Disturbances of Glucose Metabolism


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      Glucose is among the most fundamental nutrients for humans. It is present as such in some fruits (e.g. grapes), and as a monomer of di-and poly-saccharides in many foods (e.g. saccharose in fruits, lactose in milk, starch in cereals). Starch derived from cereals and other vegetables (e.g. potatoes) is the main source of calories in human diet, except under exceptional circumstances. As di- and poly-saccharides are not absorbed by the intestine, digestion (i.e. hydrolytic depolymerization) is necessary. Starch is digested by amylases from the pancreas and the salivary glands; disaccharides are digested by the four disaccharidases on the membrane of intestinal cells (maltase, isomaltase, saccharase, and lactase). Monosaccharides are adsorbed by the intestine and released in the superior mesenteric vein. The liver removes them from the blood, converts them to glucose if necessary, and stores excess glucose as glycogen (the total liver content of glycogen is 50-100g, corresponding to the daily requirement of the brain).

Audio: Sugars as nutrients

      All organs utilize some glucose for energy production and some of them use only glucose (e.g. the brain). It is of critical importance that the blood concentration of glucose is maintained constant. Glycemia, the blood glucose concentration, in the healthy fasting adult ranges between 70 and 100 mg/dL. Glycemia is regulated by the combined action of several hormones, among which insulin (a protein produced by the Langerhans islets in the pancreas) is the most relevant. Insulin causes the tissues to absorb glucose and to utilize it for their metabolism, and the liver to release glucose from glycogen; excess insulin causes hypoglycemia (lower than normal glucose concentration in the blood), lack of insulin causes hyperglycemia (excess glucose in the blood). It is important to remark that the action of insulin on peripheral tissues and liver is opposite, and that the liver function is essential for maintaining the glycemia at its constant level. Other hormones that contribute to the control of glycemia are glucagone (another protein produced by the Langerhans islets) and cortisol; moreover some cytokines produced by the adipose tissue or other tissues (e.g. resistin, adiponectin) reduce the sensitivity of the cells to insulin and thus may contribute to the causation of hyperglycemia.

Audio: Glycemia

      Glucose is metabolyzed via two main energy producing pathways, namely glycolysis (followed by the Krebs cycle) and the penthose phosphate pathway. The latter fulfills the additional function of producing ribose-5-phosphate which is necessary for the biosynthesis of nucleotides. Both pathways involve redox reactions and reduce NAD+ (or NADP+) that require oxygen to be reoxidized; however glycolysis can be carried out to some extent in excess of the availability of oxygen (anaerobic glycolysis). If this happens (e.g. during strenuous muscular effort), NAD+ is regenerated by the enzyme lactate dehydrogenase which reduces piruvate, the end product of glycolysis, to lactate. Lactate is then released in the blood and taken up by the liver which converts it back to glucose by glyconeogenesis (Cori's cycle). Except for a couple of reactions, glyconeogenesis is the reverse of gycolysis and uses the same enzymes; it is however a energy-intensive process, whose cost is approximately one fourth of the total lactate available. Glyconeogenesis requires piruvate or other glycolysis intermediates, that can be obtained by sources other than lactate: e.g. alanine (which is converted to piruvate by Alanine Aminotransferase); aspartate (which is converted to oxaloacetate by Aspartate Aminotransferase and then to phosphoglycerate); serine (which can be converted to phosphoglycerate); etc. Thus, insufficient dietary apport of glucose can be counteracted by degradation of endogenous proteins and conversion of some of their constituent aminoacids to intermediates of the glyconeogenesis. By contrast, humans (and other animals) have no metabolic pathway that converts fatty acids or their metabolytes to glucose (with the possible exception of the metabolism of propanoyl-CoA). This conversion is not impossble though: some plant seeds possess the necessary enzymes (the glyoxalate pathway); it has been lost during evolution because animals obtain excess sugars from their diet and there is no selective advantage in being able to synthesize them form fat.

