The Biochemistry of Serum Sugars
Cooperative Institute for Research in Environmental Sciences, University of Colorado at Boulde, Colorado, USA
Received date: 18 Jul 2017; Accepted date: 02 Oct 2017; Published date:
16 Oct 2017
*Corresponding author: Robertson DS, Department of Geological Sciences,
Cooperative Institute for Research in Environmental Sciences, Boulder,
Colorado, USA; E-mail: email@example.com
The biochemical reactions, the compounds formed and the biochemical control mechanisms involving serum sugars are described. It is
demonstrated that serum sugar control involves both the insulin-glucagon system and the conversion of glucose to mannose and fructose
by the Bruyn-Ekenstein sugar transformation.The formation of malic acid from glucose is shown to initiate and terminate production of insulin
and glucagon. The origin of obesity associated with both types of diabetes is demonstrated. Biochemical reactions leading to the formation of
advanced glycation end products associated with Type 1 diabetes and ageing effects are defined.
Keywords: Mono phosphoric acid; Poly phosphoric acid; Hydrogen peroxide; Hydroxylamine
Nearly one hundred years have passed since the demonstration that
insulin protein is involved in the control of serum glucose by conversion
of glucose to glycogen and the conversion of glycogen to glucose involving
glucagon protein. The biochemical conditions and reactions which initiate
and terminate the formation of insulin and glucagon by the cell of the
pancreas are not known. In the metabolism insulin can be formed at the
required rate, at a higher rate than required, at a lower rate than required
or produced at the correct rate and not used effectively. The latter two
conditions result in hype Glycaemia which is the origin of various forms
of diabetes. Hyperglycemia can lead to more serious medical conditions.
Type 1 diabetes has been proposed as an auto immune condition .
Several metabolic compounds are proposed as the antigens involved,
including insulin. The origin of Type 2 diabetes is not yet defined.It is also
proposed that sugars are circulated in metabolic fluids and pass through cell
membranes in combination with specific proteins under the mechanism
developed from the chemiosmotic membrane theory. These proteins are
designated glucose transporter isoforms. The combinations are used in
studies aimed at glucose control in Type 2 diabetes, for example gliflozin
a sodium salt transporter. It is presumed that the equivalent proteins are
available for mannose and fructose. Hexoses with or without attachments
can also enter cells by the colloidal fluid mixing mechanism membrane
mechanism . In addition to insulin numerous compounds have been
developed and tested for control of variations in the concentration of
glucose in serum.None of these is as effective as insulin. Glucose, mannose
and fructose hexosesaccharides enter the metabolism through dietary
intake. These sugars are all equally available from this origin. The dietary
concentrations are not in accord with the measured concentrations
in serum indicating either preferred use of one over the others or the
presence of a mechanism for conversion of the sugars one to the other.
Metabolic control of the three serum sugars involves one or more of the
basic cell reactions namely hydration, dehydration, oxidation, reduction,
decarboxylation and deamination. One or more of these reactions are
involved in the insulin-glucagon control of serum glucose and other dietary
sugars in the serum. The types of diabetes have been linked experimentally to
the phosphate chemical group (PO43) for a considerable period . A high
dose insulin infusion induces a rapid and a significant fall in mean plasma
phosphate concentration . Control of the concentration of therapeutic
insulin leads to a reduction in the metabolic loss of phosphorus through
phosphate excretion. Sensitivity to insulin is associated with serum
phosphate levels in non-diabetic individuals. Serum alkaline phosphates
is also increased in instances of Type 1 diabetes [5,6]. Phosphate ion is
the dominant anion in metabolic cells and can exist in metabolic cells as
mono phosphoric or poly phosphoric acids. The sodium and potassium
salts of these acids are present in intracellular fluids . The acids are
reversibly changed from one to the other by the addition or loss of water
and are identified as cellular hydration and dehydration reagents. The
formation of insulin is also experimentally linked to calcium, magnesium
and potassium ions and serum hypo magnesia is linked to both Type 1 and
Type 2 diabetes [8,9]. Sodium, chloride and potassium ions are excreted in
Type 1 diabetes and insulin affects renal handling of sodium, potassium,
calcium and phosphate [10,11]. Type 1diabetes is linked with a deficiency
of metabolic iron and Type 2 diabetes is linked with an excess of metabolic
iron. Type 1diabetes is also associated with the formation of a group of
metabolic compounds known as advanced glycation end products which
are proposed as being formed by serum glucose reacting with proteins,
lipids and nucleic acids. These compounds are considered to cause ageing
through disturbance of the chemical and physical properties of metabolic
components such as tissue. This proposal is supported by reduced lifespan
displayed by individuals with Type 1 diabetes .
