Causes of diabetes

Question 1

Insulin

Answer 1

Secreted by beta cells in pancreas

Question 2

Sodium and potassium

Answer 2

3:2
Na:K

Netflow charge -70mm
Outside more positive than inside

Question 3

ATP

Answer 3

Binds to potassium channel and closes it, stops movement of K. K accumulates in cell, equalises charge across membrane

Question 4

Charge in membrane

Answer 4

Increased uptake of glucose leads to increase ATP:ADP

Increased ATP closes K channel and membrane

Depolarisation leads to opening of Calcium channel

Increase in cytosolic Calcium promotes secretion of insulin via exocytosis

Question 5

Insulin signalling pathway

Answer 5

Binding of insulin to insulin receptor leads to receptor auto phosphorylation

Phosphorylated residues act as binding sites for Insulin receptor protein substrates

IR phosphorylates 4 tyrosin residues in IRS proteins

Lipid kinase, phosphoinositide 3-kinase binds to residue and converts PIP2 to PIP3

PIP3 activates PDK1, which phosphorylates and activates PKB

Activated PKB diffuses through cell and activates glucose transport

Question 6

Glucose transport mechanism

Answer 6

Insulin stimulates glucose uptake into adipocytes and skeletal muscle

Question 7

Insulin in adipocytes

Answer 7

Glucose transporter GLUT4 contained inside storage vesicle cells

Protein AS160 retains vesicles

Activation of PKB phosphorylates AS160 and inactivates it

Allows GLUT4 vesicles to fuse with plasma membrane

Increased levels of glucose transporters at cell surface

Question 8

Gluconeogensis

Answer 8

Fox01 synthesised in cytosol, targeted to nucleus
Regulates expression genes mediating gluconeogenesis (PEPCK, G6Pase)

Question 9

Fox01 prevention from nucleus

Answer 9

PKB phosphorylation prevents Fox01 from moving to nucleus

Insulin signalling leads to activation of PKB

PKB phosphoryltaes Fox01

Fox01 absence from nucleus leads to loss of expression of gluconeogenic genes

Loss of glucose production

Question 10

Loss of glucose metabolism

Answer 10

Loss of insulin-stimulated uptake into target cells (adipocytes)

Loss of insulin-mediated repression of gluconeogenesis in liver

Question 11

Type 1 diabetes genetic cause

Answer 11

Risk of T1D

Human Leukocytes Antigen (HLA) region contains genes that encode components of major histocompatibility complex

Question 12

Autoantibodies in type 1

Answer 12

Presence of autoantibodies against beta cell antigens is risk for development of T1D

-Glutamic acid decarboxylase-65
-Insulin
-IA-2
-ZnT8

20% risk if 1 present
75% risk if 2 present

Question 13

T1D development

Answer 13

Enteroviruses (coxsackie viruses)

Question 14

Autoimmune destruction of beta cells

Answer 14

Islet of Langerhans contain alpha, beta, delta cells

Effector T cell recognises peptides from beta cell and kills it

Glucagon and somatostatin produced by alpha and delta cells, no insulin made

Question 15

Type 1 diabetes treatment

Answer 15

Insulin injections

Question 16

Type 2 diabetes characteristics

Answer 16

Insulin resistance of target tissues
Beta cell dysfunction

Question 17

Mechanism inhibiting insulin signalling pathway

Answer 17

Protein tyrosine phosphatase 1B (PTP1B) dephosphorylates insulin receptor, leading to loss of IRS binding

PTEN dephosphorylates PIP3 back to PIP2

IRS proteins inactivated by phosphorylation of serine residues by PKC
PKC - serine phosphorylation

Prevents IR from phosphorylating tyrosine residues on IRS

Question 18

Insulin resistance

Answer 18

Lipid overflow into liver, muscle, epicardium

Excess fat leads to increased intracellular lipid signalling intermediate DAG and ceramide into cytoplasm

Ceramide = Inhibits PKB
PKC = Inhibits IRS

Question 19

Adipokines

Answer 19

Adiponectin secreted from adipocytes promotes insulin sensitivity

Affects sphingolipid metabolism

Decreased in obesity

Question 20

Obesity

Answer 20

Decrease of adiponectin

Increased cytokines

TNF Alpha cytokine cells affect adipokines

Question 21

Increased TNF levels

Answer 21

Contribute to insulin sensitivity

Induces expression of PTP1B, dephosphorylates insulin receptor

Activates JNK, causes serine phosphorylation and inactivation of IRS proteins

Question 22

PTP1B

Answer 22

Dephosphorylates IR leading to loss of IRS binding