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Diabetes: Conversion of Alpha-cells into Beta-cells

Also see:
The Streaming Organism
The Randle Cycle
Bisphenol A (BPA), Estrogen, and Diabetes
Insulin Inhibits Lipolysis
Aldosterone, Sodium Deficiency, and Insulin Resistance
Ray Peat, PhD on Brewer’s Yeast

Quotes by Ray Peat, PhD:
“Twenty-five years ago, some rabbits were made diabetic with a poison that killed their insulin-secreting pancreatic beta-cells, and when some of them recovered from the diabetes after being given supplemental DHEA, it was found that their beta-cells had regenerated. The more recent interest in stem cells has led several research groups to acknowledge that in animals the insulin-producing cells are able to regenerate.

It is now conceivable that there will be an effort to understand the factors that damage the beta-cells, and the factors that allow them to regenerate.”

“The thyroid gland is extremely adaptable and responsive, so it can go from zero to full activity in just two or three days. The adrenal glands are also very adaptive, except when they are continuously being destroyed by PUFA; they can fully regenerate in something like a couple of weeks. The pancreatic beta cells are also constantly turning over, regenerating, and “diabetes” is a condition in which they are continually being destroyed by PUFA.”

“Animals that have been made diabetic with relatively low doses of the poison streptozotocin can recover functional beta-cells spontaneously, and the rate of recovery is higher in pregnant animals (Hartman, et al., 1989). Pregnancy stabilizes blood sugar at a higher level, and progesterone favors the oxidation of glucose rather than fats.

A recent study suggests that recovery of the pancreas can be very fast. A little glucose was infused for 4 days into rats, keeping the blood glucose level normal, and the mass of beta-cells was found to have increased 2.5 times. Cell division wasn’t increased, so apparently the additional glucose was preventing the death of beta-cells, or stimulating the conversion of another type of cell to become insulin-secreting beta-cells (Jetton, et al., 2008).

That study is very important in relation to stem cells in general, because it either means that glandular cells are turning over (“streaming”) at a much higher rate than currently recognized in biology and medicine, or it means that (when blood sugar is adequate) stimulated cells are able to recruit neighboring cells to participate in their specialized function. Either way, it shows the great importance of environmental factors in regulating our anatomy and physiology.”

“I have known people who believed they had insulin deficiency, who recovered completely. The pancreas beta cells can regenerate quickly, polyunsaturated fats are continually damaging them.

The T3 component of the thyroid hormone makes muscles and other tissues oxidize sugar. Calcium, sodium, and aspirin are other things that increase the ability to use glucose.”

“Sugar can protect the beta-cells from the free fatty acids, apparently in the same ways that it protects the cells of blood vessels, restoring metabolic energy and preventing damage to the mitochondria. Glucose suppresses superoxide formation in beta-cells (Martens, et al., 2005) and apparently in other cells including brain cells. (Isaev, et al., 2008).

The beta-cell protecting effect of glucose is supported by bicarbonate and sodium. Sodium activates cells to produce carbon dioxide, allowing them to regulate calcium, preventing overstimulation and death. For a given amount of energy released, the oxidation of glucose produces more carbon dioxide and uses less oxygen than the oxidation of fatty acids.

The toxic excess of intracellular calcium that damages the insulin-secreting cells in the relative absence of carbon dioxide is analogous to the increased excitation of nerves and muscles that can be produced by hyperventilation.”

“Glucose and insulin which allows glucose to be used for energy production, while it lowers the formation of free fatty acids, promote the regeneration of the beta cells. Although several research groups have demonstrated the important role of glucose in regeneration of the pancreas, and many other groups have demonstrated the destructive effect of free fatty acids on the beta cells, the mainstream medical culture still claims that “sugar causes diabetes.”

Stem Cells. 2010 Sep;28(9):1630-8.
Pancreatic β-cell neogenesis by direct conversion from mature α-cells.
Chung CH, Hao E, Piran R, Keinan E, Levine F.
Because type 1 and type 2 diabetes are characterized by loss of β-cells, β-cell regeneration has garnered great interest as an approach to diabetes therapy. Here, we developed a new model of β-cell regeneration, combining pancreatic duct ligation (PDL) with elimination of pre-existing β-cells with alloxan. In this model, in which virtually all β-cells observed are neogenic, large numbers of β-cells were generated within 2 weeks. Strikingly, the neogenic β-cells arose primarily from α-cells. α-cell proliferation was prominent following PDL plus alloxan, providing a large pool of precursors, but we found that β-cells could form from α-cells by direct conversion with or without intervening cell division. Thus, classical asymmetric division was not a required feature of the process of α- to β-cell conversion. Intermediate cells coexpressing α-cell- and β-cell-specific markers appeared within the first week following PDL plus alloxan, declining gradually in number by 2 weeks as β-cells with a mature phenotype, as defined by lack of glucagon and expression of MafA, became predominant. In summary, these data revealed a novel function of α-cells as β-cell progenitors. The high efficiency and rapidity of this process make it attractive for performing the studies required to gain the mechanistic understanding of the process of α- to β-cell conversion that will be required for eventual clinical translation as a therapy for diabetes.

Trends Endocrinol Metab. 2011 Jan;22(1):34-43. Epub 2010 Nov 8.
β-cell regeneration: the pancreatic intrinsic faculty.
Desgraz R, Bonal C, Herrera PL.
Type I diabetes (T1D) patients rely on cumbersome chronic injections of insulin, making the development of alternate durable treatments a priority. The ability of the pancreas to generate new β-cells has been described in experimental diabetes models and, importantly, in infants with T1D. Here we discuss recent advances in identifying the origin of new β-cells after pancreatic injury, with and without inflammation, revealing a surprising degree of cell plasticity in the mature pancreas. In particular, the inducible selective near-total destruction of β-cells in healthy adult mice uncovers the intrinsic capacity of differentiated pancreatic cells to spontaneously reprogram to produce insulin. This opens new therapeutic possibilities because it implies that β-cells can differentiate endogenously, in depleted adults, from heterologous origins.

Bioessays. 2010 Oct;32(10):881-4. doi: 10.1002/bies.201000074. Epub 2010 Aug 27.
A new paradigm in cell therapy for diabetes: turning pancreatic α-cells into β-cells.
Sangan CB, Tosh D.
Cell therapy means treating diseases with the body’s own cells. One of the cell types most in demand for therapeutic purposes is the pancreatic β-cell. This is because diabetes is one of the major healthcare problems in the world. Diabetes can be treated by islet transplantation but the major limitation is the shortage of organ donors. To overcome the shortfall in donors, alternative sources of pancreatic β-cells must be found. Potential sources include embryonic or adult stem cells or, from existing β-cells. There is now a startling new addition to this list of therapies: the pancreatic α-cell. Thorel and colleagues recently showed that under circumstances of extreme pancreatic β-cell loss, α-cells may serve to replenish the insulin-producing compartment. This conversion of α-cells to β-cells represents an example of transdifferentiation. Understanding the molecular basis for transdifferentiation may help to enhance the generation of β-cells for the treatment of diabetes.

Nature. 2010 Apr 22;464(7292):1149-54. Epub 2010 Apr 4.
Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss.
Thorel F, Népote V, Avril I, Kohno K, Desgraz R, Chera S, Herrera PL.
Pancreatic insulin-producing beta-cells have a long lifespan, such that in healthy conditions they replicate little during a lifetime. Nevertheless, they show increased self-duplication after increased metabolic demand or after injury (that is, beta-cell loss). It is not known whether adult mammals can differentiate (regenerate) new beta-cells after extreme, total beta-cell loss, as in diabetes. This would indicate differentiation from precursors or another heterologous (non-beta-cell) source. Here we show beta-cell regeneration in a transgenic model of diphtheria-toxin-induced acute selective near-total beta-cell ablation. If given insulin, the mice survived and showed beta-cell mass augmentation with time. Lineage-tracing to label the glucagon-producing alpha-cells before beta-cell ablation tracked large fractions of regenerated beta-cells as deriving from alpha-cells, revealing a previously disregarded degree of pancreatic cell plasticity. Such inter-endocrine spontaneous adult cell conversion could be harnessed towards methods of producing beta-cells for diabetes therapies, either in differentiation settings in vitro or in induced regeneration.