Physical and Chemical Conditions Involved in Serum
Compound formation in metabolic cells requires the persistent presence
of primary compounds which initiate and continue the formation of cell
compounds at ambient conditions (Normal Temperature and Pressure,
NTP). Mono phosphoric and poly phosphoric acids are identified as the
two of these primary compounds which are interchangeable by addition
and removal of water. This hydrating-dehydrating action is involved
in protein and other similar reactions the former acid is released from
dietary phosphates by biochemical reactions involving hydrochloric
acid of the digestive system and hydrolyses dietary proteins producing
amino acids and poly phosphoric acid. The latter enters cells principally
as soluble potassium polyphosphate which is derived from di potassium
hydrogen phosphate (K2HPO4). This compound has a strong tendency
to form poly-forms as evidenced by being difficult to crystallise. These
conditions account for the dominance of potassium and phosphate
ions in intracellular fluid. The presence of polyphosphoric acid in cells
is maintained by water leaving the cells under osmotic transfer, electroosmotic
transfer, and exit of hydrated amino acids or transported by
the hydration shell of proteins. Mono phosphoric acid exists in a single
molecular stereo chemical form and poly phosphoric acid exists in linear,
rectangular, and hexagonal molecular stereo chemical forms. The latter act
as molecular templates influencing the molecular form of biochemical’s
produced by polyphosphate reactions. The stability of poly phosphoric acid
depends on the pH value, temperature and the ion type and concentration
in the fluid involved. The pH of the intracellular fluid changes as mono
phosphoric acid is changed to poly phosphoric acid and the reverse .
Potassium and magnesium ions enhance the hydrolysis of polyphosphoric
acid increasing the rate of biochemical dehydration reactions .
The compounds of calcium, magnesium and iron are generally
insoluble in the aqueous component of the hydrophilic colloidal fluids
which comprise biological fluids. The ions of these elements are rendered
soluble by the formation of soluble complex ions (sequestration) with
poly phosphoric acid or soluble polyphosphates [14,15]. Sequestration
of calcium ion is supported by the observation that serum calcium is
divided approximately equally into two types, designated ionized and
non-ionized. The first of the types is identified as the concentration of
calcium mono phosphate (also known as calcium orthophosphate) and
the second type as sequestered calcium polyphosphate (also known as
calcium pyrophosphate). Hydroxylamine and hydrogen peroxide are
identified as the oxidation and reduction biochemicals and are known
to be present in cells and metabolic fluids. The Raschig reaction is the
only known reaction which can produce these compounds at the normal
temperature and pressure conditions of the intracellular fluid . The
oxidizing/reducing properties of these compounds are related to the
pH value of the metabolic fluid involved [17,18]. The intracellular pH
alters as mono phosphoric acid is changed to poly phosphoric acid due
to differences in ionising properties . All four reagents operate by
association or enclosure in various different protein structures either
alone or as complexes (peroxyacids H3PO5, H4P2O8, hydroxylamine
perphosphates which comprise enzymes . The spatial structural
characteristics of the proteins involved allow selective enclosure and
controlled access to these reagents. The number of molecules of the above
reagents associated with a given weight of a specific protein is limited by
structure considerations. A hydrating enzyme encloses mono phosphoric
acid and cellular hydration reactions convert this acid to poly phosphoric
acid. This combination is structurally unstable and disintegrates.
Under conditions where the enclosed mono phosphoric acid remains
unreacted the enzyme is decomposed by internal hydration. An enzyme
enclosing poly phosphoric acid is a dehydrating enzyme and gives rise
to mono phosphoric acid which decomposes the enzyme. Enzymes
therefore have a fixed lifetime and are normally continuously formed and
reformed. Biochemical reactions precede until a specific concentration
of a reaction product or products is present in the reaction zone. The
reaction rate slows and can stop at this point and can proceed in reverse
until a reaction product or products leave the reaction zone. The figure 1
shows the formation of insulin and glucago are through dehydration of
amino acids by linear poly phosphoric acid. The formed insulin encloses
lengths of poly phosphoric acid and the dehydrating action of this acid
links glucose molecules producing glycogen. The condition of inactive
insulin is the result of deficiency of poly phosphoric acid. Glucagon
encloses mono phosphoric acid as a result of structural differences from
insulin protein. The associated mono phosphoric acid hydrolyses the
glycogen releasing glucose. A given weight of insulin and glucagon each
contain a specific weight of poly phosphoric acid and mono phosphoric
acid respectively when the entire polyphosphoric acid associated with
insulin has been converted to monophosphoric acid by the formation of
glycogen the protein is hydrated liberating the amino acids. This complies
with the observed metabolic degradation of insulin and the measured
half-life of insulin at five minutes. Glucagon has a specific lifetime in the
metabolism when not involved in the liberation of glucose from glycogen
as a result of being self-degraded by any unused mono phosphoric acid.
