Insulin action on liver and adipose tissues

Question 1

Describe the homeostasis of normal blood glucose levels

Answer 1

• narrow range
• disrupted by stimulus spiking glucose levels (detected by pancreatic beta cells)
• insulin is released in response and causes an increase of glucose uptake into cells and increase of glycogen synthesis in liver
• blood glucose levels fall to normal range again

Question 2

Physiological actions of insulin

Answer 2

• increased glucose uptake into cells
• increased glycogenesis in skeletal muscle and liver
• decreased glyconeogenesis
• decreased gluconeogenesis
  NET EFFECT = decrease blood glucose

Question 3

Describe the insulin signalling pathway in detail

Answer 3

• insulin = beta cells
• sensed by insulin receptor on sensitive tissues
• binding to receptor causes conformational change
• IR has tyrosine kinase activity, initiating autophosphorylation of inuslin receptor on tyrosine residues
• IRS proteins form scaffold (PIK3 = most important)
• lipid kinase binds to pH domains
• PDK1 and mTORC2 phosphorylate and activate Akt (makes insulin trophic)

Question 4

Akt functions

Answer 4

• stimulates glycogen synthesis through dephosphorylation of GSK3
• stimulates FOXO transcription factors via forcing them to exit nucleus
• promotes GLUT4 translocation to cell membrane (more glucose uptake)

Question 5

How is insulin signal transduction mediated

Answer 5

Akt -> has lots of different targets and makes insulin trophic. Mediates many pleiotropic responses to insulin

Question 6

Function of GSK3

Answer 6

Regulates hepatic glycogen synthesis

Question 7

Function of FOXO

Answer 7

Regulates hepatic gluconeogenesis

Question 8

GLUT4 translocation

Answer 8

• mediates insulin-stimulated glucose uptake (muscle/adipose)
• Akt stimulation
• Increased glucose uptake

Question 9

Glucose synthesis in hepatocyte

Answer 9

• glucose entering cell through GLUT2 transporter
• transformed into Glucose-6-P by glucokinase (reversible)
• Glucogen synthesis via glycogen synthase

Question 10

Glycolysis stimulation in hepatocyte

Answer 10

• Glucose-6-P converted to Fructose-6-P
• Fructose-6-P converted to Fructose-1,6-bisP
• fructose-1,6-bisP converted to PEP
• PEP converted to pyruvate
• Pyruvate converted to Acetyl CoA in mitochondria

Question 11

Gluconeogenesis suppression in hepatocyte

Answer 11

• Acetyl CoA converted to citrate in mitochondria
• citrate converted to oxaloacetate, which acts on PEP and reverses glycolysis reactions

Question 12

Insulin action

Answer 12

• promotes glucose uptake into liver
• promotes glucose storage as glycogen
• promotes glucose use in glycolysis/TCA cycle and suppresses gluconeogenesis
• promotes glucose conversion into fatty acids which are shipped to the adipose tissue
• suppresses triglyceride breakdown in the adipose tissue
• insulin treatment in diabetes tends to result in weight gain

Question 13

Glucagon action

Answer 13

• opposes many regulatory effects of insulin via cAMP
• increases glyconeolysis
• increases gluconeogenesis
• suppresses glycloysis
• increases FA oxidation
• in adipose tissues, stimulates HSL

Question 14

Diabetes mellitus

Answer 14

• most common endocrine disorder
• major feature = hyperglycaemia, inreased blood glucose
• glucosuria = glucose in urine with large osmotic diuresis - dehydration - circulatory failure, brain damage and renal failure
• high extracellular glucose levels, low intracellular glucose levels

Question 15

Criteria for diabetes

Answer 15

FPG > 7.0mmol/L
OGTT > 11.1 mmol/L after 75g glucose load

Question 16

HbA1C influenced by

Answer 16

influenced by several factors including anaemia, abnormalities of haemoglobin, pregnancy and uraemia

Question 17

T1DM definition

Answer 17

• pancreatic beta cell destruction / insulin is required for survival
• usually characterised by presence of anti-GAD / anti-islet cell antibodies