Diabetes. 2012 Mar;61(3):632-41. Epub 2012 Feb 14.
Free fatty acids block glucose-induced β-cell proliferation in mice by inducing cell cycle inhibitors p16 and p18.
Pascoe J, Hollern D, Stamateris R, Abbasi M, Romano LC, Zou B, O’Donnell CP, Garcia-Ocana A, Alonso LC.
Pancreatic β-cell proliferation is infrequent in adult humans and is not increased in type 2 diabetes despite obesity and insulin resistance, suggesting the existence of inhibitory factors. Free fatty acids (FFAs) may influence proliferation. In order to test whether FFAs restrict β-cell proliferation in vivo, mice were intravenously infused with saline, Liposyn II, glucose, or both, continuously for 4 days. Lipid infusion did not alter basal β-cell proliferation, but blocked glucose-stimulated proliferation, without inducing excess β-cell death. In vitro exposure to FFAs inhibited proliferation in both primary mouse β-cells and in rat insulinoma (INS-1) cells, indicating a direct effect on β-cells. Two of the fatty acids present in Liposyn II, linoleic acid and palmitic acid, both reduced proliferation. FFAs did not interfere with cyclin D2 induction or nuclear localization by glucose, but increased expression of inhibitor of cyclin dependent kinase 4 (INK4) family cell cycle inhibitors p16 and p18. Knockdown of either p16 or p18 rescued the antiproliferative effect of FFAs. These data provide evidence for a novel antiproliferative form of β-cell glucolipotoxicity: FFAs restrain glucose-stimulated β-cell proliferation in vivo and in vitro through cell cycle inhibitors p16 and p18. If FFAs reduce proliferation induced by obesity and insulin resistance, targeting this pathway may lead to new treatment approaches to prevent diabetes.

Diabetes March 2012 vol. 61 no. 3 560-561
Does Inhibition of β-Cell Proliferation by Free Fatty Acid in Mice Explain the Progressive Failure of Insulin Secretion in Type 2 Diabetes?
Guenther Boden

Eur J Clin Invest. 2002 Jun;32 Suppl 3:14-23.
Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction.
Boden G, Shulman GI.
Plasma free fatty acids (FFA) play important physiological roles in skeletal muscle, heart, liver and pancreas. However, chronically elevated plasma FFA appear to have pathophysiological consequences. Elevated FFA concentrations are linked with the onset of peripheral and hepatic insulin resistance and, while the precise action in the liver remains unclear, a model to explain the role of raised FFA in the development of skeletal muscle insulin resistance has recently been put forward. Over 30 years ago, Randle proposed that FFA compete with glucose as the major energy substrate in cardiac muscle, leading to decreased glucose oxidation when FFA are elevated. Recent data indicate that high plasma FFA also have a significant role in contributing to insulin resistance. Elevated FFA and intracellular lipid appear to inhibit insulin signalling, leading to a reduction in insulin-stimulated muscle glucose transport that may be mediated by a decrease in GLUT-4 translocation. The resulting suppression of muscle glucose transport leads to reduced muscle glycogen synthesis and glycolysis. In the liver, elevated FFA may contribute to hyperglycaemia by antagonizing the effects of insulin on endogenous glucose production. FFA also affect insulin secretion, although the nature of this relationship remains a subject for debate. Finally, evidence is discussed that FFA represent a crucial link between insulin resistance and beta-cell dysfunction and, as such, a reduction in elevated plasma FFA should be an important therapeutic target in obesity and type 2 diabetes.

PUFA destroy beta cells:
“The antimetabolic and toxic effects of the polyunsaturated fatty acids can account for the “insulin resistance” that characterizes type-2 diabetes, but similar actions in the pancreatic beta-cells can impair or kill those cells, creating a deficiency of insulin, resembling type-1 diabetes.” -Ray Peat, PhD

Endocrine. 2011 Apr;39(2):128-38. Epub 2010 Dec 15.
Long-term exposure of INS-1 rat insulinoma cells to linoleic acid and glucose in vitro affects cell viability and function through mitochondrial-mediated pathways.
Tuo Y, Wang D, Li S, Chen C.
Obesity with excessive levels of circulating free fatty acids (FFAs) is tightly linked to the incidence of type 2 diabetes. Insulin resistance of peripheral tissues and pancreatic β-cell dysfunction are two major pathological changes in diabetes and both are facilitated by excessive levels of FFAs and/or glucose. To gain insight into the mitochondrial-mediated mechanisms by which long-term exposure of INS-1 cells to excess FFAs causes β-cell dysfunction, the effects of the unsaturated FFA linoleic acid (C 18:2, n-6) on rat insulinoma INS-1 β cells was investigated. INS-1 cells were incubated with 0, 50, 250 or 500 μM linoleic acid/0.5% (w/v) BSA for 48 h under culture conditions of normal (11.1 mM) or high (25 mM) glucose in serum-free RPMI-1640 medium. Cell viability, apoptosis, glucose-stimulated insulin secretion, Bcl-2, and Bax gene expression levels, mitochondrial membrane potential and cytochrome c release were examined. Linoleic acid 500 μM significantly suppressed cell viability and induced apoptosis when administered in 11.1 and 25 mM glucose culture medium. Compared with control, linoleic acid 500 μM significantly increased Bax expression in 25 mM glucose culture medium but not in 11.1 mM glucose culture medium. Linoleic acid also dose-dependently reduced mitochondrial membrane potential (ΔΨm) and significantly promoted cytochrome c release from mitochondria in both 11.1 mM glucose and 25 mM glucose culture medium, further reducing glucose-stimulated insulin secretion, which is dependent on normal mitochondrial function. With the increase in glucose levels in culture medium, INS-1 β-cell insulin secretion function was deteriorated further. The results of this study indicate that chronic exposure to linoleic acid-induced β-cell dysfunction and apoptosis, which involved a mitochondrial-mediated signal pathway, and increased glucose levels enhanced linoleic acid-induced β-cell dysfunction.

J Clin Endocrinol Metab. 2013 May;98(5):2062-9. doi: 10.1210/jc.2012-3492. Epub 2013 Mar 22.
β-Cell Lipotoxicity After an Overnight Intravenous Lipid Challenge and Free Fatty Acid Elevation in African American Versus American White Overweight/Obese Adolescents.
Hughan KS, Bonadonna RC, Lee S, Michaliszyn SF, Arslanian SA.
Objective: Overweight/obese (OW/OB) African American (AA) adolescents have a more diabetogenic insulin secretion/sensitivity pattern compared with their American white (AW) peers. The present study investigated β-cell lipotoxicity to test whether increased free fatty acid (FFA) levels result in greater β-cell dysfunction in AA vs AW OW/OB adolescents. Research Design and Methods: Glucose-stimulated insulin secretion was modeled, from glucose and C-peptide concentrations during a 2-hour hyperglycemic (225 mg/dL) clamp in 22 AA and 24 AW OW/OB adolescents, on 2 occasions after a 12-hour overnight infusion of either normal saline or intralipid (IL) in a random sequence. β-Cell function relative to insulin sensitivity, the disposition index (DI), was examined during normal saline and IL conditions. Substrate oxidation was evaluated with indirect calorimetry and body composition and abdominal adiposity with dual-energy X-ray absorptiometry and magnetic resonance imaging at L4-L5, respectively. Results: Age, sex, body mass index, total and sc adiposity were similar between racial groups, but visceral adiposity was significantly lower in AAs. During IL infusion, FFAs and fat oxidation increased and insulin sensitivity decreased similarly in AAs and AWs. β-Cell glucose sensitivity of first- and second-phase insulin secretion did not change significantly during IL infusion in either group, but DI in each phase decreased significantly and similarly in AAs and AWs. Conclusions: Overweight/obese AA and AW adolescents respond to an overnight fat infusion with significant declines in insulin sensitivity, DI, and β-cell function relative to insulin sensitivity, suggestive of β-cell lipotoxicity. However, contrary to our hypothesis, there does not seem to be a race differential in β-cell lipotoxicity. Longer durations of FFA elevation may unravel such race-related contrasts.