This is supported by the glucagon half-life of two minutes. At present the
majority of insulin is considered to be degraded in the intracellular fluid
or by processes in cell membranes [20,21].
Control Mechanisms and Chemical Reactions of Serum
The insulin-glucagon serum saccharide control system requires a
means of initiating and ceasing the production of one or other of these
compounds according to the metabolic conditions involved. On entry
into serum from the digestive source glucose and mannose are converted
to methanol (formaldehyde) and fructose is converted to glycoaldehye
through oxidation by hyroxylamine and/or hydrogen peroxide supported
by the dehydrating action of polyphosphoric acid (Figure 2). Cell
hydroxylamine and/or hydrogen peroxide are produced by the Raschig
reaction . Formaldehyde is converted to malic acid by the same
reagents.Increasing concentration of glucose results in increased serum
malic acid which reduces the pH value (moreacid) ofthe intracellular
fluids of cells which the acid enters, such as alpha and beta the cells of
the pancreas. The formation of different proteins has been shown to be
dependent the intracellular pH value . The reduction of the pH value
Figure 1: The formation of insulin and glucagon
Figure 2: The Lobry de Bruyn–van Ekenstein transformation
of the beta cells favors the formation of insulin protein which converts the
increasing glucose to glycogen. As the metabolic use of glucose decreases
by lowered metabolic activity and digestive supplyof malic acid decreases
and the pH value ofintracellular fluids increases (more alkaline). The
change favors the formation of glucagon protein which releases glucose
from glycogen. This control mechanism is supported by the observation
thatcombination of malic acid and insulin has been shown to be more
effective in reducing diabetic ketosis than the same amount of insulin
alone [22,23,24]. Compounds involved in ketosis are derived from malic
produced by a metabolic excess of hydroxylamine/hydrogen peroxide .
The addition of malic acid to the metabolism under these circumstances
encourages insulin formation producing the effect observed. In addition
plasma glucagon concentrations are elevated in cases of diabetes where
insulin production is suppressed. This indicates that the metabolism
contains a lowered content of malic acid .
An additional control mechanism for serum sugars is the Lobry de
Bruyn–van Ekenstein transformation which results in the establishment
of a reversible equilibrium between glucose, mannose and fructose
. This transformation has been neglected as a serum sugar control
mechanism even though it has been shown to occur with phosphosaccharides
under the influence of muscle enzyme thus supporting the
existence of the transformation in the human metabolism . The
process takes place in warm alkaline or acid solutions of saccharides.
The conditions in metabolic fluids are compatible with the conditions of
the transformation, that is, a pH value in the range 7.35 to 7.45 and a
temperature of 37.0° Celsius. Several mechanisms have been proposed
as being involved in the transformation and a mechanism is shown in
figure 3 involving monophosphoric and polyphosphoric acid. Under this
transformation any change in the concentration of serum glucose will
result in a corresponding change in mannose and fructose and the reverse.
Metabolic Reactions of Serum Sugars
Serum sugars undergo a series of biochemical reactions producing
chemical energy which appears as heat and/or other compounds involved
in metabolic functions. Glucose and fructose are decomposed in the same
manner by the oxyform of hydroxylamine (NH3 -O) or hydrogen peroxide
(H2O2) as shown in figure 3. The reaction is supported by the hydrating
action of linear polyphosphoric acid and the cell hyroxylamine is formed
by the Raschig reaction . It is observed experimentally that metabolic
hydroxylamine is linked with insulin . The products are methanal,
penitol aldehyde hydrate and active oxygen. The latter reacts with water
producing hydrogen peroxide. The product is glycoaldehyde which reacts
with methanal forming glycerol and lipids . (Figure 4) shows the
formation lactic acid, alloxan and urea from fructose. Alloxan has been
identified in serum of insulin dependent individuals . A high fructose
intake enhances the production of glycoaldehyde producing an excess
of lactic acid, urea, alloxan and lipids. A high glucose intake is partly
converted to fructose by the Bruyn–Ekenstein transformation producing
the same result. In some mammals injected alloxan induces Type 1
diabetes which occurs through a reduction in the formation of alloxan
from fructose. The consequent increase in fructose is converted to sucrose
by the Bruyn–Ekenstein transformation. Under these conditions malic
acid production has not occurred to induce increased insulin formation.
