Lecture 5 - Insulin action

Question 1

What are the actions of insulin on glucose?

Answer 1

Decreases Hepatic Glucose Output (HGO) Increases muscle uptake

Question 2

What are the actions of insulin on proteins?

Answer 2

Decreases proteolysis

Question 3

What are the actions of insulin on lipids?

Answer 3

Decreases lipolysis and ketogenesis

Question 4

What is the general action of insulin?

Answer 4

Growth Vascular effects Ovarian function Clotting - PAI-1 Energy expenditure - relation to leptin

Question 5

Describe the GLUT-4 receptor

Answer 5

Muscle and adipose tissue Insulin responsive Lies in vesicles Recruited and enhanced by insulin Increases glucose uptake by 7x

Question 6

What is the effect of insulin on proteolysis in muscles?

Answer 6

Insulin inhibits muscle protein breakdown, but when decreased with an increase of cortisol Protein > A.A. which causes O2> CO2 Then amino acids are transported out of the muscle cell

Question 7

What is the effect of insulin on protein synthesis?

Answer 7

Increase in insulin, Growth hormone, IGF1 Causes A.A. to be synthesised into proteins

Question 8

When is glucose present?

Answer 8

In blood - all the time, not just after meals as it is essential for brain function

Question 9

How is glucose stored?

Answer 9

As glycogen in liver

Question 10

What are the pathways of gluconeogenesis and amino acids?

Answer 10

Presence of glucagon causes a.a. to enter liver.

Proteins are turned into amino acids via glucagon presence or protein deficiency OR a.a. turn into proteins via presence of insulin OR a.a. turn into glucose via GLUCONEOGENESIS - presence of glucagon, catecholamines and cortisol and inhibited by insulin.

Glucose then released as HGO

Question 11

What are the relative lasting times of the different fuel stores?

Answer 11

CHO - around 16 hrs (least amount present in body) Protein - 15 days Fats - 30-40 days (largest amount present in body)

Question 12

What is the storage mechanism for triglycerides?

Answer 12

TG in the bood are broken down by lipase in presence of insulin, increasing glycerol levels Glucose enters the adipocytes via GLUT4 (^ insulin) NEFA enters the cell and is also formed from glucose NEFA joins with glycerol-3-P (made from glucose entering cell) NEFA + Glycerol-3-P = TRIGLYCERIDE TG can then either leave the cell as glycerol (insulin absent) OR as NEFA (presence of catecholamines, cortisol and growth hormone)

Question 13

Describe the mechanism of hepatic gluconeogenesis after 10 hr fast (25% HGO)

Answer 13

Glycerol is taken up by the cells Converted to Glycerol3P which can be into TG OR can be converted into glucose, and released as HGO

Question 14

What is the main source of energy for the brain?

Answer 14

Glucose and ketone bodies

Question 15

What source of energy can the brain NOT use?

Answer 15

Fatty acids

Question 16

What is the mechanism of NEFA conversion into ketone bodies?

Answer 16

NEFA enters cell (from omental adipocytes) Forms fatty acyl CoA With presence of glucagon & absence of insulin (shuttle in mitchondrial membrane) acetyl CoA > acetoacetate > acetone + 3 hydroxybutarate Then the ketone bodies leave the cell

Question 17

Describe the mechanism of hepatic glycogenolysis after a meal

Answer 17

Glucose enters the cell G6P G6P into glycogen (presence of insulin) or the other way (presence of glucagon and catecholamine) G6P Glucose Glucose leaves the cell as HGO (when low hypoglycaemia)

Question 18

Describe glycogen metabolism in muscles

Answer 18

Glycogen enters the cell and is turned into glucose Glucose enters cell in absence of GH, Cats, Cort and presence of insulin Glucose mostly converted into acetyl CoA (which also enters the cell) Acetyl CoA enters the Kreb cycle and O2 converted into CO2

Question 19

What occurs in the fasted state?

Answer 19

LOW [INSULIN]:[GLUCAGON] [Glucose]= 3.0-5.5 mmol/litres ^ [NEFA] Decrease [amino acid] when prolonged ^ Proteolysis ^ Lipolysis ^ HGO from gluconeogenesis ^ Ketogenesis when prolonged Muscle uses lipids Brain uses glucose and later ketones

Question 20

What occurs in the fed state?

Answer 20

Stored insulin released and then 2nd phase High [Insulin]: [glucagon] HGO stopped ^ Glycogen Decreased gluconeogenesis ^ protein synthesis Decreased proteolysis ^ lipogenesis

Question 21

How does T1DM affect the mechanisms for energy?

Answer 21

Increased HGO leads to glucose and ketones release Muscle proteolysis occurs > a.a released Adipose cells cause lipolysis > glycerol and fatty acids

Question 22

How does T1DM present in the patient?

Answer 22

Absolute insulin deficiency Proteolysis with weight loss HYPERGLYCAEMIA Glycosuria with osmotic symptoms Ketonuria

Question 23

What are the main features of insulin induced hypoglycaemia?

Answer 23

^ insulin (due to subcutaneous injection) ^ glucagon ^ catecholamines, cortisol and GH (normal) Glucose enters muscle ^ HGO later with glycogenolysis and gluconeogenesis (brings patient out of hypo) Lipolysis increased

Question 24

How are glucagon and insulin delivered to diabetic patients?

Answer 24

Intra-muscular glucagon Subcutaneous insulin NB: patients can throw up the meal after injecting insulin, so could cause hypoglycaemia

Question 25

How to differentiate between T1 and T2 DM?

Answer 25

T1 - lose weight as fat stores are broken down T2 - usually overweight and won’t lose weight

Question 26

In which tissues does insulin resistance reside?

Answer 26

Liver, muscle and adipose tissues

Question 27

Where are the GLUT 4 receptors located?

Answer 27

Skeletal muscle cells and adipose tissue

Question 28

How does the insulin receptor affect the cell?

Answer 28

Insulin attaches to receptor 2 pathways occur: MAPK or PI3K-Akt pathway MAPK leads to growth/proliferation > stimulated by hyperinsulinaemia & is important for T2DM PI3K-Akt leads to metabolic actions - before this pathways IRS is present and it is converted to this molecule and when there is insulin resistance it leads to a compensatory hyperinsulinaemia

Question 29

What is the mitogenic action of insulin in insulin resistance?

Answer 29

HYPERINSULINAEMIC EFFECT Dyslipidaemia Lipoproteins Ovarian function - polycystic ovary disease Clotting Energy expenditure

Question 30

What is the metabolic effect of insulin in insulin resistance?

Answer 30

STOPS breakdown of glucose, protein and lipids

Question 31

What is the key feature of T2DM and how can it affect the patient?

Answer 31

High BP which harms vessel walls, can cause ischemic heart disease and kill

Question 32

What are the signs of insulin resistance?

Answer 32

Hypertension = BP>135/80 Fasting glucose >6 (slightly higher than normal) High [TG] and low [HDL] Adipocytokines, inflammatory state, energy expenditure Increase in waist circumference (men> 102, women>88)

Question 33

How does T2DM present?

Answer 33

Insulin resistance 60-80% obese as essential and omental fat increases Dyslipidaemia Later insulin deficiency HYPERGLYCAEMIA Less osmotic symptoms

Question 34

How to control the diet?

Answer 34

Total calorie control Reduce calories from fat, refined carbs (reduce insulin deficiency) Increase calories from complex carbs, soluble fibre (for GI tract and delays uptake of carbs) Decrease sodium uptake (helps hypotension)