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By Team FPS – July 17, 2012

Dangers of PUFA Videos

https://youtu.be/a-KdjvcDWyA?t=3m36s

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By Team FPS – July 17, 2012

Aldosterone as an endogenous cardiovascular toxin

Also see:
Sodium and Mortality: An Inverse Relationship
Aldosterone, Sodium Deficiency, and Insulin Resistance
The Randle Cycle
Free Fatty Acids Suppress Cellular Respiration
Aldosterone as an endogenous cardiovascular toxin
Aldosterone and Thrombosis
Sodium Deficiency and Stress
Low Sodium Diet: High FFA, Insulin Resistance, Atherosclerosis

Vnitr Lek. 2011 Dec;57(12):1012-6.
[Aldosterone as an endogenous cardiovascular toxin and the options for its therapeutic management].
[Article in Czech]
Horký K.
In physiological, as well as pathological situations, aldosterone significantly influences volume, pressure and electrolyte balance. Primary hyperaldosteronism is caused by autonomous over-production, most frequently due to adrenal adenoma. Patients with primary hyperaldosteronism (Conn’s syndrome) have more pronounced left ventricular hypertrophy and higher frequency of cardiovascular events than patients with essential hypertension (EH) with comparable blood pressure values. Consequently, there is an increased interest in the role of aldosterone tissue function in cardiovascular disease. The aim of the present paper is to emphasise the pleiotropic actions of aldosterone on cardiovascular system and the options for their therapeutic management. Apart from the effects of circulating aldosterone on BP and its renal actions on water and electrolyte excretion, extra-renal effects are also been explored; paracrine affects through tissue mineralocorticoid receptors (MR) may impact on endothelial dysfunction, vascular elasticity, inflammatory changes in the myocardium, vessels and kidneys. Initial oxidative stress due to increased aldosterone concentrations may initiate subclinical endothelial changes and subsequent myocardial fibrosis. The effects on all three layers of vascular wall, together with increased blood coagulation and vascular thrombogenicity increases likelihood of microthrombosis and tissue microinfarctions. Slight increase in aldosterone concentrations in cardiac tissue adversely affects myofibrils as well as coronary artery function. Similar to peripheral vessels, it increases collagen content and changes vascular rigidity and the velocity of pulse wave and facilitates development of perivascular fibrosis. Higher salt intake may potentiate these pathophysiological effects of aldosterone, while higher intake of potassium may restrict them. Aldosterone vasculopathy together with perivascular fibrosis occurring at aldosterone concentrations seen with heart failure contributes to manifestation of heart failure. Consequently, aldosterone may rightly be called “cardiovascular toxin”. The adverse effects of aldosterone in patients on long-term ACEI therapy are further facilitated by the aldosterone’s ability to evade inhibitory effects of ACEI and parallel activation of renin-angiotensin system. To manage these situations, receptors of mineralcorticoids or direct renin inhibitor aliskiren are used. The positive effect of MR blockade is based on an increased release of nitric oxide (NO) with further improvement in endothelial functions. Detailed review of pleotropic effects of aldosterone helps to clarify a number of pathophysiological situations in essential hypertension, supports the view of aldosterone as a potential cardiovascular toxin and indicates the use of mineralocorticoid receptor blockers in resistant hypertension and patients with cardiovascular or renal organ damage.

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By Team FPS – July 16, 2012

Ambien and Cancer Risk

Mayo Clin Proc. 2012 May;87(5):430-6.
Relationship of zolpidem and cancer risk: a Taiwanese population-based cohort study.
Kao CH, Sun LM, Liang JA, Chang SN, Sung FC, Muo CH.
“This population-based study revealed some unexpected findings, suggesting that the use of zolpidem may be associated with an increased risk of subsequent cancer.”

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By Team FPS – July 16, 2012

Sodium Deficiency in Pre-eclampsia

Also see:
Role of Serotonin in Preeclampsia
Aldosterone, Sodium Deficiency, and Insulin Resistance
The Randle Cycle
Free Fatty Acids Suppress Cellular Respiration
Aldosterone as an endogenous cardiovascular toxin
Aldosterone and Thrombosis
Sodium Deficiency and Stress
Low Sodium Diet: High FFA, Insulin Resistance, Atherosclerosis

BJOG. 2004 Sep;111(9):1020-2.
Severe hyponatraemia and pre-eclampsia.
Burrell C, de Swiet M.
“This case report showed severe hyponatraemia complicating pre-eclampsia in a patient with normal urine sodium and potassium excretion and urine osmolality but with decreased plasma osmolality.”

Am J Obstet Gynecol. 1998 Nov;179(5):1312-6.
Dilutional hyponatremia in pre-eclampsia.
Hayslett JP, Katz DL, Knudson JM.
OBJECTIVE:
The objective of this report is to describe a defect in water metabolism, characterized by hyponatremia, in patients with pre-eclampsia-induced nephrotic syndrom.
STUDY DESIGN:
This was an observational study of 3 women.
RESULTS:
Hyponatremia was observed in 3 women with pre-eclampsia characterized by various extrarenal manifestations, as well as by nephrotic syndrome with normal or nearly normal renal function. Restriction in water intake partially corrected hyponatremia before delivery in each case, and no complications were observed in the neonates. The mechanism of impaired excretion of water in these patients is proposed to involve persistent and inappropriate production of vasopressin through stimulation of the nonosmotic mechanism for vasopressin secretion in response to a reduction in effective plasma volume.
CONCLUSIONS:
These results indicate for the first time that women with pre-eclampsia are, at least when nephrotic, at risk for development of dilutional hyponatremia, which can cause neurologic complications that simulate those of eclampsia.

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By Team FPS – July 16, 2012

Role of Serotonin in Preeclampsia

Also see:
Estrogen Increases Serotonin
Anti Serotonin, Pro Libido
Gelatin > Whey
Thyroid peroxidase activity is inhibited by amino acids
Whey, Tryptophan, & Serotonin
Tryptophan, Fatigue, Training, and Performance
Carbohydrate Lowers Free Tryptophan
Protective Glycine
Intestinal Serotonin and Bone Loss
Hypothyroidism and Serotonin
Estrogen Increases Serotonin
Gelatin, Glycine, and Metabolism
Whey, Tryptophan, & Serotonin
Tryptophan, Sleep, and Depression
Menstrual Cycle Related Epilepsy (Catamenial Epilepsy)
Estrogen’s Role in Seizures
The Brain – Estrogen’s Harm and Progesterone’s Protection
Estrogen, Glutamate, & Free Fatty Acids
Women, Estrogen, and Circulating DHA
Epilepsy and Progesterone by Ray Peat, PhD

“In women with preeclampsia, there are abnormally high levels of serotonin, nitric oxide, and lipid peroxidation. In a study of more than 3000 women (Clausen, et al., 2001), the consumption of sugar and polyunsaturated fat was strongly associated with the development of preeclampsia. Women who don’t eat enough protein are likely to substitute sugar and fat for the absent protein, so this study is consistent with Brewer’s work, but it’s very important to see that it was polyunsaturated fats, not saturated or monounsaturated fats, that caused the problem. Eclampsia (pregnancy-related seizures) and preeclampsia are caused by oxidative stress, produced by the excessive unstable fats. The increased serotonin and nitric oxide are exactly what would be expected to result from the high consumption of polyunsaturated fats, especially with a deficiency of protein in the diet.” -Ray Peat, PhD

Hypertension. 2007 Oct;50(4):773-9. Epub 2007 Jul 23.
Pregnant rats treated with a serotonin precursor have reduced fetal weight and lower plasma volume and kallikrein levels.
Salas SP, Giacaman A, Romero W, Downey P, Aranda E, Mezzano D, Vío CP.
Pregnant women with preeclampsia have increased serotonin levels, suggesting a possible role of this amine in abnormal pregnancy. With the hypothesis that an increase in serotonin would reduce volume expansion and cause fetal growth restriction, we evaluated the maternal and fetal effects of the administration of the serotonin precursor 5-hidroxytryptophan (5-HTP) to Sprague-Dawley rats. At pregnancy day 13 (n=19) or in random cycle nonpregnant rats (n=10), animals were assigned to a single injection of 5-HTP (100 mg/kg IP) or to a control group. Animals were studied at day 21, after overnight urinary collection. Additional pregnant rats received ketanserin (1 mg/kg), a 5-HT(2) receptor antagonist, 1 hour before 5-HTP injection. In pregnant rats, 5-HTP lowered plasma volume (control: 22+/-1.1; 5-HTP: 17+/-0.7 mL; P<0.001) and creatinine clearance, whereas serum creatinine and urinary protein excretion were increased; no changes were observed in nonpregnant rats. Systolic blood pressure did not change significantly. Urinary kallikrein activity and plasma aldosterone levels decreased only in pregnant animals. Fetal (control: 5.5+/-0.1; 5-HTP: 4.2+/-0.2 g; P<0.001) and placental weights were reduced. In nonpregnant and pregnant animals, 5-HTP caused profound renal morphological alterations and decreased kallikrein immunostaining. Preadministration of ketanserin abolished all of the changes associated with the use of 5-HTP. These data indicate that the administration of a serotonin precursor to pregnant rats limits plasma volume expansion and fetal growth via 5-HT(2) receptors, suggesting a possible role for serotonin in abnormal pregnancy. We postulate that an increased vascular resistance, both at the placental and renal levels, mediates these effects.

