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Disorders of carbohydrate metabolism

- Glucose is a major energy substrate  it is the only utilizable source of
energy for some tissues (e.g. erythrocytes & CNS).
- Many tissues are capable of oxidizing glucose completely to CO2.
- Other tissues metabolize glucose to lactate which can be converted back
into glucose by gluconeogenesis.
- Even in tissues capable of completely oxidizing glucose, lactate is
produced if insufficient O2 is available (anaerobic metabolism).
- The body’s sources of glucose are:
1) Dietary carbohydrates.
2) Glycogenlysis (release of glucose stored as glycogen)
3) Gluconeogenesis (glucose synthesis from lactate, glycerol & most
amino acids)
- Glycogen is stored in the liver & skeletal muscle.
- Glycogen in the liver is the only one contributes to blood glucose.
- Blood [glucose] depends on the relative rates of influx of glucose into the
circulation & of its utilization.
- Blood [glucose] is under rigorous control  it is rarely falling < 2.5
mmol/L or rising > 8 mmol/L in healthy subjects after a meal or above 5.2
mmol/L after an overnight fasting.

- Blood [glucose] falls to pre-meal concentration within 4h after a meal.
- If fasting continues  hepatic glycogen stores are used up after about
- After 72h, blood [glucose] stabilizes & can then remain constant for many
days  the principle source of glucose becomes gluconeogenesis from
amino acids & glycerol while ketones (derived from fat) becomes the major
The control
of blood [glucose] is achieved through the action of various
1) Insulin  it lowers blood glucose concentration.
2) The counter-regulatory hormones (glucagon, cortisol,
catecholamines & growth hormone).

L = liver, M = muscle, A = adipose tissue

Insulin promotes removal of glucose from blood to: 1) Skeletal muscle & adipose tissue through stimulating the relocation of the insulin-sensitive GLUT-4 glucose transporter from the cytoplasm to the cell membrane.Other functions for insulin are summarized in the table above. . secreted by the β-cells of the pancreas islets of Langerhans in response to a rise in blood [glucose].Glucagon & gastric inhibitory peptide (GIP)  stimulate insulin secretion. . which phospholrylates glucose to form glucose-6-phosphate (a substrate for glycogen synthesis) ..It is synthesized as a prohormone (proinsulin)  this undergoes cleavage prior to secretion to form insulin & C-peptide. .Is a 51 amino acid polypeptide.Insulin & glucagon are the 2 most important hormones in glucose homeostasis: Insulin: . 2) Liver  through inducing the enzyme glucokinase. .

. . .Glucagon: .It stimulates hepatic (not muscular) glycogenlysis.Is a 29 amino acid polypeptide secreted by the α-cells of the pancreatic islets. .Its actions oppose those of insulin (see table above).Its secretion is decreased by a rise in blood [glucose].

After meal  Insulin: glucagon ratio is high  glucose is stored as glycogen & converted into fat. . .mbined effect of insulin & glucagon: .During starvation  Insulin: glucagon ratio falls  ↑ hepatic glucose & ketone production & ↓ tissue glucose utilization.

.Glucose-sensitive reagent strips are frequently used to measure glucose concentration  application on capillary blood causes a colour change proportional to glucose concentration. .Other types of reagent strips generate an electric current proportional to glucose concentration. . .These strips produce reliable results  usually used to monitor blood [glucose] by patients at home.Plasma [glucose] is 10-15% higher than that of whole blood because a given volume of RBCs contains less H2O than the same volume of plasma.Reagent strips should not be relied upon for the diagnosis of diabetes  formal laboratory measurements are recommended . .Measurement of glucose concentration: .RBCs continue to utilize glucose in vitro  sample should be analysed immediately or collected into a tube containing sodium fluoride to inhibit glycolysis  these samples are not suitable for the measurement of [K+] as the tubes contain K-oxalate as anticoagulant.

