Regulation of glucose

What are the 3 main secretory cells of the endocrine pancreas tissue and what do they secrete? What do they make up?

• β (65%)  insulin

• α (20%) - glucagon

• δ (10%) somatostatin

islets of Langerhans

How much of islets of Langerhans does each type of cell take up?

beta 65%, alpha 20%, delta 10%, endocrine tissue 1-2% other cells scattered

Are the islets of Langerhans perfused with blood? How does this compare to the myocardium?

richly, 5x that of the myocardium

Which other cells are scattered in the islets of Langerhans?

F cells (also called gamma or PP), epsilon cells, enterochromaffin cells - near but not in

What surrounds the endocrine pancreas?

Exocrine pancreas made up of acinar cells and duct cells

What are the 4 secretions of beta cells in the islets of Langerhans?

insulin

proinsulin

C peptide

amylin (IAPP)

What type of molecule is insulin?

peptide hormone

What does the combination of C-peptide and insulin result in?

proinsulin

What type of innervations allow humoral control of the islets of Langerhans?

small arteries via fenestrated capillaries forming a glomerule like structure

Does venous blood from one cell interact with other cells within the islets of Langerhans? What does this mean as to what type of communication allows the function of this system?

venous blood of one cell type bathes the others

autocrine, paracrine as well as endocrine comm.

What’s the function of somatostatin? Which cells release it?

inhibits the secretion of both insulin (from beta cells) and glucagon (from alpha cells)

Delta cells

What allows communication between cells within the islets of Langerhans?

• gap junctions between beta and alpha cells

• delta cells (somatostatin) send dendrite-like processes to beta cells

• venous blood from one cell bathes all the other

• glomerule with exchanges of arterial and venal blood allowed through fenestrated capillaries

What type of neural control regulates the glucose regulating system?

SNS - adrenergic fibres (NE) = + of alpha cells = more glucose for energy needs

PNS - cholinergic fibres (ACh) = + beta cells = less glucose in blood, more stored = digest

Peptidergic neurones

Overall, how is insulin secretion stimulated, via hormones, neural networks, glucose levels and drugs?

everything regulates via islet beta cell receptors

• GIP (K cells of SI), Amylin (β cells)

• PNS (vagus – ACh) - ↑ release, G protein coupled beta adrenergic receptors

• high blood glucose

• Sulphonylureas acting on K_ATP channels

Overall, how is insulin secretion inhibited, via hormones, neural networks, glucose levels and drugs?

• somatostatin from delta cells

• SNS prevents hypoglycaemia - α-adrenergic fibres

• low glucose levels

• Alpha-2 adrenergic agonists, somatostatin analogues

What do the 3 pathways of insulin release require to start the process? What do they activate?

• glucose + ATP = K ATPase = Ca2+ = phosphorylation of insulin storing vesicles = release

• norepinephrine/epinephrine/agonist/glucagon + ATP = increased adenyl cyclase = increased cAMP = PKA activity = phosphorylation of vesicles = insulin release

• ACh = IP3 = PKC = phosphorylation of vesicles = insulin release

What types of receptors are involved in the three pathways of insulin secertion?

• GLUT2

• CCK ACh G protein coupled q receptor

• G alpha stimulatory protein coupled receptor for glucagon/NE/adrenaline

• G alpha inhibitory protein coupled receptor for somatostatin

What do all of the pathways of insulin secretion have in common?

All allow exocytosis of insulin through phosphorylation of insulin vesicles

What is the structure of the insulin receptor? What type of protein is it closely linked to? What type of cascade does it initiate?

• heterotetramer - 2 alpha subunits, 2 beta subunits

• I.C.  tyrosine kinase

• phosphorylation events

What types of phosphorylating substrates are released after activation of insulin receptor? What types of downstream effects does this cause?

• PKC, phosphatases, phospholipases, G proteins

• cell growth, proliferation, gene expression etc

What would trigger downregulation of insulin receptor complexes? How does this occur?

high insulin levels

autophosphorylation = complex internalised = fewer receptors for insulin to bind to

How does insulin act to regulate blood glucose?

