Lecture 4

Question 1

How do plasma glucose levels vary throughout the day?

Answer 1

Circulating plasma glucose levels are maintained within very narrow limits despite variable supply and demand of glucose as a metabolic fuel, controlled via endocrine hormones. Stars = food intake so glucose levels increase.

Question 2

At what range of concentrations is plasma glucose maintained at?

Answer 2

4-7.8 mmol/L

Question 3

What are the symptoms of hypoglycaemia?

Answer 3

Too little glucose. Sweating and shaking, pounding heart, nervousness or irritability, feeling weak, hungry, tingly or confused.

Question 4

What are the symptoms of hyperglycaemia?

Answer 4

Too much glucose. Headaches, blurry vision, thirst, frequent urination, dry skin.

Question 5

What is the approximate plasma glucose concentration for hyperglycaemia?

Answer 5

10 mmol/L and above. 8 to 10 mmol/L is iffy.

Question 6

What is the approximate plasma glucose concentration for hypoglycaemia?

Answer 6

2 mmol/L and below. 2 to 4 mmol/L is iffy.

Question 7

What are the features of glucose?

Answer 7

Monosaccharide used as a rapid energy source, polar molecule, water-soluble and easy to transport, does not easily cross the cell membranes. Can control expression and localisation of glucose transporters. Easily polymerised and stored as glycogen.

Question 8

Which transporters transport glucose into cells?

Answer 8

Glucose transporters (GLUTs)

Question 9

How do we stop glucose from leaving cells?

Answer 9

Glucose is phosphorylated to glucose 6-phosphate to prevent it from leaving the cell. This can either be used in glycolysis or the pentose phosphate pathway.

Question 10

Which processes occur in glucose homeostasis?

Answer 10

Glycogenesis (production of glycogen), Glycogenolysis (breakdown of glycogen/production of glucose), Gluconeogenesis (production of glucose from lactate/AAs).

Question 11

Give some examples of organs that are obligate glucose utilisers. What do they do?

Answer 11

Brain (only ~2% of body weight but uses ~20% of glucose-derived energy), Kidneys, RBCs. Only use glucose as an energy source and cannot store glycogen.

Question 12

What are the 2 different locations for glucose sensing?

Answer 12

Centrally in the brain, and peripheral tissues like hepatocytes in liver and beta cells in pancreas.

Question 13

Where is GLUT1 expressed? What is its connection to insulin?

Answer 13

Predominantly in RBCs, also in blood-brain barrier and heart. GLUT1 is insulin-independent, does not require insulin signal to induce glucose uptake.

Question 14

Where is GLUT2 expressed? What is its affinity for glucose?

Answer 14

Expressed in liver, pancreas, small intestine. Insulin-independent, high Km, low affinity for glucose.

Question 15

Where is GLUT3 expressed? What is its affinity for glucose?

Answer 15

Expressed in brain, neurons, sperm. Insulin-independent, low Km, high affinity for glucose.

Question 16

Where is GLUT4 expressed? What is its affinity for glucose?

Answer 16

Expressed in skeletal muscle, adipose tissue, heart. Insulin-dependent, requires insulin for glucose uptake. Moderate Km, moderate affinity for glucose.

Question 17

Where is GLUT5 expressed? What is its affinity for glucose?

Answer 17

Expressed in enterocytes of the intestinal epithelium (luminal side). Insulin-independent, fructose transporter.

Question 18

What are the properties of sodium-glucose co-transporters (SGLTs)?

Answer 18

Expressed in intestinal epithelia and kidneys’ proximal tubule. Insulin-independent, sodium-dependent, ATP-dependent. SGLT1 absorbs glucose, SGLT2 retains glucose.

Question 19

What do hexokinases do?

Answer 19

Act as molecular glucose sensors, involved in the rate-limiting step of glycolysis. Convert glucose to glucose-6-phosphate. Types: Hexokinases I-III in all cells, Hexokinase IV (glucokinase) in hepatocytes and beta cells.

Question 20

What are the key features of glucokinase?

Answer 20

Only substrate is D-glucose, low affinity for glucose (active only at high glucose levels), reduces glycolysis in the liver, promotes glycogen synthesis. Stimulated by insulin and high glucose.