      Glucose transport and the role of potassium.
      Glucose transport in the direction dictated by its concentration gradient (usually from the blood to the cell cytoplasm) occurs by facilitated diffusion, thanks to glucose transporters (GLUTs) in the cell membrane. Since glucose is a non-electrolyte passive transport is not related to ion transport. This type of transport occurs in most cells, given that the concentration of glucose is higher in the blood than in the cell cytoplasm. Insulin controls (also) the activity of GLUTs.
      In some organs, however, glucose transport occurs against its concentration gradient and is an active process, which requires energy. These districts are the kidney, where glucose must be reabsorbed from the urine to the blood, and the intestine. In both these districts glucose must cross a cell to reach the blood, where its concentration is high. Active glucose transporters (SLGTs) operate by co-transporting one molecule of glucose and one sodium ion, and the energy is provided by the sodium gradient, sodium being present at low concentration inside the cells. Since active transport of glucose co-transports one cation, it must be associated to the inverse transport of a different cation, and this is potassium. The whole process is as follows: an ATP-dependent membrane pump extrudes three sodium ions in exchange for two potassium ions; this creates a sodium ion gradient. The SGLT imports one glucose and one sodium ion thus is utilizes the sodium gradient as an energy source for glucose uptake. The stoichiometry of the process is:
3 Na+intracellular + 2 K+extracellular + ATP --> 3 Na+extracellular + 2 K+intracellular + ADP + Pi
Na+extracellular + glucoseextracellular --> Na+intracellular + glucoseintracellular

      Insulin activates active transport of glucose also in tissues that would otherwise only use facilitated diffusion (e.g. the striated muscle). As a consequence of this mechanism, insulin intravenous administration may cause potassium depletion in the extracellular fluids, and should be associated to administration of potassium, and to the measurement of potassiemia. Remember that disturbances of potassium concentration are associated to potentially severe cardiac arrhytmias!

Audio: Glucose transport

      Glucose concentration is essentially the same in whole blood and in plasma. The measurement of glucose concentration can be effected with several techniques; the preferred one takes advantage of the specificity offered by enzymes. Chemical methods are economically very convenient but are at a loss in discriminating glucose from its epimers (e.g. galactose): they identify but do not discriminate all reducing monosaccharides. An example of a typical enzymatic method is as follows:
In reaction 1 glucose is converted to glucose-6-phosphate by addition of ATP and the enzyme glucokinase; in reaction 2 glucose-6-phosphate is converted to 6-phosphogluconate by addition of NADP+ and the enzyme Glucose-6-phosphate dehydrogenase. Measurement is effected by absorption spectroscopy, taking advantage of the change of extinction coefficient associated to the reduction of NADP+:

      A specific test for diabetes is the Glucose Tolerance Test. To perform this test the glycemia is measured in the fasting patient, then glucose is administered orally at a dose of 1.75 g/kg as a 25 g/dL aqueous solution, and glyecemia is measured again at 30 min intevals for at least 2 hours. Typical glycemia profiles for healthy adults and Insulin Dependent Diabetes Mellitus (IDDM) patients are reported in the figure below (attention: significance interindividual variability!):

      An important complementary test of diabetes is that of glycosylated hemoglobin. The aldehyde group of glucose can react wit proteins' amino groups to form a reversible Schiff base adductthat converts internally to an irreversible ketoamine adduct. All proteins may be involved, but a special target is the N-terminal Val of the subunits of Hb, notably, but not exclusively that of the β-subunits. The resulting product is called glycosylated Hb (or HbA1c). in normal subjects glycosylated Hb does not exceed 6% oftotal Hb, but in diabetic patients it may account for over 12% of total Hb. Glycosylated Hb is long lived and is thus an indicator of the average glycemia over several weeks before the test; thus it tells the physician about fluctuations of glycemia and compliance to therapy.

