PSC2002/L24 Glucose Homeostasis & Insulin Action

Question 1

What is normal blood glucose concentration and how much does this rise after a meal?

Answer 1

5mM (90mg/dl)
Rises to 5-7mM
Can be 60mM in disease states

Question 2

What is a normal amount of blood glucose and daily intake of glucose?

Answer 2

Blood: <5g
Intake: 300g

Question 3

What effect does hyperglycaemia have on insulin and glucagon secretion?

Answer 3

Stimulates insulin secretion
Inhibits glucagon secretion

Question 4

When is insulin secreted?

Answer 4

High blood glucose

Question 5

When is glucagon secreted?

Answer 5

Low blood glucose

Question 6

Describe pancreatic islets (islets of Langerhans). (3)

Answer 6

1-2% of pancreatic tissue
Comprise a, B and d cells that secrete hormones
<0.5mm diameter

Question 7

Describe B-cells.

Answer 7

Secrete insulin
60% of human islets

Question 8

Describe a-cells.

Answer 8

Secrete glucagon
30% of human islets

Question 9

Describe d-cells.

Answer 9

Secrete somatostatin
8-10% of human islets

Question 10

Give 3 minor regulators of insulin release.

Answer 10

+Amino acids
+Neural input (cholinergic)
+Gut hormones (GLP1, GIP, incretins)
-Adrenaline
-Somatostatin

Question 11

Give the 3 major regulators of glucagon release.

Answer 11

-Glucose
-Insulin
+Amino acids

Question 12

Give 3 minor regulators of glucagon release.

Answer 12

+Neural input (stress)
+Adrenaline
-Gut hormones
+Cortisol

Question 13

What 3 structure occur before insulin production?

Answer 13

Insulin gene
Preproinsulin
Proinsulin

Question 14

Describe the formation of proinsulin from preproinsulin.

Answer 14

Cleavage of the signal peptide

Question 15

How is insulin produced from proinsulin?

Answer 15

C peptide cleavage

Question 16

Describe the formation of insulin. (4)

Answer 16

Pre-proinsulin-> proinsulin (86aa) through signal peptide cleavage
Proinsulin packaged in vesicles from Golgi
Proinsulin -> insulin (51aa in 2 chains) through C peptide cleavage
1-30 and 66-86 (1-21) joined by disulphide bonds
Stored in heaxtrimeric complex with zinc and released from B cells

Question 17

What length are the A and B-chains in insulin?

Answer 17

A-chain 21aa
B-chain 30aa
Active, short half-life

Question 18

Describe type 1 diabetes.

Answer 18

B-cells become damaged/defective and cannot produce insulin
Take insulin injections

Question 19

Describe beta cell activity at basal glucose levels. (5)

Answer 19

K(ATP) channel open
K+ flux out of cell
Membrane hyperpolarised at -60mV
Ca2+ channel closed
Low insulin secretion

Question 20

What senses glucose levels in B cells?

Answer 20

Glucokinase

Question 21

Describe beta cell activity during raised glucose concentration. (6)

Answer 21

Raised ATP
K(ATP) channel closed
Membrane depolarised at -40mV
Ca2+ channels open
High cytoplasmic Ca2+
High insulin secretion

Question 22

Which glucose transporter is present in B-cells?

Answer 22

GLUT1 or 2 dependent on species

Question 23

In other cells types (not Islets), what is glucose to G-6-P regulated by?

Answer 23

Hexakinases

Question 24

Describe the affinity of glucokinase for glucose.

Answer 24

Low-affinity (S(0.5) ~ 8mM)

Question 25

Describe monogenic diabetes.

Answer 25

Glucokinase gene mutation Activating - hypoglycaemia (PHHI) Deactivating - Diabetes (GCK-MODY/PNDM)

Question 26

Describe how a KCNJ11 mutation might cause diabetes.

Answer 26

Encodes K(ir) 6.2 subunit of K(ATP) channel Need to inherit 2 alleles Activating - diabetes (PDNM) inactivating - hypoglycaemia (PHHI) K(ATP) closed when it shouldn't be; high-insulin, low-glucose phenotype

Question 27

What is glucose converted into in the liver in a postprandial state?

