Control of blood glucose and endocrine pancreas Flashcards
(15 cards)
explain how glucose gets into cells via sodium-glucose co transporters (SGLUTs)
secondary active transport.
-SGLT1; glucose absoprtion from the gut
-SGLT1, SGLT2; glucose reabsorption from kidney (PCT)
explain high affinity, medium affinity and low affinity in terms of GLUT transporters
High affinity:
-GLUT1 (brain, erythrocytes)
-GLUT3
Medium affinity:
-GLUT4 (muscle and adipose tissue)- insuling dependent glucose uptake
Low affinity:
GLUT2 (liver, kidney, pancreas, gut) - glucose dependent insulin release in the pancreas
describe the hormones of the endocrine pancreas
-islets of langerhans are clusters of endocrine cells surrounded by exocrine pancreas.
* a-cells; glucagon
* b-cells; insulin
* sigma- cells; somatostatin (inhibits insulin and glucagon release)
explain insulin synthesis and insulin release into the circulation
insulin synthesis:
-the signal sequence from pre-proinsulin is removed to form pro-insulin in the RER
-its transfer to the golgi apparatus where peptidases break off the C peptide leaving an A and B chain linked by disulphide bonds.
-One mole of C-peptide is secreted for each mole of insilin
Insulin release into the circulation:
-pancreas supplied by branches of the coeliac, superior mesenteric, and splenic arteries.
-the venous drainage of the pancreas is into the portal system.
-half of the secreted insulin is metabolised by the liver in its first pass; the remainder is diluted in the peripheral circulation. The portal vein can’t sample and the insulin in the peripheral circulation which can be sampled is diluted
-C-peptide is more accurate index of insulin secretion in peripheral circulation because its inert and not metabolised by the liver
discuss factors regulating insulin secretion and glucagon secretion
Factors regulating insulin secretion:
-incretin hormones increase the response of the beta cells to plasma glucose so the reaction is amplified and more insulin is produced
Factors regulating glucagon secretion:
-insulin/glucagon ratio varies over physiologically signifcant range of glucose concentrations.
-the production of neither of the hormones is completely stopped, instead its the ratio of the hormones that determines the response.
-over time the differnce between the 2 hormones ratio is increasing
How do B cells sense a rise in glucose
-B cells don’t have a glucose receptor- glucose levels are sensed by GLUT2 /glucokinase
-effector is rise in ATP due to glucose oxidation
-glucose enters via the GLUT2 receptor and produces ATP through glycolysis and TCA.
-The ATP closes the K+ channel causing depolarisation.
-Depolarisation activates Ca2+ channels so Ca2+ enters and intracellular [Ca2+] increases. Ca2+ causes the release of insulin from secretory vesicles
-muscarinic receptor activation by parasympathetic activity also increases insulin release by increasing intracellular [Ca2+]
explain insulin receptor
-insulin binds to its receptor to activate a cascade of protein phosphorylation which then affects other enzymes by modulating enzyme phosphorylation or regulating gene transcription.
-cascades; GLUT4 translocation to the plasma membrane, glucose influx, glycogen synthesis, glycolysis and fatty acid synthesis
explain insulin receptor action
1) Acetyl CoA carboxylase (ACC) is the enzyme that starts lipogenesis by converting acetyl CoA. It’s under inhibitory control by PKA (insulin reduces cAMP and so reduces PKA) so is activated under insulin.
explain insulin and glucagon and diabetes mellitus
Insulin and glucagon:
-counter-regulatory hormones act principally through activity of PKA, insulin dephosphorylates key enzymes in metabolic pathways whilst glucagon phosphorylates them.
Diabetes mellitus:
-invariarbly fatal until availability of insulin extracted from animal fetus
type 1; absolute insulin deficiency
type 2; variable combination of insulin resistance and insulin insufficiency
explain how hypoglycaemia is central to DM diagnosis
-random plasma glucose >11.1mmolL-1
-fasting plasma glucose
-oral glucose tolerance test. Drink a solution of glucose and monitor plasma glucose every 30mins for 2hours.
explain insulin and plasma glucose and the importance of glycaemic control
Insulin and plasma glucose:
-plasma glucose is kept within constant limits by insulin, despite periodic intake of sugar and bursts of exercise requiring fuels
Importance of glycaemic control:
-reduce macro and microvascular complications
-glycosylated Hb levels are a good indicator of glycaemic control
-less than 6.5% is good
-every 1% fall in A1C results in 20-30% relative risk reduction in microvascular complications.
-glycaemic control is hard due to the interplay of insulin with other hormones
explain the incretin effect
-evidence for its impairment in T2DM
-major target for new drug development
-the incretins; glucagon like peptide-1 (GLP-1) and GIP are released in response to nutrients and amplify the B-cell response to glucose. They don’t stimulate insulin release directly but rather increase glucose dependent insulin decrease.
-plasma glucose is monitored for 3 hours after being give oral glucose, it should rise slightly. Then it is repeated but with no oral glucose.
-insulin response is greater when glucose enters circulation rather than the oral route. This shows hormones in the GI tract increases insulin release to glucose since insulin release is lower when the GI tract is bypassed.
explain mechanisms controlling B-cell insulin release
-GLP-1 R activates adenylate cyclase to increase cAMP production
-more pKA is activated and so causes an increase in intracellular calcium and amplifies insulin release from the secretory granules.
explain the drug treatment of T2DM
-Metformin: decreases gluconeogenesis
-Sulfonylureas: bind and close K-ATP channels, depolarize B cell releasing insulin.
-Thiazolidinediones: activate PPARy receptor which somehow reduces insulin resistance
-SGLT2 inhibitors; promote glucose excretion via kidney
-Incretin targeting drugs: potentiate insulin release in response to raising plasma glucose;
* DPP-4 inhibitors (prevent breakdown of natural incretins)
* synthetic GLP-1 analogues
discuss key points of T1DM and T2DM
-T1DM meant inevitable death from DKA until discovery of insulin
-normal glucaemic control is not achieved with insulin therapy
-T2DM probably begins with insulin resistance and may progress to full insulin dependence
-normal insulin/glucagon ratio depends on exquisitely complex control by nutrients modulated by endocrine, paracrine and neural effects
