Lecture 13 Flashcards
Where is the pancreas found?
Behind the stomach
- overlays aorta and portal vein
- fits into a curve of the duodenum
What is the shape of the pancreas?
‘Fish like’
Head > Body > Tail
What are the regions of the GI tract?
Foregut: Supplied by blood from coeliac trunk- branch off aorta (closest to head)
Midgut: Supplied by blood from the SMA- Superior mesenteric artery (middle)
Hindgut: Supplied by blood from IMA- Inferior mesenteric artery (end)
Where does the pancreas originate from?
Outgrowth of the foregut
-supplied by coeliac trunk
What are the 2 functions of the pancreas?
- produces digestive enzymes secreted directly into duodenum/alkaline secretion into duodenum (exocrine secretion)
- hormone production from islets of langerhans (endocrine action)
What is the ratio of endocrine to exocrine tissue in the pancreas?
1% endocrine
99% exocrine
What is exocrine tissue near to?
Blood supply
What are some polypeptide hormones secreted by the pancreas and where are they made?
- insulin (beta cells)
- glucagon (alpha cells)
- somatostatin (delta cells)
- pancreatic polypeptide (PP cells)
- ghrelin (epsilon cells)
- gastrin (G cells)
- vasoactive intestinal peptide (VIP cells)
What is the overall role of insulin and glucagon?
Regulation of metabolism of carbohydrates, proteins, and fats
What is the distribution of cells in human islet?
Heterogenous
What happens if plasma glucose goes too high/low?
Osmotic effect- causes shrinking of cells (high)
Run out of energy (low)
Why does glucose need to be regulated?
Because if not there would be pulsatile additions of glucose to plasma
-don’t want it to spike up and down
What is the function of insulin and glucagon specifically?
Insulin- lowers blood glucose levels (stimulated by high plasma glucose, causes cells to remove glucose from plasma and store it)
Glucagon- raises blood glucose levels (stimulated by low plasma glucose, causes cells to break down stores into glucose and release those stores)
What are the similarities between insulin and glucose?
Insulin
-signalled by feeding
-target tissues are liver, adipose tissue, skeletal muscle
-remove glucose from plasma and storing it (to make carbohydrates, lipids, proteins = ANABOLIC)
Glucagon
-signalled by fasting
-target tissues are liver and adipose tissue
-break down carbohydrates/lipids (CATABOLIC)
What area of the body uses up glucose most quickly?
Brain
- as it relies on blood
- sensitive to rise/fall in glucose, don’t want cells in brain to shrink due to high osmolality
What is the normal plasma glucose level before and after a meal?
3.3-6 mmol/L
After a meal 7-8 mmol/L
What is the renal threshold?
Point at which tissues in the kidney can’t deal with amount of glucose in the plasma.
Too much glucose to reabsorb (normally kidneys reabsorb all of glucose)
= glucose appears in urine
10 mmol/L
What is glycosuria?
Excretion of glucose in the urine.
When does glycosuria occur in a healthy individual?
During pregnancy
-the renal threshold is lowered
What happens to the renal threshold in elderly?
Increases
What are some properties of insulin/glucagon?
- water soluble (dissolved in plasma-no special transport proteins)
- short half lives (5 mins from release to destruction)
- interact with cell surface receptors in target cells
- destroy insulin/glucagon by making an internalised/inactivated receptor
What is gluconeogenesis?
Constructing glucose from smaller units
What does insulin have effects on?
Carbohydrate/protein/lipid metabolism
What do islets of langerhans look like?
Spherical structures scattered through the exocrine tissue
How do cells in the islets of langerhans store their hormones?
Intracellularly in membrane-limited vesicles: storage granules
What do Beta/alpha cells have as a structural adaptation?
Extensive RER Well defined Golgi apparatus Many mitochondria Well defined system of microtubules and microfilaments (Synthesis of proteins)
What is the structure of insulin?
2 unbranched polypeptide chains linked covalently by 3 disulphides bridges
How is insulin synthesised?
