1- Serum albumin metabolism: A possible first messenger role in vertebrates. An old hazy vision, a new look. 1-1
Albumin metabolism: A possible role in carbohydrate recognition, utilization, and the etiology and the pathogenesis of obesity and diabetes mellitus.
Osman, Elnour, Abd Magid Head department: Food Chemistry and Nutrition, Food Research Center, P. O. Box 213, Khartoum North, Sudan. 2
3
Abstract: Albumin distinct physiological role is still obscure and had been over-looked for decades. Albumin is a prominent feature in evolution and probably adaptation of species. Albumin metabolism was hypothesized to play a first messenger role in vertebrates by alteration of capillary membrane permeability, calcium signaling and internal calcium mobilization in response to every moment changes of the animal surroundings. Intra and extra-vascular albumin metabolism might generate endogenous nicotinic acid which facilitate albumin molecule extravasation and gear a metabolic fuel cycle between FFA and glucose and the consequent cascade of metabolic events. Every tissue has a genetically coded quota of degradable albumin for the proper functioning of the tissue. Deviation from this albumin quota, for numerous reasons, might provoke to morbidity. What we consider diseases might simply be a reversion to in- uterine physiologic and genetic memory archived by prevalent albumin metabolic patterns and masked by adult albumin patterns after birth. When we grow old, our disabled albumin becomes incapable of suppressing in- uterine genes which deleteriously express themselves, we get sick, and we end exactly where we have started. Albumin metabolism is suggested to play a first messenger role between the environment and our DNA. Global warming, climatic changes, pollution and agrichemical residues, in 1
addition to numerous factors, might alter albumin metabolism thus threatening animal existence. However, some sort of environmental malnutrition concept is emerging. Albumin metabolism in relation to carbohydrate metabolism, the etiology and pathogenesis of obesity and diabetes mellitus is outlined. Blood lipids and related diseases in relation to albumin metabolism are also hypothesized. Operation of the immune system, water metabolism, hormonal actions, as well as carcinogenesis and other diverse pathophysiological issues are suggested on the light of molecular albumin metabolism. This is part one of the series of the integrated vision research hypothesis outlining, at the macro level, such possible relations. In 1-1 albumin metabolism in relation to the etiology and pathogenesis of obesity and diabetes mellitus is theorized on the light of syn-albumin insulin antagonism. Sub-titles include: synalbumin insulin antagonism,Glucose-FFA metabolic fuel cycle, etiology of obesity, diabetogenic modes of action, insulin vs oral hypoglycemic, what probably happens in the diabetic pancreas and liver, nicotinic acid vs nicotinamide, environment and diet implication, therapeutic and management approaches of obesity and diabetes.
2
1- Albumin metabolism: a possible first messenger role in vertebrates. An old hazy vision, a new look. Osman, Elnour, Abdel Magid * E-mail:
[email protected] Theodore Peters (1970) stated that albumin, the most abundant plasma protein, remains the least well understood, and its functions are still obscure. Earlier, Luetscher (1947) wrote" The common denominator of almost every pathological state is a relative or absolute decrease in the serum albumin". Other writers have confirmed and extended this observation ( Meindok, 1967; Owen, 1958; and Watson, 1965). From the above statements, one can conclude that normal levels of serum albumin might be tightly linked with health. The prompt question that arises would be: what are the probable functions of the molecule in health and what happens in disease? This integrated vision research hypothesis, at the macro level, is intended to provide a general frame-work that might accommodate a tremendous body of literature reported on albumin. However, proportional to the quantity of research and information reported on the molecule, the biological role of albumin could be the yet unidentified first messenger. A first messenger should fulfill general pre-requisites
3
such as availability, versatility, and of course involvement in almost every physiological reaction. There is little doubt that liver is the sole site of albumin synthesis (Dancis et al., 1957), and it is catabolized in almost every tissue of the body (Radovick et al., 1963). Every tissue might have its own genetically coded quota of degradable albumin to express the genetic characteristics of the tissue under question. Degradable tissue albumin might, therefore, regulate and harmonize the whole spectrum of tissue activities such as metabolic fuel selection, immune responses, cell cycle, and diverse specialized tissue functions. It is probable that the quota catabolized by every tissue might determine, to a large extent, the normal functioning of that tissue as would be discussed in the etiology of diabetes mellitus on the light of syn-albumin insulin antagonism. The previous statements, according to the hypothesis, emphasize the central role of the liver in the metabolism. Phospholipid synthesis in the liver besides bile synthesis (Baxter, 1966), make the liver the exclusive tissue responsible for membrane permeability as would be touched upon throughout this series. They also indicate the significance of albumin catabolism in all tissues the thing that indirectly point out to the involvement of the molecule degradation products in the common reactions shared by almost all tissues in the form of enzymes. The catabolism of albumin molecule, as would be explained, might influence membrane permeability and calcium 4
signaling, as well as internal calcium mobilization. The failure of tissues to degrade the genetically assigned albumin quota might impair its function, while excessive utilization of the upper genetically coded degradable albumin quota might exhaust the tissues. Capillary membrane permeability to albumin might be detrimental in both cases. It is possible that the catabolic mode is more important than albumin level or of equal importance as the later might be influenced by diet and environment. In fact, albumin synthesis and catabolism are correlated, to some extent, to each other (Theodore Peters, 1970). Albumin synthesis, however, remains one of life mysteries. Certain aspects of the catabolism of plasma proteins were believed to be directly linked to the basal metabolic rate (Schultze and Heremans, 1966), which might point out to a possible involvement
of
albumin
in
body
temperature
regulation.
Mobilization of FFA via albumin result in the release of hydrogen ions (Rudman and Shank, 1966). This is probably why large meat eaters excrete strongly acidic urine (Passmore and Eastwood, 1986). Again, a possible involvement of albumin in acid-base balance of the body is pointed out. Administration of salt-free solution of albumin have an inhibitory effect on aldosterone secretion (Bratter et al, 1959). Albumin might, therefore, have a role in water and electrolyte metabolism. However, to assimilate the proposed first messenger role of albumin, the excellent review on serum albumin 5
(Theodore Peters, 1970), should be always recalled. He also presented information on albumin as a prominent feature in evolution of species. Recently, albumin was reported to be involved in the origin of vertebrates (Baker, 2002). Sandor (1966), concluded that serum albumin of bovine, rabbit, and man have small differences which might be of little, if any, significance. Males have higher circulatory albumin levels with higher catabolic velocity (Steinfeld, 1960). All gender diseases, including all sexual disturbances, prior to menopause or andropause might be caused by disturbances of such albumin metabolic patterns imposed by sex hormones. It is not only sex hormones that influence serum albumin metabolism, but also food and the whole environment as would be broadened in subsequent publications. A gender difference was also observed in serum major bile acids (Trautwein et al, 1999), chenodeoxycholic acid being higher in males while cholic acid is higher in females. This situation suggests that sex hormones might operate via other metabolic tools. Here, sex differences at the level of calcium signal transduction might occur as would be suggested later. This gender difference might explain, at least in part, the longer life of females than males as chenodeoxycholic acid might be an inflammatory agent with augmented calcium signaling the thing that tear men bodies earlier. Therapeutic potentials of dermal major bile acids were patented (Osman and Abdel Gadir, 2001; Abdel Gadir, 2003). However, bile secretion under food and nervous 6
control, almost the whole external environment, might suggest numerous and crucial physiological roles for bile acids in health and disease probably via influencing albumin metabolism. Bile might, therefore, have an important role in animal adaptation and evolution. Dermal chenodeoxycholic acid was patented as a hypoglycemic agent (Osman and Abdel Gadir, 2000) as well as other probable physiological functions (Osman and Abdel Gadir, 2000). The idea behind the dermal application of bile acids, in addition to convenience, is to deliver them to the blood in a pure form away from possible interactions in the GIT. However, the anti-microbial activity of metronidazole might be correlated, in no small way, to the drug ability to increase serum chenodeoxycholic acid (Low-Beer and Nutter, 1978). The link between albumin metabolism and the operation of the immune system will be presented in a subsequent article. Cholic acid by the suggested induction of albumin hypo catabolism might present new horizons for half-hormone therapy. Cholic acid might function as half estrogens, half GH as both hormones induce albumin hypo catabolism. It might, therefore, decrease
membrane
permeability,
retard
calcium
signals
transduction, and induce internal calcium mobilization. It was observed (Friedman et al, 1952) that hypercholatemia induced hyper cholesterolemia.
