Pancreas DSA- by objectives

Question 1

1. Describe insulin structure and the significance of the C peptide as a diagnostic tool.

Answer 1

Insulin is a peptide hormone consisting of two straight chains, an A chain (21 amino acids) and a B chain (30 amino acids). Two disulfide bridges link the A chain to the B chain, and a third disulfide bridge is located within the A chain.

Connecting peptide (C peptide) connects A and B in preproinsulin and proinsulin, but is cleaved during packaging into secretory vesicles (on the golgi apparatus). 
Insulin and the cleaved connecting peptide are packaged together in secretory granules, and when the β cell is stimulated, they are released in equimolar quantities into the blood. The secretion of connecting peptide ( C peptide ) is the basis of a test for β-cell function in persons with type I diabetes mellitus who are receiving injections of exogenous insulin. (In these persons, serum insulin levels do not reflect endogenous secretory rates.)

Question 2

2. Describe the effect of insulin on glucose uptake and carbohydrate metabolism in muscle, liver, brain, and adipose tissue.

Answer 2

Insulin is known as the hormone of “abundance” or plenty. When the availability of nutrients exceeds the demands of the body, insulin ensures that excess nutrients are stored as glycogen in the liver, as fat in adipose tissue, and as protein in muscle. These stored nutrients are then available during subsequent periods of fasting to maintain glucose delivery to the brain, muscle, and other organs.

Insulin has the following actions on liver, muscle, and adipose tissue:

♦ Decreases blood glucose concentration.
♦ Decreases blood fatty acid and ketoacid concentrations.
♦ Decreases blood amino acid concentration.

Other: Insulin promotes K + uptake into cells (at the same time that it promotes glucose uptake) by increasing the activity of the Na + -K + ATPase. Also impacts the satiety center in the hypothalamus.

Question 3

3. Describe the effect of insulin on fat and protein metabolism.

Answer 3

The overall effect of insulin on fat metabolism is to inhibit the mobilization and oxidation of fatty acids and, simultaneously, to increase the storage of fatty acids. As a result, insulin decreases the circulating levels of fatty acids and ketoacids. In adipose tissue, insulin stimulates fat deposition and inhibits lipolysis. Simultaneously, insulin inhibits ketoacid (β-hydroxybutyric acid and acetoacetic acid) formation in liver because decreased fatty acid degradation means that less acetyl coenzyme A (acetyl CoA) substrate will be available for the formation of ketoacids.

The overall effect of insulin on protein metabolism is anabolic. Insulin increases amino acid and protein uptake by tissues, thereby decreasing blood levels of amino acids. Insulin stimulates amino acid uptake into target cells (e.g., muscle), increases protein synthesis, and inhibits protein degradation.

Question 4

4. Describe the effect of insulin on serum potassium homeostasis

Answer 4

Insulin promotes K + uptake into cells (at the same time that it promotes glucose uptake) by increasing the activity of the Na + -K + ATPase. This action of insulin can be viewed as “protecting” against an increase in serum K + concentration. When K + is ingested in the diet, insulin ensures that ingested K + will be taken into the cells with glucose and other nutrients.

Question 5

5. Relate the onset of ketosis to insulin-deficiency and summarize the changes to cellular physiology and acid-base status in diabetic ketoacidosis.

Answer 5

Type I diabetes mellitus is characterized by the following changes: increased blood glucose concentration from decreased uptake of glucose into cells, decreased glucose utilization, and increased gluconeogenesis; increased blood fatty acid and ketoacid concentration from increased lipolysis of fat, increased conversion of fatty acids to ketoacids, and decreased utilization of ketoacids by tissues; and increased blood amino acid concentration from increased breakdown of protein to amino acids. There also is loss of lean body mass (i.e., a catabolic state) and loss of adipose tissue. Disturbances of fluid and electrolyte balance are present in type I diabetes mellitus. The increased levels of ketoacids cause a form of metabolic acidosis called diabetic ketoacidosis ( DKA ). The increased blood glucose concentration results in an increased filtered load of glucose, which exceeds the reabsorptive capacity of the proximal tubule. The nonreabsorbed glucose then acts as an osmotic solute in urine, producing an osmotic diuresis, polyuria, and thirst. The polyuria produces ECF volume contraction and hypotension. Lack of insulin also causes a shift of K + out of cells (recall that insulin promotes K + uptake), resulting in hyperkalemia. Treatment of type I diabetes mellitus consists of insulin replacement therapy, which restores the ability of the body to store carbohydrates, lipids, and proteins and returns the blood values of nutrients and electrolytes to normal.

Question 6

6. Describe the effects of glucagon on blood glucose concentrations

Answer 6

Glucagon increases the blood glucose concentration by the following coordinated actions: (1) Glucagon stimulates glycogenolysis and simultaneously inhibits glycogen formation from glucose, and (2) Glucagon increases gluconeogenesis by decreasing the production of fructose 2,6-bisphosphate, which decreases phosphofructokinase activity. Thus, substrate is di­­rected toward the formation of glucose. Amino acids are utilized for gluconeogenesis, and the resulting amino groups are incorporated into urea.

Question 7

7. Categorize the factors that promote and suppress both insulin and glucagon secretion.

Answer 7

Insulin stimulation:

Increased glucose concentration
Increased amino acid concentration
Increased fatty acid and ketoacid concentration
Glucagon
Cortisol
Glucose-dependent insulinotropic peptide (GIP)
Potassium
Vagal stimulation; acetylcholine
Sulfonylurea drugs (e.g., tolbutamide, glyburide)
Obesity

Insulin suppression:

Decreased blood glucose
Fasting
Exercise
Somatostatin
α-Adrenergic agonists
Diazoxide

Glucagon stimulation:

Fasting
Decreased glucose concentration
Increased amino acid concentration (especially arginine)
Cholecystokinin (CCK)
β-Adrenergic agonists
Acetylcholine

Glucagon inhibition:

Insulin
Somatostatin
Increased fatty acid and ketoacid concentration

Question 8

How does insulin decrease blood glucose concentration?

Answer 8

(1) Insulin increases glucose transport into target cells such as muscle and adipose by directing the insertion of glucose transporters (GLUT 4) into the cell membranes. As glucose enters the cells, the blood glucose con­centration decreases.
(2) Insulin promotes the formation of glycogen from glucose in the liver and in muscle and, simultaneously, inhibits glycogenolysis (glycogen breakdown).
(3) Insulin inhibits gluconeogenesis (synthesis of glucose) by increasing the production of fructose 2,6-bisphosphate, which increases phosphofructokinase activity. In effect, substrates are directed away from the formation of glucose.

Question 9

Potassium Homeostasis and Insulin:

Answer 9

The majority of potassium excretion occurs in the kidney and potassium homeostasis is largely determined by the aldosterone-renin-angiotensin pathway. Of the total body potassium, 98% is intracellular and approximately 2% is extracellular. After ingestion, insulin secretion promotes the movement of potassium to the intracellular space.