Answer 27

Glycogen, triglyceride (TG)

Question 28

What is glucose converted to in muscle in a postprandial state?

Answer 28

Glycogen Metabolised by glycolysis/oxidation

Question 29

What is glucose converted into in adipose tissue in a postprandial state?

Answer 29

Triglyceride (TG)

Question 30

Describe the structure and formation of glycogen.

Answer 30

Branched polymer of glucose residues Glucose absorbed from gut converted to liver glycogen First line of defence against declining blood glucose conc. Hepatic glycogen degraded between meals to maintain blood glucose conc.

Question 31

Give 2 key enzymes in conversion of glucose to glycogen.

Answer 31

Glycogen synthase - 1,4 Glycogen synthase - 1,6

Question 32

Give 2 key enzymes in breakdown of glycogen.

Answer 32

Glycogen phosphorylase Debranching enzymes

Question 33

What happens to dietary glucose when liver glycogen stores are full? (5)

Answer 33

Liver converts glycogen to fat Metabolises and enters TCA cycle - leaves as citrate Converted to acetyl CoA Acetyl CoA -> Malonyl CoA by acetyl CoA carboxylase Malonyl CoA -> Palmitate by fatty acid synthase TG packaged into vesicles and exocytosed into blood

Question 34

What is glucose converted into in the liver in a fasted state?

Answer 34

Produce ketone bodies for energy

Question 35

What is converted in muscle in a fasted state?

Answer 35

Protein to amino acids Metabolise fatty acids for fuel

Question 36

What is converted in adipose tissue in a fasted state?

Answer 36

Triglyceride to fatty acids and glycerol

Question 37

Describe glucose usage after ingestion of 100g of glucose.

Answer 37

During fasting, glucose produced by glycogenolysis, gluconeogenesis

Question 38

What is the effect of insulin action on the liver?

Answer 38

+Glycogen synthesis +Fatty acid/TG synthesis +Protein synthesis -Glycogen degradation -Gluconeogenesis

Question 39

What is the effect of insulin action on muscle?

Answer 39

+Glucose transport +Glycogen synthesis +Glucose oxidation +Protein synthesis

Question 40

What is the effect of insulin action on adipose tissue?

Answer 40

+Glucose transport +Triacylglycerol synthesis -Triacylglycerol breakdown release of fatty acids

Question 41

Describe the stimulation of GLUT4 translocation and glucose metabolism in muscle.

Answer 41

Insulin action triggers: Translocation of GLUT4 from intracellular vesicular site to plasma membrane Activation of glycogen synthase (dephosphorylation) Activation of pyruvate dehydrogenase (dephosphorylation)

Question 42

Describe insulin action in adipose tissue.

Answer 42

Stimulation of GLUT4 translocation and fatty acid synthesis - increased acetyl-CoA carboxylase and fatty acid synthase transcription Inhibition of TAG breakdown Decreased hormone sensitive lipase (HSL): covalent modification

Question 43

Describe stimulation of TAG uptake in adipose tissue. (3)

Answer 43

Insulin activates lipoprotein lipase Breaks down triacylglycerol which crosses capillary wall Can then be resynthesised and neutralised

Question 44

Describe insulin action in the liver (covalent modification).

Answer 44

Serine, threonine phosphorylation-dephosphorylation Activation: glycogen synthase (+ve); acetyl CoA carboxylase (+ve) Inactivation: phosphorylation (-ve)

Question 45

Describe enzymes involved in insulin action in the liver (insulin gene transcription (chronic)).

Answer 45

Induction: glucokinase (GCK), acetyl-CoA carboxylase, fatty acid synthase (FAS) Repression: glucose-6-phosphatase (G6PC or G6Pase; PEPCK (phosphoenolpyruvate carboxykinase)

Question 46

Which form of glycogen synthase is active?

Answer 46

Dephosphorylated

Question 47

Which form of glycogen phosphorylase is active?

Answer 47

Phosphorylated

Question 48

What is the effect of increased G6P and glucose in the liver?

Answer 48

Moves glycogen synthase/phosphorylase to unphosphorylated form

Question 49

What is the role of glucagon in the liver?

Answer 49

Activates Ph-kinase which phosphorylates glycogen phosphorylase (active form)