Cholesterol is a membrane component. It is
probable that this is how cholic acid might decrease membrane permeability and retard calcium signal transduction. Cholic acid 7
might have sedative and tranquilizing effects. However, the statements might explain, at least in part, why females are more patient and persistent. Chenodeoxycholic acid might act as half androgen as it is supposed to accelerate albumin catabolism, increase membrane permeability, and augment calcium signals transduction. Both compounds might have profound therapeutic potentials. However, the bile acid of choice and its therapeutic potentials depend, to a large extent, on the stage of the disease. Factors that influence bile acids metabolism must be sufficiently studied. Clinical determination of serum major bile acids might prove to be a useful diagnostic and monitoring procedure in health and disease. It is probable that the deteriorating environment might promote chenodeoxycholic acid production conducive to morbidity and mortality. Exogenous cholic acid might be a good human hope for existence. Does cholic acid transmitted from the mother to the embryo via the placenta play any role in maternal inheritance. However, according to the hypothesis, cholic acid might promote blood clotting while chenodeoxycholic acid might be involved in hemorrhage. Both acids might be beneficial in treatment of blood flow disturbances. Developmental approach of albumin: Embryo organs are complete by the fourth month (Guyton, 1986). Fetal albumin increases in absolute concentrations from less than 2g/100ml at the fourth month to near adult-type at term (Schultze 8
and Heremanns, 1966). Neonatal serum albumin is at adult level at birth, but in elderly subjects it decreases by 20% (Timberell, 1982). The previous chronological development of serum albumin might be regarded as independence declaration of the neonate from his mother. He has developed his own first messenger to interact with the extra-uterine environment separately from the mother's physiological back-up (Fig 1-1). The steady increase of albumin might repress embryonic, fetal, and neonatal physiologic memory that are finely tuned and archived by prevalent albumin levels and /or metabolic modes in-uterine. What really happens, when we grow old, our albumin reverts back to intra-uterine patterns and we display the same metabolism dominant at that characteristic albumin metabolic patterns. In 1733, Alexander Pope wrote that man was" Created half to rise , and half to fall" (Martin and Saira Mian, 1997). In other words "we first ripen, then we rot". It seems that Pope was 250 years ahead of his time in anticipating the modern evolutionary theory of ageing (Medawar, 1957; Williams, 1957). This theory states that organisms in age-structured population senesce because of the weakening of the force of natural selection as they grow older, which allows certain gene action to reach deleterious levels of expression. In human populations, common examples includes cataracts, Alzeheimer's disease and other dementias, type 2 diabetes mellitus, osteoporosis, many types of cancer, and several types of arteriosclerosis. Albumin is involved 9
in evolution of species (Hafleigh and Williams, 1966), and is decreased by age (Timberell, 1982), and continues to fall postmortem (Hamferkamp, 1965). The maestro is thence absent and life symphony seizes. It is extremely tempting to assume that the weakening of the force of natural selection might entail albumin reduction and/or metabolic changes and the deleterious levels of expression of certain gene actions are related, in no small way, to albumin changes. What we call diseases might simply be normal in-uterine physiology that is archived in embryonic, fetal, and neonatal physiological memory and finely tuned by albumin levels and/or metabolic modes prevailing before birth. We revert to those metabolic events when we grow old and loose some of our albumin and we end exactly where we have started. We cannot cope-up owing to the lack of the maternal physiological back- up in-uterine and our extra- uterine disabled first messenger. Albumin might, therefore, be the ghost in our genes. Critical formulation of the hypothesis: Nicotinic acid was reported to influence acetate partitioning between lipogenesis and sterologenesis in a reciprocal manner with apparent tissue differences (Hardy et al , 1960).The process is altered by simple factors such as food ( Tomkins et al, 1953 ), temperature
( Masoro et al,1954), and different
physiological
stresses ( Brady and Gurin , 1950; Hotta and Chaikoff, 1952; 10
Masoro et al, 1954; Tepperman and Tepperman, 1958). It might be concluded that the whole environment might influence the process. It was thought that it would be very inspiring if an endogenous biological mechanism to generate nicotinic acid, does exist. Indeed, it was observed that serum albumin activated nicotinamide deamidase probably by binding endogenous inhibitor (Petrack et al., 1965). Nicotinamide deamidase enjoys wide distribution in diverse organisms and sub-cellular structures (Greenberg, 1961), and man (Johnson et al, 1945). Nicotinic acid generated via such albumin-mediated mechanism appears to occur antagonistically, at least in part, with that generated from tryptophan. High dietary protein increased serum albumin synthesis (Rothschild and Waldman, 1970), and decreased tryptophan conversion into niacin (Shibata, 1999). More links between the two pathways are suggested by the observation that the N-terminal of albumin is involved in the binding of L-tryptophan (Meister, 1965). He also wrote on the considerable literature on the urinary excretion of tryptophan metabolites in various human disorders including tuberculosis, diabetes, leukemia, bladder cancer, and other conditions the thing that reflected that tryptophan metabolism is a very sensitive indicator of disease. The antagonism between the two pathways is further supported by the reported decreased nicotinic acid generated from L-tryptophan in diabetic animals (Mehler et al, 1958), and nicotinic acid was reportedly diabetogenic (Hochstein, 11
1965). The paradox will be reconciled in the next publication dealing with the possible role of albumin metabolism in the etiology of obesity and diabetes mellitus. However, it appears that niacin generated from tryptophan has very specialized functions in different tissues. It was indicated that the initial step in the biosynthesis of nicotinamide adenine dinucleotide in mammalian liver involves the enzymatic deamination of nicotinamide to nicotinic acid (Petrack et al, 1963; Greengard et al, 1963). The nicotinic acid is then converted to NAD via the pathway described by Pries and Handler (1958), involving the formation of nicotinic acid mononucleotide and dinucleotide. It is extremely sensational to suggest that the biological significance of this pathway is to switch the metabolic fuel from glucose to FFA, and probable operation of some calcium mobilization mechanisms as suggested in Fig. (2-2). This critical pathway might be altered by excessive nicotinic acid be it external or endogenously generated via albumin-activated nicotinamide deamidase. Atkinson and Morton (1960) have shown that nicotinic acid nucleotide was a competitive inhibitor of enzymic adenyl transfer from ATP to beta nicotinamide nucleotides. NAADP induced internal calcium release in a biphasic manner preceded by a profound latent period (Genazzini et al, 1997). What is the probable relation between such incidence and the reciprocal manner of acetate partitioning between fatty acid synthesis and sterologenesis? 12
However, Calcium inhibited glutamine synthetase (Dixon and Webb, 1964) required for the amination of nicotinic acid analogue to NAD (Greenberg, 1961) and other amination reactions. The result would be NAD deficiency and metabolic fuel shift to FFA. This is probably how nicotinic acid is diabetogenic and how synalbumin insulin antagonism operates. More elaboration is presented in the article dealing with the possible role of albumin in the etiology of obesity and diabetes mellitus. However, diverse links indicating albumin involvement might exist among apparently different disorders, but practically of similar origin and the difference might only be the target tissue and/or sub-cellular fraction. Diabetics are more susceptible to pulmonary tuberculosis (Duncan, 1959), and tuberculosis infection decreased instead of increased the severity of diabetes. Isonicotinic acid hydrazide ( isoniazid ) is used in the treatment of tuberculosis, which by forming NAD analogue disturbed lipid metabolism (Albert, 1981). He also reported that nicotinic acid antagonized isoniazid in vitro. The antileukaemic activity of methotrexate might be attributed to its ability to increase NAD synthesis (Shuster et al, 1958). Cancer incidence is higher in diabetic population (Duncan, 1959). Nicotinamide deamidase was found to be active in different types of mammalian neoplasms ( Marki and Greengard, 1966 ). NAD inhibited the enzyme (Robinson, 1966).
However, it might be
concluded that albumin by interacting probably with the whole 13
environment and consequently activating or inhibiting nicotinamide deamidase to variable extents in different tissues and sub-cellular fractions, according to the stimuli, might regulate and harmonize animal physiology in health. The harmony is lost in disease. As would be discussed later, albumin might function, in addition to transport vehicle, mainly via alteration of membrane permeability, thus initiating the metabolic responses via appropriate calcium signaling channels, to the second messenger c-AMP (Fig.1-2). According to Don Haris et al (1980), manipulation of c-AMP levels might be beneficial in improving so many disorders among which are diabetes mellitus and fertility. Albumin might influence membrane permeability in different ways. Being involved in generation of endogenous nicotinic acid, and the consequent acetate partitioning between lipogenesis and sterologenesis, albumin might influence the lipid component of membranes. It might also influence the protein component of membranes in addition to enzyme activity involved. Being involved in colloid-osmotic pressure (Schultze and Heremanns 1966), albumin might also influence membrane permeability via calcium and bile acids transported by albumin. However, the molecules transported by albumin might determine, to some extent, the target tissue intended. Binding of molecules to albumin might change its shape, or a related event, which facilitate its entry according to the specific tissue membrane composition. However, membrane permeability is 14
developed and established during fetus life (Witschi -, 1956). Albumin has a special affinity in transporting calcium ions (Webb, 1963). Calcium decreases membrane permeability (Cantrow, 1959). NAADP, c-ADPR, and IP3 were identified as internal calcium signaling molecules (Cancela et al, 2000). Adenosine Diphosphate Ribose (ADR ribose) is the product of the action of DPN-ase, which is localized in membranous structures, on DPN and TPN with the liberation of nicotinamide probably as initial free radical (Greenberg,
1961).
