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Blood Glucose Regulation Glucose is the most common respiratory substrate utilised by cells, and is the sole energy source for the brain and red blood cells In normal circumstances, blood glucose levels remain remarkably stable as they are under the homeostatic control of two pancreatic hormones – insulin and glucagon In 1923, Banting and Macleod were awarded the Noble Prize for the discovery and isolation of the hormone insulin, a breakthrough that was to have a profound effect on the lives of sufferers of diabetes

Many body tissues can use fatty acids as a source of metabolic energy in addition to, or instead of, glucose In contrast, the brain and red blood cells require glucose as their sole energy source; brain disturbance rapidly occurs if this nervous tissue is deprived of glucose Red blood cells lack mitochondria and can only obtain their energy by anaerobic glycolysis

Sources of Blood Glucose The glucose that circulates in the bloodstream is derived from three main sources: Dietary intake and digestion of carbohydrates Glycogenolysis; the breakdown of stored glycogen into glucose Gluconeogenesis; the conversion of non-carbohydrate sources, such as amino acids, into glucose

Dietary carbohydrates include sugars, starch and cellulose; during digestion, disaccharide sugars (e.g. maltose) and starch are hydrolysed to yield glucose Glycogenolysis is the conversion of glycogen (storage carbohydrate found in liver and muscle tissue) into glucose; the released glucose enters the bloodstream The conversion of non- carbohydrates (e.g. amino acids and glycerol) into glucose by liver cells is called gluconeogenesis

Blood Glucose Regulation Blood glucose levels are controlled by two principal hormones, insulin and glucagon, secreted by the endocrine portion of the pancreas The pancreas is predominantly an exocrine gland (secreting many digestive enzymes into the gut); the pancreas also contains clusters of endocrine cells, called the Islets of Langerhans, which secrete the hormones insulin and glucagon into the bloodstream The concentration of glucose in the blood normally lies in the range of 90 – 100 mg/100 cm 3 ( 5 – 5.6 mmol/l) A rise in blood glucose level to above the norm, for example after a meal, is detected by the beta cells of the Islets of Langerhans, which respond by secreting insulin If the blood sugar level drops below the norm, for example between meals, or after fasting, then the alpha cells of the Islets of Langerhans detect this change and respond by secreting glucagon

Negative feedback mechanisms operate to achieve glucose homeostasis

Blood Glucose Regulation Insulin decreases levels of blood glucose by: Increasing the permeability of body cells to glucose by stimulating the incorporation of additional glucose carriers into cell membranes Glycogenesis; activation of the liver enzymes that convert glucose into glycogen (also occurs in muscle cells) Lipogenesis; stimulates the conversion of glucose into fatty acids in adipose tissue (fat cells)

A diabetic person and a non diabetic person ate the same amount of glucose. One hour later, the glucose concentration in the blood of the diabetic person was higher than that of the non diabetic person. Explain why 3 marks

answer In a diabetic person: Lack of insulin produced/reduce sensitivity of cells to insulin because lack of receptors. Reduced uptake of glucose by body/liver/muscles cells Reduced conversion of glucose to glycogen

Blood Glucose Regulation Glucagon increases levels of blood glucose by: Glycogenolysis; activation of the liver enzymes that convert glycogen into glucose Gluconeogenesis; activation of the liver enzymes that convert non-carbohydrates into glucose Lipolysis; stimulates the breakdown of triglycerides into fatty acids and glycerol in adipose tissue

glucose  glycogen glycogen  glucose non-carbohydrates  glucose detected by the alpha cells detected by the beta cells glucagon secretion insulin secretion release of fatty acids from adipose tissue uptake of glucose for fatty acid synthesis increased permeability of body cells to glucose Dual Hormonal Control achieves Glucose Homeostasis

detected by the beta cells of the Islets of Langerhans in the pancreas rise in blood glucose fall in blood glucose detected by the alpha cells of the Islets of Langerhans in the pancreas restoration of the norm (negative feedback) activation of enzymes that promote the conversion of glycogen into glucose in liver tissue and fatty acid release in adipose tissue activation of enzymes that promote the conversion of non-carbohydrates, such as amino acids, into glucose (gluconeogenesis) restoration of the norm (negative feedback) activation of enzymes that promote the conversion of glucose into glycogen in liver and muscle tissue increase in the permeability of body cells to glucose activation of enzymes that promote fat synthesis insulin secretion glucagon secretion

Effect of insulin on the glucose permeability of cells Insulin binds to receptors on cell surface membranes intracellular chemical signal signal triggers the fusion of carrier- containing vesicles with the surface membrane The additional carriers increase glucose permeability glucose carrier for facilitated diffusion plasma membrane

Hormone Action Protein hormones, like insulin and glucagon, are polar, lipid-insoluble molecules that are unable to diffuse through the lipid bilayer of plasma membranes These hormones bind to receptor proteins in the plasma membranes of their target cells, and trigger a chain of events that activate or inhibit the enzymes required for specific biochemical reactions The hormone itself is the ‘first messenger’; on binding to a receptor at the surface of a target cell, the hormone activates specific molecules at the membrane that lead to the release of a ‘second messenger’, which enters the cytoplasm and triggers a response The glucagon second messenger is a small molecule called cyclic AMP; the involvement of two messengers – the hormone and cyclic AMP – amplifies the original signal; cyclic AMP is a widely studied second messenger molecule although other molecules perform this function for certain hormones

Hormone binds to surface receptor Binding induces a change in the shape of the receptor, which activates a G-protein located on the inner surface of the membrane The G-protein activates the enzyme adenyl cyclase Adenyl cyclase converts ATP into cyclic AMP Cyclic AMP (second messenger) cAMP activates enzymes required for specific biochemical reactions inactive enzyme active enzyme Activated enzymes produce specific changes in the cell Hormone - induced change