      The glycemic index is a measure of the ability of glucose containing foods to cause a rapid increase of the glycemia. To measure the glycemic index of a given food, the fasting experimental subjects are feed with the amount of food necessary to provide 50 g of sugars and their glycemia is measured at 15-30 min. intervals for two hours. The glycemic index is expressed as the ratio between incremental area of the glycemic curve divided by the area of the control food (50 g of pure glucose), and expressed as a percentage. A high GI (>70%) food is one whose sugars are rapidly absorbed and produces a fast increase of the glycemia and an equally fast decrease, coupled to a strong insulin response; a low GI (=50% or less) food produces a slower and less marked increase of the glycemia and a more gradual insulin response. As a general rule low GI foods are preferable, and high GI foods are to be reduced for diabetic patients.
High GI (>70)Glucose, maltose, maltodextrins, breakfast cereals
Medium GI (55-70)Fruit juices, bread, rice, potatoes
Low GI (<55)Raw fruits and vegetables, beans, nuts and dried fruits

Audio: Hyperglycemias and hypoglycemias


      Autoimmune destruction of the insulin producing cells (the β-cells of the Langerhans islets in the pancreas) results in type I diabetes mellitus. The term diabetes (from the greek flow-through) indicates a clinical condition characterized by polyuria (increased urine production) and polydipsia (thirst, increased water uptake); there are several diseases associated to these symptoms. A basic dichotomy is whether the urine contains glucose (diabetes mellitus: in this case diuresis is increased because of the osmotic effect of glucose) or not (diabetes insipidus; diuresis is increased because of reduced reabsorption of water, usually due to insufficient production of the antidiuretic hormone vasopressin by the neurohypophysis).
      Type I diabetes mellitus accounts for approx. 15% of all cases of diabetes mellitus, but is the most severe form and if untreated is lethal within months or at most a few years after diagnosis. It usually occurs in infants or adolescents, and since it can be effectively treated by subcutaneous administration of insulin at regular time intervals, correct diagnosis is of utmost importance. Strictly speaking, what we call type I diabetes mellitus is not truly a disease: rather it is the anatomophysiological condition resulting from one (the autoimmune destruction of insulin producing cells), in some sense similar to a palsy or to the traumatic loss of a limb. However, since it causes symptoms and it damages several organs, thus exhibiting a progression, it behaves and must be treated like a disease.

Audio: Insulin-Dependent Diabetes Mellitus (IDDM)

      Diagnostic criteria for IDDM are fasting glycemia >140 mg/dL and peak glycemia in the oral glucose tolerance test >200 mg/dL. However a fasting glycemia >115 mg/dL in the adult or >130 mg/dL in the child strongly suggest further analysis for IDDM and other types of hyperglycemias. The insulin concentration in the serum can be measured (by Insulin RadioImmunoassay, IRI) to demonstrate its decreased or absent production, but this is rarely necessary, and may present false positives because insulin concentration exhibits large fluctuations.
      Biochemistry and pathophysiology of IDDM (Insulin-Dependent Diabetes Mellitus) are surprisingly complex, and some details remain unclear. The main consequence of the lack of insulin is that most tissues of our body cannot uptake glucose (the brain does not require insulin for this and is not damaged), which accumulates in the blood (causing hyperglycemia) and is filtered by the kidney at a rate incompatible with reabsorption (causing glycosuria and osmotic polyuria). Loss of water in the urine causes thirst. Free glucose is chemically reactive, because of its aldehydic group and may combine with the amino groups of lysyl residues of proteins, causing protein glycosylation, most notably hemoglobin glycosylation.
      Hyperglycemia, though important, is not the cause of the most relevant damages due to IDDM: in fact, the most damaging events occur inside the cells, and are due to lack of glucose, and consequent shift to consumption of fatty acids. The β-oxidation of fatty acids yields acetyl-CoA to fuel the Krebs cycle, thus it can sustain the cell's energy requirements. However the Krebs cycle requires a small but continuous apport of oxaloacetate to replace losses due to removal of metabolytes for anabolic requirements (e.g. α-chetoglutarate may be used to produce glutamate and glutamine; oxaloacetate may be used to produce aspartate and asparagine; succinyl-CoA is used to produce delta-aminolevulinc acid, required by heme biosynthesis; etc.). Oxaloacetate can be produced from piruvate by the enzyme piruvate carboxylase, but cannot be produced starting from any metabolyte of the β-oxidation, with the exception of the small amount of succinyl-CoA produced during the metabolysm of propanoyl-CoA (in the case of the rare fatty acids with uneven number of carbons).