Niacin
and
inositol
appear
to
act
antagonistically (Sebrell and Harris, 1954). During the daily life, alteration of serum albumin as a result of interaction with food and environment might alter membrane permeability in a genius way relevant to regulate calcium signaling, membrane-bound enzymes, diffusion of nutrients, and disposal of cell waste. More and above is the fact that albumin is the sole source of tissue proteins (Schultze and Heremans, 1966), the thing that regulate a broad spectrum of protein synthesis as coded in the DNA including enzymes and, of course, reactions catalyzed by them. A hypothetical rough model for a role of albumin in regulation of membrane permeability and calcium signaling will start with intravascular changes of albumin levels. Any factor, probably uncountable, that decrease serum albumin level might, of course, decrease the concentration of calcium carried by albumin and consequently increase capillary permeability to albumin with its 15
load of molecules and ions. The event might resemble the waves or circles generated by throwing a stone into a stagnant pond. Albumin, now, becomes extra-vascular tissue albumin. Each tissue has a genetic quota of albumin to be degraded for the normal function of the tissue. Decreased intravascular albumin might, therefore, increase extra-vascular tissue albumin. The situation starts with calcium signaling, concurrent glucose utilization for ATP production, c-AMP formation, immunological reactions and other common or specific functions of tissues. The in-fluxed albumin might similarly regulate membrane permeability of subcellular fractions. At the highest level of the genetic allocated quota of degradable tissue albumin, the hyper situation occurs, for example hyper-insulinism, hyperthyroidism … etc which ultimately end with tissue exhaustion. The extreme events that might occur provided that albumin molecule itself remains degradable via different modes, are mutagenesis and auto-immune reactions. This is probably what happens in type 1 diabetes mellitus(IDDM). However, if albumin extravasation to the pancreas is elevated or the degradation modes or machinery are not competent, the undegraded albumin will induce metabolic events mentioned throughout the text, probably through activation of nicotinamide deamidase in sub-cellular fractions. This situation might perfectly 16
be represented by type two diabetes mellitus (NIDDM). It appears that no sharp boarders might be established between the two types of diabetes at least at some stage of the disease pathogenesis. Increased intravascular albumin, for numerous reasons, and owing to increased calcium on the increased albumin molecules, might decrease capillary membrane permeability to albumin molecules. Extra vascular tissue albumin will definitely be lower than the genetically coded quota of degradable albumin necessary for common or specialized functions of the tissue conducive to tissue malfunction as in hypothyroidism and type one diabetes mellitus (IDDM) according to the severity of the situation. Increased plasma albumin availability might extract calcium from bones rendering them fragile. It might also activate blood nicotinamide deamidase with its metabolic consequences. The permeability in the reverse direction i.e. from extravascular to the intravascular compartment might be accomplished via hormones e.g. steroids. Cortisone induced such effect as would be presented later. This is probably how our bodies slow down the metabolism and how we prepare to sleep. As albumin synthesis is probably increased during night time because of decreased temperature, in addition to other reasons, in addition to didunal rhythm of glucocorticoid secretion in response to light-darkness cycle, the increased albumin availability might decrease membrane 17
permeability and calcium signaling thus slowing down the metabolism. The sleep-wakefulness cycle might be conceivable. However, fine specialization make us concentrate on the molecules and ions transported by albumin but we pay less attention to the transporter itself e. g. albumin. The situation resembles Plato's cow. Some people see its ear, others see the tail but no one is able to see the whole cow. However, alteration of coded albumin metabolism, beyond or below the physiological range, might be the essential biochemical lesion which initiate and maintain ageing process and pathology in different tissues. Hypoalbuminemia is a feature of protein malnutrition (Cooper et al, 1960). The feature is probably a relative and not absolute value. It varies with food and climate. It is well established that hypoalbuminemia is associated by much severe extra-vascular albumin reduction (Schultze and Heremans, 1966). Because the reduction in plasma albumin is associated with reduction in plasma volume, the concentration of albumin per unit volume may not change (Salter, 1959). This event might present an eternal metabolic trick conducive to tissue albumin hypo catabolism at critical plasma albumin levels. However, the most severely affected tissue (s) might develop pathology. The situation might suggest tissue association in this regard, which might be beneficial in understanding some morbid phenomenon e. g. metastasis.
18
Hypoalbuminemia
and
the
consequent
albumin
hypo
catabolism might not be restricted only to dietary insufficiency (Kirsch et al, 1968), but could also be induced by global warming, climatic changes, and pollution in addition to numerous factors. Pollutants decreased serum albumin levels (Theodore Peters, 1970), and high temperature as well as latitude reduced its synthesis. Irrespective of the complex nature of mechanisms involved in albumin metabolism, decreased albumin synthesis might be more serious than level reduction. On the light of intensive agricultural and industrial production and the persistent global warming, some sort of environmental malnutrition concept is emerging. Is it hidden that Kwashiorkor, a severe form of protein deficiency, was first identified in tropical and subtropical areas (Cooper et al, 1963). Hypoalbuminemia, in this respect, might be a natural mechanism to retain water for cooling purposes in hot climate and to maintain some type of internal vital pressure or permeability functions. More discussions are presented in a subsequent report dealing with possible links of albumin metabolism with water metabolism. Some local pathological states in relation to global warming are presented in Fig 1- 3 (Source: Statistics of State Health Ministry, 2011, Khartoum, Sudan). For the first instance one can observe the ascending trends of the pathological curves taking into account the day-to-day changes in the nutritional status of individuals, climatic changes, and other factors. An important observation is that the 19
decline in reported malaria cases might not be attributable only to improved health approaches but sadly to deterioration of the nutritional status and the global warming. It is well established that malaria infections are suppressed during malnutrition (Murry et al, 1978). A good support in this respect could be deduced from Fig (1.3.1.) where higher temperatures were reported towards the year 2000. Strikingly, the lowest reported malaria incidences appeared at the same period as could be seen in Fig. (1.3.3.). It might be concluded that global warming might induce malnutrition. Infectious diseases might be more sensitive to nutritional deterioration, and hypoalbuminemia might be the essential feature of protein malnutrition, provoking to morbidity and mortality. Migrant groups develop serum protein formula and also diseases of the country of adoption (Guyton, 1986). The statement directly points out to the possible link between serum proteins and type of morbidity. It, indirectly, points out to a possible role of serum proteins in the adaptation process and probably evolution. It appears that humans have the same versatile broad genome and what really differs is the environment and food which operate the gene expression via influencing albumin metabolism. It appears that at every albumin level and/or catabolic mode, a physiological reaction is triggered in a definite tissue essentially by albumin-induced altered membrane permeability. Redistribution and equilibrium of total albumin pool might alter membrane permeability to varying 20
extents in different tissues at the same time allowing for different types of physiological reactions to proceed simultaneously with high harmony. The permeability alteration process might proceed, when necessary, to the nucleus membrane thus influencing DNA– related processes. We all know the addition of BSA in polymerase chain reaction (PCR) probably for such purpose. It must always be recalled that albumin changes are inevitably accompanied by calcium signaling and mobilization processes. Subsequent publications will individually discuss the possible roles of albumin in carbohydrate sensation and utilization and the corresponding pathological states of obesity and diabetes mellitus. They will also address lipidemia and the possible Coronary Heart Diseases (CHD) in relation to albumin metabolism. A separate article will touch upon the link of albumin with protein synthesis with some emphasis on the formation of immune components, operation of the immune system, and drug resistance. Another article will be dedicated to outline the possible role of albumin in cell proliferation and carcinogensis. Water metabolism, hormonal actions, and basal metabolic rate (BMR) in relation to albumin metabolism will be the theme of a separate article. All topics will be presented in a form that establishes some possible broad links with food and environment. It is tempting to assume that life is an every moment dynamic interaction between our genes as coded in our DNA and our environment mediated by albumin metabolic 21
changes. A smile, an eye blink, everything outside our bodies including temperature, light and darkness, and few to count, might influence our albumin metabolism and the consequent metabolic changes. That is probably why when we travel we lose the usual harmony of our albumin metabolism as we leave behind our surroundings. This is also how we lose our biological rhythm and feel
home
sick.
Nutritional
standards,
specially
protein
requirements, might need revision. Detailed studies on the effects of different foods, environment elements, stresses, and xenobiotics on albumin metabolism might provide better understanding horizons in the face of the killing environment. Environmental changes if did not kill us, they push us crazy! As one of the features of protein malnutrition is mental apathy (Coopers et al, 1960), the suggested environmental malnutrition must also affect human behavior. Mental apathy might entail the lack of the calibration mechanism to match our intended deeds against the good values of religions, and social morals. At such point, the sub-conscious or the instinct dominates and imposes its own big value e. g. conservation. The madness of sex, wars, violence, corruption, and diverse bad deeds are probably unconscious human conservation responses towards the threat of disappearance as sensed by protein malnutrition. It might be
22
conceivable how the deteriorating environment makes us bad humans and makes life more sad and difficult. **** All solid lines in the drawings throughout the series do not indicate direct steps or reactions.
