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 ones take 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. The method described by P. Trinder makes use of glucose oxidase (GOD), an enzyme produced by the fungus Aspergillus niger, which converts glucose and oxygen to gluconic acid and hydrogen peroxide; and of horseradish peroxidase (POD), which uses hydrogen peroxide to oxidize a chromogenic substrate (o-tolidine; adrenaline; o-dianisidine; etc.); the absorbance change is proportional to the glucose concentration in the sample and is read using a spectrophotometer. An alternative method (more expensive, but possibly more familiar to students who remember the pentose phosphate pathway) is based on glucokinase and glucose-6-phosphate dehydrogenase:
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.
      Other forms of IDDM occur as a consequence of diseases that destroy or severely compromise the pancreas, e.g. acute pancreatitis or cancer. These may occur at any age, but aside from this feature are clinically indistinguishable from typical IDDM.

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)
glycemia to insulin (G/I) ratio
hemogas analysis (for ketoacidosis)
determination of ketone bodies
electrolytes and anion gap (for ketoacidosis)

Audio: Laboratory analyses for the study of hyperglycemias

Clinical examples
1) ketoacidosis in a 11 year old patient suffering of type I diabetes mellitus, poorly compliant to insulin therapy. Laboratory findings:

Analysis of the case: hyperglycemia, metabolic acidosis (the anion gap though not reported in the slide was increased). Reduced PCO2 is characteristic of the respiratory compensation. Caution: this is a medical emergency, and the patient is probably entering into a comatous state if untreated.


      LATE ONSET DIABETES MELLITUS (NIDDM; Insulin Resistent Diabetes Mellitus; type 2 DM) 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, and reduced response to insulin. The onset of NIDDM is slow and insidious; an important laboratory test for the initial phases of the disease is the glycemia /insulin ratio, where glycemia is measured in mg/dL and insulin in U/mL Values of G/I ratio lower than 4.5 are indicative of insulin resistence. In conclamated NIDDM or IDDM the G/I ratio is not indicative.
      The relationship between NIDDM and insulin is complex; in the initial stages of the disease, insulin is usually increased; actually the disease's onset has normal glycemia and increased insulinemia (higher insulin levels are required to keep glycemia to the normal level); in later stages of the disease one observes a functional echaustion of the pancreas, and insulin levels diminish to normal or below normal; this effect is usually reversible. Important associations are with obesity (the adipose tissue produces hormones that reduce insulin sensitivity, e.g. resistin, see below) and with Cushing's disease (excess secretion of glycocorticoid hormones). Therapy of NIDDM in the early stages may use drugs that stimulate insulin production (e.g. sulfonylureas); in later stages may require insulin.
      In NIDDM 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.
      There is an important association between NIDDM and obesity, mediated by insulin antagonizing hormones released by the adipose tissue, as discussed in the lecture on lipoproteins.
      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 may be 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 years
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.

Clinical examples
2) Obesity-related insulin resistence. Adolescent boy markedly overweight decides to start a diet aiming at reducing body weight. Before starting the diet the following laboratory parameters were recorded:
Fasting glycemia: 85 mg/dL
Plasma insulin concentration: 21.5 microU/mL
Glycemia to insulin ratio: 3.95
Eight months after starting the diet, 10 kg weight loss are recorded, together with the following parameters:
Fasting glycemia: 75 mg/dL
Plasma insulin concentration: 8.0 microU/mL
Glycemia to insulin ratio: 9.4
Analysis of the case: fat tissue produces insulin resistence hormones, and the boy had a mild level of insulin resistence, as revealed by the G/I ratio. Notice that the inital condition is non-diabetic: glycemia is normal, but increased levels of insulin are required to avoid hyperglycemia. This type of condition is often referred to as pre-diabetic, and has high risk of evolution to NIDDM. The boy was remarkably constant in his diet and achieved a significant reduction of body weight; the reduced fat tissue caused the insulin resistence to disappear and normalized the G/I ratio.


      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. Hypoglycemias are relatively uncommon: glucose is necessary to the brain metabolism and its concentration in the blood is maintained at the expenses of all other tissues; e.g. in starvation, muscle protein is reabsorbed and glycogenic aminoacids are converted to glucose via glyconeogenesis. The most common causes of hypoglycemias are as follows:
Chronic liver failure: the liver contains the largest fraction of glycogen reserves of our body; in advanced stages of liver failure the functional parenchyma is reduced and glycogen reserves are severely depleted.
Excess insulin (or sulfonylureas) administration in an DM 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). These conditions are detected in the infancy, and have usually a poor prognosis.
Deficiency of hormones causing increase of glycemia: glucagon, cortisol, growth hormone, hypothyroidism.
      Hypoglycemia appearing in newborns or infants may be due to prematurity or 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.


