AAP diabetes, concepts, and research ...
Harry Horton

Pittsboro, NC

#456 Aug 18, 2012
The earliest reaches of the earths history 4.6 billion years ago consisted of pH and temperature variances. The temperature variances resulted from the alternation of daylight and night time. So pH and temperature became the mainstay phenomena that constituted the earliest dimensions of the energy processes that would emerge within biological life during these non oxygenated years of earth's existence. #Post 445 on the UCSD discovery with the cryptochrome and the KL001 circadian rhythm embodied processes within the metabolism brings forth two important points. Anaerobic glycolysis started in the non oxygented regions 3.8 billion years ago and this metabolic energy process has a lot to do with the nature of present day glucose production. Glucose production as such as where the anaerobic glycolysis, and the production of glucose is intimately tied into and regulated even by these other two features of the circadian rhythm: KL001 and cryptochrome. KL001 and cryptochrome are nothing more than representative feature of the pH and temperature items that constituted earth's non oygenated environs 4.6 billion years ago. The most fundamental and earliest features of earth's energy processes, the temperature and pH that is heavily embedded in the circadian rhythm. So diabetes is expressive at its most fundamental origins as arising from these early non oxygenated areas of earths history 4.6- 3.8 billion years ago. Where the first sophisticated energy system anaerobic glycolysis that emerged 3.8 billion years ago is regulated by an even earlier in evolutionary history process: Sunlight and nigthtime alternations that essentially constitute the phenomena of temperature. Temperature thus interwoven into pH processes. These features are what cryptochrome and KL001 are items part of also.
Harry Horton

Pittsboro, NC

#457 Aug 20, 2012
The most fundamental and earliest features of earth's energy processes, the temperature and pH along with calcium exert a strong regulatory action on glucose production. And most significantly such glucose production is a later evolutionary biological process that came afterwards to pH, temperature and calcium. Temperature is an expression of circadian rhythm phenomena since the nature of temperature on the earth and hence within biological cells is characterized by the circadian rhythm dimension that characterizes temeperature, whether earth temperature or intra cellular temperature status and functioning. Thus the earliest features of biological cells, temperature, pH and calcium amounts, once these features enter into biological cells processes at the most earliest point in evolutionary history. The result is the three features form the earliest foundation energy process attributes of the biological cell. And because of that fundamental first position in the cells these three attributes then exert a sturdy and strong regulatory process over & on the subsequent evolved later energy process called glucose production---such glucose production appearing at the 3.8 billion year ago mark in the earth's non oxygenated regions of evolutionary history. One significant issue is, since circadian rhythm and its temperature characteristic that would then in turn extend to pH and calcium processes, as an early tableau of functions and features, would also extend its regulatory actions further and later into the mitchondrial operations as expressed as such as the alternation of oxidative phosphorylation with the uncoupling protein and proton leak phenomena. Since the alternation does serve one purpose and that is to increase heat (i.e. temperature increase as such) in myocytes. That action is a segment feature of the circadian rhythm in itself. And thus such feature's original dynamics can be traced back to the 4.6 billion year ago earth domain characteristics of temperature and pH and calcium as they come together and interweave as a tableau of earliest energy functions to comprise biological cellular life in these very earliest stretches of earth's geo historical domains. Thus this mitochndrial alternation could be regulated by circadian rhythm processes no different that the earlier evolved glucose production also regulated by circadian rhythm processes. Both glucose production and miotchondrial ETC operations are linked back, constituted and most likely regulated by the earliest earth evolutionary features of the non oxygenated regions: daylight and nighttime alternation---that is the circadian rhythm. And the circadian rhythm also expressive and containing of the temperature characteristic that Richard Fiddian Green made so much about in his rapid response piece: "Worshipping a new God pH".
Harry Horton

Pittsboro, NC

#458 Aug 20, 2012
With the previous post in mind: The fact that TRPV1 hypofunctional mutant gene was successfully treated by capsaicin and diabetes I and Diabetes II disappeared rather thoroughly, according to a study in the journal Cell December 15 2006. THe therapeutic thrust of the capsaicin treatment of the pancreatic islet TRPV1 nerve was: pH, Temperature functions and calcium then fall back into an orderly and health functioning and relationship between themselves. One major healthy functioning is the regulatory role of regulating glucose production and mitochondrial ETC operations by circadian rhythm temperature, pH and calcium processes. THere is no need to elevate the pain sensation in a 'capsaicin TRPV1 nerve hypofunctional mutant' because there is no weak pain signal and operation extant with the dead hpofunctioanl tRPV1 mutant's existence. Once treatment of killing the nerve took place. Thus alkaline pH returns to a more healthier neutral pH and coordinated with pH: temperature,--- too also normalizes along with calcium amount transferance normalcy reinstituted with the treatment of the TRAPV1 mutant nerve that has the weak pain signal.
Harry Horton

Pittsboro, NC

#459 Aug 20, 2012
Further studies and content concerning the previous two posts: "Biogenesis and early life on earth and Europa: Favoured by an alkaline OCean?" Stephan Kempe Jozef Kazmierczak" Quote:"Such an environment could be favourable to biogenesis since it may have provided for very low Ca2+ concentrations mandatory for the biochemcial functions of proteins."

