BCHEM - DM Flashcards
Describe the underlying metabolic problem in type I and II diabetes mellitus (2)
In diabetes, the underlying problem is either the lack of insulin synthesis/secretion (type I diabetes) or the lack of sensitivity to insulin (type II).
Explain why elevated levels of plasma glucose for extended periods are a health risk. Motivate your answer fully (6)
If plasma glucose increases above normal levels for long periods, these glucose molecules react with protein molecules in a non-enzymatic reaction. Glucose forms covalent links with these protein molecules, resulting in their glycation. The glucose molecules linked to the proteins alter the conformation of the glycated proteins, ultimately affecting the function of these proteins. The glycation affects a wide range of proteins, and consequently impact on the function of a wide range of processes in the body. This is associated with poor kidney function, vascular disorders, poor eyesight commonly observed in poorly controlled diabetic subjects. Furthermore, the high plasma levels of glucose, exceed the renal threshold, and consequently, glucose enters the renal filtrate. This increases the osmotic pressure of the filtrate, and increased levels of water is excreted with the urine. This can ultimately lead to dehydration of the subject.
Explain the effect of long term elevated blood glucose levels on protein structure and function (2)
Long term elevated levels of blood glucose leads to the covalent conjugation of glucose to tissue proteins. This reaction takes place non-enzymatically. Proteins that have been glycated display an altered conformation, which could result in altered protein function.
The homeostasis of blood glucose is due to a balance of addition and utilization of glucose. Name the processes and sources of glucose addition vs utilization (3)
Addition: Dietary carbohydrates, glycogenolyis, gluconeogenesis
Utilization: Glycolysis, glycogenesis, conversion to lipids, synthesis of biomolecules
Hyperglycaemia (2-4) (Super NB)
Diabetes is associated with the absence of insulin (type 1) or reduced sensitivity of target cells to the regulatory effects of insulin (type 2). Thus, no activation of glucose transporters in peripheral tissues (especially muscle), no transport of glucose from plasma into cytoplasm of cells, plasma glucose remains high after meal. In addition, lack of insulin and elevated glucagon levels activates gluconeogenesis in liver, more glucose enters bloodstream, plasma glucose.
Dehydration (3) (Super NB)/ Thirst and increased urinary frequency (3)
Since the plasma glucose levels exceeds the renal threshold, glucose remains in the filtrate (not reabsorbed from the renal tubules). The osmotic pressure of the glucose prevents water re-absorption, resulting in increased water loss in the urine, resulting in dehydration.
Explain frequent urination in an uncontrolled diabetic (2)
Increased glucose concentration in the urine leads to an osmotic diuresis.
Tissue damage (3) (NB)
Elevated glucose levels facilitates the non-enzymatic linkage of glucose to cellular macro molecules, particularly proteins. This linkage results in the alteration of protein conformation, ultimately affecting protein function, and resulting in tissue damage.
Plasma ketone bodies (4) (NB)
In diabetes, because of a hormonal dysregulation (lack of functional insulin responses), the body switches to a fasting/ starvation mode of metabolism, despite adequate dietary carbohydrate intake. Elevated glucagon levels are associated with the activation of gluconeogenesis and increased lipolysis and fatty acid breakdown. In the liver, oxaloacetate from the mitochondria (that could be used in the TCA cycle) is transported into the cytosol as a precursor for gluconeogenesis. Since low levels of oxaloacetate are available in the mitochondria for the TCA cycle, there is an excess of acetyl CoA (from fatty acid breakdown). This acetyl CoA is converted into ketone bodies in the liver, which enters the plasma.
“Sweet breath” (3) (NB)
Is due to the high levels of ketone bodies that are synthesised in diabetic subjects. (See above) The excess acetyl CoA instead condenses to form ketone bodies that are volatile and evaporate from the blood into the air of the lung and are expired.
Explain in detail, the reason for the dehydration observed in some uncontrolled diabetic subjects (10)
Dehydration is observed in diabetic subjects, because plasma glucose levels increase to very high levels during diabetes. This is either because no insulin is secreted by the pancreas or the cells of the body are insensitive to insulin. Consequently, the extrahepatic cells in the body are not activated to import glucose from the plasma in the face of high plasma glucose levels. The high concentration of glucose in the plasma results in substantial amounts of glucose entering the glomerular filtrate. This glucose exerts an osmotic pressure, thus drawing a substantial amount of water into the urine. This loss of water in the urine leads to the dehydration associated with diabetes.
Explain the role of glucagon in maintaining elevated blood glucose levels in diabetes (4)
Glucagon levels in diabetic patients are frequently elevated, despite high blood glucose levels. The elevated glucagon levels act on the liver to inhibit glycogen synthesis, and activate glycogen breakdown, making glucose available for export from the liver (if any such stores are present). More importantly, elevated glucagon levels inhibit glycolysis and activate gluconeogenesis, resulting in glucose export from the liver into the plasma.
Explain (with the aid of a diagram) the main steps involved in the activation of glycogenolysis and inhibition of glycogen synthesis subsequent to the binding of glucagon to its receptor (8)
Glucagon binds its receptor on the plasma membrane resulting in the activation of Ga. This involves the exchange of GDP for GTP on Ga. Activated Ga diffuses from the glucagon receptor and binds adenyl cyclase, activating this enzyme in the process. Activated adenyl cyclase generates cAMP from ATP. The cAMP binds protein kinase A (PKA), resulting in the activation of this kinase. Activated PKA, phosphorylates phosphorylase kinase. P-phosphorylase kinase in turn phosphorylates inactive glycogen phosphorylase b to the active form. Glycogen phosphorylase b catalyses the cleavage of glycogen to glucose. The simultaneous activation of glycogen synthesis is prevented because PKA also converts active glycogen synthase a to the inactive form by phosphorylation.
Outline any two (2) mechanisms of how insulin reduces blood glucose levels (2)
Stimulating the conversion of glucose to glycogen
Inhibiting new production of glucose (gluconeogenesis)
Increasing the uptake of glucose into muscle cells
Increasing cellular uptake of glucose for respiration
Explain the main effects of insulin on fuel metabolism in the body, and explain the overall objective of the processes involved. Your answer should explain the effects of insulin on carbohydrate, lipid and protein metabolism in the three major tissue sites in the body, viz: the liver, adipose tissue, and muscle tissue (8)
Insulin is released from the pancreas in response to high plasma glucose levels and signals the body to respond to a carbohydrate containing meal. In the liver, insulin activates glycogen synthesis, glycolysis, the TCA cycle, protein synthesis, fatty acid synthesis and VLDL secretion from the liver. Simultaneously, glycogenolysis, gluconeogenesis, and beta-oxidation is inhibited. In muscle, glucose uptake is promoted (Glut 4 receptors diverted to plasma membrane), glycogen synthesis, glycolysis, lipogenesis, and protein synthesis is promoted, and the reverse reactions are inhibited. Furthermore, in adipocytes, glucose is used as a source of energy, and lipogenesis is promoted, and lipolysis is inhibited.
The overall objective of these actions is to stimulate the tissues to use plasma glucose as a source of energy in the first place, and then to store extra energy either as glycogen (in the liver and muscle) or as lipids in adipocytes.