.DM secondary to other diseases may occur (uncommon)  e. oral hypoglycemics and/or insulin  pathogenesis is uncertain (genetics. . Chronic pancreatitis. .g. after pancreatic surgery & in conditions where there is increased secretion of insulin antagonistic hormones (e. obesity & lifestyle)  progressive disease that may ends with complete β-cell dysfunction.g. -syndrome 2 types of&DM: 1) Type 1 (Insulin dependent): .Causes  defect in insulin secretion or action or both. fat & protein metabolism. 2) Type 2 (Insulin independent): .Diabetes Mellitus (DM): -Is a systemic metabolic disorder characterized by a tendency to chronic hyperglycemia with disturbances in carbohydrate.Insufficient insulin secretion or resistance to its action  treated with diet.Autoimmune disease  destruction of β-cells initiated by activation of Tlymphocytes directed against antigens on the cell surface  ↓ insulin secretion  ends with complete cessation of insulin secretion  patients have absolute requirement for insulin. environmental factors. Cushing’s acromegaly).

Type 1 DM  autoimmunity  strong association with certain histocompatability antigens (e. HLA-DR3. DR-4 & various DQ alleles. .g.

.These complications occur in both type 1 & type 2 DM and the prevalence increases with the duration of the disease & if the glycemic control is poor.Pathophysiology & clinical features of DM: .Hyperglycemia is mainly a result of increased production of glucose by the liver &.If Untreated  profound metabolic disturbances  life-threatening -ketoacidosis.  Renal threshold is higher in elderly & lower during pregnancy. Long-term DM complications: non-ketotic hyperglycemia or lactic acidosis. . reabsorption becomes saturated  glucose appears in the urine.In the kidney. of decreased removal of glucose from the blood. to a lesser extent. neuropathy & retinopathy. . 1) Microvascular complications nephropathy. Glycosuria  osmotic diuresis (↑H2O excretion)  ↑ plasma osmolality  stimulates thirst centre  classic symptoms of polyuria & polydipsia. . 2) Macrovascular complications  related to atherosclerosis. glucose is reabsorbed from the proximal tubules but after the renal threshold (10 mmol/L).

The common pathological feature in microvascular disease is narrowing of the lumens of small blood vessels. 3) Generation of free radicals & activation of tissue injury responses secondary to intracellular hyperglycemia. whereas that of macrovascular disease is more closely related to insulin resistance. 2) Formation of advanced glycation end products (glucose can react with amino groups in proteins to form glycated plasma & tissue protein)  these can undergo cross-linking & accumulate in vessel walls & tissues  structural & functional damage. . This is directly related to prolonged exposure to high glucose concentrations: (Mechanisms): 1) ↑ formation of sorbitol (an alcohol derived from glucose) by the action of enzyme aldose reductase  sorbitol accumulation in cells  causes osmotic damage & alter redox state. ..The development of microvascular disease appears to be directly related to hyperglycemia.

.Diagnosis of DM: . . any of these limits must be exceeded on more than one occasion for the diagnosis to be made.2h post glucose = random (not fasting). . even in the presence of classic clinical features.Diagnosis depends on demonstration of hyperglycemia. .Glycosuria is not diagnostic .If clinical features are not present.

.Impaired fasting glycaemia (IFG)  elevated fasting blood glucose concentration but less than the diabetic range  oral glucose tolerance test (OGTT) should be performed for patients with IFG to determine whether they have diabetes or not..

The OGTT also defines a category of hyperglycemia termed impaired glucose tolerance (IGT). Some individuals with IFG are found to be diabetic & others have IGT after doing the OGTT. ..  Patients with IGT should be given dietary & lifestyle advice. It represents a stage in the natural history of transition from normal glucose tolerance to diabetes  it defines a risk category for progression to diabetes.

Regular follow-up is essential to monitor treatment. 2) Increase dietary fibres. . .Patients treated with insulin  risk of hypoglycaemic episodes. .The aims of treatment are: 1) To maintain blood [glucose] within the physiological range. 2) To alleviate symptoms. . .Insulin  is given by injection  it is degraded in the gut.Dietary control: 1) Substitute complex carbohydrates for simple carbohydrates. .Education of patients about the disease. 3) To prevent the acute metabolic complications. 4) To prevent long-term complications. 3) Restriction of energy intake when necessary. .Type 1 DM  dietary control + insulin. .Type 2 DM  dietary control ± oral hypoglycaemic agents  insulin is usually required later in the course of the disease.Management of DM: .