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By Team FPS – July 16, 2012

Aldosterone, Sodium Deficiency, and Insulin Resistance

Also see:
The Randle Cycle
Free Fatty Acids Suppress Cellular Respiration
Aldosterone as an endogenous cardiovascular toxin
Aldosterone and Thrombosis
Sodium Deficiency and Stress
Low Sodium Diet: High FFA, Insulin Resistance, Atherosclerosis

Dietary salt restriction, which increases aldosterone levels, is also associated with an increase in insulin resistance. -Garg and Adler, 2012

Curr Opin Endocrinol Diabetes Obes. 2012 Jun;19(3):168-75.
Role of mineralocorticoid receptor in insulin resistance.
Garg R, Adler GK.
PURPOSE OF REVIEW:
Recent data suggest that mineralocorticoid receptor activation can affect insulin resistance independent of its effects on blood pressure. This review discusses new evidence linking mineralocorticoid receptor to insulin resistance and the underlying mechanisms of these effects.
RECENT FINDINGS:
Observational studies have shown mineralocorticoid activity to be associated with insulin resistance irrespective of race, blood pressure or body weight. Increased mineralocorticoid activity may be the common link between obesity, hypertension, dyslipidemia and insulin resistance, features that make up the metabolic syndrome. Treatment of primary aldosteronism is associated with a decrease in insulin resistance and provides one of the most convincing evidences in favor of the contribution of mineralocorticoid receptor to insulin resistance. Dietary salt restriction, which increases aldosterone levels, is also associated with an increase in insulin resistance. Potential mechanisms by which mineralocorticoid receptor may contribute to insulin resistance include a decreased transcription of the insulin receptor gene, increased degradation of insulin receptor substrates, interference with insulin signaling mechanisms, decreased adiponectin production and increased oxidative stress and inflammation. Advantages of mineralocorticoid receptor antagonists on insulin resistance have been demonstrated in animal models.
SUMMARY:
There may be a benefit of mineralocorticoid receptor antagonists in human insulin resistance states, but more clinical research is needed to explore these possibilities.

Prog Cardiovasc Dis. 2010 Mar-Apr;52(5):401-9.
Aldosterone: role in the cardiometabolic syndrome and resistant hypertension.
Whaley-Connell A, Johnson MS, Sowers JR.
The prevalence of diabetes, hypertension, and cardiovascular disease (CVD) and chronic kidney disease (CKD) is increasing in concert with obesity. Insulin resistance, metabolic dyslipidemia, central obesity, albuminuria. and hypertension commonly cluster to comprise the cardiometabolic syndrome (CMS). Emerging evidence supports a shift in our understanding of the crucial role of elevated serum aldosterone in promoting insulin resistance and resistant hypertension. Aldosterone enhances tissue generation of oxygen free radicals and systemic inflammation. This increase in oxidative stress and inflammation, in turn, contributes to impaired insulin metabolic signaling, reduced endothelial-mediated vasorelaxation, and associated cardiovascular and renal structural and functional abnormalities. In this context, recent investigation indicates that hyperaldosteronism, which is often associated with obesity, contributes to impaired pancreatic beta-cell function as well as diminished skeletal muscle insulin metabolic signaling. Accumulating evidence indicates that the cardiovascular and renal abnormalities associated with insulin resistance are mediated, in part, by aldosterone’s nongenomic as well as genomic signaling through the mineralocorticoid receptor (MR). In the CMS, there are increased circulating levels of glucocorticoids, which can also activate MR signaling in cardiovascular, adipose, skeletal muscle, neuronal, and liver tissue. Furthermore, there is increasing evidence that fat tissue produces a lipid soluble factor that stimulates aldosterone production from the adrenal zona glomerulosa. Recently, we have learned that MR blockade improves pancreatic insulin release, insulin-mediated glucose utilization, and endothelium-dependent vasorelaxation as well as reduces the progression of CVD and CKD. In summary, aldosterone excess exerts detrimental metabolic effects that contribute to the development of the CMS and resistant hypertension as well as CVD and CKD.

Ann Intern Med. 2009 Jun 2;150(11):776-83.
Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension.
Sowers JR, Whaley-Connell A, Epstein M.
The prevalence of obesity, diabetes, hypertension, and cardiovascular and chronic kidney disease is increasing in developed countries. Obesity, insulin resistance, and hypertension commonly cluster with other risk factors for cardiovascular and chronic kidney disease to form the metabolic syndrome. Emerging evidence supports a paradigm shift in our understanding of the renin-angiotensin-aldosterone system and in aldosterone’s ability to promote insulin resistance and participate in the pathogenesis of the metabolic syndrome and resistant hypertension. Recent data suggest that excess circulating aldosterone promotes the development of both disorders by impairing insulin metabolic signaling and endothelial function, which in turn leads to insulin resistance and cardiovascular and renal structural and functional abnormalities. Indeed, hyperaldosteronism is associated with impaired pancreatic beta-cell function, skeletal muscle insulin sensitivity, and elevated production of proinflammatory adipokines from adipose tissue, which results in systemic inflammation and impaired glucose tolerance. Accumulating evidence indicates that the cardiovascular and renal abnormalities associated with insulin resistance are mediated in part by aldosterone acting on the mineralocorticoid receptor. Although we have known that mineralocorticoid receptor blockade attenuates cardiovascular and renal injury, only recently have we learned that mineralocorticoid receptor blockade improves pancreatic insulin release, insulin-mediated glucose utilization, and endothelium-dependent vasorelaxation. In summary, aldosterone excess has detrimental metabolic effects that contribute to the metabolic syndrome and endothelial dysfunction, which in turn contribute to the development of resistant hypertension as well as cardiovascular disease and chronic kidney disease.

Curr Hypertens Rep. 2011 Apr;13(2):163-72.
The role of aldosterone in the metabolic syndrome.
Briet M, Schiffrin EL.
The metabolic syndrome associates metabolic abnormalities such as insulin resistance and dyslipidemia with increased waist circumference and hypertension. It is a major public health concern, as its prevalence could soon reach 30% to 50% in developed countries. Aldosterone, a mineralocorticoid hormone classically involved in sodium balance regulation, is increased in patients with metabolic syndrome. Besides its classic actions, aldosterone and mineralocorticoid receptor (MR) activation affect glucose metabolism, inducing insulin resistance through various mechanisms that involve oxidative stress, inflammation, and downregulation of proteins involved in insulin signaling pathways. Aldosterone and MR signaling exert deleterious effects on the cardiovascular system and the kidney that influence the cardiovascular risk associated with metabolic syndrome. Salt load plays a major role in cardiovascular injury induced by aldosterone and MR signaling. Large multicenter, randomized clinical trials testing the beneficial effects of MR antagonists on cardiovascular events and mortality in patients with metabolic syndrome are needed.

Curr Hypertens Rep. 2010 Aug;12(4):252-7.
Mineralocorticoid receptor antagonists and the metabolic syndrome.
Tirosh A, Garg R, Adler GK.
Key components of the metabolic syndrome (MetS), ie, obesity and insulin resistance, are associated with increased aldosterone production and mineralocorticoid receptor (MR) activation. Both MetS and hyperaldosteronism are proinflammatory and pro-oxidative states associated with cardiovascular disease. This review discusses emerging data that MR activation may contribute to abnormalities seen in MetS. In view of these data, MR antagonists may be beneficial in MetS, not only by controlling hypertension but also by reversing inflammation, oxidative stress, and defective insulin signaling at the cellular-molecular level. Clinical trials have demonstrated benefits of MR antagonists in heart failure, hypertension, and diabetic nephropathy, but additional trials are needed to demonstrate the clinical significance of MR blockade in MetS.

Klin Wochenschr. 1991;69 Suppl 25:51-7.
Short-term dietary sodium restriction increases serum lipids and insulin in salt-sensitive and salt-resistant normotensive adults.
Ruppert M, Diehl J, Kolloch R, Overlack A, Kraft K, Göbel B, Hittel N, Stumpe KO.
Evidence suggests that dietary salt reduction similar to diuretic therapy may adversely affect lipid and glucose metabolism. We studied 147 non-obese normotensive subjects (60 females and 87 males) aged 19-78 years who entered a single-blind crossover trial and were randomly assigned to a low salt diet of 20 mmol or a high salt diet of 300 mmol sodium per day, for 7 days each. Sodium restriction lowered mean arterial blood pressure (MAP) by a mean of 7.5 mmHg in 17% (salt-sensitive), had no hemodynamic effect in 67% (salt-resistant) and raised MAP by a mean of 6 mmHg in 16% of the subjects (reverse reactors). With dietary salt restriction serum total- and LDL-cholesterol as well as serum insulin and uric acid concentrations increased significantly in all three groups. The largest increases in total (10%) and LDL- (12%) cholesterol occurred in the reverse reactors. Salt-sensitives had significant higher lipoprotein(a) values than the other two groups. Salt-restriction had no significant effect on this parameter. Plasma renin activity, as well as plasma aldosterone and noradrenaline concentrations rose in all three groups during the low salt diet, the largest increases being observed in the reverse reactors. Short-term sodium restriction in normotensive adults has unfavourable effects on lipid and glucose metabolism, especially in subjects who do not derive hemodynamic benefit. Further studies are necessary to examine the effects of more moderate salt reduction for longer periods on the risk factor profile for cardiovascular disease before a low salt diet can be regarded as a safe public health measure for the general population.

