Insulin (Secretion and Action)

Question 1

What is an exocrine gland?

Answer 1

A gland that secretes into a duct

Question 2

What is an endocrine gland?

Answer 2

A gland that secretes directly into the bloodstream and surrounding tissues

Question 3

What are incretins?

Answer 3

These are a group of metabolic hormone that stimulate a decrease in blood glucose levels by increasing insulin release from pancreatic beta cells prior to blood glucose level elevation

Question 4

Why is the brain so dependent on extracellular glucose?

Answer 4

It can’t synthesis or store glucose or metabolise substrates other than glucose (except for ketones) and it also can’t extract enough glucose for the extracellular fluid at lower concentrations

Question 5

What 5 cell types are present in the pancreatic Islet of Langerhans?

Answer 5

Alpha cells, beta cells, delta cells, PP cells and epsilon cells

Question 6

What is the role of alpha cells in the pancreatic Islets of Langerhans?

Answer 6

Produce glucagon

Question 7

What is the role of beta cells in the pancreatic Islets of Langerhans?

Answer 7

Produce insulin

Question 8

What is the role of delta cells in the pancreatic Islets of Langerhans?

Answer 8

Produce somatostatin

Question 9

What is the role of PP cells in the pancreatic Islets of Langerhans?

Answer 9

Produce pancreatic polypeptide

Question 10

What is the role of epsilon cells in the pancreatic Islets of Langerhans?

Answer 10

Produce ghrelin

Question 11

Describe the process of insulin production

Answer 11

Pancreatic beta cells synthesis pre-proinsulin which is then transported to the ER where it is modified and cleaved to form proinsulin. This proninsulin enters the golgi apparatus and is converted to active insulin by endopeptidases (carboxypeptidase E); this cleaves off the C group and the B and A groups connect by a disulphide bond

Question 12

At what four stages can insulin production be regulated?

Answer 12

At the transcription from the insulin gene, mRNA stability, mRNA translation and post-translational modification

Question 13

Outline the process that leads to insulin secretion from pancreatic beta cells

Answer 13

Glucose enters the beta cell via the GLUT2 transporter which stimulates glucokinase (GK) which phoshorylates the glucose to prevent it leaving the cell. The glucose is then used in aerobic respiration where it generates a ATP; the resultant increase ATP:ADP ratio closes the K+ channels which leads to membrane depolarisation which opens the Ca2+ channel which then acts on the vesicles containing insulin and facilitates exocytotic release

Question 14

What type of GLUT receptor is present on pancreatic beta cells?

Answer 14

GLUT2

Question 15

Where is the glucokinase enzyme found?

Answer 15

Only in the liver, hexokinase is found everywhere else

Question 16

What three substances amplify insulin secretion?

Answer 16

Amino acids, incretins and phospholipase C

Question 17

How can amino acids act to amplify insulin secretion?

Answer 17

Increasing the ATP: ADP ratio to shut the K+ channel:

• Increased breakdown of amino acids in cells leads to an increased ATP
• Leucine can activate glutamate dehydrogenase (GDH) which can contribute a molecule to the Kreb’s cycle (alpha-ketoglutarate)
• Leucine can be converted by transamination into alpha-ketoisocaproate (KIC) which is converted to acetyl CoA and increases ATP ratio again

Direct depolarisation:
Some amino acids such as arginine can directly depolarise the plasma membrane to cause Ca2+ channel opening

Question 18

How can incretins act to amplify insulin secretion?

Answer 18

After food intake there is GLP-1 (glucagon-like peptide 1) secretion which stimulates insulin secretion by acting on the GLP-1R which stimulates the beta cell, but glucose is required for this activation of insulin secretion

Question 19

How can phospholipase C amplify insulin secretion?

Answer 19

Phospholipase C cleaves PIP2 into IP3 and diacylglycerol (DAG). The IP3 binds to receptors in the endoplasmic reticulum of beta cells which allows Ca2+ release which can stimulate further vesicle release

Question 20

What signals trigger insulin release besides glucose?

