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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)