Aust J Exp Biol Med Sci. 1976 Feb;54(1):71-8.
Regulation of aldosterone in the guinea-pig–effect of oestrus cycle, pregnancy and sodium status.
Whipp GT, Wintour EM, Coghlan JP, Scoggins BA.
The blood concentrations of aldosterone, corticosterone and cortisol were measured in conscious, non-stressed guinea-pigs using a double isotope dilution derivative assay procedure. Aldosterone levels in the guinea-pig were high when compared with those of other species. The concentration of aldosterone, 37-7 +/- 15-9 ng/100 ml (x +/- SD), and cortisol, 31-8 +/- 10-1 mug/100 ml, found in non-pregnant females on a moderate sodium intake was significantly greater than in males (aldosterone 22-2 +/- 2-4 ng/100 ml and cortisol 19-3 +/- 5-7 mug/100 ml). There was no sex difference in corticosterone concentrations; females, 0-25 +/- 0-06 mug/100 ml and males, 0-23 +/- 0-10 mug/100 ml. The oestrus cycle had no effect on levels of the three steroids measured. Two thirds of the way through the 68-day gestation period aldosterone levels were significantly elevated compared with non-pregnant values (68-7 +/- 50-9 ng/100 ml, p less than 0-05). Values at day 20 (33-2 +/- 11-7 ng/100 ml) and day 60 of gestation (51-9 +/- 21-7 ng/100 ml) were similar to those of non-pregnant animals. Cortisol and corticosterone levels were significantly elevated at 20 days gestation and they continued to rise until, at day 60, cortisol was 9 times and corticosterone 4 times higher than the non-pregnant values. Compared with a moderate Na intake, salt loading suppressed aldosterone levels and Na restriction raised them.

J Clin Invest. 1972 October; 51(10): 2645–2652.
Studies of the control of plasma aldosterone concentration in normal man III
Robert G. Dluhy, Lloyd Axelrod, Richard H. Underwood, and Gordon H. Williams
The peripheral plasma levels of aldosterone, renin activity, potassium, sodium, corticosterone, and cortisol were measured in six normal subjects four times daily—10 a.m., 2 p.m., 5 p.m., 11 p.m.—on 3 consecutive days. A constant daytime activity program was maintained throughout the study. After 5 days on a 10 mEq sodium/100 mEq potassium isocaloric intake, the mean upright 10 a.m. plasma renin activity was 1773±186 ng/100 ml per 3 hr and the mean plasma aldosterone, 81±14 ng/100 ml. These two parameters fell continuously throughout the day parallel to the fall in plasma cortisol and corticosterone. In response to 2 liters of normal saline infused from 10 a.m. to 2 p.m. on 2 consecutive days, plasma aldosterone levels fell significantly to 13±5 ng/100 ml at 2 p.m. after the 1st day’s infusion and to 6±1 ng/100 ml at 2 p.m. after the 2nd. Plasma renin activity demonstrated a parallel fall to 368±63 ng/100 ml per 3 hr and 189±27 ng/100 ml per 3 hr at 2 p.m. on the 1st and 2nd days, respectively. There was no significant alteration in plasma levels of cortisol, corticosterone, potassium, or sodium on the 2 days of sodium loading in comparison with the control day. In an additional study, five normal supine subjects received 500 ml saline/hr for 6 hr. As in the 2 day study, plasma aldosterone and renin activity had parallel decrements at 1, 2, 4, and 6 hr after the start of the saline infusion. From these studies, it is concluded that plasma renin activity is the dominant factor controlling plasma aldosterone when sodium-depleted normal subjects are acutely repleted.

A low salt diet increases the free fatty acids, leading to insulin resistance, and contributing to atherosclerosis (Prada, et al., 2000; Mrnka, et al., 2005; Catanozi, et al., 2003; Garg, et al., 2011). -Ray Peat, PhD

J Endocrinol. 2005 Jun;185(3):429-37.
Low salt intake modulates insulin signaling, JNK activity and IRS-1ser307 phosphorylation in rat tissues.
 Prada PO, Coelho MS, Zecchin HG, Dolnikoff MS, Gasparetti AL, Furukawa LN, Saad MJ, Heimann JC.
A severe restriction of sodium chloride intake has been associated with insulin resistance and obesity. The molecular mechanisms by which the low salt diet (LS) can induce insulin resistance have not yet been established. The c-jun N-terminal kinase (JNK) activity has been involved in the pathophysiology of obesity and induces insulin resistance by increasing inhibitory IRS-1(ser307) phosphorylation. In this study we have evaluated the regulation of insulin signaling, JNK activation and IRS-1(ser307) phophorylation in liver, muscle and adipose tissue by immunoprecipitation and immunoblotting in rats fed with LS or normal salt diet (NS) during 9 weeks. LS increased body weight, visceral adiposity, blood glucose and plasma insulin levels, induced insulin resistance and did not change blood pressure. In LS rats a decrease in PI3-K/Akt was observed in liver and muscle and an increase in this pathway was seen in adipose tissue. JNK activity and IRS-1(ser307) phosphorylation were higher in insulin-resistant tissues. In summary, the insulin resistance, induced by LS, is tissue-specific and is accompanied by activation of JNK and IRS-1(ser307) phosphorylation. The impairment of the insulin signaling in these tissues, but not in adipose tissue, may lead to increased adiposity and insulin resistance in LS rats.

Physiol Res. 2000;49(2):197-205.
Low-salt diet alters the phospholipid composition of rat colonocytes.
Mrnka L, Nováková O, Novák F, Tvrzická E, Pácha J.
he effect of low-salt diet on phospholipid composition and remodeling was examined in rat colon which represents a mineralocorticoid target tissue. To elucidate this question, male Wistar rats were fed a low-salt diet and drank distilled water (LS, low-salt group) or saline instead of water (HS, high-salt group) for 12 days before the phospholipid concentration and fatty acid composition of isolated colonocytes were examined. The dietary regimens significantly influenced the plasma concentration of aldosterone which was high in LS group and almost zero in HS group. Plasma concentration of corticosterone was unchanged. When expressed in terms of cellular protein content, a significantly higher concentration of phospholipids was found in LS group, with the exception of sphingomyelin (SM) and phosphatidylserine (PS). Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) accounted for more than 70% of total phospholipids in both groups. A comparison of phospholipid distribution in LS and HS groups demonstrated a higher percentage of PE and a small, but significant, decrease of PC and SM in LS group. The percentage of phosphatidylinositol (PI), PS and cardiolipin (CL) were not affected by mineralocorticoid treatment. With respect to the major phospholipids (PE, PC), a higher level of n-6 polyunsaturated fatty acids (PUFA) and lower levels of monounsaturated fatty acids were detected in PC of LS group. The increase of PUFA predominantly reflected an increase in arachidonic acid by 53%. In comparison to the HS group, oleic acid content was decreased in PC and PE isolated from colonocytes of the LS group. Our data indicate that alterations in phospholipid concentration and metabolism can be detected in rats with secondary hyperaldosteronism. The changes in phospholipid concentration and their fatty acid composition during fully developed effect of low dietary Na+ intake may reflect a physiologically important phenomenon with long-term consequences for membrane structure and function.

