Lecture 17: Glucose Homeostasis

Question 1

Where does glucose come from in the body?

Answer 1

• Ingestion
• Gluconeogenesis (AA)
• Glycogenolysis

Question 2

Write some notes on the islets of langerhan:

Answer 2

1-2% of pancreas mass but receive 20% blood flow

Neurovascular bundle enters each islet through beta cell core

Venous effluent to portal vein and liver

Question 3

How is glucose transported?

Answer 3

GLUT (facilitated)

SGLT 1 & 2 transporters (Na dependent)

Question 4

Where is a drug target to alter blood gucose?

Answer 4

Kidneys SGLT1-2 transporters. Blocks Na and glucose uptake

Question 5

Where are GLUT 1 transporters located? and why is this important?

Answer 5

GLUT1 = RBC and Brain

Non-insulin mediated glucose uptake

Question 6

What are GLUT 2,3,4 located?

Answer 6

GLUT 2 = Pancreas and liver
GLUT 3 = Neurons (Placenta)
GLUT 4 = Fat and Muscle (Insulin mediated and present in vesicles, also exercise induced - reduces glucose)

Question 7

What happens to glucose once it enters the cell?

Answer 7

Glucose -> Glycolysis -> ATP

Question 8

How does rising glucose cause insulin release?

Answer 8

Rising blood glucose influxes into islet cells via GLUT2. They are then broken down via glycolysis and produce ATP which drives a K pump. This depolarises the cell and causes Ca to influx. Ca causes insulin vesicle binding release

Question 9

How does glucose in the gut result in insulin release?

Answer 9

The gut releases GLP-1 and other factors which influence insulin release

Question 10

What are the possible drugs targets for influence insulin release?

Answer 10

GLP-1 agonist.
DPP4 inhibitors (enzyme for GLP-1)

Sulphonylureas that influence K ATPase and islet cell depolarisation

Question 11

Describe the structure of insulin in beta cells and what happens as it is released:

Answer 11

• Pro-insulin in the beta cells is cleaved to release insulin and C-peptide

Question 12

What can c peptide be used for?

Answer 12

• C-peptide measurement can be used to assess endogenous insulin secretory capacity

If hypoglyceamic case presents can measure to see if they need insulin or not.

Question 13

Describe the signalling mechanism of insulin:

Answer 13

Insulin signalling pathway: Insulin binds to its receptor results in autophosphorylation of the insulin receptor beta sub units on tyrosine amino acids

Insulin receptor autophosphorylation activates the insulin receptor substrates (IRS 1/2) and phosphatidylinositol (PI3) kinases leading to a cascade of events that ultimately leads to GLUT-4 translocation and glucose uptake into tissues.

Question 14

Describe the time course released of insulin at basal levels and after a meal:

What factors regulate insulin release?

What are insulins generics effects?

Answer 14

Basal: Pulsatile 9-14 mins.

Major regulator is glucose - Acute phase then slower second phase.

Other regulators: AA, glucagon, incretins i.e GLP1 (all increase insulin)

Somatostatin - Decreases insulin release

Effect: Anabolic increasing storage of glucose, fatty and amino acids.

Question 15

Describe glucagon and its effects:

Answer 15

Catabolic mobilising glucose, fatty and amino acids from stores

Question 16

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Answer 16

now

Question 17

What is often lost in the insulin phase response to glucose challenge?

Answer 17

1st acute phase is often lost in diabetes

Question 18

What are GIP and GLP1?

Answer 18

GIP = Glucose dependent insulintropic polypeptide

GLP-1 = Glucose like peptide 1

Question 19

Describes what happens following the consumption of food with incretins and their effects:

Answer 19

GI tract : releases incretins (gut hormones) i.e GLP1 and GIP

-> Act on beta and alpha cells:

Glucose dependent: Increase insulin from beta cells (GLP1 and GIP) = Insulin increased peripheral glucose uptake i.e muscle and fat.

Decrease glucagon (alpha cells) GLP-1, glucose dependent = Increased insulin and decreased glucagon reduce hepatic glucose output

= Blood glucose control

Question 20

What happens to incretins in a diabetic patient?

Answer 20

Incretin effect is deminished

Question 21

What does sitagliptin do?

Answer 21

Inhibits DPP-4 enzyme responsible for GIP and GLP1 breakdown thus prolonging their effect

Question 22

What does insulin do to carbs?

Answer 22

1. Liver - inhibits glycogenolysis and gluconeogensis
2. Muscle - increase glucose transport and glycolysis
3. Adipose tissue - same as muscle

Question 23

What does insulin do to fat?

Answer 23

Increase TG storage and inhibits lipolysis (dec. hormone sensitive lipase) and FFA production

Inhibits ketone production

Question 24

Describe the action of insulin on protein:

Answer 24

Anabolic by increasing transport of AA into liver and muscle

Question 25

Fat represents 20-30% of bw and 70-80% stored energy. Whats it broken down into and what does that enter to produce energy?

Answer 25

Lipolysis -> FFA and Ketones -> Glycerol -> Krebs cycle

Question 26

How much energy stores are in carbs and protein?

Answer 26

Protein ~20%, hydolysed to AA

Carbs ~1-2% but are readily available

Question 27

What cells dont have mitochondira?

Answer 27

RBC, thus dont have krebs cycle

Question 28

In a nutshell what does the krebs cycle do?

Answer 28

Oxidizes acetyle CoA for Energy (ATP)

Interconnects carbohydrate, protein and fat metabolism

Question 29

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Answer 29

now please

Question 30

What is ketogenesis?

Answer 30

When FFA are oxidated in the krebs cycle they produce ketones i.e Aceto acetate, acetone, beta hydroxybutyrate

Fuel for muscle and liver but not acutely for brain or RBC

Question 31

How does ketogenesis occur in the setting of insulin deficiency and what are the implications of this?

Answer 31

Insulin deficiency
- Uncontrolled gluconeogenesis and protein hydrolysis
- GLUT 4 inactive
- Overall net result:
Diabetic ketoacidosis 

Compensatory resp. alkalosis = Hyperventiliate to blow off CO2

Question 32

What is normal fasting glucose?

Answer 32

3.5-5.5 mmol/l

Question 33

As hypoglycemia occurs, what are the symptoms and how do they change?

Answer 33

Level 1-2: Neuroendocrine symtpoms i.e FFF response, insulin secretion inhibited, glucose released from liver.

Level 2-3: Neuroglycopenic symptoms i.e severe cognitive impairment requiring external assistance for recovery

Sustained hypoglyceamia can lower BG set point and thus have no early symptoms before severe hypoglyceamia

Question 34

What causes hypoglycaemia?

Answer 34

Insulin in patients with diabetes
Sulphonyurea therapy (enhanced GLP and GIP effect)

Insulinoma (rare)
Severe horone deficiency i.e addinsons disease