As a result of the available insulin is inadequate to deal with increased
sucrose and Type 1 diabetes occurs. Serum succinic acid is produced in
the metabolism by reduction of malic acid demonstrating the existence of
an effective metabolic reducing agent. This is identified as hydroxylamine
with hydrogen peroxide as an auxiliary reagent.
Advanced glycation products include hydroimidazolone,
N-carboxymethyl-lysine, pentosidine, glucosepane. Biochemical groups
involved in the production of these compounds include imidazole which
is formed by reaction ofmethanal (formaldehyde), glyoxal, andammonia.
The first two of these compounds are formed from glucose and fructose
as shown and ammonia is formed as the result of the operation of the
mechanism controlling metabolic hydroxylamine. Imidazole is also
formed from glycine, hydroxylamine and methanal . The figure 5
shows the formation of N-carboxymethyl-lysine by the linking of two
Figure 3: The reactions of fructose
Figure 4: The formation of lactic acid, alloxan and urea
Figure 5: The formation of N-carboxymethyl-lysine
glycine molecules with one molecule of succinic acid. Succinic acid is
formed by reduction of either malic or tartaric acid both of which are
linked to serum sugars. Tartaric acid is involved in the six sided ring of
glucosepane which is formed in the same manner as N-carboxymethyllysine.
All the advanced glycation products are formed similarly. The
involvement of hydroxylamine and hydrogen peroxide in the above
reaction necessitates a metabolic control mechanism for these compounds
to prevent overproduction. This is provided by the ions of iron. When
the intracellular fluid is acidic the Fe3+state of iron is reduced to the
Fe2+ state by hydroxylamine producing nitrous oxide. Under alkaline
conditions hyroxylamine and oxidises Fe2+ to Fe3+ producing ammonia.
Hydrogen peroxide can act similarly producing water in each case. The
change of intracellular and intercellular pH when monophosphoric acid
is converted to polyphosphoric acid and the reverse by the reactions
described establishes is the origin of the pH change involved.
A series of observations support the reactions presented. The
generation of methanol from glucose is supported by the observation
that ingested methanol produces symptoms common to Type 1 diabetes,
namely the development of hyperglycaemia and coma . Formic acid
is produced in the brain by oxidation of the ingested methanol and results
in tissue inflammation causing diabetic coma. Simultaneously ingested
methanol reduces the production of methanal from glucose giving rise
to hyperglycaemia. Glucose is present in the cerebrospinal fluid and
will undergo the same reactions. In cases of Type 1 diabetes the serum
concentration of fructose increasesin sympathy with the increased
glucose. This indicates that part of the glucose increase is converted to
fructose by the Bruyn–Ekenstein transformation. The result is an increase
in the production of lipids from glycerol contributing to the development
of obesity associated with both types of diabetes. Hypophosphatemia
linked to Type 1 diabetes is the result of the use of polyphosphoric acid
to form ketone bodies deriving insulin of this component . Type 1
diabetes is linked to decrease in the concentration of metabolic nitrates
which reduces the formation of the oxidation/reduction reagents by the
Raschig reaction affecting all the reactions described . Potassium
ion supports the hydration of polyphosphoric acid and hypokalemia
has been linked to the initiation of Type 1 diabetes . Deficiency of
this ion reduces the hydration rate of polyphosphoric acid enclosed in
insulin and consequently the reduces the rate of conversion of glucose to
glycogen. Serum hypomagnesia associated with diabetic conditions and
has the same effect. Intravenous iron is observed to cause pancreas cell
degradation plus failure of insulin production and induction of Type 1
diabetes . The intravenous iron forms soluble polyphosphate diverting
polyphosphoric acid from the formation of insulin.