Hormone Action and Amplification When a protein hormone binds to its cell-surface receptor, a cascade of events is triggered with one event leading inevitably to another Each molecule within the cascade system activates many molecules of the next stage, such that there is an amplification of the original message triggered by the hormone A single molecule of hormone promotes the synthesis of thousands of the molecules of the final product

G-proteinAdenyl cyclase Each activated receptor protein activates many molecules of adenyl cyclase Each activated adenyl cyclase molecule converts many molecules of ATP into cyclic AMP Each cyclic AMP molecule activates many copies of the desired enzyme Each enzyme molecule catalyses the formation of many molecules of product The binding of one hormone molecule at the cell surface promotes the synthesis of thousands of cyclic AMP molecules (amplification); a small concentration of hormone in the blood produces a massive response within the target cell

Glucagon binds to surface receptor Many molecules of adenyl cyclase are activated, each of which converts many molecules of ATP into cyclic AMP Many molecules of Cyclic AMP cAMP activates many copies of the enzyme that splits glycogen into glucose inactive enzyme active enzyme A phosphorylase enzyme catalyses the conversion of glycogen into glucose Glucose enters the bloodstream

Diabetes mellitus A breakdown in the homeostatic control of blood glucose concentration may lead to a condition called diabetes mellitus Diabetes mellitus is characterised by an inability of cells to take up glucose from the blood which, in untreated cases, forces the cells to draw on other sources of energy, such as fat and protein reserves; blood glucose concentrations exceed the renal threshold and glucose is excreted in the urine Diabetes mellitus may arise when the pancreatic beta cells fail to produce insulin (or produce insufficient amounts), or when the insulin receptors at cell membranes become abnormal

Diabetes mellitus There are two principal types of diabetes mellitus: Type I or Juvenile-onset Diabetes appears suddenly during childhood as a result of the destruction of the insulin-producing cells of the pancreas; this is thought to arise from either a viral infection or an attack by the individual’s own antibodies (autoimmune reaction); sufferers of Type I diabetes are insulin-dependent Type II or Maturity-onset Diabetes is generally a less severe form of the condition, in which insulin levels may be normal or reduced, but the target cells fail to respond to the hormone due to receptor abnormalities

The Glucose Tolerance Test When an individual is suspected of having diabetes, a glucose tolerance test is usually performed The test is used to determine the capacity of the body to tolerate ingested glucose The glucose tolerance test involves the following steps: Fasting for eight hours A blood test to determine fasting, blood glucose concentration (time 0 minutes) Ingestion of a glucose load (usually 50 grams) Blood tests for monitoring blood glucose concentrations at regular intervals over a period of 2½ hours Results are graphed to give a glucose tolerance curve

Time after ingesting glucose (mins) Blood Glucose Concentration (mmol/l) normal mild diabetes severe diabetes Present these results in graphical form

Describe and explain the differences between the three curves

Effects of Diabetes mellitus Undersecretion of insulin, and the subsequent inability of cells to utilise glucose as a respiratory substrate, leads to a variety of metabolic effects in untreated diabetics - these include: Hyperglycaemia; an increase in blood glucose concentration and the excretion of glucose by the kidneys Protein Catabolism; the breakdown of muscle protein to amino acids in response to the inability to use glucose as a principal respiratory substrate; excess amino acids are converted into both glucose and urea in the liver, increasing the excretion of nitrogen and raising blood glucose levels (an unwanted effect) Fat Catabolism; stored fats are hydrolysed to fatty acids and utilised by cells for respiration; excessive fatty acid oxidation produces an excess of acetyl CoA molecules that are converted to ketones by the liver; the release of ketones into the blood lowers the pH (acidosis) Osmotic Diuresis; the high concentration of glucose in the urine creates a hypertonic urine that reduces water reabsorption from the collecting ducts; a large volume of urine is excreted

Muscle protein is broken down into amino acids producing a surplus that is converted into both urea and glucose in the liver; increased excretion of urea leads to a loss of nitrogen from the body Stored fats are converted to fatty acids and used by body cells for respiration; large quantities of acetyl CoA are a by-product of fatty acid oxidation and these are converted to ketones in the liver; ketones make the blood acidic

If the glomerular filtrate of a diabetic person contains a high concentration of glucose, he produces a larger volume of urine. Explain why?

The high concentrations of glucose in the blood are such that they exceed the renal threshold and are excreted in the urine; this produces a hypertonic urine that enters the collecting ducts of the kidney tubules The hypertonic urine reduces the water potential gradient between the urine and the hypertonic tissue of the kidney medulla As the urine flows through the collecting ducts, less water is reabsorbed and a large volume of urine is produced (diuresis) This loss of water can lead to dehydration, and extreme thirst may be experienced Large volume of urine

Treatment of Type I diabetes is by subcutaneous injection of insulin; insulin cannot be taken orally as the protein nature of this hormone would result in its digestion within the gut The insulin dose needs to be adjusted carefully; an excessive dose of insulin together with a low carbohydrate intake results in hypoglycaemia (low blood sugar level) Blood glucose levels are regularly monitored to determine the need for insulin; biosensors are used by individuals to keep track of their sugar levels

Treatment of Type II diabetes largely involves dietary control Nutritionists work with sufferers to devise a healthy eating plan that limits sugar intake and is balanced by an appropriate level of exercise Modern methods of treatment enable individuals, with either Type I or Type II diabetes, to lead normal lives

A test for glucose in urine uses immobilised enzymes on a plastic test strip. One of these enzymes is glucose oxidase. Explain why the test strip detect glucose and no other substance. 2 marks

Enzyme has an specific shape to active site/active site has an specific tertiary structure. Only glucose fits/has complementary structure/can form ES complex