diabetes pathogenesis and metabolic abnormalities 1/2 W6 Flashcards
what is diabetes mellitus
a condition associated with an elevated blood glucose
this is a consequence of deficiency of insulin, or of its reduced action, or of a combination of both.
what is insulin? important features/functions?
main hormone regulating blood glucose levels
secreted in pancreas (islets)
anabolic
essential for fuel storage and cell growth
promotes uptake of glucose into cells for energy
prevents breakdown of fat and protein
where are islets of the pancreas? where do their secretions go?
pockets of cells studded throughout the pancreas gland. secretions released directly into bloodstream (portal circulation)
islets of Langerhans structure?
around outside - acinus cells of exocrine pancreas
beta cells dominant in centre of islet
alpha cells present around beta cells
rich blood supply
pancreatic cells and their secreted hormones? % of total islet cell mass?
alpha cells - glucagon -11%
beta cells - insulin - 85%
delta cells - somatostatin - 3%
F cells - pancreatic polypeptide - 1%
insulin structure? how is it made?
peptide hormone
synthesised initially as proinsulin - A and B chains linked by C chain
C chain cleaved off by B-cell peptidases to create insulin and C-peptide
what is insulin secretion from beta cells directly coupled to
prevailing blood glucose levels
how does glucose cause the secretion of insulin in beta cells?
glucose enters beta cell via GLUT2 transporters (non active, permissive process directly related to prevailing blood glucose level).
glucose metabolism occurs producing ATP.
ATP directly inhibits the opening of a potassium channel.
potassium levels raise within cells causing membrane depolarisation, opens voltage gated calcium channel allowing Ca2+ into cell.
this promotes exocytosis of insulin molecules (from secretory granules in cell)
rate limiting step in glycolysis?
glucokinase (aka GCK) converts glucose to glucose-6-phosphate
what insulin is first released in response to ingestion of food? what does this create?
stored insulin is released first, followed by newly synthesised insulin.
creates a biphasic response of insulin secretion
biphasic response of insulin secretion?
first phase - stored insulin
second phase - newly synthesised insulin
what can C-peptide be used as a measure for
used as a measure of endogenous insulin secretion (not present in manufactured insulin)
principle actions of insulin - promotes?
glucose uptake in fat and muscle
glycogen storage in liver and muscle
amino acid uptake in muscle
protein synthesis
lipogenesis in adipose tissue
cell proliferation
principle actions of insulin - inhibits?
gluconeogenesis (from 3-Carbon precursors)
ketogenesis
apoptosis
insulin signalling - glucose uptake?
insulin binds to cell surface receptor, complicated intermediate steps but final result is translocation of GLUT4 vesicles from the cytoplasm to the cell membrane, allowing insulin-dependent glucose uptake into cell
name for new glucose formation? where does this occur? how?
gluconeogenesis
occurs in liver and partly kidneys
glucose formed from breakdown products of fat and protein (3-carbon precursors)
where is glucose stored?
liver and muscle
glycogenolysis/glycogenesis/gluconeogenesis?
glycogenolysis = breakdown of glycogen
glycogenesis = formation of glycogen
gluconeogenesis = formation of glucose from 3 carbon precursors
3 carbon precursors?
alanine (from ingested protein)
pyruvate (from muscle protein)
lactate (from muscle glycogen)
glycerol (from fat)
insulin effects on glucose metabolism?
glycogenesis and inhibition of gluconeogenesis
glucagon effects on glucose metabolism?
favours glycogenolysis and gluconeogenesis
other hormones involved in glucose homeostasis other than insulin and glucagon? what is their action?
epinephrine/norepinephrine
growth hormone
glucocorticoids
cortisol
all promote increase in blood glucose levels (fight or flight hormones)
important role in protection from hypoglycaemia.
why is blood glucose maintained within such a narrow range?
optimal functioning of brain (no glycogen reserves)
maintenance of energy source for most tissues
integrity and health of blood vessels
what are the fundamental causes of diabetes
insulin deficiency
insulin resistance
when does absolute deficiency of insulin occur
toxic insult to the pancreas - autoimmune, chemical (alcohol), surgery etc
what causes insulin resistance?
insulin(??)
specific insulin resistance syndromes? features?
due to single gene defects (usually in insulin receptor itself). autosomal dominant. very rare.
leprechaunism
Rabson-Mendenhall syndrome
Type A insulin resistance
dark pigmentation in axillary and skin folds
which type of fat is more metabolically active?
visceral fat is more metabolically active than subcutaneous fat
mechanism behind insulin resistance in obesity?
visceral fat produces hormones which can affect the mechanism of insulin - still unsure for sure
other causes of insulin resistance?
pathogenic states of growth hormone, adrenaline, cortisol
eg acromegaly (growth hormone resistance), pheochromocytoma (adrenaline secreting tumour of adrenal glands), Cushing’s disease (pituitary tumour, excess cortisol)