Crytochrome -(from Wikipedia)

Evolutionary history and structure:

Cryptochromes (CRY1, CRY2) are evolutionarily old and highly conserved proteins that belong to the flavoproteins superfamily that exists in all kingdoms of life. All members of this superfamily have the characteristics of an N-terminal photolyase homology (PHR) domain. THe PHR domain can bind to the flavin adenine dinucleotide (FAD) cofactor and a light harvesting chromophore."
Later the article stated this:
Recently researchers have observed that oxidized FAD is readily reduced to FAD.- by light" ENd quote.

ITs intersting that FAH2 is produced by the TCA cycle with reactions involving fumarate and succinyl entity. And thus FADH2 presence introduces the biochemical stretches of the earliest light and dark cycle operations within the much later evolutionary appearing mitochondria and its oxygenated operations.
Cryptochrome is a biochemical entity that UCSD researchers have shown that have a role of which crytochrome can regulate glucose production as earlier posts have related. Cryptochrome is thus an entity of the circadian rhythm.
Harry Horton

Pittsboro, NC

#460 Aug 20, 2012
FAD- wikipedia

THe primary biochemical role of FADH2 in eukaryotes is to carry high energy electrons used for oxidative phosphorylation. FAD is a prosthetic group in the enzyme complex succinate dehydrogenase
(complex II) that oxidizes succinate to fumarate in the eighth step of the citric acid cycle to the high energy electrons from the oxidation are stored momentarily by reducing FAD to FADH2. FADH2 then reverts to FAD sending its high energy electrons through the electron transport chain; the energy in FADH2 is enough to produce 1.5 equivalents of ATP by oxidative phosphorylation.
A flavoprotein is a protein that contains a flavin moiety, this may be in the form of FAD or FMN (Flavomononucleotide). THere are many flavoproteins besides components of the succinate dehydrogenase complet, including a- ketoglutamate dehydrogenase and a component of the pyruvate dehydrogenase complex." End quote.

With such a central association between cryptochrome and flavo proteins, which is another way of saying the regulatory circadian rhythm processes that one finds in the light producing and processing metabolisms in the body----such influences can extend to the mitochondrial ETC chain and TCA operations via FAD and its reduced form FADH2 presence and functioning in the Mitochondria. FADH2 presence with its ATP production capacities could also be a statement of the circadian rhythm's light and dark cycle operations embodied in FADH2 also, in a sense. The circadian rhythm's light and dark cycles thus have an ATP production role in a sense via FAD and FADH2 operations in the mitochondria. THus a regulatory role also could be present with such above role.
Harry Horton

Pittsboro, NC

#461 Aug 21, 2012
In regards to the previous five posts several facets and dimensions stand out. Cryptochrome is know to play a substantial regulatory role in glucose production.(2) Cryptochrome interestingly is interwoven with FAD since the cryptochrome entity can bind with FAD cofactor. This brings the issue does FAD via----(its evolutionary historical relationship and present day relationship in mind),----"FAD cofactor" exhibit a regulatory role of the circadian rhythm into the TCA cycle since cryptochrome being a circadian rhythm feature binds to a FAD metabolism feature---such feature being the FAD cofactor. Thus the issue does FAD and FADH2 presence within the TCA cycle, do such FAD comprised interactions harken the arrival and presence of the regulatory actions of the circadian rhythm. And such regulatory actions span from the earliest circadian rhythm areas of earth's evolutionary history (Circadian Rhythm essence present in the day to nightime cycle of the earth 4.6 billion years ago, for example) extending into the later evolved oxygenated era mitochondria operations. And thus FAD and FADH2 process carry additionally in some manner regulatory weight and authority over their associated areas in the TCA cycle. Most significantly FAD and FADH2 are involved in ETC oxidative phosphorylation processes of the mitochondria. The circadian rhythm presence as noted by R.F. Green is present in the alternation of ETC oxidative phosphorylation with uncoupling protein operations. R.F. Green noted in one of his rapid response pieces,the alternation as such is reminiscent of division or labour of light and dark cycle of photosynthesis. COntinued next post.....
Harry Horton