      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.

In Reed and Frost model: I haven't understood what is the relationship
between K and R reproductive index. Thank you Professor!
Bellelli: in the Reed and Frost model K is the theoretical upper limit of
R0. R the reproductive index is the ratio (new cases)/(old cases) measured after
one serial generation time. R0 is the value of R one measures at the beginning
of the epidemics, when in principle all the population is susceptible.

What is the link between nucleotide metabolism and immunodeficiencies and mental retardation?
Bellelli: the links may be quite complex, but the principal ones are as follows:
1) the immune response requires a replication burst of granulocytes and lymphocytes, which in turn requires
a sudden increase of nucleotide production, necessary for DNA replication. Defects of nucleotide metabolism
impair this phase of the immune defense. Notice that the mechanism is similar to the one responsible of
anemia which requires a sustained biosynthesis of nucleotides at a constant rate, rather than in a burst.
2) Mental retardation is mainly due to the accumulation of nulceotide precursors in the brain of the
newborn, due to the incompletely competent blood-brain barrier.

How can ornithine transaminase defects cause hyperammonemia? Is it due to the accumulation
of ornithine that blocks the urea cycle or for other reasons?
Bellelli: ornithine transaminase is required for the reversible interconversion of ornithine
and proline, and thus participates to both the biosynthesis and degradation of ornithine. The enzyme is
synthesized in the cytoplasm and imported in the mitochondrion. Depending on the metabolic conditions
the deficiency of this enzyme may cause both excess (when degradation would be necessary) or defect
(when biosynthesis would be necessary) of ornithine; in the latter case, the urea cycle slows down. Thus
there is the paradoxical condition in which alternation may occur between episodes of hyperammonemia
and of hyperornithinemia.

When we use the Berthelot's reaction to measure BUN do we also have to
measure the concentration of free ammonia before adding urease?
Bellelli: yes, in principle you should. Berthelot's reaction detects ammonia,
thus one should take two identical volumes of serum, use one to measure free ammonia,
the other to add urease and measure free ammonia plus ammonia released by urea. BUN is
obtained by difference. However, free ammonia in our blood is so much lower than urea that
you may omit the first sample, if you only want to measure BUN.

Why do we have abnormal electrolytes in hematological neoplasia e.g.
Bellelli: I do not have a good explanation for this effect, which may have
multiple causes. However, you should consider two factors: (i) acute leukemias cause a massive
proliferation of leukocytes (or lymphocytes depending on the cell type affected) with a very
shortened lifetime; thus you observe an excess death rate of the neoplastic cells. The dying
cells release in the bloodstream their content, which has an electrolyte composition different
from that of plasma: the cell cytoplasm is rich in K and poor in Na, thus causing hyperkalemia.
(ii) the kidney may be affected by the accumulation of neoplastic white cells or their lytic products.

Gaussian curve: If it is bimodal is it more likely to be a "certain diagnosis" than if it is
unimodal or does it only show the distinguishment from health?
Bellelli an obviously bimodal Gaussian curve indicates that the disease is clearly
separated from health: usually it is a matter of how precise and clear-cut is the definition of the disease.
For example tuberculosis is the disease caused by M. tuberculosis, thus if the culture of the sputum is
positive for this bacterium you have a "certain" diagnosis (caution: the patient may suffer of two diseases,
e.g. tuberculosis and COPD diagnosis of the first does not exclude the second). However, in order to have
a "certain" diagnosis it is not enough that distribution of the parameter is bimodal, it is also required that the
patient's parameter is out of the range of the healthy condition: this is because a distribution can be
bimodal even though it is composed by two Gaussians that present a large overlap, and the patient's
parameter may fall in the overlapping region. Thus, in order to obtain a "certain" diagnosis you need to
consider not only the distribution of the parameter(s) but also the patient's values and the extent of the
overlapping region.

Prof can you please elaborate a bit more on the interhuman variability and its difference
with the interpopulation variability please?
Bellelli: every individual is a unique combination of different alleles of the same genes;
this is the source of interindividual variability. Every population is a group of individuals who intermarry and
share the same gene pool (better: allele pool). Every allele in a population has its own frequency. Two
population may differ because of the diffferent frequencies of the same alleles; in some cases one
population may completely lack some alleles. The number and frequencies of alleles of each gene
determine the variance. If you take two populations and calculate the cumulative interindividual variance
of the population the number you obtain is the sum of two contributions: the interindividual variance within each population, plus the interpopulation variance
between the means of the allele frequencies. For example, there are human population in which the frequency of blood group B is close to 0% and other populati
ons in which it is 30% or more.