Urine ketones in patients at risk of ketoacidosis.  urine glucose excretion also depends on renal threshold for glucose  if low  +ve urine glucose when blood [glucose] is normal. 4) Glycated haemoglobin  monitor glycemic control over a longer time span (6-8 weeks)  haemoglobin undergoes glycation that is proportional to the blood glucose concentration  HbA1c  persists for the life span of the RBC  normal HbA1c < 6% of the total haemoglobin  the aim is to maintain HbA1c < 7%. 3) Urine testing for glucose  used much less than formerly  it is only semi-quantitative & is of no value in the detection of hypoglycaemia (urine is free of glucose at normal blood glucose concentrations). Plasma [creatinine]  renal disease. 2) Measurement of blood [glucose]  reagent strips & glucose meters are also available for use at home. . 5) 6) 7) 8) Microalbuminuria  diabetic nephropathy. Lipids  because of the risk of atherosclerosis.Monitoring of treatment: 1) Ensure that the symptoms are controlled.

. Non-ketotic hyperglycemia. Lactic acidosis.Metabolic complications DM: 1) 2) 3) 4) Diabetic ketoacidosis. Diabetic nephropathy.

MI or trauma). As a result of infection. Pathogenesis of ketoacidosis: 4) It has a rare occurrence in patients with type 2 DM. 2) It may develop in patients known to be diabetic who omit to take their insulin. ↑proteolysis. 3) Diabetic patients whose insulin dosage becomes inadequate because of an increased requirement (e. ↑gluconeogenesis. Insulin deficiency combined with increased secretion of glucagon ( & other counter regulatory hormones) = ↑glucagon: insulin ratio  this leads to: 1) 2) 3) 4) 5) ↓tissue glucose uptake. ↑glycogenlysis. ↑lipolysis.g.Diabetic ketoacidosis: When does it happen? 1) It may be the presenting feature of type 1 DM  newly diagnosed patients account for 20-25% of the cases. .


initially polyuric (osmodiuresis). - The patient. - Ketogenesis = Triglycerides are converted to acetoacetic acid & 3hydroxybutyric acid  these acids are the major acids responsible for acidosis but FFAs & lactic acid also contribute to acidosis  some of the acetoacetate is spontaneously decarboxylated to acetone  Patient’s breath smells like fruit or nail polish remover (acetone). contributes to the hyperglycemia. resulting from insulin lack & preferential metabolism of FFAs & ketones as energy substrates.- Decreased peripheral utilization of glucose. becomes oliguric  established renal failure is uncommon. - Ketones stimulate the chemoreceptor trigger zone causing vomiting. - Hyperkalemia is invariably present as a result of loss of K+ from the tissues to the ECF (due to acidosis) & decreased K+ renal excretion (↓GFR)  (hyperkalemia in spite of total body K+ depletion). .


v fluid is changed to 5% dextrose & the rate of insulin infusion decreased to maintain euglycemia until the metabolic abnormalities have resolved.v infusion at a rate of 6-10 U/h  monitor blood [glucose]  once glucose has fallen to near normal levels. 3) Treat any identifiable precipitating event (e. .It is treated as medical emergency.Treatment: 1) i. .Treatment must be started immediately after diagnosis. 2) Blood glucose measurement.g.Diagnosis is based on: 1) The presence of typical clinical features.v isotonic saline should be given initially to restore the ECF volume to normal. i. 3) Blood gas analysis to confirm metabolic acidosis & determine its severity.Management of ketoacidosis: . .Aims of treatment: 1) To maintain tissue perfusion by replacement of lost fluid & minerals. . Infection). 2) K+ supplement  although are hyperkalemic. 4) Bicarbonate is seldom necessary except in the severest cases because restoration of normal renal perfusion allows excretion of H+ load & . 2) To reverse the metabolic disturbances by providing insulin. 3) Insulin by i. hypokalemia will develop during treatment with insulin as insulin causes rapid K+ uptake into cells.