Pittsboro, NC

#462 Aug 21, 2012
Once again the Richard Fiddian Green rapid response piece: "A call to worship a new god pH".
Temperature is major component along with pH, for regulating the most basic processes of human health and also when in dysfunctional status for bringing on diabetes and metabolic syndrome. Temperature is the core essence of the circadian rhythm. Studies are beginning to show that temperature and circadian rhythm have a strong regulatory role over glucose production. Yet also circadian rhythm and temperature could likewise have a strong regulatory role over TCA cycle operations and the ETC processes too. FAD and FADH2 could be a conduit for such a connectivity of these earlier pH and temperature features way back in earth's evolutionary history, thus connecting the circadian rhythm regulatory roles based in these early evolutionary history areas into the much later evolved mitochondria. And thus into the TCA cycle and the ETC chain. With FAD and FADH2.

i.The glucose production is representative of anaerobic glcolysis operations that first appeared 3.8 billion years ago.
ii. The FAD FADH2 components of the mitochondria operations are representative of biochemical operations that came into being roughly 400 million years ago.
The light and dark cycle biological features exhibit a regulatory presence over the above i. and ii. And a rather strong and thorough presence over the two entities.
Harry Horton

Pittsboro, NC

#463 Aug 21, 2012
The following internet articles:
"Lecture VII. The citric Aicd cycle II."
"Glutamine: the MEperor or his clothes?"
"The Pyruvate Dehydrogenase (PDH) and the TCA cycle (Krebs cycle)."
"Citric Acid Cycle - Oregon State University."

The above articles center on interesting features and in depth analysis of the anapleurotic metabolites.
Harry Horton

Pittsboro, NC

#464 Aug 23, 2012
The following articles are some good internet pieces to read in sequence that can throw some light on the beginnings of diabetes and metabolic syndrome.

"Biogenesis and Early Life on Earth and Europa: Favoured by an alkaline OCean?" Stephan Kempe.

"Recent life relies on highly sophisticated proteins located in the cell membranes, the so called Ca-pumps which continously remove Ca2+ from the protoplasm of the cell and keep calcium level <10-6M (Orrenius et al. 1989; Trump and Berezesk, 1995). Since these pumps most likely did not arise ab initio environments and allow for a very low Ca2+ concentration are arguably a promising site for biogenesis. Kempe & Kazmierczak, 1994).

"Discovery of chemical that affects biological clock offers new way to treat diabetes." UC SanDiego.

"A Call to Worship a new God, tissue pH" Richard Fiddian Green.

"Circadian rhythms in the development of obesity: potential role for the circadian clock within the adipocyte" M.S. Bray and M.E. Young.
a subsection of the article:'Circadian rhythms and the regulation of body mass and fat.'

"Metabolic Dysregulation with Atypical Antipsychtoics occurs in the absence of underlying Disease a placebo - controlled study of olanzapine and risperidone in Dogs." Diabetes the journal. Marilyn Ader author.

A quote from the study: "The present studies revealed a dramatic impairment in B-cell compensation during OLZ."

"Atypical antipsychotics rapidly and inappropriately switch peripheral fuel utilization to lipids impairing metabolic flexibility in rodents." Albaugh VL.

"The ability of antipsychotics to lower dark cycle RER in mice corresponded to cause metabolic side effects. Our studies indicate that lipocentric mechanisms or altered intermediary metabolism could underlie the FFA lowering and hyperglycemia (Randle cycle) as well as some of the other dies effects of atypical antipsychotics."

THe above are some intersting articles that relate the central and potential role of temperature, pH, and calcium within the dark light dynamics of earth's history as major dimensions for creating meatbolic syndrome conditions. Following posts will expound on these articles.
Harry Horton

Pittsboro, NC

#465 Aug 23, 2012
The article: "Biogenesis and Early Life on Earth and Europa: Favoured by an alklaine Ocean." adsabs.harvard.edu/abs/202AsBio...2....123k . Stephan Kempe.