Prof can you please explain again the graph you have showed us in class about thromboplastin?
(Y axis=abs X axis= time)
Bellelli: the graph that I crudely sketched in class represented the signal
of the instrument (an absorbance spectrophotometer) used to record the turbidity of the
sample (turbidimetry). The plasma is more or less transparent, before coagulation starts.
When calcium and the tissue factor (or collagen) are added. thrombin is activated and begins
digesting fibrinogen to fibrin; then fibrin aggregates. The macroscopic fibrin aggregates cause
the sample to become turbid, which means it scatters the incident light. The instrument reads
this as a decrease of transmitted light ( an increase of the apparent absorbance) and the
time profile of the signal presents an initial lag phase, which is called the protrombin or
thromboplastin time depending on the component which was added to start coagulation
(tissue factor or collagen).

Prof can you please explain the concept you have described in class about
the simultaneous hypercoagulation and hemorrhagic syndrome? How can this occur?
Bellelli: The condition you describe is observed only in the Disseminated
Intravascular Coagulation syndrome. Suppose that the patient experiences an episode of
acute pancreatitis: tripsin and chymotripsin are reabsorbed in the blood and proteolytically
activate coagulation causing an extensive consumption of fibrinogen and other coagulation
factors. Tripsin and chymotripsin also damage the vessel walls and may cause internal
hemorrages, but at that point the consumption of fibrinogen may have been so massive that
not enough is left to form the clot where the vessel has been damaged, causing an internal
hemorrage. Pancreatitis is a very severe, potentially lethal condition, and DIC is only one of
the reasons of its severity.

You said that certain drugs (ethanol, cocaine, cannabis, opiates...) cause a
necessity of higher and higher dosage, for two reasons: the enzyme in the liver is inducible and
the receptors in the brain are expressed less and less. So, first, I am not sure I got it right, and
second I did not understand how expressing less receptors leads to a necessity of higher
Bellelli: You got it correctly, but the detailed mechanism of resistance may
vary among different substances, and not all drugs cause adaptation.
The reason why reducing the number of receptors may require an increased dosage of the drug
is as follows: suppose that a certain cell has 10,000 receptors for a drug. When bound to its
agonist/effector, each receptor produces an intracellular second messenger. Suppose that in
order for the cell to respond 1,000 receptors must be activated. The concentration of the
effector required is thus the concentration that produces 10% saturation. You can easily
calculate that this concentration is approximately 1/10 of the equilibrium dissociation constant
of the receptor-effector complex (its Kd), the law being
Fraction bound = [X] / ([X]+Kd)
where [X] is the concentration of the free drug.
After repeated administration, the subject becomes adapted to the drug, and his/her cells
express less receptors, say 5,000. The cell response will in any case require that 1,000
receptors are bound to the effector and activated, but this now represents 20% of the total
receptors, instead of 10%. The drug concentration required is now 1/4 of the Kd.
Continuing administration of the drug further reduces the cell receptors, but the absolute
number of activated receptors required to start the response is constant; thus the fewer
receptors on the cell membrane, the higher the fraction of activated receptors required.

Why does hyperosmolarity happen in type 2 diabetes and not in type 1?
Bellelli: Hyperosmolarity can occur also in type 1 diabetes, albeit
infrequently. The approximate formula for plasma osmolarity is reported in the lecture on
osmolarity = 2 x (Na+ + K+) + BUN/2.8 + glucose/18
this is expressed in the usual clinical laboratory units (mEq/L for electrolytes, g/dL for non-
electrolytes). The normal values are:
osmolarity = 2 x (135 + 5) + 15/2.8 + 100/18 = 280 + 5.4 + 5.6 = 291 mOsmol/L
Let's imagine a diabetic patient having normal values for electrolytes and BUN, and glycemia=400 mg/dL:
osmolarity = 280 + 5.4 + 22.4 = 307.8 mOsmol/L
The hyperosmolarity in diabetes is mainly due to hyperglycemia, even though other factors
may contribute (e.g. diabetic nefropathy); however the contribution of glucose to osmolarity is
relatively small. As a consequence in order to observe hyperosmolarity the hyperglycemia
should be extremely high; this is more often observed in type 2 than in type 1 diabetes, for
several reasons, the most relevant of which is that in type 1 diabetes all cells are starved of
glucose, and the global reserve of glycogen in the body is impoverished: there is too much
glucose in the blood and too few everywhere else, thus reducing, but not abolishing, the risk of
extreme hyperglycemia. Usually in type 2 diabetes the glycogen reserve in the organism is not
impoverished, thus the risk of extreme hyperglycemia is higher.

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