Diabetic nephropathy: .Hypertension & hyperlipidemia are frequently present & should be treated. -All diabetic patients (except young children & very old) should their albumin excretion measured annually (screening). .Microalbuminuria progresses through clinical albuminuria (albumin excretion > 300 mg/day) with gradual decline in GFR & increased plasma [creatinine]. . . .Occurs in about 30% of patients with type 1 DM & 25% of patients with type 2 DM.Angiotensin-converting enzyme inhibitors can delay progression of microalbuminuria. .The earliest detectable abnormality is microalbuminuria (albumin excretion 30-300 mg/day).

. Severe shock = extreme dehydration). severe hyperglycemia can develop (blood [glucose] > 50 mmol/L) with extreme dehydration & very high plasma osmolality but with no ketosis & minimal acidosis.Not all patients with uncontrolled DM develop ketoacidosis. .Is more associated with severe systemic illness (e. .Non-Ketotic hyperglycemia: (Hyperosmolar non-ketotic hyperglycemia) .If tissue perfusion is affected by extreme dehydration (hyperosmolality). Heparin (sometimes is given prophylactically to prevent thrombosis Lactic acidosis: because of hyperviscosity) -Uncommon complication of DM. . tissue anoxia may lead to lactic acidosis. .g.Management: Rehydration (isotonic saline) K+ supplement ( but less is needed than in ketosis).In type 2 DM.

Lipoprotein metabolism in DM: In type 1 DM: . 2) ↑activity of hormone-sensitive lipase (which insulin inhibits) leading to increased flux of FFAs from adipose tissue that act as a substrate for hepatic triglyceride synthesis. . -) Plasma lipid concentrations become normal in well-controlled type 1 DM. -) Both 1) & 2) are reversed by insulin administration. -) LDL concentration can also be increased & HDL decreased. -) The degree of hypertriglyceridemia correlates well with glycemic control.If glycemic control deteriorates  marked hypertriglyceridemia (↑VLDL & chylomicronemia) as a result of: 1) ↓activity of lipoprotein lipase (which insulin stimulates).

. . .The VLDL contains increased triglyceride & cholesterol esters in relation to the amount of apoprotein.In type 2 DM: . .HDL is decreased. .LDL are more atherogenic (smaller & denser).Abnormalities in plasma lipid concentrations in type 2 DM persist despite adequate glycemic control  increased risk of cardiovascular disease  treatment with lipid-lowering agents is recommended.Hypertriglyceridemia is common & is usually due to increased hepatic synthesis.

predisposing to difficult delivery & neonatal hypoglycaemia.Diabetes in pregnancy (Gestational Diabetes): . . . .↑risk of congenital malformation  risk can be reduced by ensuring excellent glycemic control at conception & during early pregnancy.Maintenance of excellent glycemic control reduces these risks. .remain at increased risk of developing diabetes in the future.Maternal hyperglycemia increases fetal insulin secretion & can cause fetal macrosomia.Patients with gestational diabetes often revert to normal glucose tolerance after delivery but: .

2) Reactive hypoglycaemia ( hypoglycaemia follows a stimulus) . .Hypoglycaemia: .Blood [glucose] < 2.It is potentially dangerous  physiological responses lead to glucose release into the circulation (mediated by catecholamines & other counterregulatory hormones) 2 types of hypoglycaemia: 1) Fasting hypoglycaemia (failure to maintain a normal blood [glucose] in the fasting state).8 mmol/L (although symptoms typically begin to develop at concentrations around 3 mmol/L).

severe portal cirrhosis & acute hepatic necrosis.g.g. .Causes of fasting hypoglycaemia: . -Defective glucose production caused by: 1) Endocrine disorders  e. starvation.g. 5) Miscellaneous  e. glycogen storage disease type 1).g. Insulinoma. pancreatic tumours & hyperinsulinism of childhood (nesidioblastosis). adrenocortical insufficiency (↓ACTH). 2) Liver disease e.g. adrenal insufficiency (↓cortisol) & growth hormone deficiency. hepatic tumours.Enhanced glucose utilization occurs in endogenous insulin overproduction  e. Severe malnutrition. pancreatitis. inherited metabolic disorders (e. 3) Renal disease  end-stage renal disease (gluconeogenesis occurs in the kidney) 4) Septicaemia  cytokine release stimulates insulin secretion .

