Control of Blood Glucose and the Endocrine Pancreas Flashcards
RECAP: how does glucose get into cells (details of transporters)?
It can do so by utilising SGLT or GLUT transporters.
SGLTs are sodium-glucose cotransporters. They rely on secondary active transport.
SGLT1: glucose absorption in the gut
SGLT1, SGLT2: glucose reabsorption from the kidney (PCT, proximal convoluted tubule)
GLUTs are a family of glucose transporters.
GLUT1 (brain, erythrocytes) - high affinity for glucose: constant uptake of glucose at 2-6 mM.
GLUT2 (liver, kidney, pancreas, gut) - low affinity for glucose: glucose equilibrates across the membrane, so this is the glucose-dependent release of insulin in the pancreas
GLUT3 (brain) - high affinity
GLUT4 (muscle and adipose tissue) - medium affinity: insulin recruits transporters, so this is the insulin-dependent uptake of glucose into cells
Where are the hormones of the pancreas made?
They are made in ‘Islets of Langerhans’; these are clusters of endocrine cells surrounded by exocrine pancreas cells.
Examples of such cells would be:
- α-cells (A cells): produce glucagon
- β-cells (B cells): produce insulin
- δ-cells: produce somatostatin (GHIH)
RECAP: how do we get mature insulin from the precursor?
Mature insulin is formed from its large precursor preproinsulin by proteolytic processing.
Removal of a 23 amino acid segment (signal sequence) at the amino acid terminus of preproinsulin and the formation of 3 disulphide bonds produces proinsulin.
Further proteolytic cuts remove the C peptide from proinsulin to produce mature insulin, composed of A and B chains.
Describe the release of insulin into the circulation.
The pancreas is supplied by branches of the coeliac trunk, the superior mesenteric artery and the splenic arteries.
The venous drainage of the pancreas is into the portal system.
This means that half of the secreted insulin is metabolised by the liver in its first pass, while the remainder is diluted into the peripheral circulation.
Testing for the C-peptide is a more accurate index of insulin secretion in the peripheral circulation (as it is not metabolised by the liver).
[one mole of C-peptide is secreted for each mole of insulin]
List some factors regulating insulin secretion (ie. affecting B-cells).
- plasma glucose (+), affected by incretin hormones (+)
- amino acids (+)
- glucagon (+)
- alpha adrenergic (+)
- parasympathetic (+)
- somatostatin (-)
List some factors regulating glucagon secretion (ie. affecting A-cells).
- amino acids (+)
- beta adrenergic (+)
- parasympathetic (+)
- insulin (-)
- plasma glucose (-)
- somatostatin (-)
How do β-cells sense a rise in glucose?
They do not have any glucose receptors.
The GLUT2 can be thought of as a sensor; glucose is brought into the cell via the GLUT2 transporter. The glucose is then metabolised to G6P, which in turn generates ATP.
This ATP stimulates an ATP-sensitive K+ channel, so K+ efflux is stopped. This causes cell depolarisation, which activates VGCCs. These bring in Ca2+, which is the final signal for vesicle mobilisation (the vesicles contain insulin).
Describe the insulin receptor action pathway.
The insulin receptor is part of the tyrosine kinase superfamily.
Insulin binds to its receptor, which, in turn, starts many protein activation cascades. These include:
- translocation of GLUT4 transporters to the plasma membrane and influx of glucose
- glycogen synthesis
- glycolysis
- fatty acid synthesis
The insulin binding to its receptor:
- activates a cascade of protein phosphorylation, which stimulates or inhibits specific metabolic enzymes by modulating enzyme phosphorylation
- modulates the activity of metabolic enzymes by regulating gene transcription
Describe the glucagon receptor action pathway.
Glucagon binds to its receptor, activating an αGs subunit. This stimulates Adenylate Cyclase, which generates more cAMP, which activates more PKA, which goes on to phosphorylate many other substances.
How do insulin and glucagon act together?
They are counter-regulatory hormones that act principally (not exclusively) through the activity of PKA, which phosphorylates key enzymes in metabolic pathways.
Insulin action leads to dephosphorylation of these same enzymes.
Describe diabetes mellitus.
There are two types:
- TYPE 1 - where there is an absolute insulin deficiency (due to the destruction of insulin-producing pancreatic β-cells)
- TYPE 2 - where there is a variable combination of insulin resistance and insulin deficiency
How do we diagnose diabetes mellitus?
Hyperglycaemia is central to diabetes mellitus diagnosis.
Random plasma glucose would be ≥11.1 mmol/L
Fasting plasma glucose would be ≥7.0 mmol/L
Oral glucose tolerance test (OGT) would be ≥11.1 mmol/L
How does insulin affect plasma glucose?
Plasma glucose is kept within constant limits by insulin and glucagon, despite periodic intakes of sugar and bursts of exercise, requiring fuels.
Insulin is released in response to high plasma glucose, acting to lower it to within a suitable range.
What is the importance of glycaemic control, and what would be a good indicator of glycaemic control?
Controlling glucose levels reduces macro- (increased risk of CVD and stroke, etc.) and microvascular (damage to capillary beds in retina, kidney, etc.) complications.
Glycosylated haemoglobin (A1C) levels are a good indicator of glycaemic control. Less than 6.5% is good, and, with every 1% fall in A1C, there is a 20-30% relative risk reduction in microvascular complications.
However, glycaemic control is hard, as you will never be able to achieve fine physiological control with just peripheral injections of insulin (as it can be lethal, sending the patient into hypoglycaemic shock).
Describe the role of incretin hormones in glucose homeostasis.
Examples of incretin hormones are GLP-1 and GIP. Both of these are released by gut endocrine cells in response to nutrients in the gut.
They circulate in the bloodstream till they reach the pancreas, where they potentiate (increase) the production of insulin from β-cells, thus decreasing blood glucose.
There are multiple mechanisms of insulin release from β-cells. With GLP-1, it activates adenylate cyclases, which increases cAMP, which increases PKA, which is involved in the release of insulin-rich secretory granules.