23
1-1: Albumin metabolism: A possible role in carbohydrate utilization, etiology and pathogenesis of obesity and diabetes mellitus. Osman, Elnour, Abdel Magid Email:
[email protected] Syn-albumin insulin antagonism: Embryo organs are complete by the fourth month (Guyton, 1986). Fetal albumin increases in absolute concentrations from less than 2g/100ml at the fourth month to near adult type at term (Schultze and Heremans, 1966). Insulin concentration is higher in the fetus than in the adults (Wellman et al, 1971). It is probable that during organogenesis which is completed at four months, fatty acids might be the metabolic fuel which is compatible with rapid cell proliferation to accomplish organs build-up. The issue is complex, but the moral of the story is that the prevalent albumin levels and/or catabolic modes might determine the choice of the metabolic fuel. It is then archived in some sort of metabolic memory, and when we grow old and revert back to such embryonic albumin metabolism the metabolic memory is then activated. We utilize FFA as the dominant metabolic fuel and reject glucose. This is probably diabetes mellitus. The situation might also explain gestation diabetes. However, from the above chronological development of albumin pattern, it might be 24
suggested that higher insulin levels are associated with lower albumin levels. The opposite i.e. higher albumin levels might diminish insulin concentrations. Syn-albumin insulin antagonism (Vallence- Owen et al, 1958), was proportional to albumin concentrations (Davidson and Goodner, 1966). As high dietary protein increased albumin synthesis (Rothschild and Waldmann, 1970), the insulin sparing action of protein diets is conceivable as protein assimilation does not require much insulin as carbohydrates. However, the nature and extent of such antagonism referred to in the literature by different synomenous i. e. insulin resistance and insulin insensitivity, will be mentioned throughout the text. Antagonism might depend on albumin levels and/or catabolic mode from blockage of insulin synthesis and secretion to interference with insulin receptors. Albumin hypo catabolism might expand albumin bioavailability and consequently insulin antagonism to varying extents. Albumin hypo catabolism might take place by different simple metabolic means. However, it might be suggested that synalbumin insulin antagonism might be the dominant metabolic process. When carbohydrates are ingested, albumin levels are decreased and the antagonism is reduced to accomplish their sensation and assimilation and syn-albumin insulin antagonism prevails again. Because food is a complex system, so its digestion, 25
the phenomenon is not sharp. However, there are some indications that the molecule attached to albumin and cause albumin hypo catabolism might be cholic acid. Likewise, chenodeoxycholic acid might induce accelerated albumin catabolism thus reducing synalbumin insulin antagonism and inhibition of nicotinamide deamidase which generates the diabetogenic nicotinic acid. Dermal chenodeoxycholic acid exhibited hypoglycemic action (Osman and Abdel Gadir, 2001). Both major bile acids are transported
by
albumin
molecule.
It
is
probable
that
chenodeoxycholic acid, or a related metabolite, might be the endogenous
inhibitor
of
nicotinamide
deamidase
on
the
assumption that cholic acid is somehow saturated with oxidized NAD at the completion of carbohydrate assimilation. The metabolic fuel is then shifted to FFA as described. However, the situation points out to the integrated picture of the interaction between different food components, environment, bile acid metabolism and colonic flora in a way similar to bile acid media known to microbiologist. Probiotics are not far from such discussions. Recently, bile acids were established to be involved in calcium signal transduction (Nguen and Bouscarel, 2008). However, the common factor between these metabolic processes is always albumin metabolism. Hormones might be the dynamic endogenous mechanism to correct albumin metabolism. Generally, 26
all factors that decrease serum albumin might accomplish that by increasing chenodeoxycholic acid, or a related metabolite, with increased membrane permeability, excessive calcium signaling, augmented glucose utilization, and fat deposition. Cholic acid or a related metabolite might induce albumin hypo catabolism with decreased membrane permeability, internal calcium mobilization, metabolic fuel shift to FFA, and fat consumption. As our food, deteriorating environment, pollution, and stresses might cause serum albumin reduction via the above suggested mode, cholic acid administration might present a big hope for mankind. However, the liver is not a target tissue for insulin probably due to syn-albumin insulin antagonism or related events as liver is the sole site of albumin synthesis. Again, rabbit liver nicotiamide deamidase was inhibited, up to 100%, by deoxycholate (Kirchner et al, 1966). They also reported on tissue distribution of the enzyme. It might not be surprising if we discovered, one day, that the crucial factor in obesity, in addition to numerous diseases, is only bile disorders that entails excessive chenodeoxycholic acid, or a related metabolite, secretion and the consequent cascade of the erratic metabolic events characteristic to the affected tissue. It is probable that cholic acid might decrease albumin catabolic rate thus functioning as half estrogen in relation to albumin metabolism while chenodeoxy cholic acid might resemble 27
half androgen action in the same respect, a suggestion which might have a paramount importance in replacement of sex hormone therapy. Moreover, chenodeoxycholic acid might have a role in humoral immunity while cholic acid might participate in cell-mediated immunity. The later, by decreasing albumin catabolism might have anti-viral and anti-dote activities. It, by decreasing calcium signaling and increasing internal calcium mobilization, it might posses sedative and analgesic properties. Via the same mode of action, it might be hyperglycemic, hyperlipedimic, and hypercholesterolemic. Fig (1-1-1) outlines a proposed metabolic fuel cycle. The increased albumin availability owing to increased synthesis and / or hypo catabolism might operate as outlined. Albumin is essential for the output of free fatty acids (FFA) by adipose tissue and their mobilization (Desgrez and De Traverse, 1966). Calcium has specific affinity to certain groups on albumin molecule (Webb, 1963). Calcium promoted lipolysis in the presence of albumin (Masaka et a l, 1972). Calcium and FFA uncoupled oxidative phosphorylation (Bartely et al, 1974). Such events might favor metabolic fuel shift to FFA at the expense of glucose. It might be concluded that elevated albumin availability might impose FFA as the compulsory metabolic fuel. As anything in life tends to relax, FFA might be preferred by tissues as they yield less energy than 28
glucose. Some metabolic events that might regulate the fuel cycle are mentioned in Fig (1-1-1). However, the proposed metabolic fuel cycle is probably intimately involved in calcium signaling as outlined in Fig (1-2). Carbohydrate recognition and insulin secretion: Carbohydrates were observed to depress serum albumin levels (Rothschild and Waldman, 1970). Glucose infusion decreased blood albumin levels (Strautmane , 1966) . The mechanism of that decrease is unclear but might probably be by binding to albumin molecule similar to glycation (Guerin et al, 2012). However, by decreasing serum albumin levels, syn-albumin insulin antagonism is probably reduced and insulin is secreted proportional to albumin decrease. It was reported that insulin is released in response to concentration of blood glucose (Yalow and Berson, 1960). It is very important to notice that sensation of glucose and carbohydrates, of course, and the consequent insulin release might be accomplished via the extent of albumin decrease within the physiologic range. However, in uncontrolled diabetes, the accumulated blood glucose might continue to decrease albumin to critical levels with probable more aggressive albumin hypo catabolism. Syn-albumin insulin antagonism is thence exaggerated with the consequent elongated metabolic fuel shift to FFA and other metabolic changes conducive to malfunction of tissues. 29
Imposed FFA as metabolic fuel might make tissues in the resting state not the active one. The pathogenesis of obesity and diabetes might generally follow such pattern. On the assumption that hypoalbuminemia
is
the
primary
biochemical
lesion
in
malnutrition, most types of diabetes mellitus might be caused by malnutrition. Uncontrolled diabetes, in turn, aggravates the malnutrition by decreasing blood albumin. Such vicious cycle causes resistance to hypoglycemics and precipitates diabetic complications in different tissues. It is of interest to discuss, in this context, some aspects of sucrose being a health hazardous carbohydrate. Sucrose depressed albumin synthesis more than dextran and other carbohydrates (Rothchild and Waldmann, 1970). Such potent effect of sucrose on serum
albumin
synthesis
might
have
deleterious
health
consequences. Sucrose raised plasma triglycerides greater than starch (Mc Donald and Braithwaite, 1964). Sucrose was once suspected to be involved in the etiology of atherosclerosis, maturity onset diabetes mellitus in addition to other diseases (Yudkin, 1957). An increase in serum lipids and cholesterol was caused by sucrose or fructose (Shufir, 1986). Hyperlipemia induced hypercholesterolemia (Friedman and Byers, 1955). The previous statements incriminate sucrose probably via a unique behavior towards serum albumin, i.e. reduction of plasma levels, 30
probably attributable to the glucose moiety, and reduction of synthesis. Fructose moiety of the molecule is not innocent from such effect. The overall albumin reduction might ultimately reach critical
albumin
levels
conducive to
permanent
albumin
hypocatabolism which appears difficult to correct. However, it was once speculated that sucrose might be a foreign metabolite (Osman, 1973).
More discussions will be presented in a
subsequent article dealing with the links between serum albumin metabolism, lipidemia, and (CHD). Etiology of obesity: As shown in the suggested glucose- fatty acid fuel cycle (Fig 1-1-1), factors that decrease serum albumin within the physiological range might reduce syn-albumin insulin antagonism and consequently augment insulin response and glucose utilization as metabolic fuel. Hyperinsulinism was reported in Obesity (Ducan, 1959). This might indicate a state of low serum albumin levels as an etiological factor in obesity. However, insulin is essential in fat deposition by the body (Guyton, 1986). Some factors predisposing to obesity might be of genetic origin related to albumin metabolism. Other factors might be related to intra and extra-uterine nutrition. Obesity might also be induced by the environment!! . As albumin synthesis is depressed during heat acclamization (Rothschild and Waldmann, 1970), global warming 31
might reduce syn-albumin insulin antagonism and the consequent hyper-insulinism
and
fat
deposition.