- pre-proinsulin (singe chain polypeptide) synthesised on ribosomes of RER
- ‘pre’ part is the signal peptide ensuring the protein enters cisternal space of RER
- signal peptide is removed once it enters the RER
- remaining proinsulin folds to ensure correct alignments of cysteine residues so the correct disulphide bonds form
- proinsulin is transported to trans-Golgi apparatus and packed into storage vesicles
- proteolysis removes C-peptide from near middle of chain
- breaking the chain into 2 chains held together by disulphide bonds
- storage vesicles contain both insulin and C-peptide in equimolar amounts
- entire contents of the vesicle are released during secretion
How do you monitor endogenous insulin secretion?
Level of C-peptide in the blood (as it is released with insulin in equimolar amounts)
What type of receptor is the insulin receptor?
Tyrosine kinase receptor
What are the major actions of insulin on carbohydrate/lipid/amino acid metabolism?
- increases glucose transport into adipose tissue and skeletal muscle via GLUT4 channels
- increases glycogenesis and decreases glycogenolysis in liver and muscle
- decrease gluconeogenesis in liver
- in muscles increases uptake of AA’s, promoting protein synthesis
- in liver it inhibits breakdown of AA’s
- in adipose tissue it increases storage of triglycerides
- inhibits breakdown of fatty acids
What is the action of insulin?
Hormone of energy storage
- anabolic
- anti-gluconeogenic
- anti-lipolytic
- anti-ketogenic
What are KATP channels?
ATP sensitive K+ channel senses metabolic changes in pancreatic beta cells.
- glucose closes KATP channels
- when KATP channels open, beta cells hyperpolarise (K+ leaves) and insulin secretion is suppressed
When do KATP channels open?
- metabolism is low (low ATP, high ADP)
- no insulin secreted
- calcium channels closed
When do KATP channels close?
- metabolism is high (high ATP, low ADP)
- insulin secreted
- calcium channels open so moves into beta cell causing exocytosis of vesicles containing insulin
What is the structure of an insulin receptor?
Dimer: 2 identical subunits spanning the membrane
- each subunit made from and alpha and a beta chain connected by a disulphide bond
- alpha chain: exterior
- beta chain: interior and spans membrane
Give a brief overview of the uptake and metabolism of insulin:
- insulin binds to insulin receptor
- glucose floods in through GLUT4 transporter
- glucose either converted to glycogen, or broken down into pyruvate
- pyruvate goes on to make fatty acids via acetyl coA
What does glucagon act to do?
Oppose insulin
- raise blood glucose levels (mobilises energy release)
- glycogenolytic
- gluconeogenic
- lipolytic
- ketogenic
How is glucagon synthesised and secreted?
- synthesized in RER transported to golgi
- packaged in granules
- secreted by alpha cells due to low glucose levels
- mainly effects the liver (glycogen stored)
- granules move to surface via margination and released by exocytosis
What is margination and exocytosis?
Margination: movement of storage vesicles to cell surface
Exocytosis: fusion of vesicle membrane with plasma membrane releasing its contents
What is the structure of glucagon?
No disulphide bridges so is flexible
How is glucagon synthesised?
- large precursor molecule (pre-proglucagon)
- post translational processing to produce active molecule
What are the effects of glucagon?
Glycogenolysis: liver increases glycogen breakdown
Gluconeogenesis: stimulates synthesis of glucose from AA’s
Stimulates lipolysis: increases plasma fatty acid
=rise in plasma glucose levels
When is glucose used in emergency medicine?
When a person with diabetes is experiencing hypoglycaemia and cannot take sugar orally
What is it called when there are abnormal insulin levels and how does high/low levels of glucagon affect it?
Hypoglycaemia: high insulin levels
-low levels of glucagon can contribute to hypoglycaemia
Hyperglycaemia: low insulin levels (diabetes mellitus)
-high levels of glucagon makes diabetes worse
What happens to KATP channels in diabetes?
They become ATP insensitive
How does glucagon act upon its receptor?
- binds to specific receptor on membrane
- receptor is GPCR
- binding activates adenylate cyclase, increasing cAMP, activating PKA, which phosphorylates many enzymes
