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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 bodys sources of glucose are:Dietary carbohydrates.Glycogenlysis (release of glucose stored as glycogen)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.1 Blood [glucose] falls to pre-meal concentration within 4h after a meal.

If fasting continues hepatic glycogen stores are used up after about 24h.

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 energy source. The control of blood [glucose] is achieved through the action of various enzymes:

Insulin it lowers blood glucose concentration. The counter-regulatory hormones (glucagon, cortisol, catecholamines & growth hormone). After 72h of a meal and starvation:blood [glucose] stabilizes the principle source of glucose becomes gluconeogenesis from amino acids & glycerol major energy source are ketone bodies All of above are true2

L = liver, M = muscle, A = adipose tissueAll of the following are principal actions of insulin except :Increase fatty acid and TG synthesis in Liver and adipose tissues Increase glycogen , protein synthesis in liver and muscleIncrease cellular glucose uptake in liver and RBCsDecrease lipolysis in adipose tissues and protolysis in musclesReduces ketogenesis in liver

Regarding hormones involved in glucose homeostasis , which of the following is false Glucagon is catabolic hormones while insulin is anabolic Adrenaline reduce lipolysis Insulin increase cellular glucose uptake in muscles and adipose tissueCortisol reduces tissue glucose utilization including liver , muscles and adipose tissues Growth hormone GH increase lipolysis 3 Insulin & glucagon are the 2 most important hormones in glucose homeostasis:Insulin:

Is a 51 amino acid polypeptide, secreted by the -cells of the pancreas islets of Langerhans in response to a rise in blood [glucose].

It is synthesized as a prohormone (proinsulin) this undergoes cleavage prior to secretion to form insulin & C-peptide.

Glucagon & gastric inhibitory peptide (GIP) stimulate insulin secretion. 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.

2) Liver through inducing the enzyme glucokinase, which phospholrylates glucose to form glucose-6-phosphate (a substrate for glycogen synthesis)

- Other functions for insulin are summarized in the table above. Which of the following are correct pairs regarding glucose transporters in body :Skeletal muscle GLUT 2Brain GLUT 4 Adipose tissues GLUT 4 Liver GLUT 4 All of above 4Glucagon:

Is a 29 amino acid polypeptide secreted by the -cells of the pancreatic islets.

Its secretion is decreased by a rise in blood [glucose].

Its actions oppose those of insulin (see table above).

It stimulates hepatic (not muscular) glycogenlysis.

Combined effect of insulin & glucagon: During starvation Insulin: glucagon ratio falls hepatic glucose & ketone production & tissue glucose utilization.

After meal Insulin: glucagon ratio is high glucose is stored as glycogen & converted into fat.Measurement of glucose concentration:

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.

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. 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.

Reagent strips should not be relied upon for the diagnosis of diabetes formal laboratory measurements are recommendedDiabetes Mellitus (DM):

Is a systemic metabolic disorder characterized by a tendency to chronic hyperglycemia with disturbances in carbohydrate, fat & protein metabolism.

Causes defect in insulin secretion or action or both.

DM secondary to other diseases may occur (uncommon) e.g. Chronic pancreatitis, after pancreatic surgery & in conditions where there is increased secretion of insulin antagonistic hormones (e.g. Cushings syndrome & acromegaly). 2 types of DM:

1) Type 1 (Insulin dependent):Autoimmune disease destruction of -cells initiated by activation of T-lymphocytes directed against antigens on the cell surface insulin secretion ends with complete cessation of insulin secretion patients have absolute requirement for insulin.

2) Type 2 (Insulin independent):Insufficient insulin secretion or resistance to its action treated with diet, oral hypoglycemics and/or insulin pathogenesis is uncertain (genetics, environmental factors, obesity & lifestyle) progressive disease that may ends with complete -cell dysfunction.

Type 1 DM autoimmunity strong association with certain histocompatability antigens (e.g. HLA-DR3, DR-4 & various DQ alleles. Pathophysiology & clinical features of DM:

Hyperglycemia is mainly a result of increased production of glucose by the liver &, to a lesser extent, of decreased removal of glucose from the blood.

In the kidney, glucose is reabsorbed from the proximal tubules but after the renal threshold (10 mmol/L), reabsorption becomes saturated glucose appears in the urine. Renal threshold is higher in elderly & lower during pregnancy.

Glycosuria osmotic diuresis (H2O excretion) plasma osmolality stimulates thirst centre classic symptoms of polyuria & polydipsia.

- If Untreated profound metabolic disturbances life-threatening ketoacidosis, non-ketotic hyperglycemia or lactic acidosis.- Long-term DM complications:Microvascular complications nephropathy, neuropathy & retinopathy.Macrovascular complications related to atherosclerosis.

- 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.

Regarding Long-term DM complications all of the following are Microvascular complications except :NephropathyAtherosclerosis NeuropathyRetinopathyNone of above 10 The development of microvascular disease appears to be directly related to hyperglycemia, whereas that of macrovascular disease is more closely related to insulin resistance.

The common pathological feature in microvascular disease is narrowing of the lumens of small blood vessels. This is directly related to prolonged exposure to high glucose concentrations: (Mechanisms):

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.

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.

Generation of free radicals & activation of tissue injury responses secondary to intracellular hyperglycemia.Common mechanisms of microvascular complications of DM include : High formation of sorbitol (an alcohol derived from glucose) by the action of enzyme aldose reductaseFormation of advanced glycation end products Generation of free radicals activation of tissue injury responses secondary to intracellular hyperglycemiaAll of above 11Diagnosis of DM:

Diagnosis depends on demonstration of hyperglycemia.

Glycosuria is not diagnostic , even in the presence of classic clinical features.

2h post glucose = random (not fasting).

If clinical features are not present, any of these limits must be exceeded on more than one occasion for the diagnosis to be made. 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.

All of the following are true regarding IFG except :It is elevated fasting blood glucose concentration but less tan the diabetic range OGTT should be performed Fasting glucose levels >6.1 and