J Lipid Res. 2003 Apr;44(4):727-32. Epub 2003 Jan 16.
Dietary sodium chloride restriction enhances aortic wall lipid storage and raises plasma lipid concentration in LDL receptor knockout mice.
Catanozi S, Rocha JC, Passarelli M, Guzzo ML, Alves C, Furukawa LN, Nunes VS, Nakandakare ER, Heimann JC, Quintão EC.
This study aimed at measuring the influence of a low salt diet on the development of experimental atherosclerosis in moderately hyperlipidemic mice. Experiments were carried out on LDL receptor (LDLR) knockout (KO) mice, or apolipoprotein E (apoE) KO mice on a low sodium chloride diet (LSD) as compared with a normal salt diet (NSD). On LSD, the rise of the plasma concentrations of TG and nonesterified fatty acid (NEFA) was, respectively, 19% and 34% in LDLR KO mice, and 21% and 35% in apoE KO mice, and that of plasma cholesterol was limited to the LDLR KO group alone (15%). Probably due to the apoE KO severe hypercholesterolemia, the arterial inner-wall fat storage was not influenced by the diet salt content and was far more abundant in the apoE KO than in the LDLR KO mice. However, in the less severe hypercholesterolemia of the LDLR KO mice, lipid deposits on the LSD were greater than on the NSD. Arterial fat storage correlated with NEFA concentrations in the LDLR KO mice alone (n = 14, P = 0.0065). Thus, dietary sodium chloride restriction enhances aortic wall lipid storage in moderately hyperlipidemic mice.

Metabolism. 2011 Jul;60(7):965-8. Epub 2010 Oct 30.
Low-salt diet increases insulin resistance in healthy subjects.
Garg R, Williams GH, Hurwitz S, Brown NJ, Hopkins PN, Adler GK. Low-salt (LS) diet activates the renin-angiotensin-aldosterone and sympathetic nervous systems, both of which can increase insulin resistance (IR). We investigated the hypothesis that LS diet is associated with an increase in IR in healthy subjects. Healthy individuals were studied after 7 days of LS diet (urine sodium <20 mmol/d) and 7 days of high-salt (HS) diet (urine sodium >150 mmol/d) in a random order. Insulin resistance was measured after each diet and compared statistically, unadjusted and adjusted for important covariates. One hundred fifty-two healthy men and women, aged 39.1 ± 12.5 years (range, 18-65) and with body mass index of 25.3 ± 4.0 kg/m(2), were included in this study. Mean (SD) homeostasis model assessment index was significantly higher on LS compared with HS diet (2.8 ± 1.6 vs 2.4 ± 1.7, P < .01). Serum aldosterone (21.0 ± 14.3 vs 3.4 ± 1.5 ng/dL, P < .001), 24-hour urine aldosterone (63.0 ± 34.0 vs 9.5 ± 6.5 μg/d, P < .001), and 24-hour urine norepinephrine excretion (78.0 ± 36.7 vs 67.9 ± 39.8 μg/d, P < .05) were higher on LS diet compared with HS diet. Low-salt diet was significantly associated with higher homeostasis model assessment index independent of age, sex, blood pressure, body mass index, serum sodium and potassium, serum angiotensin II, plasma renin activity, serum and urine aldosterone, and urine epinephrine and norepinephrine. Low-salt diet is associated with an increase in IR. The impact of our findings on the pathogenesis of diabetes and cardiovascular disease needs further investigation.

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By Team FPS – July 16, 2012

Stress and Aging: The Glucocorticoid Cascade Hypothesis

Also see:
The Streaming Organism
Stress, Portrait of a Killer – Full Documentary (2008)
Belly Fat, Cortisol, and Stress

Sci. Aging Knowl. Environ., 25 September 2002
Vol. 2002, Issue 38, p. cp21
The Neuroendocrinology of Stress and Aging: The Glucocorticoid Cascade Hypothesis
Robert M. Sapolsky, Lewis C. Krey, and Bruce S. McEwen
Abstract: Over the past 5 yr, we have examined some of the sharpest edges of the pathology of aging. We have studied the capacity of aged organisms to respond appropriately to stress and the capacity of stress to cumulatively damage aging tissue. The idea of a relationship between stress and aging has permeated the gerontology literature in two forms. First, senescence has been thought of as a time of decreased adaptiveness to stress. This idea has been supported frequently, as many aged physiological systems function normally under basal conditions, yet do not adequately respond to a challenge. For example, aged and young humans have similar basal body temperatures, but the former are relatively impaired in thermoregulatory capacities when heat- or cold-challenged. A second theme in gerontology concerning stress is that chronic stress can accelerate the aging process. Selye and Tuchweber for example, postulated a finite “adaptational energy” in an organism, with prolonged stress prematurely depleting such reserves, thus accelerating the onset of senescence. This idea was derivative of earlier idea that the “rate of living” could be a pacemaker of aging. Experimentally, varied approaches have supported the notion that at least some biomarkers of age can be accelerated by stress.

The above hypotheses led us to examine the adrenocortical axis, the endocrine axis which is among the most central to the stress response. Our findings support both of these concepts. We find that the aged male rat is impaired in terminating the secretion of adrenocortical stress hormones, glucocorticoids, at the end of stress. This hormonal excess may be due to degenerative changes in a region of the brain which normally inhibits glucocorticoid release; the degeneration, in turn, is caused by cumulative exposure to glucocorticoids. Together, these effects form a feed-forward cascade with potentially serious pathophysiological consequences in the aged subject.

In the adrenal glands, renewing cells stream from the capsule on the surface of the gland toward the center of the gland. The first cells to be produced in a regenerating gland are those that produce aldosterone, the next in the stream are the cortisol producing cells, and the last to be formed are the cells that produce the sex hormones, the androgens, including DHEA, and progesterone. In aging, after the age of thirty, the renewal slows, but the dissolution of the sex hormone zone continues, so the proportion shifts, increasing the ration of aldosterone and cortisol producing cells to the layer that produces the protective androgens and progesterone (Parker, et al., 1997). -Ray Peat, PhD

J Clin Endocrinol Metab. 1997 Nov;82(11):3898-901.
Aging alters zonation in the adrenal cortex of men.
Parker CR Jr, Mixon RL, Brissie RM, Grizzle WE.
Whereas aging has been shown to be associated with striking reductions in circulating levels of adrenal androgens in humans, the alteration in adrenal function that occurs in aging has not been identified. We sought to determine if there are changes in the zonation of the adrenal in aging men by performing histomorphologic analyses of adrenal specimens that had been obtained at autopsy following sudden death due to trauma. We evaluated adrenals from 21 young men (20-29 yrs) and 12 older men (54-90 yrs); inclusion criteria required the presence of medullary tissue in the specimen and fixation within the first 24 hrs postmortem. Sections stained with H/E were examined microscopically and areas of the cortex that included adjacent medullary tissue were chosen for quantitative evaluation by use of a computerized image analysis system. The average width (arbitrary units, pixels) of the zona reticularis and that of the combined zonae fasciculata/glomerulosa were determined from sections stained for reticulum fibers. The zona reticularis represented 37.1 +/- 1.9% of the total cortical width in the young men, which was significantly greater than that of the older men (27.1 +/- 3.3%, P = 0.0082). The zona fasciculata/glomerulosa to zona reticularis ratio in the young men (1.84 +/- 0.15) was significantly less that that of the older men (3.29 +/- 0.47, P = 0.0011). There was no significant difference in the total width of the cortex in young compared to older men. These data suggest that aging results in alterations within the cortex of the adrenals in men such that there is a reduction in the size of the zona reticularis and a relative increase in the outer cortical zones. A reduced mass of the zona reticularis could be responsible for the diminished production of dehydroepiandrosterone and dehydroepiandrosterone sulfate that occurs during aging.

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By Team FPS – July 11, 2012

Estrogen, Glutamate, & Free Fatty Acids

Also see:
Menstrual Cycle Related Epilepsy (Catamenial Epilepsy)
Phospholipases, PUFA, and Inflammation
Brain Swelling Induced by Polyunsaturated Fats (PUFA)
Women, Estrogen, and Circulating DHA
Arachidonic Acid’s Role in Stress and Shock
Estrogen’s Role in Seizures
The Brain – Estrogen’s Harm and Progesterone’s Protection
PUFA Kill Thymocytes
PUFA Breakdown Products Depress Mitochondrial Respiration
PUFA, Fish Oil, and Alzheimers
Fish Oil Toxicity
Benefits of Aspirin

“Estrogen increases the activity of the excitatory transmitter glutamate (Weiland, 1992), and glutamate increases the release of free fatty acids (Kolko, et al., 1996). DHA (more strongly even the arachidonic acid) inhibits the uptake of the excitotoxic amino acid aspartate, and in some situations glutamate, prolonging their actions.” -Ray Peat, PhD

“Albumin, besides maintaining blood volume and preventing edema, serves to protect respiration, by binding free fatty acids. Estrogen blocks the liver’s ability to produce albumin, and increases the level of circulating free fatty acids. Free fatty acids cause brain edema. This is probably another aspect of estrogen’s contribution to seizure susceptibility.” -Ray Peat, PhD