Treatment of Type 2 diabetes with biguanidine (metformin) gives
rise to a reduction in serum glucose concentration. This compound
is a water soluble strong base (biguanidine pK1 =11.52, pK2 = 2.93 cf.
ammonia pK1 = 9.61). Biguanidine is not degraded in the metabolism.
The effect of the compound is to increase the pH (increased alkalinity)
of metabolic fluids.An excess use of biguanidine leads to lactic acidosis as
a result of transformation of glucose to fructose by the Bruyn–Ekenstein
transformation. The increase in serum urea and lactic acid associated with
Type 2 diabetes are produced from increased metabolic fructose formed
by the same transformation from increased glucose. Sulphur and nitrogen
containing compounds which reduce serum glucose concentration
(thiazolinine dione, sulphonyl urea, miliglinide) are a source of
sulphite and nitrite for the Raschig reaction increasing the formation
of hydroxylamine/hydrogen peroxide. The overall effect is increased
conversion of glucose to methanal thereby lowering serum glucose.
Both types of diabetes are associated with thirst, an increase in arginine
vasopressin antidiuretic plus urine with reduced metabolic products and
increased loss of water from the metabolism . These results indicate
an increase in protein/enzyme formation resulting in transfer of water
from the cells by protein halo. The enzyme involved is serum alkaline
phosphatase which is observed to increase in both types of diabetes .
Advanced glycation product compounds are the result of formation of
unusual links between amino acids and dicarboxylic acids.The presence
of amino adipic acid in serum has been advanced as predicting the
development of diabetes . This is possible based on the formation
of dicarboxylic acids from from serum sugars . Advanced glycation
product compounds are considered to interrupt the production tissue
by the formation of abnormal links between amino acids such as glycine
which is involved in the formation of collagen.The link to diabetes occurs
by diversion of amino acids such as glycine from use in the formation
of insulin. Advanced glycation product compound formation indicates
an excess of hydroxylamine or ammonia in the cells involved. This is the
result of over production due to reduced metabolic iron. Healthy adults
manifest a low-grade diet-dependent metabolic acidosis, the severity of
which increases with age. This condition interferes with the first stage of
the iron ion control of hydroxylamine and/or hydrogen peroxide leading
to an increase in these compounds .
Production of insulin and glucagon are initiated by alteration of the
pH of the intracellular fluid of the alpha and beta cells of the pancreas
by change in the concentration of serum malic acid formed from
glucose. Under normal conditions these pH changes from the start/
stop mechanism for insulin/glucagon release. The reduced serum iron
observed in case of for Type 1 diabetes results in an excess cell production
of hydroxylamine and/or hydrogen peroxide which converts malic acid
to ketone bodies bodies and stops insulin production . The reduction
in malic acidfavors the formation of glucagon which is known to increase
in the case of Type 1 diabetes  the result is an increase inglucose from
glycogen. When combined with the dietary intake of glucose causes the
hyperglycaemia associated with Type 1 diabetes. The operation of the
Bruyn–Ekenstein sugar transformation under these conditions converts
part of the glucose increase to fructose leading to lipid formation through
glycerol as described. In the case of Type 1 diabetes the low metabolic
iron concentration is linked to reduced metabolic polyphosphate which
sequesters iron which could be improved by the ingestion of iron
sequestered in potassium polyphosphate. Type 2diabetes is linked with
an excess of metabolic iron which gives rise to areduction of metabolic
hydroxylamine and /or hydrogen peroxide. The consequent reduction
in the formation of malic acid and the increase in alkalinity (increased
pH value) of the intracellular fluid of the alpha cells of the pancreas
favours the formation of glucagon. This leads to increased conversion of
glycogen to glucose producing an increase in serum glucose. The increase
in serum alkalinity also favours the operation of Bruyn–Ekenstein
sugar transformation. Although the latter r converts glucose to fructose
controlling the onset of hyperglycaemia tis change also leads to lipid
production as observed. A supportive treatment for Type 2 diabetes is
the controlled ingestion of hydroxylamine phosphate ((NH3OH)3 PO4) or
hydroxylamine dissolved in dipotassium hydrogen phosphate solution.
Hyroxylamine has a measured LD50 toxicity rating of 0.4 to 1.0 gm
per kilogram of body weight . The formation of advanced glycation
end products originates with a progressive increase in the metabolic
concentration or the accumulation of hydrogen peroxide/hydroxylamine
with age. This change occurs though progressive development of anaemia
with age or from any other origin which reduces the iron ion control of
these cell oxidation/reduction compounds.
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