massive chronic tension all the time instead! My PMT always went away immediately that my period started.

Affective lability, prevalent at parturition, occurs when estrogen, progesterone, and aldosterone levels are first high and later falling. Exogenous estrogen and progesterone profoundly affect mating activity in castrated rhesus monkeys, and cyclic fluctuations in sexual activity in humans may occur during the menstrual cycle. Much information links manic and depressive reactions with alterations in brain monoamines. Lithium, monoamine oxidase inhibitors, and tricylic antidepressants, specifically used to treat affective disorders, are reported useful in treating ovarian hormone—linked upsets. Similarities exist between changes in animal behavior caused by drugs altering affective states and the effects of ovarian hormones.

Like certain antidepressants, estrogen induces hyperactivity in rats. Like reserpine, progesterone exhibits sedative and soporific effects. Sexual behavior in female rats is reported linked to changes in brain monoamines. Agents increasing brain monoamine levels and availability decrease mating responses, and monoamine depletors, such as reserpine may be substituted for progesterone in activating mating behavior.

Serotonin and dopamine appear to be important in the regulation of ovulation. Brain norepinephrine varies with the phases of the rat estrus cycle. Castration increases brain norepinephrine and decreases brain dopamine. Exogenous estrogen decreases rat brain norepinephrine content. The monoamine-destroying enzymes, monoamine oxidase, and catechol O-methyl transferase are affected by ovarian steroids and show fluctuating levels during the reproductive cycle. The effects of reserpine, monoamine oxidase inhibitors, tricyclic antidepressants, and lithium on monoamines in neurophysiological preparations have been used as evidence supporting theories linking monoamine changes with human affective disorders. Estrogen, progesterone, and angiotensin also exhibit effects on in vitromonoamine systems.

Like the tricyclic antidepressants, uptake of norepinephrine and dopamine by nerve endings is inhibited in the presence of estrogen, progesterone, and angiotensin. As with reserpine, the flow of these monoamines from nerve endings is increased by progesterone. Estrogen slows the flow of norepinephrine from nerve endings and decreases the electrically induced release of serotonin and norepinephrine from brain slices. The above information provides clues that ovarian hormone—linked psychopathology, like affective disorders in general, may be related to alterations in brain monoamines. Monoamines and ovarian hormone-linked sexual and emotional changes: A review

Aldosterone is also responsible for water retention, by acting on the central nervous system to release vasopressin, the hormone which tells the kidneys to conserve water.

Written by alienrobotgirl

21 April, 2008 at 7:09 pm

Posted in The Genetics of FCI?

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ACE interactions

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Angiotensin I-converting enzyme (ACE) is a zinc metallopeptidase whose main known functions are to convert angiotensin I into the vasoactive and aldosterone-stimulating peptide angiotensin II, and to inactivate bradykinin. ACE is believed to have other physiological roles because of its wide enzymatic specificity and wide distrubution. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels.

Analysis of ACE genotypes reveal[s] that patients with the wild type ACE gene (ACE I/I) have normal angiotensin II levels, while patients with a deletion in both alleles (ACE D/D) have far higher levels, and those with a single allele deletion have intermediate levels. New Approaches to Heart Failure: From Pharmacogenomics to Drug Development

Mild quantitative changes in the expression of ACE do not affect plasma angiotensin II level or BP because of the concomitant changes in the level of angiotensin I. However, plasma [bradykinin] level changes with changes in ACE expression. Minireview: Computer Simulations of Blood Pressure Regulation by the Renin-Angiotensin System

D/D homozygotes have a 25% increase, and I/I homozygotes have a 25% decrease in plasma ACE activity relative to the I/D heterozygotes. In otherwords, feedback causes angiotensin I levels to lower to maintain correct angiotensin II levels. Examine Figure 3B in the minireview linked to above. It displays D/D types as having lower angiotensin I levels whilst maintaining relatively normal angiotensin II levels.

Now check out the interaction with monoamine oxidase:

It is concluded that diminished [angiotensin I] receptor stimulation decreases cardiac MAO activity, probably by regulating MAO expression, since ANG, ACE inhibitors, and AT(1) antagonists had no effect on MAO activity in vitro. Angiotensin I-converting enzyme inhibition increases cardiac catecholamine content and reduces monoamine oxidase activity via an angiotensin type 1 receptor-mediated mechanism.

Stressed all the time?

Angiotensin II increases thirst sensation[…] It also potentiates the release of norepinephrine by direct action on postganglionic sympathetic fibers. Angiotensin Wiki

Another interaction with COMT:

Angiotensin-converting enzyme (ACE) modulates dopamine turnover in the brain and catechol-O-methyltransferase (COMT) enzyme is an important agent in the metabolic inactivation of dopamine and norepinephrine. Functional polymorphism in the COMT and ACE genes causes variation in enzyme activities. We investigated the relationship of COMT and ACE gene polymorphism with response to conventional neuroleptic treatment in schizophrenia. In this study population we had earlier detected that COMT genotype is associated with unsatisfactory drug response. A total of 94 schizophrenic patients were evaluated either as responders (n=43) or non-responders (n=51). The responders had experienced a fair and steady response to conventional neuroleptics. The non-responders had failed to achieve an acceptable response to conventional neuroleptics. We also used a control population of 94 age- and gender-matched blood donors. Genotyping of the COMT and ACE genes was performed by polymerase chain reaction. The risk of having both low activity COMT and high activity ACE genotypes was over 10 times higher (odds RATIO=10.89, 95%CI 1.14–103.98, P=0.04) in the non-responders compared to responders. ACE genotype alone did not differ between any groups. This finding may suggest a possible interaction with low activity COMT and high activity ACE genotype in association with poor response to conventional neuroleptics. Interaction between angiotensin-converting enzyme and catechol-O-methyltransferase genotypes in schizophrenics with poor response to conventional neuroleptics

One interesting fact I stumbled upon recently is that a low sodium diet increases monoamine oxidase activity in rats, and this operates via an angiotensin II mechanism. So does a high sodium diet decrease monoamine oxidase activity?

And check out the interaction with vitamin D receptors:

Mice lacking the Vitamin D receptor (VDR) have elevated production of renin and angiotensin (Ang) II, leading to hypertension, cardiac hypertrophy and increased water intake. These abnormalities can be prevented by treatment with an ACE inhibitor or AT(1) receptor antagonist. Vitamin D: a negative endocrine regulator of the renin-angiotensin system and blood pressure

In fact the lower your vitamin D levels the higher your whole renin-angiotensin sytem. Vitamin D is an extremely effective way to lower your blood pressure.

Written by alienrobotgirl

19 April, 2008 at 3:48 pm

Posted in The Genetics of FCI?

Tagged with ,