diabetes pathogenesis and metabolic abnormalities 1/2 W6

Question 1

what is diabetes mellitus

Answer 1

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.

Question 2

what is insulin? important features/functions?

Answer 2

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

Question 3

where are islets of the pancreas? where do their secretions go?

Answer 3

pockets of cells studded throughout the pancreas gland. secretions released directly into bloodstream (portal circulation)

Question 4

islets of Langerhans structure?

Answer 4

around outside - acinus cells of exocrine pancreas
beta cells dominant in centre of islet
alpha cells present around beta cells
rich blood supply

Question 5

pancreatic cells and their secreted hormones? % of total islet cell mass?

Answer 5

alpha cells - glucagon -11%
beta cells - insulin - 85%
delta cells - somatostatin - 3%
F cells - pancreatic polypeptide - 1%

Question 6

insulin structure? how is it made?

Answer 6

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

Question 7

what is insulin secretion from beta cells directly coupled to

Answer 7

prevailing blood glucose levels

Question 8

how does glucose cause the secretion of insulin in beta cells?

Answer 8

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)

Question 9

rate limiting step in glycolysis?

Answer 9

glucokinase (aka GCK) converts glucose to glucose-6-phosphate

Question 10

what insulin is first released in response to ingestion of food? what does this create?

Answer 10

stored insulin is released first, followed by newly synthesised insulin.

creates a biphasic response of insulin secretion

Question 11

biphasic response of insulin secretion?

Answer 11

first phase - stored insulin
second phase - newly synthesised insulin

Question 12

what can C-peptide be used as a measure for

Answer 12

used as a measure of endogenous insulin secretion (not present in manufactured insulin)

Question 13

principle actions of insulin - promotes?

Answer 13

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

Question 14

principle actions of insulin - inhibits?

Answer 14

gluconeogenesis (from 3-Carbon precursors)
ketogenesis
apoptosis

Question 15

insulin signalling - glucose uptake?

Answer 15

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

Question 16

name for new glucose formation? where does this occur? how?

Answer 16

gluconeogenesis
occurs in liver and partly kidneys
glucose formed from breakdown products of fat and protein (3-carbon precursors)

Question 17

where is glucose stored?

Answer 17

liver and muscle

Question 18

glycogenolysis/glycogenesis/gluconeogenesis?

Answer 18

glycogenolysis = breakdown of glycogen
glycogenesis = formation of glycogen
gluconeogenesis = formation of glucose from 3 carbon precursors

Question 19

3 carbon precursors?

Answer 19

alanine (from ingested protein)
pyruvate (from muscle protein)
lactate (from muscle glycogen)
glycerol (from fat)

Question 20

insulin effects on glucose metabolism?

Answer 20

glycogenesis and inhibition of gluconeogenesis

Question 21

glucagon effects on glucose metabolism?

Answer 21

favours glycogenolysis and gluconeogenesis

Question 22

other hormones involved in glucose homeostasis other than insulin and glucagon? what is their action?

Answer 22

epinephrine/norepinephrine
growth hormone
glucocorticoids
cortisol

all promote increase in blood glucose levels (fight or flight hormones)

important role in protection from hypoglycaemia.

Question 23

why is blood glucose maintained within such a narrow range?

Answer 23

optimal functioning of brain (no glycogen reserves)
maintenance of energy source for most tissues
integrity and health of blood vessels

Question 24

what are the fundamental causes of diabetes

Answer 24

insulin deficiency
insulin resistance

Question 25

when does absolute deficiency of insulin occur

Answer 25

toxic insult to the pancreas - autoimmune, chemical (alcohol), surgery etc

Question 26

what causes insulin resistance?

Answer 26

insulin(??)

Question 27

specific insulin resistance syndromes? features?

Answer 27

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

Question 28

which type of fat is more metabolically active?

Answer 28

visceral fat is more metabolically active than subcutaneous fat

Question 29

mechanism behind insulin resistance in obesity?

Answer 29

visceral fat produces hormones which can affect the mechanism of insulin - still unsure for sure

Question 30

other causes of insulin resistance?

Answer 30

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)