• insulin binds to receptor

• signal transduction cascade

• exocytosis of GLUT 4, inserted into muscle and liver cell membranes

• Glucose enters cell

What effect does insulin have on blood glucose concentration?

decreased

What effect does insulin have on liver/muscle cells glucose concentration?

increased

Which cells in the body are insulin target cells? Which are the 3 main types?

all body cells bc all need energy

muscle, liver, adipose

Under which form is glucose initially stored in the body? What happens to excess glucose, once glyocgen stores are replenished?

glycogen (glycogenesis)

stored as fat (lipogenesis)

What actions does insulin have on the liver ?

• Promotes formation of glycogen from glucose (glycogenesis)

• Inhibits glycogenolysis

• Inhibits gluconeogenesis

Which enzymes are activated by insulin in the liver? What does this inhibit?

• glycogen synthase and glucokinase hexokinase

• glycogen being made into glucose

What action does insulin have on muscle cells?

1. Promotes glucose uptake (↑ GLUT4 transporters to plasma membrane)

2. Promotes glycogen synthesis from glucose 

3. Promotes glycolysis and carbohydrate oxidation (little or no gluconeogenesis in muscle)

4. Promotes proteins synthesis (anabolic) and inhibits protein breakdown, ↓ blood amino acid concentration by ↑ uptake

What action does insulin have on adipocytes?

• ↑ GLUT4 transporters expression – rapid glucose uptake

• Glucose converted into FA – stored as triglycerides

• ↑ Lipoprotein lipase - liberates FA for triglyceride synthesis

• Insulin inhibits mobilisation and oxidation of fat stores (lipolysis)

• Therefore decreases circulating levels of FA and keto acids

Broadly, how does insulin affect potassium uptake and the hypothalamus?

• potassium uptake promoted through increased Na+/K+ ATPase activity

• Direct effect on hypothalamic satiety centre (feeling full)

What are the 2 types of diabetes caused by insulin issues and the broader term for them?

• type 1: insulin dependent/pancreatic islet destruction

• type 2: non insulin dependent / obesity linked

diabetes mellitus

Define diabetes mellitus

high blood sugar over prolonged periods

What causes type 1 diabetes mellitus? How is hyperglycaemia caused? How does this impact blood fatty acid levels?

autoimmune response that destroys beta cells = inadequate secretion of insulin

decreased glucose uptake into cells = more in blood

increased

What issues arise within the body due to type 1 diabetes ?

• Increased blood fatty acid + [ketoacid] → ↑ lipolysis

• ↑ blood [amino acid] 

• Osmotic diuresis/ Polyuria, excess glucose pulls water to be excreted with it

• Hypotension bc loss of water

• K⁺ movement out of cells ‘hyperkalaemia’ (insulin no longer taking up)

What symptom is typical of type 1 diabetes mellitus ?

fruity smell on the breath diabetic ketoacidosis (DKA), happens when fat is burnt for energy instead of glucose = release of acetone in breath = fruity smell

Which symptonms are common to type 1 and 2 diabetes mellitus?

• increased thirst and hunger

• increased weight loss, urination

• increased fatigue, blurry vision

What symptom is specific to type 2 diabetes mellitus?

headaches

What is a treatment for diabetes type 1?

insulin replacement therapy

How are insulin receptors affected by type 2 DM?

Down regulation of insulin receptors in target tissue + insulin resistant

Which type of DM associates with obesity?

2

What are 2 cures for type 2 DM?

sleeve gastrectomy and gastric bypass

What are 3 treatments for type 2 DM?

• Sulphonyurea drugs (e.g. tolbutamide) stimulate insulin secretion

• Biguanide drugs (e.g. metformin) upregulate receptors on target tissues

• Calorie restriction/weight reduction

On insulin receptors, where is the glycosylation site found? And the tyrosine kinase domain/the phosphorylation site?

• alpha subunit in cytoplasm

• beta subunit in cytoplasm of beta cell

What would elevated blood glucose postprandial (after eating) with normal levels of insulin after fasting indicate?

blood glucose not being regulated but insulin levels are normal so the issue is the receptors, ie type 2 DM

What type of molecular compound is glucose?

simple sugar/nutrient