Likewise,
other
environmental pollutants might be red-handed in the existing growing obesity incidences and health complications mainly via decreased serum albumin irrespective of sufficient dietary nitrogen intake. From the nutritional point of view, obesity was suggested to result from overeating of carbohydrates and sweets, (Passmore and Eastwood, 1986). Starch, dextrin, lactose and glucose depressed albumin levels (Rothschiold and Waldmann, 1970) and sucrose depressed albumin synthesis much more than other carbohydrates. For a reason, sugar is the least of foodstuff to increase the metabolism (Guyton, 1986). The effect might be attributed to sucrose effect on albumin metabolism as would be elucidated when albumin relation to BMR is discussed in a subsequent article. However, Munro (1969) has observed that by increasing weight of species, protein synthesis, protein appetite, and albumin turnover are progressively decreased. Decreased albumin turnover might entail decreased synthesis and a resulting hyperinsulinism with augmented glucose utilization. It might also entail decreased albumin catabolism and the consequent synalbumin insulin antagonism with metabolic fuel shift to FFA. Indeed, a distributed glucose- free fatty acid cycle was observed in obesity (Randle et al, 1965). Obesity-associated albumin hypo 32
catabolism might be of essential importance in understanding obesity-associated
endocrine
hypofunction
(Passmore
and
Eastwood, 1986) as would be explained in a subsequent article dealing with albumin metabolism in relation to hormones. However, many hormonal actions might be
endogenous
mechanisms for albumin metabolism correction as would explained later. Again it might be concluded that decreased serum albumin levels within the normal physiologic range might be the essential biochemical lesion in the etiology of obesity. This is the probable explanation of why obesity occurs more in women than men (Passmore and Eastwood, 1986), as males were reported to have higher circularly albumin with higher catabolic velocity (Steinfeld, 1960). The previous statement might be well correlated to the common culture that meats are foods for men while carbohydrates are for women. Diet might, therefore, act like hormones e.g. carbohydrates like estrogens because they decrease serum albumin while meats might mimic androgens by increasing serum albumin synthesis. As albumin synthesis is decreased during heat adaptation (Rothschild and Waldmann, 1970) and its levels are reduced by pollutants (Theodore Peters, 1970), global warming and pollution might contribute, in no small way, in the growing obesity and diabetes incidences. Here, the polluted environment might act like carbohydrates, obesity, and estrogens. 33
Any factor that decreases serum albumin by different modes, within the physiologic range, might accentuate insulin secretion probably via increased calcium signaling to the pancreas thus predisposing to obesity. It is probable that obesity might emerge from raised plasma chenodeoxycholic acid and/or diminished serum cholic acid. Administration of cholic acid, which is suggested to decrease albumin catabolism, might replace the same metabolic event on albumin catabolism imposed by the augmented mobilized saturated fatty acids. It is probable that altered serum lipid in this case is a down-hill process whereas the same effect induced by chenodeoxycholic acid is an up-hill process i. e. fat synthesis. Saturated fatty acids are no more deposited as before and they are oxidized as fuel. It is probable that cholic acid might reduce body weight. Cholic acid might also, by induction of albumin
hypo
catabolism,
promote
syn-albumin
insulin
antagonism, FFA utilization as metabolic fuel, and consequently depressing glucose utilization for fatty acid synthesis and their deposition as body fats. However, the question of obesity is inspiringly rounded up by the observations of Flatt (1972). In obese subjects elevated plasma FFA levels in spite of a state of hyperinsulinism was observed and the return to normal upon weight reduction. In fact, the seemingly paradoxical situation might be reconciled by the observations of Munro (1969), that by 34
increasing weight of species protein synthesis, protein appetite and albumin turnover are progressively decreased. Decreased albumin synthesis and the consequent reduction of syn-albumin insulin antagonism might explain the state of hyperinsulinism while decreased albumin catabolism might avail longer albumin half-life time to mobilize FFA as discussed throughout the text. Weight reduction will reverse the situation with regards to albumin metabolism and normalize glucose- FFA metabolic fuel cycle. Weight reduction might entail consumption of long chain saturated fatty acids and the consequent elevation of albumin hypo catabolism. It is probable that albumin hypo catabolism, and the concurrent expanded albumin availability, might give intrinsic feeling of protein satisfaction and because of that protein appetite is probably depressed. It might now be conceivable why obese persons like sweets. However, as the body is unable to synthesize poly unsaturated fatty acids, albumin bound FFA might decrease its hydrolytic rate and expands
the
bioavailability of
molecule with its load among which, of course,
the
are FFA.
Saturated fatty acids (non-polar group) decreased albumin catabolic rate (Raven, 1957). Such altered albumin metabolism might influence calcium signaling mechanisms proposed in fig (12). The situation might be initiated by carbohydrate overeating which decrease albumin levels which, in turn, increase membrane 35
permeability to albumin. Increased albumin extra vasculated to the pancreas, to the upper limits of the genetically allocated albumin quota,
might
augment
insulin
response
conducive
to
hyperinsulinism with ultimate long chain saturated fatty acids synthesis and fat deposition. The pancreas might not withstand the situation for a long time. Excess pancreatic albumin with its load of calcium and fatty acids will contribute to the metabolic events mentioned elsewhere. At the same time, enhanced albumin extra vasation to relevant tissues might assure lipolysis in the presence of calcium bound to the molecule. The resultant fatty acids are thence transported by albumin making it less susceptible to degradation and imposing FFA as the metabolic fuel. Here, via many metabolic events mentioned throughout the text, glucose tolerance is decreased and more insulin is secreted to correct the situation. This story must always be remembered in understanding diabetes mellitus. As a general rule, any factor be it genetic, nutritional, or environmental that decrease serum albumin synthesis or accelerate its catabolism, within the physiological range, might predispose to obesity via increased pancreatic membrane permeability to albumin, increased calcium signaling to the pancreas to secrete insulin. It might be suggested that the higher serum albumin reduction, the longer the carbon chain of the synthesized fatty 36
acids and the more aggressive albumin hypocatabolism upon their attachment to the molecule. High caloric intake concurrent with diminished syn-albumin antagonism will furnish adequate acetate units for saturated fatty acids synthesis which, in turn, decrease albumin catabolism and eventually precipitate diabetes. The higher the caloric value of foods the longer carbon chain of the saturated fatty acids and the more aggressive albumin hypocatabolism. The concept appears as intrinsic mechanism to reject glucose and utilize FFA as fuel as in rest intervals. Diabetogenic modes of action: Diabetes mellitus, according to this hypothesis, might be regarded as perpetuation of the transient phenomenon of synalbumin insulin antagonism. The sensitivity of albumin decrease in response to carbohydrates is diminished at critical low albumin levels at the expense of more crucial functions for albumin related to pressure regulation or permeability functions. The event is essentially triggered and maintained via albumin hypo catabolism initially at the pancreatic level and the concurrent impaired glucose sensation, insulin response, and metabolic fuel shift from glucose to FFA as discussed in the text. The term hypo catabolism is used throughout the text to denote decreased albumin catabolism below the normal rate. That what probably happens in old-onset diabetes mellitus (NIDDM). In juvenile diabetes 37
(IDDM), pancreatic capacity to degrade albumin and the consequent insulin response are suggested to be massively lost. Initially, capillary membrane permeability to albumin towards the pancreas is probably exaggerated in juvenile diabetes the thing that operate auto-immune genes which, in turn, attack the pancreas and destroy it, whereas albumin is extravasated to the pancreas towards the upper limits of the genetically assigned quota of tissue degradable albumin with concurrent excessive calcium signaling and insulin response is greatly maximized which, in turn, yield obesity. In old-onset diabetes, when serum albumin is decreased, no sufficient albumin is available to the pancreas which might be considered as pancreatic albumin hypo catabolism. In both types of diabetes, plasma albumin hypo catabolism, evident by increased plasma FFA, might prevail. However, the pancreas was assigned to degrade 1% of the total albumin and globulin pool (Jarnum et al, 1966). It appears that this quota is genetically coded for normal insulin response. This trait might be genetically transmitted, as per is, to descendants. The failure to degrade this exact quota, for numerous reasons, might affect insulin synthesis and /or secretion. As hypoalbuminemia might be associated with increased capillary permeability to albumin and concurrent increased calcium signaling in the pancreas, prolonged reduction of serum albumin, for numerous reasons, might increase the pancreatic 38
quota of albumin thus gradually decreasing pancreatic glucose utilization and the consequent impaired insulin response and ultimately precipitate old-onset diabetes. Accelerated albumin catabolism in the pancreas, as in severe infections or auto-immune reactions might lead, ultimately, to severe loss of insulin reaction as in (IDDM). However, BSA was suspected (Deryck and Mendoza, 2004) to
cause (IDDM). BSA might induce
immunological responses. More discussion is presented in a report describing the link between albumin metabolism and the operation of the immune system to approach the auto-immune or viral etiological causes of type 1 diabetes. Serum albumin is decreased by age (Timbrell, 1982), infection, trauma, and stress (Sandor, 1966). This category of diabetogenic modes of action, might perfectly fit into old-onset diabetes mellitus. Other synonyms are type II diabetes mellitus and Non Insulin Dependent Diabetes Mellitus (NIDDM).