      In the absence of glucose, piruvate is produced to a reduced extent, only from the metabolism of glycogenic aminoacids; as a consequence the mitochondrion is starved of oxaloacetic acid and the Krebs cycle slows down. Acetyl-CoA is thus produced in excess with respect to the ability of the Krebs cycle to oxidize it and accumulates in the mitochondrion. Acetyl-CoA polymerizes spontaneously to acetoacetyl-CoA and is finally released as acetoacetic acid. Two metabolytes of acetoacetic acid are also formed: acetone (by decarboxylation) and beta-hydroxy butanoic acid (by reduction). These three compounds, collectively called ketone bodies, accumulate in the blood and are ultimately excreted by the kidney (acetone, being volatile, is also excreted by the lung, causing acetone breath).

      Since two ketone bodies are non volatile acids, they cause an important metabolic acidosis called diabetic ketoacidosis. Diabetic ketoacidosis is the most severe consequence of the disruption of cellular metabolism, and is the cause of coma and death in untreated insulin dependent diabetes mellitus. By contrast, in type 2 diabetes, cellular usage of glucose is impaired but not abolished, and ketoacidosis, if present at all, is neither severe nor life treatening.
      Since glucose is lost in the urine and its metabolic role in the cell is played by aminoacids, protein waste occurs, with weight loss and negative nitrogen balance (more nitrogen is excreted than it is introduced with the diet). Hyperglycemia and increased glucose concentration in the extracellular fluids favour the proliferation of microorganisms and cause increased susceptibility to opportunistic infections (e.g. candidiasis).
      IDDM is associated to peripheral, predominantly sensory, neuropathy (causing pain), atherosclerosis of large arteries and microvascular damage. The pathogenetic mechanism of these complications has not been completely unravelled. These complications occur on a chronic basis in insulin-treated patients (untreated patients did not survive enough to provide casistics), and probably depend on multiple factors. Minor hyperglycemia or scattered periods of hyperglycemia are common in insulin-treated diabetic patients; this occurs because excess insulin may cause hypoglycemic coma and thus the patient and the physician prefer to use it careully. Over long times, frequently repeated minor episodes of hyperglycemia may damage the cell membranes, because of osmotic reasons and because of the reaction of glucose with membrane proteins. Ketone bodies may contribute to the damage, as well as the cellular metabolic inbalance. Vascular and neural damage may cause the diabetic ulcer of the extremities, which in turn is worsened by the increased susceptibility to infection. Another complication is damage of the retina which is to be ascribed to the combined effects of microvascular and neural damage.
      In untreated patients, accumulation of acetoacetic and β-hydroxy butanoic acids cause a metabolic acidosis with reduced blood pH and compensatory hyperpnea (Kussmaul's breath) and hypocapnia (reduced CO2 and bicarbonate). Vomiting, and drowsiness are common symptoms of this condition; coma and death result if the blood pH drops to 7.1 or less.
      The cardinal symptoms of untreated IDDM: polyuria, polydipsia, acetone breath, and weight loss in an infant or adolescent should indicate dedicated laboratory tests.