Question 21

What do central glucose sensors do?

Answer 21

Glucose-sensing neurons in the hypothalamus and area postrema detect blood glucose levels. These neurons regulate neuroendocrine and autonomic mechanisms through peripheral tissues, such as pancreas insulin release.

Question 22

Give some examples of peripheral glucose sensors.

Answer 22

Hepatocytes, Beta cells.

Question 23

What do hepatocytes do?

Answer 23

Respond to feeding (store glucose as glycogen) or fasting (produce glucose from glycogen).

Question 24

What do the beta cells of the pancreas do?

Answer 24

Uptake glucose via GLUT1/2, phosphorylate glucose, increasing ATP:ADP ratio. This closes ATP-dependent potassium channels, depolarizing the membrane, opening calcium channels, and stimulating insulin release.

Question 25

How do insulin levels in the blood change throughout the day?

Answer 25

Insulin levels rise with rapid increases in blood glucose levels, leading to rapid insulin secretion.

Question 26

What is the pancreatic islet/islet of Langerhans composed of?

Answer 26

Alpha cells (10-20%), Beta cells (60-80%), Delta cells (~5%). The islet has an extensive capillary network.

Question 27

Where is insulin produced and secreted from?

Answer 27

Beta cells of the pancreas.

Question 28

What is the structure of insulin?

Answer 28

Composed of two peptide chains (A and B) linked by disulphide bonds. Highly conserved structure across species.

Question 29

What does the highly conserved structure of insulin across species allow?

Answer 29

Insulin from different species can be used in other species, and still induce a normal cellular response.

Question 30

During processing of the gene for insulin, the C peptide is released. What does this allow?

Answer 30

Release of C peptide can be measured as a proxy for insulin production in diagnostics.

Question 31

Describe what happens in the beta cells when glucose levels are low.

Answer 31

Less glucose enters the cell, slower glucose metabolism, lower ATP production, open ATP-dependent potassium channels, no insulin secretion.

Question 32

Describe what happens in beta cells when glucose levels are high.

Answer 32

Glucose enters cells, increases metabolism, raises ATP, closes potassium channels, depolarizes the cell, opens calcium channels, triggers insulin exocytosis.

Question 33

How can we describe beta cell responses? How can we measure them?

Answer 33

Responses are oscillatory and coordinated. Measured by calcium-sensitive fluorescent reporters that show oscillations in calcium levels reflecting insulin secretion.

Question 34

How is the membrane potential of beta cells reset?

Answer 34

Calcium-dependent potassium channels open, potassium ions exit, repolarizing the membrane.

Question 35

What effect does sulphonylureas have on insulin secretion?

Answer 35

Inhibits glucose metabolism, inhibits ATP-dependent potassium channels, increasing insulin secretion.

Question 36

What effect do diazoide, cromakalin, and pinacidil have on insulin secretion?

Answer 36

Activate ATP-dependent potassium channels, decreasing insulin secretion.

Question 37

What effect does somatostatin have on ATP-dependent potassium channels?

Answer 37

Activates KATP channels, hyperpolarizing the cell and preventing calcium channel opening, thus decreasing insulin release.

Question 38

How can we describe stimulated insulin release? Why?

Answer 38

Biphasic (2 stages). Early rapid release from a readily available insulin pool, followed by slower release from a reserve pool.

Question 39

What do we need to consider when carrying out insulin treatments/transplants?

Answer 39

Insulin release is biphasic, so hormone replacement therapy should mimic this response.

Question 40

How is insulin release regulated by the autonomic nervous system?

Answer 40

Parasympathetic: increases insulin and glucagon release. Sympathetic: decreases insulin, increases glucagon, vasoconstriction.

Question 41

Which regulatory hormone do the delta cells of the pancreatic islets release? What effect does this have?

Answer 41

Delta cells release somatostatin, influencing KATP channel activity.

Question 42

Which regulatory hormone do the alpha cells of the pancreatic islets release? What effect does this have?

Answer 42

Alpha cells release glucagon, antagonistic to insulin’s effects.

Question 43

What are incretins and what effects do they have?

Answer 43

Gut hormones like GLP-1 and GIP, stimulate insulin release from beta cells and reduce appetite, thereby regulating blood glucose and promoting weight loss.