39
Fig (1.1.3) outlines the diabetogenic modes of action in type 2 diabetes. The essential difference between this type and type I (IDDM), might be that in type II the pancreas still retains some of its catabolic capacity to degrade albumin and secrete insulin. In other words, normal albumin levels might be extravasated to the pancreas but still higher than the degradative capacity. The residual
pancreatic
albumin
might
activate
nicotinamide
deamidase and the consequent metabolic fuel shift to FFA with impaired insulin response, whereas in type I there might be a sudden and massive loss of albumin degradation potential in the pancreas. More albumin is available without degradation in the pancreas which, in turn, impose syn-albumin insulin antagonism. However, albumin hypocatabolism in the plasma might weaken the sensation of glucose and decrease albumin extravasation and calcium signaling to the pancreas and the consequent failure of insulin response. Type 1 diabetes might also be precipitated by growth hormone secretion as would be explained later. It might also be caused by severe pancreatic infections, local auto-immune reactions. The arguments in this respect will be broadened in a subsequent publication describing the possible role of albumin metabolism in the operation of the immune system. A shouting evidence of the involvement of albumin hypocatabolism in the etiology of diabetes mellitus is the higher incidence of the disease in women and obese persons (Passmore 40
and Eastwood,1986). Women have lower circulatory albumin with lower catabolic velocity (Steinfeld, 1960).
Gestation diabetes
might be understood on the light of, among many arguments, the finding that at birth, albumin concentration in the human fetus is higher than that of the mother (Watson, 1965). However, by increasing weight of species, protein synthesis, protein appetite, and albumin turnover are progressively decreased (Munro, 1969). The diabetogenic modes of glucocorticoids and thyroxine (Passmore and Eastwood, 1986) might broadly be attributed to their influence on albumin metabolism. Cortisone increased albumin synthesis and caused albumin shift from the extravascular compartment into the plasma (Rothschild and Waldmann, 1970), thus provoking to type one diabetes mellitus. It is clear that shifting albumin from the pancreas will abort insulin response. Cortisone also diverted tryptophan to pathways other than niacin generation (Mehler et al, 1958). Niacin is required for NAD synthesis necessary for glucose assimilation. These cortisone effects in relation to diabetogenesis are touched upon throughout the text. Greengard et al (1965) concluded that NAD biosynthesis could be regulated by the pituitary gland through its control on the thyroid and adrenal glands. Such conclusion might explain the reported relationship between insulin and growth hormone (Duncan, 1959). It might also suggest a possible synergism between NAD and insulin. However, the immune-depressive 41
action of cortisone might be related, in no small way, to its effects on albumin metabolism. More elaboration is presented in a subsequent publication on the relationship between albumin metabolism and the immune system. The diabetogenic mode of action of thyroxin might be understood on the light of the finding that very minute concentrations of thyroxin inhibited nicotinamide deamidase (Kirchner, 1966). The enzyme, as discussed elsewhere, generates the endogenous diabetogenic nicotinic acid via albumin activation. This is probably why hypothyroidism lessened diabetes while thyrotoxicosis intensified it (Duncan, 1959). Any stress evoked ACTH secretion. Lipolytic activity and insulin resistance are associated with ACTH (Duncan, 1959). Adrenalectomy resulted in smaller resistance to insulin (Reichstein and Shoppee, 1945). These arguments on the diabetogenic modes of hormones might be oversimplified. However, the level of activity of nicotinamide deamidase in rat liver was susceptible to hormone-induced fluctuations (Greengard et al, 1965). Growth Hormone (GH) decreased albumin catabolic rate and increased protein synthesis (Grabuzda et al, 1963). GH is diabetogenic (Guyton, 1986). Albumin hypocatabolism is the probable Diabetogenic mode of GH. However, the destructive effect of GH on the pancreatic beta cells not noticed with ACTH
42
(Duncan, 1959) might be attributed to the fact that GH by increasing protein synthesis might increase insulin, a protein, synthesis in the face of ensuing insulin resistance which ultimately exhaust and destroy the beta cells. In this respect, syn-albumin antagonism might be a broad term ranging from blocking of insulin response, passing by insulin resistance, to insulin insensitivity. In all cases, increased albumin bioavailability and the consequent availability of FFA might be the reason. Hypoalbuminaemia and elevated plasma FFA are seen in malnutrition (Passmore and Estwood, 1986). The above line might represent Malnutrition Related Diabetes Mellitus (MRDM) with more or less similar metabolic events. As albumin synthesis is decreased during heat adaptation (Rothschild and Waldmann, 1970), hypoalbuminaemia of global warming origin might occur with ultimate diabetogenic albumin hypo catabolism. Global worming might, therefore, exert estrogenic activity. This is what probably happens in Tropical Diabetes Mellitus (TDM). It might be caused by GH secretion which is closely related to the amount of protein depletion (Guyton, 1986).
ADH secretion is also
increased. The edema in malnutrition is, therefore, conceivable and the primary biochemical lesion in malnutrition might be hypoalbuminaemia. This is probably how animals retain water during heat exposure for cooling purposes and maintenance of some types of internal pressures or critical permeability 43
characteristics. Thirst and polyuria in diabetes might be understood accordingly.
More arguments are presented upon
discussing the links between serum albumin metabolism in relation to water metabolism. The speculation that protein malnutrition might be the initiating cause of pancreatic calcification (Greevarghess et al, 1969), might be correct. Protein deficiency might cause albumin hypo catabolism. Calcium carried by albumin is then precipitated as a stone. Other stone types might follow a similar pattern. However, a new emerging concept of environmental, not dietary, malnutrition is emerging. One of the probable environmental involvement in the etiology of diabetes mellitus, and probably other morbidity, is the deterioration of ozone layer. U. V. light was reported to decrease the hydrolysis rate of albumin (Colson, 1967), and increase serum albumin levels (Pasynkov, 1960). U.V. light, by decreasing albumin catabolism, might act, at least in part, as obesity, growth hormone, and estrogens thus provoking to diabetes. By raising serum albumin levels, U.V. light might act, at least in part, like androgens, glucocorticoids, thyroxin, and dietary nitrogen. How complex life is! What probably happens in the diabetic pancreas islets : Elevated serum albumin levels were reported in diabetes (Ganong, 1976). Serum albumin formed by the liver has been found not to be significantly reduced in diabetic rats (Hendley et 44
al, 1957). Decreased capillary permeability to albumin was observed in diabetes (El- Mofti et al, 1965). Such decreased albumin extravasation to the pancreas might not fulfill the exact genetic quota necessary for normal insulin synthesis and/or secretion. This situation might be considered as plasma albumin hypo catabolism as failure of shifting albumin to extravascular tissues might be considered as plasma albumin hypocatabolic mode. It must be recalled that diabetes, according to the hypothesis, might be a chronic albumin hypo catabolic state with the resultant increased albumin half-life time and the consequent syn-albumin insulin antagonism. The situation might be complex but the net effect might be materialized in the pancreatic failure to degrade its exact genetically assigned-quota of albumin (Jarnum et al, 1966) necessary for normal insulin response. The release of albumin–bound fatty acids to the blood may be increased in the diabetic state and during ketosis (Duncan, 1959). Again albumin hypo catabolism or increased bioavailability might mediate FFA release as alternative fuel for glucose among the prevalent synalbumin insulin antagonism. However, many tissues, among which is pancreas, might utilize FFA as the metabolic fuel which, in turn, makes them in a resting condition with regards to insulin response. Oxidation of FFA diminished ATP production (Weiland, 1965). FFA might be imposed as the metabolic fuel in the pancreas to varying extents owing to the extent of plasma albumin
45
hypocatabolism. Such pancreatic albumin hypocatabolism might expand the availability of calcium ions transported by the molecule. The internal calcium mobilization mechanisms (Cancela et al, 2000) might lead to inhibition of cystolic adenyl cyclase and activation of c AMP phosphordiesterase (Anderson, 1980). Calcium inhibited glutamine synthetase (Dixon and Webb, 1964) responsible for amination of nicotinic acid analogue to NAD (Greenberg, 1961). Nicotinic acid nucleotide was a competitive inhibitor of enzymic adenyl transfer from ATP to beta nicotinamide (Atkinson and Morton, 1960). The net effect might be reduced energy production as ATP due to NAD deficiency and accelerated destruction of c AMP and the ultimate impaired and sluggish
insulin
response.