Important analyses for the diagnosis and clinical monitoring of diabetes mellitus
fasting glycemia
glucose tolerance test
glycosylated hemoglobin concentration
insulin concentration (by radio immunoassay)
hemogas analysis (for ketoacidosis)
determination of ketone bodies
electrolytes and anion gap (for ketoacidosis)

Audio: Laboratory analyses for the study of hyperglycemias


      LATE ONSET DIABETES MELLITUS (NIDDM; Insulin Resistent Diabetes Mellitus) accounts for the great majority of the cases of DM, but is less severe than IDDM and has a better prognosis even if untreated or poorly treated. NIDDM (non Insulin Dependent DM) is a metabolic imbalance of the cells that causes a reduction of the insulin receptors on the cell surface. Hyperglycemia and glycosuria are present but the cells are not starved of glucose and ketoacidosis is uncommon. In extreme cases the blood glucose concentration may reach such high levels to cause hyperosmolarity and possibly coma and death.
      The cardinal symptoms of untreated NIDDM: polyuria, polydipsia, possibly obesity, and drowsiness in an adult should indicate at least the determination of the fasting glucose level, and a glucose tolerance test. Special attention should be given to pregnant women as pregnancy may favor the clinical manifestation of a previously sub-clinical NIDDM condition. The prevalence of NIDDM in the general population is high, possibly higher than 1%, thus Bayes formula tells us that in the presence of the above symptoms NIDDM is a highly plausible hypothesis.

Three possible causes of coma and death in diabetic patients
Ketoacidosis coma in IDDM
Hyperosmotic coma in NIDDM
Hypoglycemic coma due to excess insulin or insufficient dietary apport of glucose in insulin treated patients

      Since the hyperglycemia overstimulates insulin production the β-cells of the Langerhans islets may undergo degeneration and the NIDDM may convert, with time, into IDDM albeit the mechanism of destruction of the insulin producing cells is not due to autoimmunity. NIDDM is associated to obesity and hypertension (see the description of the metabolic syndrome, in the lecture on lipoproteins), and causes renal damage (because of glycosuria) and atherosclerosis of large arteries; microangiopathy is neither common nor prominent. Peripheral neuropathy, and diabetic ulcers of the extremity may appear in chronic poorly treated cases. The main differences between IDDM and NIDDM are summarized in the Table below.

Characteristic IDDM NIDDM
age of onset usually <30 years usually >30 year
obesity absent (weight loss) present in >80% of the cases
ketoacidosis yes (possible cause of coma and death) absent
hyperosomolarity usually absent possible (possible cause of coma and death)
Insulinemia strongly reduced to absent may be normal or increased
Predominant vascular disease microangiopathy atherosclerosis of large vessels
Association with specific hystocompatiblity antigents HLA DR3/DR4 absent
Antibodies against Langerhans cells present absent
Familiarity modest important
Identical twin concordance low high
Histopathology Loss of the β-cells of the Langerhans islest Hyperplasia of the β-cells of the Langerhans islets

      DIABETES ASSOCIATED WITH OTHER ENDOCRINE DISEASES: other hormones participate to the control of glycemia and imbalances in their production (e.g. by hormone producing adenomas of the gland tissue) may cause hyperglycemia and glycosuria. Usually there are other symptoms associated with the specific hormone involved and no metabolic symptoms of diabetes (e.g. no ketoacidosis). The principal hormone that may cause a diabets-like syndrome is cortisol (and in general all glycocorticoids). The syndrome is suspected because of polyuria, and confirmed by the finding of hyperglycemia and glycosuria; the hormone involved must then be searched for in the blood (usually resorting to immunological methods). Morphological and functional study of the involved gland (e.g. NMR, PET and scintigraphy) is the next step.


