Lecture 4: Hormonal Control of Metabolic Pathways

what cells/organs have an absolute requirement for glucose?

brain, nerves, erythrocytes, testes and kidney medulla

hyperglycaemia

high blood glucose

hypoglycaemia

low blood glucose

which cells release insulin and when

pancreatic β-cells when blood glucose increases

which cells release glucagon and when

pancreatic α-cells when blood glucose levels fall

insulin action

• increases glucose uptake → fat and muscle

• increase glycogen synthesis in liver

• inhibit gluconeogenesis in liver

glucagon action

• stimulates gluconeogenesis

• inhibits glycogen synthesis in the liver

• triggers lipid breakdown

key events in the absorptive (fed) state

• glucose used by cells to produce ATP

• excess glucose stored in liver and skeletal muscle as glycogen and in adipocytes as fat

key events in post-absorptive (fasted) state

• fatty acids are the main energy source

• glucose made by the liver via gluconeogenesis and glycogen breakdown

• liver releases glucose into blood

• glycogen breakdown in skeletal muscle but no release into blood

primary function of pancreas

bile production secreted through bile duct into small intestine

typical fasting range of glucose levels

4 to 4.5 mM

describe the release of insulin in response to high blood glucose concentration

Glucose enters β cells via GLUT2 → glycolysis producing ATP. ATP:ADP ratio increases → ATP sensitive K+ channels closing which depolarises the membrane. Depolarisation causes voltage gated calcium ion channels to open. Calcium enters triggering insulin vesicles to fuse with the membrane and release insulin.

glucose metabolism in fed state: liver

• increased glucose uptake

• increased glycogen synthesis

• decreased glycogen breakdown

• decreased gluconeogenesis

glucose metabolism in fed state: skeletal muscle

• increased glucose uptake

• increased glycogen synthesis

• decreased glycogen breakdown

glucose metabolism in fed state: adipose tissue

• increased glucose uptake

• increased triglyceride/fatty acid synthesis

• triglyceride breakdown

How does insulin activate intracellular signalling?

• insulin binding to IR → receptor auto-phosphorylation

• phosphorylated residues on IR act as binding sites for insulin receptor substrate proteins

• IR phosphorylates 4 tyrosine residues in IRS proteins

• phosphoinositide 3-kinase binds to IRS protein residues and converts PIP2 → PIP3

• binding PIP3 activates PDK1

• PDK1 phosphorylates and activates kinases eg PKB

How does PKB stimulate glucose uptake into adipocytes and muscle?

• protein AS160 retains GLUT4 storage vesicles (GSVs) inside the cell preventing them moving to the plasma membrane

• activated PKB phosphorylates AS160 at threonine-642, inactivating it

• GSVs can fuse with the membrane so there’s more GLUT4 in the membrane

what regulates glycogen synthase activity?

phosphorylation deactivates the enzyme

How does activating PKB lead to an increase in glycogen synthesis?

PKB phosphorylates glycogen synthase kinase (GSK), inactivating it. Active glycogen synthase levels increase and more glycogen is synthesised.

Fox01

transcription factor which regulates genes that mediate gluconeogenesis

phosphorylation of Fox01 by PKB

prevents Fox01 from entering nucleus → decreased expression of gluconeogenic genes and loss of glucose production

effects of the binding of glucagon to its receptor on cAMP levels and protein kinase A

cAMP levels are elevated and protein kinase A is activated

effects of PKA on metabolism

• directly phosphorylates and inactivates glycogen synthase

• activates glycogen phosphorylase → glycogen breakdown

• activates key gluconeogenesis enzyme

leptin

polypeptide released by adipocytes when fat storage hits a certain level. Activation of brain leptin receptors → feeling full

ghrelin

released by cells in GI tract when stomach empty. Acts on hypothalamus receptors to increase hunger

What % of diabetes cases are type 1?

5%

What causes type 1 diabetes?

loss of insulin synthesis/release from beta cells due to autoimmune destruction of beta cells

what causes type 2 diabetes?

associated with insulin resistance of target tissues and decreased insulin secretion. Strong association with obesity

potential evidence for genetic component of type 2 diabetes

certain populations eg Pema Indians, south Indians and aboriginal populations have a much higher incidence of developing type 2 diabetes

when are type 1 and 2 diabetes typically diagnosed?

type 1 usually in childhood/adolescence and type 2 usually adulthood (age of onset getting earlier)