HR Lesson 5: Endocrine Pancreas, structure, function and dysfunction

What type of hormone is insulin?

Peptide hormone

How is insulin produced?

protein synthesis as a large pro-hormone by pancreatic beta cells.

The insulin precursor is cleaved into what?

proinsulin

C-chains fold over proinsulin, causing A and B chains at the ends to form sulfite bridges. Once the C-chain is cut of, what is the result?

Insulin and C-peptide

Where are Insulin and C-peptides stored until release?

In the vesicle

What is the role of storing insulin and c-peptides in the vesicles?

Enables fast, and precise regulation of the BG levels

What is the half-life of Insulin?

A few minutes

What stimulates insulin and C-peptide secretion?

Exocytosis of insulin and C-peptides depends on beta cell glucose oxidation causing a Ca+ influx

Describe the process of insulin secretion?

• Increased BG

• Increases ATP

• Closes K_atp Channels

• K is retained intracellulary

• Depolarization opens Ca+

• Ca influx

• excytosis of granules

• releases of insulin and C-peptides

What is the main stimulus for insulin secretion?

Hyperglycemia

What is additional stimuli of insulin?

Elevated amino acids

GI hormones called Incretin

What are the inhibitors of insulin secretion?

Hypoglycemia

Epi/Norepinephrine

Where are the insulin-receptors located on the target cell?

Membrane-bound

What happens after insulin binds to the membrane bound receptor?

Tyrosine kinase becomes phosphorylated which activates several signaling pathways

What are the main insulin target tissues?

Muscles

fat

liver

What are GLUTs

Glucose transporters

What is the role of GLUTs?

Absorb glucose from circulation via facilitated diffusion.

How are GLUT-4s controlled?

Insulin

Where are the dominant GLUT located?

in striated muscles and fat cells

When does Glucose uptake into muscles and fat tissues occur in the presence of insulin?

hyperglycemia

What does glucose uptake into the muscles an fat cause?

a decrease in BG

Without insulin what happens to GLUT-4 and Muscles/fats?

GLUT-4s detach and are stored

Muscles and Fats have to utilize other energy sources

What are the insulins metabolic actions on Carbohydrates?

• increased GLUT-4

• increased ATP

• Increased Glycogenesis

• Decreased gluconeogenesis

What is insulins metabolic actions on lipids?

• Increased FFA uptake

• Increased lipogenesis from excess glucose

• Increase storage as triglycerides

• Decreased Lipolysis

What is insulins metabolic actions on proteins?

• increased amino acid uptake

• increase protein synthesis

• increased cell growth

• decreased proteolysis

What processes are inhibited by insulin?

Gluconoegenesis

lipolysis

proteolysis

What is the relationship between insulin and potassium?

Insulin moves potassium into cells

How does insulin move potassium into cells?

By stimulating the NA-K-ATPase

inhibiting K+ efflux

What can happen to K+ if there is an insulin deficiency/excess?

It can alter K+ homeostatsis

What is the function of C-peptides?

used as a marker for insulin secretion

What does C-peptides do in the body?

It increases blood flow/vasodilators

It facilitates neuron function

Where is glucagon synthesized?

In pancreatic Alpha-cells as a peptide hormone

The secretion of glucagon is mainly stimulated by what?

hypoglycemia

What inhibits the secretion of glucagon?

hyperglycemia and insulin increase

What is the target tissue for glucagon?

the liver

What is the function of glucagon?

Increases Blood Glucose

How does glucagon raise Blood glucose?

Glycogenolysis

Gluconeogenesis

How long does it take for glycogen stores to empty and gluconeogenesis to begin?

4-8hrs

What are the three modulators of the pancreatic endocrine secretions and food intake?

Somatostatin

Amylin

Pancreatic Polypeptide

Where is somatostatin secreted?

From delta cells

Where is amylin secreted?

Co-secreted with insulin

Where is pancreatic polypeptide secreted?

From PP cells

How do all three hormones effect food intake?

• induce satiety

• reduce gastric emptying

• reduce digestive enzyme secretion

How do all three hormones effect the GI tract?

They reduce and delay nutrient absorption

What is the function of Somatostatin?

It inhibits insulin and glucagon and many other endocrines including GH. It can also be used to suppress functional tumors.

What is the function of Amylin?

Reduced glucagon secretion, analogs can be used therapeutically

What is the function of PP?

Reduced insulin secretion, analogs can be used to reduce functional tumors.

What happens when there is excess amylin in the body?

Excess amylin can lean to pancreatic amyliodisis, this leads to the destruction of beta cells.

What is pancreatic amyloidosis?

protein-misfolding disease

What are endocrinopathies?

Hornone excess/hormone deficiency situations

What is the approach to clinical signs of endocrinopathies?

Normal function → dysfunction if hormones is produced in excess or is deficient and metabolic effects → deduction of clinical signs

What are the major pancreatic dysfunctions?

Insulin excess

Insulin deficiency

What is the effect of Insulin excess (insulinoma)?

Hypoglycemia

Hypokalemia

What is hypoglycemia?

Lack of ATP in glucose-dependent cells

What is hypokalemia?

Hyper polarizes membrane potentials which reduces nerve muscle excitability.

What are the drug targets for insulinoma?

Somatostatin: reduces secretion of insulin

Diazoxide: Opens ATP sensitive K channels which reduces insulin secretion

What is Diabetes Mellitus?

the absolute or relative lack of insulin, leading to metabolic disturbances of carbohydrates, fats, and protein metabolism

What happens during Type 1 Diabetes?

Beta cells become dysfunctional and fail to produce enough insulin causing an insulin

What can cause Type 1 diabetes?

Auto immine destruction

age related degeneration

pancreatic inflammation

What happens during type 2 diabetes?

Tissue develop insulin resistance

What is insulin resistance?

The insulin/insulin-receptor interaction becomes inefficient, insulin does not exert its effects fully.

What is the cause of Type 2 diabetes?

Obesity-related with fat metabolites interfering with insulin receptors.

What is the three stages of type 2 diabetes?

1. insuline resistance

2. prediabetic stage

3. diabetes type 2 stage

What happens during the first stage of type 2 diabetes?

Beta cells produce more insulin as compensation for receptor inefficiency causing insulin increase.

What happens during the second stage of type 2 diabetes?

Metabolic stress on beta cells leads to progressive beta cell exhaustion causing the insulin levels to decline and BG to increase.

How does the metabolic challenges of stage 2 type 2 diabetes effect the body?

Causes subtle changes in nerves and blood vessels without causing overt clinical signs. beta cells exhaustion is mostly reversible.

What happens during the third stage of diabetes?

Exhaustion progresses to beta cell dysfunction (unrecoverable)

Insulin is low to absent, diabetic blood glucose levels with overt clinical signs.