The
hypoglycaemic
action
of
sulphonylurea compounds was attributed to elevated islet cAMP via inhibition of cAMP PDE (Sandler, 1980).Other consequences of pancreatic albumin hypocatabolism is insufficient supply of amino acids necessary for insulin synthesis. Albumin was reported to be the sole source of tissue proteins (Schultze and Heremanns, 1966). Albumin also transported the β chain of insulin (Desgrez and De Traverse, 1966). What probably happens in the diabetic liver: At some time, increased plasma albumin bioavailability e.g. increased synthesis and/or hypo catabolism might impose FFA as the more available metabolic fuel as outlined throughout the text.
46
Hepatic oxidation of FFA elevated reduced NAD (NADH) levels (Weiland, 1965) the thing that promote gluconeogensis (Datta and Ottway, 1975). The elevated NADH levels might augment hydroxy methyl glutaryl Co.A (HMG Co. A) reductase, the limiting step in cholesterol synthesis . Increased sterol synthesis was reported in alloxan diabetic liver (Hotta and Chaikoff, 1952). By condensation of two molecules of acetyl Co A, acetoacetate ultimately accumulates as a result of long chain acyl CoA inhibition of lipogenosis (Weiland, 1965). This probably how ketone bodies are formed. Sulphonylurea oral hypoglycaemics V. insulin: The activity within a series of Sulphonylurea hypoglycaemics is positively correlated with binding serum albumin (Seydel et al, 1975). Albuminuria is observed upon tolbutamide administration (Latner, 1975) . Tolbutamide was reported to induce a small decrease in serum albumin and produce a small fall in FFA levels earlier to the fall in blood sugar (Jackson, 1969). Glucose enters into the skeletal muscle in the absence insulin as induced
by
exercise
(Ganong,
1967).
Exercise
induced
albuminuria (Schultze and Heremanns, 1970). Exercise increased NAD levels (Rogozkin and Afar, 1965). Long exercise increased plasma growth hormone levels (Fonseca et al, 1965). GH decreased albumin catabolic rate as cited elsewhere.
Duncan
(1959), stated that the need for insulin becomes less when
47
tuberculosis infection proceeded. Infections were reported to accelerate albumin catabolism (Sandor, 1966). It might be concluded that there is some sort of relationship between NAD and decreased serum albumin levels with regards to glucose utilization. A similar conclusion could be true about a close relation between GH and insulin. It might be observed that the first step in glucose utilization by tissues might entail albumin reduction and /or increased NAD level, the thing that might potentiate glucose admission to the cell. It is not clear whether such metabolic events might resemble or compose a part of insulin-NAD synergism. The benefit of exercise might generally be attributed to albumin disposal through the urine, and the consequent reduction of syn-albumin insulin antagonism with improved glucose utilization. Nicotinic acid V. Nicotinamide: Nicotinic acid and related compounds influenced acetate partitioning between fatty acid synthesis and sterologenesis in a reciprocal manner with apparent tissue differences (Hardy et al, 1960).
Nicotinic
acid
was
reportedly
diabetogenic
(Hochstein,1965), and ketogenic (Sebrell and Harris,1954), and induced insulin resistance (Mc Culoch et al, 1991). This is about exogenous nicotinic acid. The same compound is endogenously generated via albumin with probably similar metabolic effects. Albumin activated nicotiamide deamidase probably by binding
48
endogenous inhibitor (Petrack et al, 1965), which appears to be the first step in Pries and Handler pathway for the biosynthesis of nicotinic acid mononucleotide and nicotinic acid adenine dinucleotide. It is probable that such pathway is a regulatory mechanism of extremely essential significance by which the metabolic fuel cycle is reciprocated between FFA and glucose. The pathway might also be involved in membrane permeability, calcium signaling and mobilization processes.
However, the
extent of inhibition of glutamine synthetase, as discussed elsewhere, might be one of the limiting steps in switching the metabolic fuel from glucose to FFA, and vice versa . Carbohydrates decreased albumin levels (Rothschild and Waldman, 1970). Dextrin, starch, alcohol, lactose, and glucose have a nicotinic acid sparing action (Krechl et al, 1946). From the above statements it might be suggested that at low serum albumin levels, nicotinamide deamidase is inhibited and endogenous nicotinic acid generation is diminished the thing that allows glucose utilization as fuel. On high serum albumin availability, endogenous nicotinic acid might be generated with a concurrent glucose rejection, metabolic fuel shift to FFA, and the concurrent syn-albumin insulin antagonism. Another dimension is the niacin generated from tryptophan. Tryptophan conversion to niacin is increased on carbohydrate diets and decreased on protein diets (Shibata, 1999). High dietary protein increased albumin synthesis
49
(Rothschild and Waldman, 1970). As tryptophan has a stimulatory effect on albumin synthesis (Rothschild and Waldmann, 1970), the protein diet-induced increased albumin synthesis might decrease tryptophan conversion to niacin as regulatory mechanisms for both albumin and pyridine nucleotides synthesis. Nicotinic acid was reported to increase bile production (Seberll and Harris, 1954). The beneficial effect of dietary fiber on diseases (Passmore and Eastwood, 1986), might be related, at least in part, to its effect on intestinal bile acid metabolism (Thornton and Heaton, 1981), and fecal flora (Wyatt et al, 1986). Nicotinic acid is the prevalent from of the vitamin in plant material (Greenberg, 1961). Some external or internal potential sources of high nicotinic acid activity are coffee (Passmore and Eastwood, 1986), cigarette smoking as nicotine volatilize without decomposition (Stecher, 1960) which might have nicotinic acid activity or metabolized to such compound, and the nicotinic acid sparing action of alcohol (Seberll and Harris, 1954). Habituation to such nicotinic acid sources might elevate the risk of diabetes as well as other health complications. Quinolinic acid which decomposes to nicotinic acid and carbon dioxide (The Merck Index, 2006) increased brain micro vessel permeability to albumin (St, astny et al, 2000) and was effective in the treatment of pellagra. Pellagra is related to maize eating which is notoriously deficient in nicotinic acid
50
(Robinson, 1966), and its protein zein is deficient in tryptophan (Ihekoronye and Ngoddy, 1992). It is clear that by the same logic, nicotinic acid might provide extra-vascular tissues with higher albumin levels to the boarders or exceeding the genetically coded quota of tissue degradable albumin. The target tissue(s) will then operate at near maximum capacity which makes us feel good and ultimately exhaust the tissue, and tissue albumin hypo catabolism might prevail. This is probably, in addition to other mechanisms, what happens in diabetes mellitus with regards to glucose utilization. Is diabetes incidence is lower among maize eaters? Indeed, normal ground maize was not diabetogenic (Robert et al, 2009). The same events if occurred in the nervous system might lead to addiction or habituation. Does assumed decreased brain micro vessel permeability to albumin, alleviated by quinolinic acid, is part of pellagra dementia? However, it was found that the C.S.F. protein pattern is affected by changes in the plasma proteins (Schultze and Heremanns, 1966). The impact of such discussion on the concept of habituation and mental deterioration is still to be investigated. However, large doses of niacin (200-300 times the recommended allowance) administered orally have resulted in lowering of serum cholesterol and beta-lipoproteins levels. The mechanism of the action is not understood but only the acid form, is effective, not the amide (Coopers, 1963). According to this hypothesis, the effect might be related, in no small way, to the
51
reciprocation of acetate partitioning between sterologenesis and fatty acid synthesis under the influence of the massive doses of ingested nicotinic acid. The concept will be broadened in a subsequent article dealing with serum albumin metabolism in relation to blood lipids and (CHD). Nicotinic acid antagonists or/and nicotinamide deamidase inhibitors might be useful in management of diabetes and diverse diseases. However, external nicotinic acid or internally generated one by the action of nicotinamide deamidase might be responsible for increased capillary permeability of albumin to extra-vascular tissues and possibly to sub-cellular fractions thus influencing the tissue genetically allocated quota of albumin. Elevated endogenously
serum
albumin
generated
availability
serum
nicotinic
guarantees acid
by
more blood
nicotinamide deamidase, the thing that any more nicotinic acid is denied and tryptophan is disposed to pathways others than niacin generation according to the specific tissue mechanisms. It is probable that nicotinic acid generated from L-tryptophan is highly specialized in vital processes in the form of NAD, according to tissue function, because of molecular vicinity or other causes. However, nicotinic acid generated from tryptophan is decreased in diabetic animals (Mchleeret et al, 1958). Again the event might be attributed to the assumed albumin hypo catabolism in diabetes, and its increased bioavailability with probable feedback inhibition
52
or minimization of albumin and/or NAD synthesis. Tryptophan is diverted to xanthurenic formation which was abundant in diabetic urine and was once suspected to cause diabetes (Duncan, 1959). The beneficial effect of Nicotinamide on diabetes (Beals et al, 1999), might be related to its inhibitory effect on nicotinamide deamidase (Petrack et al, 1965), and RNA synthesis (Revel et al, 1961). RNA is essential for albumin synthesis (Brewer et al, 1969). Nicotinamide lowered blood sugar and creatine and it intensified the action of insulin on them (Ottgobel, 1940). The situation might open doors for the question of the natural form of the vitamin is it nicotinic acid or nicotinamide or both at distinct proportions. In other words, are we designed to eat bulk amounts of plant material.Herbivorous or carnivorous? At any rate, physiological deamination of nicotinamide by nicotinamide deamidase preceeded by liberation of nicotinamide as initial free radical, might be a very special process to lower NAD levels via the described mechanisms to enable the fuel shift to FFA to take place. The metabolic disorder might emerge from the chronic excessive nature of this process. Nicotinamide might act via better NAD formation as far as glutamine synthetase is inhibited. NAD was reported to inhibit nicotamide deamidase (Robinson, 1966). However, exercise was reported to increase NAD levels, (Rogzkin and Far, 1965), and accelerated albumin disposal as indicated by albuminuria post to exercise (Latner, 1975). FFA is the dominant
53
fuel in the resting muscle (Andreas et al, 1965). During exercise the metabolic fuel is turned to a mixture of FFA and glucose (Felig and Wahren ,1975). Imposing FFA as metabolic fuel, might likewise, make the muscle or tissue in the resting state. Diabetic sexual impotency might be one of the consequences. However, it might all be about deficiency of electron transfer chain and the consequent free radical chain reaction. Diet and environment impacts: Diet (Tomkins et al, 1953) and environment (Masoro et al, 1954) were observed to influence acetate partitioning between fatty acid synthesis and sterologensis.
