#13340 - Endocrine Pancreas - Organisation of the Body

Endocrine pancreas

Development

-pancreas develops from the endoderm of pancreatic buds- embryonic epithelium of pancreatic ducts contain both potential exocrine and endocrine cells. In development endocrine cells migrate from duct system and aggregated around capillaries to form Islets of langerhans- scattered throughout exocrine tissue

has two types of glands: exocrine glands (secrete digestive enzymes into small intestine) and endocrine glands (islets of langerhans)

-islets contain 4 types of secretory cells (alpha, beta, sigma, F Light microscopy: each islet has 3000 secretory cells surrounded by fine collagenous network which has numerous fenestrated capillaries. A capsule surrounds each islet. Endocrine cells are small, pale stained, granular cytoplasm

-immunoperoxidase technique: identify different secretory cells based on their specific products

-B cells – 60% of cells in the islets, make up the central region, secrete insulin, proinsulin, C peptide

-alpha cells- 15% , found in the peripheral area, secrete glucagon

-sigma cells – 10% , scattered, secrete somatostain

-F cells -15% , found in the ventral region, secrete pancreatic polypeptide

Innervation

-level of islet secretion occurs through innervations from both sympathetic and parasympathetic divisions of the ANS

-Parasympathetic innervations via the ‘vagus nerve’ increases insulin secretion

-sympathetic innervations-can be stimulatory/inhibitory depending on wheter B adrenergic (stimulatory) or a-adrenergic (inhibitory)

Blood supply of the pancreas

-Rich blood supply- shown in specimens stained with red dye before fixation- each islet is supplied by three arterioles which ramify into a network of highly fenestrated capillaries

-Supply from branches of superior mesenteric and celiac arteries

-pancreatic veins drain into the hepatic portal vein- the liver is directly below the pancreas

Insulin

Function: replenish fuel reserves in muscle, liver, adipose tissue

-during fasting B cells secrete less insulin- insulin decreases lipids are mobilised from adipose tissue, amino acids are mobilised from body proteins

-during feeding: insulin secretion increases-this decreases mobilisation of glycogen, triglycerides and stimulates uptake of carbohydrate, lipid and amino acid uptake by insulin sensitive target tissues

-insulin maintains the concentration of glucose in the plasma within narrow limits, allows the brain to have a constant supply of glucose very important for its function as it relies on glucose as its main energy supply

Synthesis of insulin

-protein: made in the B cells of the islets of langerhans and expression of the gene forms preproinsulin

-the preproinsulin enters the rough endoplasmic reticulum where that starting sequence of 24 amino acids is cleaved to form proinsulin (has A,B,C domains)

-the trans-golgi packages the proinsulin and creates secretory granules. Proteases cleave the proinsulin at two spots and forms the C peptide, A and B chains

-the A and B chains are linked by two disulfide linkages and forms mature insulin. 21 amino acids on the A chain and 30 amino acids on the B chain.

-the secretory vesicle contains, proinsluin, insulin, C peptide – all three are released into the portal blood when glucose stimulates the B cell.

-C peptide has no biological action- but released in 1:1 ratio with insulin- concentration measured in urine determines the concentration of insulin in the blood

-proinsulin has some action, has 1/20^th the potency as insulin

-60% secreted is insulin

Control of insulin release

a) increase in plasma glucose increases insulin secretion

-glucose enters the B cell through GLUT2 glucose transporter by facilitated diffusion- GLUT-2 transporters have a very high Km, low affinity to glucose, so uptake is propotional to glucose concentrations, amino acids enter through a different set of transporters

-in the presence of glucokinase, the entering glucose undergoes glycolysis and raises (ATP)i . Amino acids enter the citric acid cycle and produces an increase in ATP. The NADH/NAD+ ratio also increases

-elevated NADH/NAD+ and ATP/ADP ratio causes K_ATP channels to close

-reducing the conductance of potassium causes the B cell to depolarise and this activates voltage gated calcium channels to open

-the influx of calcium ions leads to the exocytosis of the secretory granules containing peptide insulin

b) nervous inputs

-increased parasympathetic input increases secretion of insulin

-increased sympathetic activity, via the alpha adrenergic receptors decreases secretion of insulin

c) somatostatin

-secretion from sigma cells from the islets of langerhans releases somatostatin and this inhibits insulin release by inhibiting adenylate cyclase

-less cAMP

d) Blood borne

-uptake of amino acids into B cells increases insulin release

-gastrointestinal hormones: Glucagon like peptide , glucose dependent insulinotrophic peptide, secreted by the small intestine in response to rise in blood glucose concentrations- increases insulin release by sensitising B cells to glucose

Insulin receptors

-once insulin is released into portal blood it travels to the liver- more than 50% attaches here

-the insulin that escapes stimulates insulin sensitive processes in other tissues

-insulin binds to specific receptor tyrosine kinase on plasma membrane and this leads to the autophosphorylation of the receptor

-in muscle cells the phosphorylation of the receptor leads to more GLUT-4 receptors on the surface of the membrane

Actions of insulin

• Main action is promotes widespread anabolism and lowers plasma levels of glucose (normal fasting levels 4-5mM, 8mM after a meal)

• Increases transport of glucose and amino acids into cells

• Increases protein synthesis and inhibits proteolysis

Liver

-decreases the rate of breakdown of glycogen and promotes the formation of glycogen from blood glucose through activation of glucokinase and through dephosphorylation activation of glycogen synthase but inhibition of glycogen phosphorylase

-insulin also inhibits glucose-6-phosphatase that converts glucose-6-P into glucose

-Lipogenesis: insulin promotes the storage of fats and inhibits oxidation of fatty acids, insulin dephosphorylates acetyl coA carboxylase and activates the enzyme- increased amount of malonyl coA- this allosterically inhibits carnitine acyltransferase 1 and inhibits fatty acid oxidation. Insulin also dephosphorylates fatty acyl synthase and activates it so increased fatty acid synthesis

-insulin stimulates synthesis of proteins

Muscle

-major insulin sensitive tissue

-GLUT4-insulin sensitive transporter, presence of insulin increases recruitment of GLUT4 transporters to the cell membrane and increases the Vmax- greater uptake of glucose into muscle tissue

-insulin activates hexokinase and glycogen synthase and increases the formation of glycogen

-stimulates the synthesis of proteins and prevents the break down

Adipocytes

-increase glucose uptake through increase in GLUT4 transporters

-insulin promotes the break down of glucose to metabolites that are used to synthesise fatty acids- little glucose stored as glycogen

-promotes the formation of triglycerides

Diabetes mellitus

Diagnosis: glucose tolerance test, oral glucose load (75g) is given after 10-16 hour fast and the concentration of glucose in the blood and urine is determined at 30 minute intervals for the next 2 hours

-if blood glucose remains elevated after two hours > 10mM –signifies diabetes mellitus

Type 1 diabetes

-autoimmune disorder leads to the breakdown of B cells of the islets of langerhans

-symptoms:

• thirst/polyuria/dehydration- due to failure of glucose to be absorbed and leads to presence of some glucose in the collecting duct and water osmoses into the duct.

• weight loss

• ketosis- continous mobilisation of fatty acids into the...