Endocrinology. 1992 Dec;131(6):2697-702.
Glutamic acid decarboxylase messenger ribonucleic acid is regulated by estradiol and progesterone in the hippocampus.
Weiland NG.
Ovarian steroids modulate learning, memory, and epileptic seizure activity, functions that are mediated in part by the hippocampus. Normal function depends on precise interactions between the inhibitory gamma-aminobutyric acid (GABA)ergic and excitatory glutamatergic neurons of the hippocampus. To determine whether estradiol and progesterone interact with GABAergic neurons, the levels of mRNA for glutamic acid decarboxylase (GAD), the rate-limiting enzyme for GABA synthesis, were measured by in situ hybridization histochemistry with 35S-labeled riboprobes complimentary to the feline GAD cDNA. The levels of mRNA for GAD were analyzed in selected region of the dorsal hippocampus and medial basal hypothalamus in ovariectomized, ovariectomized estradiol-treated, and ovariectomized estradiol- and progesterone-treated rats. In estradiol-treated rats, GAD mRNA levels increased in GABAergic neurons associated with the CA1 pyramidal cell layer, but not in the stratum oriens of CA1 or any other region of the hippocampus. Estradiol plus progesterone treatment reversed the estradiol-induced increase in GAD mRNA in CA1 and induced a small decrease in the hilus. No effect of estradiol or progesterone was observed in the dorsomedial, ventromedial, or arcuate nuclei of the hypothalamus. Estradiol or progesterone may alter cognitive performance and seizure activity by increasing or decreasing, respectively, the activity of GABAergic neurons in the hippocampus.

J Biol Chem. 1996 Dec 20;271(51):32722-8.
Synergy by secretory phospholipase A2 and glutamate on inducing cell death and sustained arachidonic acid metabolic changes in primary cortical neuronal cultures.
Kolko M, DeCoster MA, de Turco EB, Bazan NG.
Secretory and cytosolic phospholipases A2 (sPLA2 and cPLA2) may contribute to the release of arachidonic acid and other bioactive lipids, which are modulators of synaptic function. In primary cortical neuron cultures, neurotoxic cell death and [3H]arachidonate metabolism was studied after adding glutamate and sPLA2 from bee venom. sPLA2, at concentrations eliciting low neurotoxicity (Synergy in neurotoxicity and [3H]arachidonate release was observed when low, nontoxic (10 ng/ml, 0.71 nM), or mildly toxic (25 ng/ml, 1. 78 nM) concentrations of sPLA2 were added together with glutamate (80 microM). A similar synergy was observed with the sPLA2 OS2, from Taipan snake venom. The NMDA receptor antagonist MK-801 blocked glutamate effects and partially inhibited sPLA2 OS2 but not sPLA2 from bee venom-induced arachidonic acid release. Thus, the synergy with glutamate and very low concentrations of exogenously added sPLA2 suggests a potential role for this enzyme in the modulation of glutamatergic synaptic function and of excitotoxicity.

Increased intracellular calcium activates lipolysis (by phospholipases), producing more free fatty acids, as well as excitation and protein breakdown, and in the brain neurodegenerative diseases, calcium excess contributes to clumping synuclein (Wojda, et al., 2008), an important regulator of cytoskeleton proteins. -Ray Peat, PhD

IUBMB Life. 2008 Sep;60(9):575-90.
Calcium ions in neuronal degeneration.
Wojda U, Salinska E, Kuznicki J.
Neuronal Ca(2+) homeostasis and Ca(2+) signaling regulate multiple neuronal functions, including synaptic transmission, plasticity, and cell survival. Therefore disturbances in Ca(2+) homeostasis can affect the well-being of the neuron in different ways and to various degrees. Ca(2+) homeostasis undergoes subtle dysregulation in the physiological ageing. Products of energy metabolism accumulating with age together with oxidative stress gradually impair Ca(2+) homeostasis, making neurons more vulnerable to additional stress which, in turn, can lead to neuronal degeneration. Neurodegenerative diseases related to aging, such as Alzheimer’s disease, Parkinson’s disease, or Huntington’s disease, develop slowly and are characterized by the positive feedback between Ca(2+) dyshomeostasis and the aggregation of disease-related proteins such as amyloid beta, alfa-synuclein, or huntingtin. Ca(2+) dyshomeostasis escalates with time eventually leading to neuronal loss. Ca(2+) dyshomeostasis in these chronic pathologies comprises mitochondrial and endoplasmic reticulum dysfunction, Ca(2+) buffering impairment, glutamate excitotoxicity and alterations in Ca(2+) entry routes into neurons. Similar changes have been described in a group of multifactorial diseases not related to ageing, such as epilepsy, schizophrenia, amyotrophic lateral sclerosis, or glaucoma. Dysregulation of Ca(2+) homeostasis caused by HIV infection or by sudden accidents, such as brain stroke or traumatic brain injury, leads to rapid neuronal death. The differences between the distinct types of Ca(2+) dyshomeostasis underlying neuronal degeneration in various types of pathologies are not clear. Questions that should be addressed concern the sequence of pathogenic events in an affected neuron and the pattern of progressive degeneration in the brain itself. Moreover, elucidation of the selective vulnerability of various types of neurons affected in the diseases described here will require identification of differences in the types of Ca(2+) homeostasis and signaling among these neurons. This information will be required for improved targeting of Ca(2+) homeostasis and signaling components in future therapeutic strategies, since no effective treatment is currently available to prevent neuronal degeneration in any of the pathologies described here.

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By Team FPS – July 8, 2012

Women, Estrogen, and Circulating DHA

Also see:
Fish Oil Toxicity
PUFA, Fish Oil, and Alzheimers
The Randle Cycle
Estrogen, Glutamate, & Free Fatty Acids
Menstrual Cycle Related Epilepsy (Catamenial Epilepsy
Estrogen’s Role in Seizures
Phospholipases, PUFA, and Inflammation

Quotes by Ray Peat, PhD:
“Women are known to have a greater susceptibility than men to lipolysis, with higher levels of free fatty acids in the serum and liver, because of the effects of estrogen and related hormones.

Women on average have more DHA circulating in the serum than men (Giltay, et al., 2004; McNamara, et al., 2008; Childs, et al., 2008). This high unsaturated fatty acid is the first to be released during stress, and biologically, the meaning of estrogen is to mimic stress. Estrogen and polyunsaturated fatty acids have similar actions on cells, increasing their water content and calcium uptake. Long before the Women’s Health Initiative reported in 2002 that the use of estrogen increased the risk of dementia, it was known that the incidence of Alzheimer‘s was 2 to 3 times higher in women than in men.”

“Under the influence of estrogen, or unsaturated fats, brain cells swell, and their shape and interactions are altered. Memory is impaired by an excess of estrogen. Estrogen and unsaturated fat and excess iron kill cells by lipid peroxidation, and this process is promoted by oxygen deficiency. The fetus and the very old have high levels of iron in the cells. Estrogen increases iron uptake. Estrogen treatment produces elevation of free fatty acids in the blood, and lipid peroxidation in tissues. This tends to accelerate the accumulation of lipofuscin, age-pigment. Lactic acid, the production of which is promoted by estrogen, lowers the availability of carbon dioxide, leading to impairment of blood supply to the brain.”

“One of estrogen’s effects is to chronically increase the circulation of free fatty acids, and to favor the long chain polyunsaturated fatty acids, such as EPA and DHA.”

“Some types of dementia, such as Alzheimer’s disease, involve a life-long process of degeneration of the brain, with an inflammatory component, that probably makes them comparable to osteoporosis and muscle-wasting. (In the brain, the microglia, which are similar to macrophages, and the astrocytes, can produce TNF.) The importance of the inflammatory process in Alzheimer’s disease was appreciated when it was noticed that people who used aspirin regularly had a low incidence of that dementia. Aspirin inhibits the formation of TNF, and aspirin has been found to retard bone loss. In the case of osteoporosis (A. Murrillo-Uribe, 1999), as in Alzheimer’s disease, the incidence is two or three times as high in women as in men. In both Alzheimer’s disease and osteoporosis, the estrogen industry is arguing that the problems are caused by a suddenly developing estrogen deficiency, rather than by prolonged exposure to estrogen.”

“Estrogen, which is promoted intensively as prevention or treatment for Alzheimer’s disease was finally shown to contribute to its development.”

“Our innate immune system is perfectly competent for handling our normal stress induced exposures to bacterial endotoxin, but as we accumulate the unstable fats, each exposure to endotoxin creates additional inflammatory stress by liberating stored fats. The brain has a very high concentration of complex fats, and is highly susceptible to the effects of lipid peroxidative stress, which become progressively worse as the unstable fats accumulate during aging.”

“Estrogen causes elevation of free fatty acids, and there are many interactions between the unsaturated fatty acids and estrogen, including their metabolism to prostaglandins, and their peroxidation.”