      Galactosemia is a genetic disease inherited as an autosomal recessive trait. It is caused by absence of the enzyme galactosyl-1-phosphate uridyl transferase, whose gene is located on chromosome 9. The incidence is 1 newborn / 80,000 births and the diagnosis is usually established early, given the large apport of galactose from the milk lactose. The symptoms appear a few weeks after birth with vomiting, reduced weight gain and jaundice. Treatment is dietary, by substituting the mother's milk with an artificial one in which lactose has been replaced with glucose. In the absence of treatment reduced growth and impaired IQ are unavoidable and the life expectancy is reduced. Diagnosis is suspected upon finding a non glucose sugar in the urine, which can be demonstrated to be lactose or lactose-1-phosphate; genetic demonstration of the defect offer definitive confirmation. Other, less common, inherited causes of galactosemia and galactosuria are the inherited deficiencies of the enzymes galactokinase or galactose epimerase. The prognosis is less severe than in the case of defect of galactosyl-1-phosphate uridyl transferase.
      Fructosuria is caused by genetically determined lack of fructokinase; the incidence is 1/130,000 and the disease is benign.
      Hereditary fructose intolerance is due to the genetically determined defect of the enzyme phosphofructoaldolase, inherited as an autosomal recessive trait. In some countries or populations this defect may be relatively common (e.g. its frequency is 1/20,000 births in Switzerland). Fructose-1-phosphate accumulates in the body tissues and in the blood and appears in the urine. Severe symptoms follow the ingestion of fructose or suchrose (table sugar); renal damage may occur. Treatment require the elimination of fructose from the diet (not easy given that suchrose, the fructose containing disaccharide, is almost ubiquitary in fruits).
      Pentosuria is a harmless metabolic disorder due to lack of the enzyme L-xylulose dehydrogenase, and associated to excretion of L-xylulose in the urine. In some populations it is very common (e.g. 1/2,500 births among american Jews). The only risk for the patient is that his condition is misdiagnosed (and treated) for IDDM.
      Fanconi's syndrome is a defect of the tubular reabsorption of glucose and other solutes (aminoacids, bicarbonate, etc.), causing a normoglycemic mellituria. It is genetically heterogeneous, and its severity is variable.


      Hypoglycemic conditions may cause fainting and coma. They may be due to several causes and, if severe, may cause death: thus they may present as medical emergencies. The most common causes of hypoglycemias are as follows:
Excess insulin administration in an IDDM patient, a quite common condition, may be life treatening and requires prompt diagnosis (caution! hypoglycemic coma needs to be distingushed from the two other possible types of coma in the diabetic patients: ketoacidosis and hyperosmotic).
Insulin secreting adenoma of the Langerhans islets.
Some hereditary diseases of carbohydrate metabolism: e.g. hereditary fructose intolerance, galactosemia, some types of liver glycogenosis (see below).
Deficiency of hormones causing increase of glycemia: glucagon, cortisol, growth hormone, hypothyroidism.
      As a general rule hypoglycemia conditions are uncommon. Hypoglycemia appearing in infants may be due to hereditary defects of metabolism; hypoglycemia that appears in children or adults is usually due to other causes. Malnutrition may aggravate hypoglycemia but is rarely its direct cause because in the course of malnutrition or famine humans destroy proteins, especially in the muscular tissue, and utilize glycogenic aminoacids for glyconeogenesis: thus the glycemia is maintained at nearly normal levels even under severe fasting, and wastage of muscular mass.


      Inherited defects of glucose metabolism are extremely rare (< 1:50,000). The single most important one is Pyruvate dehydrogenase complex deficiency (PDCD). Symptoms are poorly specific symptoms (lethargy, poor feeding, tachypnea, neurological disturbances), and are exacerbated by high carbohydrate intake. The disease is recessive and X-linked (only males are affected). Severity is variable; in severe cases prognosis is poor. Laboratory diagnosis relies on the demonstration of increased piruvate and lactate levels in the urine, blood and Cerebro Spinal Fluid (CSF). Alanine is also increased because of transamination of piruvate. Gene sequencing confirms the diagnosis.
      Glycogen storage disease (glycogenoses) are a group of (usually severe) genetic diseases of glycogen metabolism, causing accumulation of glycogen in several types of cells. A summary of the principal glycogeneoses is reported in the table below.