Answer 20

• Amino acids arginine and leucine
• GLP-1 (gastrointestinally-derived incretins)
• GIP (glucose-dependent insulinotropic peptide)
• Fatty acids
• Acetylcholine (parasympathetic release via phospholipase C)
• CCK (cholecystokinin via phospholipase C)

Question 21

What are the metabolic actions of insulin on muscle tissue?

Answer 21

Stimulates glycogen synthesis as it activates protein kinase B (Akt) which induces GLUT4 translocation in smooth muscle and phosphorylates/inactivate glycogen synthase kinase leading to activation of glycogen synthesis –> increased glycogenesis

Question 22

What are the major metabolic actions of insulin on adipocytes?

Answer 22

Stimulates glucose uptake, lipogenesis and inhibits lipolysis (via inhibiting lipase)

Question 23

How can incretins act to amplify insulin secretion?

Answer 23

After food intake there is GLP-1 (glucagon-like peptide 1) secretion which stimulates insulin secretion by acting on the GLP-1R which stimulates the beta cell, but glucose is required for this activation of insulin secretion

Question 24

How can phospholipase C amplify insulin secretion?

Answer 24

Phospholipase C cleaves PIP2 into IP3 and diacylglycerol (DAG). The IP3 binds to receptors in the endoplasmic reticulum of beta cells which allows Ca2+ release which can stimulate further vesicle release

Question 25

What signals trigger insulin release besides glucose?

Answer 25

• Amino acids arginine and leucine
• GLP-1 (gastrointestinally-derived incretins)
• GIP (glucose-dependent insulinotropic peptide)
• Fatty acids
• Acetylcholine (parasympathetic release via phospholipase C)
• CCK (cholecystokinin via phospholipase C)

Question 26

What are the metabolic actions of insulin on muscle tissue?

Answer 26

Stimulates glycogen synthesis as it activates protein kinase B (Akt) which induces GLUT4 translocation in smooth muscle and phosphorylates/inactivate glycogen synthase kinase leading to activation of glycogen synthesis –> increased glycogenesis

Question 27

What factors can reduce insulin signalling?

Answer 27

Endocytosis/degradation of the insulin receptor, dephosphorylation of the tyrosine residues on the beta subunit of the IR due to tyrosine phosphatases, decrease in the number of receptors and serine/threonine kinases reduce the activity of insulin by phosphorylating IRS so it can’t bind to the tyrosine kinase end of the IR.

Question 28

What are the major metabolic actions of insulin on hepatocytes?

Answer 28

Increases glucose uptake by increasing GK activity, increases glycogenesis, increase lipogenesis (form lipoproteins) and inhibits gluconeogenesis

Question 29

How does insulin affect protein synthesis?

Answer 29

It stimulate amino acid uptake and translation of mRNAs in order to increase protein synthesis, and inhibits protein breakdown; promotes an anabolic state

Question 30

Outline how the insulin receptor is activated

Answer 30

Two molecules of insulin bind to the extracellular alpha subunits which causes a conformational change in the chains. This change activates the kinase domain of the receptor on the intracellular portion of the beta subunits. The activated kinase domain then phosphorylates the tyrosine residues on the C-terminus of the receptor as well as those on the adaptor protein (IRS)

Question 31

Outline the mechanism of intracellular insulin signalling

Answer 31

Insulin binds to the IR and causes the receptor to become phosphorylated which allows IRS to bind. PI3K (lipid kinase) is then recruited which works to phosphorylate PIP2 to PIP3. As a result, protein kinase (Akt) can bind to PIP3 which then allows the phosphorylation of downstream factors which allows translocation of GLUT4 to the surface of muscle and adipocytes

Question 32

What are the consequences of insulin resistance on the liver?

Answer 32

Reduced glycogen synthesis, reduced lipogenesis, increased gluconeogenesis and increased glycogenolysis

Question 33

What are the consequences of insulin resistance on the muscle?

Answer 33

Reduced glucose uptake, reduced glycogen synthesis and increased protein catabolism

Question 34

What are the consequences of insulin resistance on adipocytes?

Answer 34

Reduced glucose uptake, reduced lipogenesis and increased lipolysis

Question 35

How does the metabolism react to short-term fasting?

Answer 35

The liver releases glucose into the bloodstream via glycogenolysis and gluconeogenesis (amino acids and glycerol can be used as precursors)