“Estrogen increases the free fatty acids circulating in the blood, and this shifts metabolism away from the oxidation of glucose to oxidation of fat, and it reduces oxidative metabolism for example by lowering thyroid function (Vandorpe and Kuhn, 1989)”

“In the 1970s, after reading Szent-Gyorgyi’s description of the antagonistic effect of progesterone and estrogen on the heart, I reviewed the studies that showed that progesterone protects against estrogen’s clotting effect. I experimented with progesterone, showing that it increases the muscle tone in the walls of veins, which is very closely related to the effects Szent-Gyorgyi described in the heart. And progesterone opposes estrogen’s ability to increase the amount of free fatty acids circulating in the blood.“

“For example, the brain toxic effects of estrogen were usually neglected, and the much higher incidence of Alzheimer’s disease in women was usually interpreted as evidence that the disease is caused by a deficiency of estrogen. The neurotoxic effects of lipid peroxides and prostaglandins were ignored, while fish oil was advocated to prevent and treat dementia. The toxic effects of serotonin and nitric oxide were seldom considered, whle drugs to increase those were advocated to treat Alzheimer’s.”

“Acrolein’s self-stimulating production from DHA is another factor that could account for the predominance of Alzheimer’s disease in women, since, under the influence of estrogen, women accumulate significantly more DHA than men (Giltay, et al., 2004), and similar effects can be seen in animal studies (McNamara, et al., 2008).”

Am J Clin Nutr. 2004 Nov;80(5):1167-74.
Docosahexaenoic acid concentrations are higher in women than in men because of estrogenic effects.
Giltay EJ, Gooren LJ, Toorians AW, Katan MB, Zock PL.
BACKGROUND:
During pregnancy there is a high demand for docosahexaenoic acid (DHA), which is needed for formation of the fetal brain. Women who do not consume marine foods must synthesize DHA from fatty acid precursors in vegetable foods.
OBJECTIVE:
We studied sex differences in DHA status and the role of sex hormones.
DESIGN:
First, DHA status was compared between 72 male and 103 female healthy volunteers who ate the same rigidly controlled diets. Second, the effects of sex hormones were studied in 56 male-to-female transsexual subjects, who were treated with cyproterone acetate alone or randomly assigned to receive oral ethinyl estradiol or transdermal 17beta-estradiol combined with cyproterone acetate, and in 61 female-to-male transsexual subjects, who were treated with testosterone esters or randomly assigned for treatment with the aromatase inhibitor anastrozole or placebo in addition to the testosterone regimen.
RESULTS:
The proportion of DHA was 15 +/- 4% (x +/- SEM; P < 0.0005) higher in the women than in the men. Among the women, those taking oral contraceptives had 10 +/- 4% (P = 0.08) higher DHA concentrations than did those not taking oral contraceptives. Administration of oral ethinyl estradiol, but not transdermal 17beta-estradiol, increased DHA by 42 +/- 8% (P < 0.0005), whereas the antiandrogen cyproterone acetate did not affect DHA. Parenteral testosterone decreased DHA by 22 +/- 4% (P < 0.0005) in female-to-male transsexual subjects. Anastrozole decreased estradiol concentrations significantly and DHA concentrations nonsignificantly (9 +/- 6%; P = 0.09).
CONCLUSION:
Estrogens cause higher DHA concentrations in women than in men, probably by upregulating synthesis of DHA from vegetable precursors.

Psychoneuroendocrinology. 2009 May;34(4):532-9. Epub 2008 Nov 28.
Gender differences in rat erythrocyte and brain docosahexaenoic acid composition: role of ovarian hormones and dietary omega-3 fatty acid composition.
McNamara RK, Able J, Jandacek R, Rider T, Tso P.
The two-fold higher prevalence rate of major depression in females may involve vulnerability to omega-3 fatty acid deficiency secondary to a dysregulation in ovarian hormones. However, the role of ovarian hormones in the regulation of brain omega-3 fatty acid composition has not been directly evaluated. Here we determined erythrocyte and regional brain docosahexaenoic acid (DHA, 22:6n-3) composition in intact male and female rats, and in chronically ovariectomized (OVX) rats with or without cyclic estradiol treatment (2 microg/4d). All groups were maintained on diets with or without the DHA precursor alpha-linolenic acid (ALA, 18:3n-3). We report that both male (-21%) and OVX (-19%) rats on ALA+ diet exhibited significantly lower erythrocyte DHA composition relative to female controls. Females on ALA+ diet exhibited lower DHA composition in the prefrontal cortex (PFC) relative males (-5%). OVX rats on ALA+ diet exhibited significantly lower DHA composition in the hippocampus (-6%), but not in the PFC, hypothalamus, or midbrain. Lower erythrocyte and hippocampus DHA composition in OVX rats was not prevented by estrogen replacement. All groups maintained on ALA- diet exhibited significantly lower erythrocyte and regional brain DHA composition relative to groups on ALA+ diet, and these reductions were greater in males but not in OVX rats. These preclinical data corroborate clinical evidence for gender differences in peripheral DHA composition (female>male), demonstrate gender differences in PFC DHA composition (male>female), and support a link between ovarian hormones and erythrocyte and region-specific brain DHA composition.

Proc Nutr Soc. 2008 Feb;67(1):19-27.
Gender differences in the n-3 fatty acid content of tissues.
Childs CE, Romeu-Nadal M, Burdge GC, Calder PC.
Dietary n-3 PUFA have many beneficial effects on cell and tissue function and on human health. In mammals the n-3 essential fatty acid alpha-linolenic acid (ALNA) can be converted into longer-chain (LC) n-3 PUFA such as EPA and DHA via a series of desaturase and elongase enzymes that are mainly active in the liver. Human studies have identified that males and females appear to differ in their ability to synthesise EPA and DHA from ALNA, with associated differences in circulating concentrations. Based on studies of women using the contraceptive pill or hormone-replacement therapy and of trans-sexual subjects it is suggested that sex hormones play a role in these differences. The rat has been used to investigate gender differences in n-3 PUFA status since this model allows greater dietary control than is possible in human subjects. Like human subjects, female rats have higher plasma DHA concentrations than males. Rats also respond to increased dietary ALNA in a way that is comparable with available human data. The concentrations of LC n-3 PUFA in rat plasma and tissues are positively associated with circulating concentrations of oestradiol and progesterone and negatively associated with circulating concentrations of testosterone. These findings suggest that sex hormones act to modify plasma and tissue n-3 PUFA content, possibly by altering the expression of desaturase and elongase enzymes in the liver, which is currently under investigation.

Am J Clin Nutr. 2006 Dec;84(6):1330-9.
Dietary fish intake and plasma phospholipid n-3 polyunsaturated fatty acid concentrations in men and women in the European Prospective Investigation into Cancer-Norfolk United Kingdom cohort.
Welch AA, Bingham SA, Ive J, Friesen MD, Wareham NJ, Riboli E, Khaw KT.
BACKGROUND:
The n-3 polyunsaturated fatty acids (n-3 PUFAs) docosahexaenoic acid and eicosapentaenoic acid, found in fish and fish-oil supplements and also formed by conversion of alpha-linolenic acid in soy and rapeseed (canola) oils, are thought to have cardioprotective effects.
OBJECTIVE:
Because the relative feasibility and measurement error of dietary methods varies, this study compared fish and fish-oil intakes obtained from 4 dietary methods with plasma n-3 PUFAs in men and women in a general population.
DESIGN:
The study participants were 4949 men and women aged 40-79 y from the European Prospective Investigation into Cancer-Norfolk United Kingdom cohort. Measurements of plasma phospholipid n-3 PUFA concentrations and fish intakes were made with the use of 4 dietary methods (food-frequency questionnaire, health and lifestyle questionnaire, 7-d diary, and first-day recall from the 7-d diary).
RESULTS:
Amounts of fish consumed and relations with plasma phospholipid n-3 PUFAs were not substantially different between the 4 dietary methods. Plasma n-3 PUFA concentrations were significantly higher in women than in men, were 20% higher in fish-oil consumers than in non-fish-oil consumers, and were twice as high in fatty fish consumers as in total fish consumers. Only approximately 25% of the variation in plasma n-3 PUFA was explained by fish and fish-oil consumption.
CONCLUSIONS:
This large study found no substantial differences between dietary methods and observed clear sex differences in plasma n-3 PUFAs. Because variation in n-3 PUFA was only partially determined by fish and fish-oil consumption, this could explain the inconsistent results of observational and intervention studies on coronary artery disease protection.

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By Team FPS – July 5, 2012