When arriving at this article site via the internet, once on the page find the Full Text Article site. It is in the upper right hand corner of the page. Click on the Full Text Article site. ANd the full article will flash up. The internet page is "The Smithsonian/NASA Astrophysics Data System". This page contains "the Full Text article" entry.
Harry Horton

Pittsboro, NC

#466 Aug 23, 2012
The quote from the Ader article "the Metabolic dysregulation in absence of underlying disease article":'the dramatic B cell compensation impairment' could be related in the altered healthy normal calcium metabolism. Calcium is a mandatory metabolic process for release of the insulin in B-Cell compensation, when the B cells are presented with initial spikes and rises in glucose. This b Cell compensation process did not occur. This phenomena can be compared to the Stephan Kempe article on alkaline oceans article involving Europa and earth. Low amounts of calcium were necessary in the alkaline oceans for biochemical processes to transpire. And this early feature of earth's evolutionary history when unicellular biological life was commencing, involved calcium metabolism presence to be apparent in the earliest cell's operations. And this earliest feature is dysregulated and dysfunctional with the B cell compensation phenomena. Since calcium plays a central role in insulin release in the B cells. The calcium presence in B cell metabolism may as well be an expression the earliest features of earth' evolutionary history---calcium in this case that is----as exhibiting a regulatory role in regulating all later energy homeostasis systems such as hepatic liver functions and mitochondrial functions as well as anaerobic glycolysis.
Harry Horton

Pittsboro, NC

#468 Sep 8, 2012
Further thoughts on the Marilyn Ader article on Metabolic dysregulation in absence of underlying disease. THe impairment of Beta cell compensation could be an expression of the deranged calcium metabolism that results from zyprexa usage. Calcium metabolism would be in the role of regulatory processes. In regards to the Ader phenomena involving beta cell impairment. Calcium is a major component for insulin release in the body and evidently calcium's mechanisms are repressed with the zyprexa usage. These findings can be combined with the articles on the circadian rhythm exerting a regulatory role over the body's metabolic functions such as the fact whether people get obese or not. THe combination of pH, temperature--(and that is temperature being an expression of the circadian rhythm operations)---and calcium metabolism play major roles in regulating the later evolved energy systems in the body. THe Richard Fiddian Green study worshipping a new God, pH, the article includes temperature as a major factor for creating balance or imbalances in the body that lead to disease. Also the Stephan Kempe study on the presence of alkaline conditions along with calcium as the two most prominent features for generating life on the planet. And along with these features in their eventual destiny of a regulatory role they would play in relation and also upon later evolved energy systems in the world. In other words the features for giving rise to bio genesis, the first cells on the planet, would be also the rise of the first regulatory functions of these features pH and temperature, on later evolved energy systems.
Harry Horton

Pittsboro, NC

#469 Sep 8, 2012
"Circadian rhythms and the regulation of metabolic tissue function and energy homeostasis" Zvonics Obesity 2007 March. This study relates the recent studies centering on the circadian rhythm's regulatory role over the development and characterization of obesity.
Harry Horton

Pittsboro, NC

#470 Sep 22, 2012
In regards to the previous five posts content the issue concerning the Marilyn Ader Beta Cell compensatory response to glucose challenges as related in her study----one perspective towards this is, the failure of calcium in a regulatory role, for maintaining proper evolved insulin functions, in the body's cells. One can read the the earlier posted article of Stephan Kempe: "Biogenesis and Early Life on Earth and Europa: Favoured by an alkaline Ocean?" In the article and the quote presented in recent August-Sept posts, the calcium pumps in cell membranes, operating adequately down through life, maintain energy homeostasis functions normalcy. Most significant is the fact such calcium operations are an expression of the earliest items and processes in the biological cells of the nonoxygenated era, in earth's earliest times: 3.8 billion years ago. Secondly the calcium pumps and calcium metabolism too, would exert a regulatory role within its participation, with other aspects and functions of the later evolved cell's processes. The Ader article's fact: that the failure of B cell compensation is one which relates the loss of regulatory operations of calcium metabolism over the healthy insulin functions. In the case of the Ader study, the insulin response does not operate adequately because the underlying dysfunctionality of calcium metabolism is present. Hence, the calcium metabolism dysfunctionality is an expression of calcium metabolism, and calcium metabolism is one of the earliest appearing items and processes in the earliest cells in the body, 3.8 billion years ago. And thus gives one an idea that the earliest areas of the biological cell: pH, temperature, and calcium go out of balance and become dysfunctional among themselves and with this dysfunctionality comes metabolic syndrome conditions, and diabetes.
Harry Horton

Pittsboro, NC

#471 Oct 6, 2012
Recent articles on atypical antipsychotics and their side effects from the web.