3) Inherited metabolic disorders  e.g. galactosaemia & hereditary fructose intolerance. 2) Drug-induced  e. Chlorpropamide has long t1/2 & is excreted renally so it is accumulated in RF). hypoglycaemia develops 90-150 min after a meal (particularly a meal rich in sugar)  rapid passage of glucose from the stomach into the small intestine  insulin secretion  hypoglycaemia. sulphonylureas ( e. alcohol (↑insulin release in response to oral glucose load & also can inhibit gluconeogenesis) & salicylate poisoning in children & paracetamol poisoning (cause liver damage). .g.g.g. Insulin (missed meal or exercise). After gastric surgery or idiopathic  after gastric surgery.Causes of reactive hypoglycaemia: 1) Postprandial  e.

tremor & anxiety. dizziness. 2) Due to sympathetic stimulation  palpitation & tachycardia. lack of concentration. ataxia (lack of voluntary coordination of muscle movement). -) Dementia (loss of global cognitive ability) .  these symptoms precede those of neuroglycopenia 3) Non-specific  hunger. -) Psychosis (serious mental disorder characterized by defective or lost contact with reality). profuse sweating. hemiparesis (weakness on one side of the body). weakness & blurred vision.. Chronic: -) Personality changes.Clinical features of hypoglycaemia: Acute: 1) Due to neuroglycopenia  tiredness. paraesthesiae. facial flushing. confusion. detachment (a behaviour pattern characterized by general aloofness in personal interactions). -) Memory loss. convulsions & coma.

These features can be enhanced if cerebral blood flow is impaired while they may be attenuated in patients taking β-blockers (e. .Sympathetic features may become attenuated in insulin-treated diabetics who experience frequent episodes of hypoglycemia (hypoglycemic unawareness)  frequent episodes occur because of the decreased threshold at which the autonomic nervous system becomes activated.g.Hypoglycemic unawareness is reversible if frequent hypoglycemia can be avoided. propranolol) . . .-Typical signs & symptoms are more likely to occur if the blood glucose falls rapidly & if the hypoglycemic episodes are separated by periods of normoglycemia.

g.Diagnosis of hypoglycaemia: . 2) Elucidate the cause of hypoglycaemia (e. .5 mmol/L.There are 2 stages in the diagnosis: 1) Confirm the low blood [glucose].Reagent strips of glucose meters are insufficiently accurate at low blood [glucose] to provide a definitive diagnosis of hypoglycaemia  Formal laboratory glucose measurement should be used.There is a considerable variation in the blood [glucose] at which symptoms begin to appear: e.g. In children & young adults  < 2. . From the patient history we can determine if it is reactive hypoglycaemia). . .2 mmol/L. In neonates  < 1.The clinical features of hypoglycaemia should be confirmed by giving glucose (oral or parenteral)  symptoms that are caused by acute neuroglycopenia & catecholamine release should resolve immediately.

.Drug-induced hypoglycemia is treated by administration of glucose until the effect of the drug has worn off. .The treatment of self-poisoning with sulphonylureas can be difficult  giving glucose itself stimulates the secretion of insulin  exacerbate hypoglycaemia. . .Treatment of hypoglycaemia: .Glucose administration. .Glucagon  causes rapid mobilization of hepatic glycogen  it is not effective in starved individuals.β-blockers  mask the adrenergic symptoms of hypoglycaemia (except sweating).

Tumours of the insulin secreting β-cells of the pancreas.High plasma [insulin] (> 20 pmol /L) at time when the blood [glucose] is low (< 2. .Insulinoma: . . .Patients who are chronically hypoglycemic (e. .It causes fasting hypoglycaemia.Measurement of plasma [3-hydroxybutyrate] is informative  insulin inhibits lipolysis & hence inhibits production of 3-hydroxybutyrate  [3hydroxybutyrate] > 600 µmol/L occur in hypoglycaemia with suppressed insulin secretion.C-peptide measurement can confirm the diagnosis  it is produced in equimolar amounts with insulin & is cleared more slowly  it is more reliable marker of endogenous insulin secretion than insulin itself.  In hyperinsulinemia  [3-hydroxybutyrate] is low. due to an insulinoma) often present with behavioural disturbance or frank psychosis while acute manifestations of hypoglycaemia may be absent.g. . .2 mmol/L).