Such factors must,
therefore, influence diabetgenesis. Management of diabetes mellitus might not be a simple task. Long chain saturated fatty acids (non-polar groups) decreased albumin catabolic rate (Raven, 1957). This is the probable endogenous mechanism in obese subjects that predispose to diabetes where albumin catabolism is decreased. In fact, albumin hypo catabolism in obesity might result from increased synthesis of long chain saturated fatty acids bearing in mind the very limited capacity of the body, if any, to synthesize poly unsaturated fatty acids. Again, high caloric intake will be translated into long chain saturated fatty acids. Saturated fats might, therefore, act like obesity, estrogens, and growth hormone so they are potentially diabetogenic. Likewise the beneficial nutritional effect of poly
54
unsaturated fats (polar groups) might be concluded. The concept of dietary essential fatty acids might be related, at least in part, to their effect on albumin metabolism. However, if the effect of saturated fats is combined with that of
high dietary nitrogen
content of meats, in addition to other reasons, the phobia of dietary red meats is conceivable. As part of the fat in red meats is inseparable, the combined effect of saturated fat and dietary nitrogen, i.e. decreased albumin catabolism with increased albumin synthesis might exert diabetogenic potential and related blood lipid alterations and ultimately (CHD). Meats and offals have high nicotinic acid content (Passmore and Eastwood, 1986). The
assumption
that
red
meats
might
also
contain
chenodeoxycholic acid or a compound related to antigen city might aggravate the situation. The situation is also applicable to other animal products such as milk but milk might contain cholic acid rather than chenodeoxycholic acid as females produce milk. Plenty, in this context, is like poverty in terms of expanded albumin bioavailability, and consequently the life-style diseases of the metabolism as would be individually theorized.
Life is
incredibly fair! Miscellaneous: permeability changes: As mentioned throughout the text alteration of serum albumin
metabolism
might
directly
55
change
membrane
permeability. Decreased serum albumin levels and/or accelerated catabolism might increase membrane permeability. Increased albumin levels and / or albumin hypo catabolism might decrease membrane permeability. The permeability changes might be mainly related to the load of albumin molecule of calcium ions which decrease permeability. This concept allows for active contribution of the stimuli in its distribution and penetration. Cell coats contain glycopoteins, glycolipids, and mucopoly saccharides
(Eric
et
al,
1987).
In
hypoalbuminaemia,
glycoproteins are increased (Davidson and Henrry, 1969). As calcium which decreased membrane permeability (Ducan, 1959) has a special affinity to certain groups on albumin molecule (Webb, 1963), deceased serum albumin level might transport lesser calcium and consequently alter cell coat and probably increase permeability. There is indirect line of evidence that increased
albumin
availability
might
decrease
mucopolysaccharides. Cortisone increased albumin synthesis and depressed mucpolysaccharide formation (Bartoy et al, 1968). However, decreased skin mucopolysaccharides were reported in diabetic patients which is corrected by insulin (Bartley et al, 1974). Sexual, fertility, and other disturbances: Delayed development of secondary sexual characteristic, disturbances or absence of menstruation, reduced fertility and
56
libido are frequently observed in diabetes (Duncan, 1959). Cyclic AMP is effective as contraceptive in female mice (Ryana and Cornel, 1969; Pearce and Mc Clurg, 1971). Giabers et al (1978) reported that spermatozoa
contain some of the highest
concentration of c AMP enzymes of any group of cells in the body. Exogenous c AMP PDE inhibitors and c AMP increase motility, respiration, and metabolism of sperm cells (Garber et al, 1971) . The normal situation is the fact that males have higher circulatory albumin with higher catabolic velocity (Steinfeld , 1960). Any alteration in albumin metabolism might cause sexual and fertility disturbances in both sexes. In diabetes, the assumed albumin hypocatabolism might create a similar situation to that suggested earlier to take place in the diabetic pancreas with ultimate malfunction of the testis and ultimately impaired testosterone production. In obese and diabetic females the hypocatabolic state of albumin imposed by the disease is added to that one characteristic of estrogens.
However, even in non
diabetic subjects, sexual disturbances might be approached by correction of albumin metabolism in males and female. The suggested albumin hypo catablosim in diabetes might affect the metabolism in ovaries and testis in a way similar to that mentioned under the diabetic pancreas as corrected by sulphonylurea oral hypoglycaemics. However, correction of albumin metabolism by
57
different ways would, influence calcium signaling process and generally, restore the sexual performance in both sexes. As mentioned elsewhere in the text, FFA is the metabolic fuel in resting muscle. Is it possible that imposing FFA as fuel might make the tissue or the muscle in a resting state. What is the implication of such event on erection and impotency in diabetic males. However, diabetic complications in different tissues might emerge from utilization of FFA as metabolic fuel instead of glucose. Glucose utilization might be one of the basic cell mandates to express the other gene functions. Cancer incidence is higher in diabetic population (Duncan, 1959). Nicotinamide deamidase was found to be active in different types of mammalian neoplasm (Marki and Greengard, 1966). It is probable that cycles of metabolic fuel shifts between glucose and FFA might take place in-uterine. studying fetal albumin metabolism in relation to general metabolism might, therefore, facilitate the prediction and prevention of diabetes extrauterine when albumin metabolic patterns revert back to fetal ones. A marvelous opportunity for gene therapy might emerge. The situation might validate the heavy emphasis on protein nutrition of the mother which will be reflected on the newborn and probably their health for lifetime. The environment is becoming more morbid and mortal, albumin might express its full vigor as the adaptation and evolution tool. The measurement of albumin
58
hypocatabolism might provide a good tool for diagnosis and monitoring of diabetes mellitus. Promising horizons for potent and more safe hypoglcaemics might be achieved as more intervention points are becoming more clear. Any factor that can boost serum albumin catabolism near the normal range might be of use in management of diabetes mellitus. As albumin infusion raised the catabolic rate of albumin (Rothschild and Waldmann, 1970). Albumin infusion might assist in critical diabetic complications i.e. ketoacidosis. Likewise, factors that promote albumin synthesis might accelerate its catabolism. Protein nutrition is critical for diabetics. However, the situation might be much more complex.
59
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76
77
78
79
Fig (1.3.1) Global warming
80
Reported cases Years 1995
Renal failure 0
Angina 57
Heart Failure 0
2000
209
11
738
2005
3679
2047
2886
2009
4082
4611
3462
5000
Reported cases
4000
3000 Renal failure 2000
Angina Heart Failure
1000 0 1990 -1000
1995
2000
2005
2010
Year
Fig (1.3.2): Reported cases of renal failure, angina, and heat failure (1995- 2009)
81
Reported cases Years
Thyroid
Dehydration
Malaria
1995
266
1674
23617
2000
315
1550
12547
2005
856
11268
20117
2009
1790
14644
11321
25000
Malaria Dehydration Thyroid
Reported cases
20000 15000 10000 5000
0 1990
1995
2000
2005
2010
Year
Fig (1.3.3): Reported cases of thyroid, dehydration, and malaria (1995- 2009)
82
Reported cases Years
Diabetes
TB
Hypertention
1995
2888
1990
2446
2000
3689
1270
3010
2005
7522
3474
8691
2009
12559
7607
10543
14000
Diabetes TB hypertention
Reported cases
12000 10000 8000 6000 4000
2000 0 1990
1995
2000
2005
Year
Fig (1.3.4): Reported cases of diabetes, tuberculosis, and hypertension (1995- 2009)
83
2010
Reported cases Years
Malignancy
Anaemias
Malnutrion
1995
1554
1795
1283
2000
1913
3610
1928
2005
3005
5865
8106
2009
5826
10567
5581
12000
Reported cases
10000
8000 Malnutrion
6000
Anaemias 4000
Malignancy
2000 0 1990
1995
2000
2005
2010
Year
Fig (1.3.5): Reported cases of anaemias, malnutrion, and malignancy (1995- 2009)
84
85
86
87