Disease name Enzyme involved Organs affected and symptoms
Deficiency of UDPG-glycogen transferase Enlargement and steatosis of the liver, fasting hypoglycemia, muscular weakness
Von Gierke Disease Glucose-6-phosphatase Damage of the liver and the kidneys; growth retardation, hypoglycemia, acidosis, hyperlipemia
Deficiency of Glucose 6-phosphate translocase Damage of liver and kidney; neutropenia and susceptibility to bacterial infections
Pompe Disease Lysosomal glucosidase(s) Damage of the liver and the heart
Forbes Disease Debrancher enzyme Damage of the liver and muscle; fasting hypoglycemia
Andersen Disease Brancher Enzyme system Progressive epatic cirrhosis
McArdle Disease Muscle Glycogen phosphorylase Faticability; muscular cramps on exercise
Hers Disease Liver Glycogen phosphorylase Enlarged liver, possible hypoglycemia

Further readings
The Lancet monographic issue on diabetes mellitus
Greene D, The pathogenesis and prevention of diabetic neuropathy and nephropathy.
Hajer G.R, van Haeften T.W., and Visseren F.L.J. Adipose tissue disfunction in obesity, diabetes and vascular diseases.
SC Patino, SS Mohiuddin Biochemistry: glycogenoses.

Questions and exercises:
1) Fasting glycemia in a healthy adult is:
< 70 mg/dL
< 100 mg/dL
< 130 mg/dL

2) In diabetic ketoacidosis the anion gap is:

3) The prevalence of type 1 and type 2 diabetes mellitus in the population are, respectively
0.1% and 1%
1% and 0.1%
0.5% and 0.5%

4) The order in which the following laboratory tests should be carried out is:
fasting glycemia, glucose tolerance test, insulin radioimmunoassay
insulin radioimmunoassay, fasting glycemia, glucose tolerance test
insulin radioimmunoassay, glucose tolerance test, fasting glycemia

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Thank you Professor (lecture on bilirubin and jaundice).

The fourth recorded part, the one on hyper and hypoglycemias is not working.
Bellelli: I checked and in my computer it seems to work. Can you better specify
the problem you observe?

This Presentation (electrolytes and blood pH) feels longer than previous lectures
Bellelli: it is indeed. Some subjects require more information than others. I was
thinking of splitting it in two nest year.

Bellelli in response to a question raised by email: when we compare the blood pH
with the standard pH we do not mean to compare the "normal" blood pH (7.4)
with the standard pH. Rather we compare the actual blood pH of the patient, with
the pH of the same blood sample equilibrated under standard conditions.
Thus, if we say that standard pH is lower than pH we mean that equilibriation with
40 mmHg CO2 has caused absorption of CO2 and has lowered the pH with respect
to its value before equilibration.

(Lipoproteins) Is the production of leptin an indirect cause of type 2 diabetes since
it works as a stimulus to have more adipose tissue that produces hormones?
Bellelli: in a sense yes, sustained increase of leptin causes the hypothalamus to adapt
and to stop responding. Obesity ensues and this in turn may cause an increase in the
production of resistin and other insulin-suppressing protein hormones produced by the
adipose tissue. However, this is quite an indirect link, and most probably other factors
contribute as well.

(Urea cycle) what is the meaning of "dissimilatory pathway"?
Bellelli: a dissimilatory pathway is a catabolic pathway whose function is not to produce
energy, but to produce some terminal metabolyte that must be excreted. Dissimilatory
pathways are necessary for those metabolytes that cannot be excreted as such by the
kidney or the liver because they are toxic or poorly soluble. Examples of metabolytes
that require transformation before being eliminated are heme-bilirubin, ammonia,
sulfur and nitrogen oxides, etc.

Talking about IDDM linked neuropathy can be the C peptide absence considered a cause of it??
Bellelli: The C peptide released during the maturation of insulin, besides being an indicator
of the severity of diabetes, plays some incompletely understood physiological roles. For
example it has been hypothesized that it may play a role in the reparation of the
atherosclerotic damage of the small arteries. Thus said, I am not aware that it plays a direct
role in preventing diabetic polyneuropathy. Diabetic neuropathy has at least two causes: the
microvascular damage of the arteries of the nerve (the vasa nervorum), and a direct
effect of hyperglycemia and decreased and irregular insulin supply on the nerve metabolism.
Diabetic neuropathy is observed in both IDDM and NIDDM, and requires several years to
develop. Since the levels of the C peptide differ in IDDM and NIDDM, this would suggest
that the role of the C peptide in diabetic neuropathy is not a major one. If you do have
better information please share it on this site!