(1) "Atypical antipsychotics and the neural regulation of food intake and peripheral metabolism" Karen Teff Sangwon Kim.
(2) Role of histaminergic H1 and H3 receptors in food intake: a mechanism for...[Pro Neuropsychopharmacol Biol Psychiatry]
(3) Novel insulin Sensitizer Drug candidate - BGP-15 can prevent metabolic side effects of atypical antipsychotic.
(4) "A potential role for adjunctive vitamin D therapy in the management of weight gain and metabolic side effects of the atypical antipsychotics."
(5) "The HSP co-inducer BGP-15 can prevent the metabolic side effects of the atypical antipsychotics"
(6)"overcoming insulin resistance with ciliary neurotorhic factor."
(7) "Olanzapine increases cell miotic activity and oligodendrocyte - lineage cells in the hypothalamus"
(8) Atypical antipsychotics rapidly and inapproiately switch peripheral fuel utilization to lipids, impairing metabolic flexibility in rodents"
Harry Horton

Pittsboro, NC

#472 Oct 6, 2012
"BGP-15 a New type of insulin sensitizer" professional.diabetes.org/content/poster .

The above web site illustrates the BGP-15 insulin sensitizer and its operations and processes.
Harry Horton

Pittsboro, NC

#473 Oct 8, 2012
Further internet articles and studies:

"VEGF-B drug candidate may be diabetes research breakthrough" www.science 20.com .
"Breakthrough for type 2 diabetes treatment: Therapy involves the blockade of signalling by VEGF-B Protein." Science Daily. Sept 27, 2012.
Harry Horton

Pittsboro, NC

#474 Oct 11, 2012
The following medical study posting is for reference primarily for my own research. I could not e email it to my hotmail account so the next best thing is to post it here. The article:

"The HSP- co inducer BGP-15 can prevent the metabolic side effects of the atypical antipsychotics" Zsuzanna Literati-Nagy" www.hspsandddiabetes.com/Literat-Nagy EtA!2012.pdf.

A quote "BGP-15 administration improves clozapine induced insulin sensitivity after 1 month clozapine treatment." end quote.

* Most significant is the fact that this is a whole article. Not just the abstract. All of the methods and scientific protocols and operations are present in the medical study. Most importantly, the discussion at the end of the study is also included and present in the above article.
Harry Horton

Pittsboro, NC

#475 Oct 11, 2012
"The HSP-co inducer BGP-15 can prevent the metabolic side effects of the atypical antipsychotics" Zsuzanna Literati-Nagy" www.hspsanddiabtets.com/Literat-Nagy EtA12012.pdf

Excerpts from the medical study:

"BGP-15 administration improves clozapine-induced insulin sensitivity after chronic (1 month) clozapine treatment." Further excerpt material: "Four different experiments are reported on the AAPD BGP-15 intervention in a human trial of healthy men, a rodent animal model, and an in vitro adipocyte cell culture system. Olanzapine caused rapid insulin resistance in healthy volunteers and was associated with decreases level of HSP72 in peripheral mononuclear blood cells. Both Changes were restored by the administration of BGP_15. In Wistar rats, weight gain and insulin resistance induced by clozapine were abolished by BGP-15." End quote.
Further excerpted material from the study: "Previously, we observed that BGP-15 administrated could improve insulin sensitivity in insulin- resistant subjects (LIterati-Nagy et al. 2009). We then examined whether BGP-15 could restore insulin sensitivity in healthy subjects administered Olanzapine. Indeed, the double blind, paralell, placebo- controlled phase I study found that BGP-15 administration prevented olanzapine induction of insulin resistance.
BGP-15 had no significant effect on the pharmacokinetics of olanzapine and an olanzapine induced weight gain. We have previously demonstrated that it did not alter the pharmaco-dynamics of olanzapine and has a good safety profile in humans (Literati -Nagy et al. 2010). ANother bio active compound,alpha lipic acid, both increases HSP's (Gupte et al 2009 a,b) and limits and weight gain from AAPDs in patients with schizophrenia, supporting the concept that HSP induction can reverse negative AAP metabolic effects.(Kim et. al. 2008).

E. Kim, Park DW -(2008) "A preliminary investigation of alpha-lipoic acid treatment of antipsychotic drug induced weight gain in patients with Schizophrenia" J. Clin Psychopharmacol 28:138-146.
Harry Horton

Pittsboro, NC

#477 Oct 13, 2012
"Beneficial effects of the insulin sensitizer (HSP inducer) BGP-15 on olanzapine-induced metabolic disorders" Literati Nagy B.

Excerpt: "Administration of BGP-15 significantly reduced olanzapine induced insulin resistance. The protective effect of BGP-15 on insulin stimulated glucose utilization had the highest magnitude in the values calculated for the muscle tissue (p=0.002)."
End quote.

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