In acute intermitted porphyria and congenital erythropoietic porphyria why do the end product
of the affected enzymes accumulate instead of their substrate??
Bellelli: First of all, congratulations! This is an excellent question.
Remember that a condition is which the heme is not produced is lethal in the foetus; thus
the affected enzyme(s) must maintain some functionality for the patient
to be born and to come to medical attention. All known genetic defects of heme
biosynthesis derange but do not block this metabolic pathway.
Congenital Erythropoietc Porphyria (CEP) is a genetic defect of uroporphyrinogen
III cosynthase. This protein associates to uroporphyrinogen synthase (which is present
and functional in CEP) and guarantees that the appropriate uroporphyrinogen isomer is produced
(i.e. uroporphyrinogen III). In the absence of a functional uroporphyrinogen III
cosynthase other possible isomers of uroporphyrinogen are produced together with
uroporpyrinogen III, mostly uroporphyrinogen I. The isomers of uroporphyrinogen
that are produced differ because of the positions of propionate and acetate side chains,
and this in turn is due to the pseudo symmetric structure of porphobilinogen. Only
isomer III can be further used to produce protoporphyrin IX. Thus in the
case of CEP we observe accumulation of abnormal uroporphyrinogen derivatives, which, as
you correctly observed are the products of the enzymatic synthesis operated by
uroporphyrinogen synthase.
The case of Acute Intermittent Porphyria (AIP) is similar, although there may be variants
of this disease. What happens is that either the affected enzyme is a variant that does not
properly associate with uroporphyrinogen III cosynthase or presents active site mutations
that impair the proper alignement of the phoprphobilinogen substrates. In either case
abnormal isomers of uroporphyrinogen are produced, as in CEP.
Also remark that in both AIP and CEP we observe accumulation of the porphobilinogen
precursor: this is because the overall efficiency of the biosynthesis of uroporphyrinogens is
reduced. Thus: (i) less uroporphyrinogen is produced, and (ii) only a fraction of the
uroporphyrinogen that is produced is the correct isomer (uroporphyrinogen III).

is it possible to take gulonolactone oxidase to synthesize vitamin C
instead of vitamin C supplement?
Bellelli: no, this approach does not work. The main reason is that
the biosynthesis of vitamin C, as almost all other metabolic processes, occurs intracellularly.
If you administer the enzyme it will at most reach the extracellular fluid but will not be
transported inside the cells to any significant extent. Besides, there are other problems
in this type of therapy (e.g. the enzyme if administered orally, may be degraded by digestive
proteases; if administered parenterally, may cause the immune system to react against a
non-self protein). In theory one could think of a genetic modification of the inactive human
gene of gulonolactone oxidase, but the risk and cost of this intervention would not be
justified. In addition to these considerations, except for cases of shipwreckage or
other catastrophes, a proper diet or administration of tablets of vitamin C is effective,
risk-free and unexpensive, thus no alternative therapy is reasonable. However, I express my
congratulations for your search on the biosynthesis pathway of ascorbic acid.

Resorption and not reabsorption would lead to hypercalcemia ie bone matrix being broken down.
Bellelli: I am not sure to interpret your question correctly. Resorption indicates destruction of the bone matrix and release of calcium and
phosphate in the blood, thus it causes an increase of calcemia. Reabsorption usually means active transport of calcium from the renal tubuli to the blood, thus
it prevents calcium loss. It prevents hypocalcemia, and thus complement bone resorption. To avoid confusion it is better use the terms "bone resorption" and "
renal reabsorption of calcium". If you have a defect in renal reabsorption, parthyroid hormone will be released to maintain a normal calcium level by means of
bone resorption; the drawback is osteoporosis.

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