Insulin And Glucogan Flashcards
What is the function of insulin and glucogan?
Insulin and glucagon are hormones which respond to blood glucose. They are horns with a short half life in blood 4-6 second
-they allow fast response to changes in blood glucose levels and prevent in healthy individuals hypo-glycemia or hyper-glycemia
Describe the beta cells of the islets
70% beta cells of islets
-release insulin which lowers the blood glucose level and stimulates synthesis of glycogen in liver and muscle and stimulates in general protein synthesis
High blood glucose level favors synthesis of fatty acids and cholesterol in the liver
Describe the alpha cells of islets
20% of islets
Release glucagon which increases the blood glucose level by glycogen degradation in liver and by gluconeogenesis in liver and renal cortex cells
Glucagon receptors are mainly found in liver and kidney
Explain the stimulation of insulin secretion
- The primary stimulus of insulin secretion is the blood rise of glucise
- Enhancement of glucose-induced insulin release by amino acids and gut hormones
Amino acids: arginine, leucine and glutamine
Gut hormones: Glucagon-like peptide-1(GLP-1) and gastric-inhibitory polypeptide (GIP) are called in regions as they enhance the insulin release.
Inhibition of insulin release: in cases of physiological stress epinephrine inhibits directly they release of insulin
How does the high blood glucose lead to insulin release?
- Blood glucise levels greater than 5mM generate a high level of ATP which leads to the closing of ATP-sensitive K+ channels
- B-cells take up glucose(GLUT-2) and Glucokinase forms glucose 6-P which is used in oxidative metabolism for ATP formation
- Membrane depolarization results in calcium influx via a voltage-gated calcium channel
- High levels of Intracellular calcium trigger release of the stored granules containing mainly insulin and C-peptide (ratio 1:1)
How do beta cells play a role in the synthesis and release of insulin ?
- Genes coding for insulin are transcribed to mRNA in the nucleus
- After moving into the cytoplasm, translation of the mRNA is initiated in cytosolic ribosomes, with formation of an N-terminal hydrophobic signal sequence that aids in the transport of the mRNA and ribosomes to the RER
- The N-terminal signal sequence penetratesthe membrane of the RER. Further elongation directs the polypeotide chain into the lumen of the RER, resulting in the formation of preproinsulin
- The signal sequence is cleaved and proinsulin is formed in the lumen(cisternal space)
- Proinsulin is transported from RER to the Golgi complex, where it is cleaved forming insulin and C-peptide
- Insulin and C-peptide in secretory granules
- Secretory granules are secreted by exocytosis, releasing insulin and C-peptide
Describe insulin structure
Insulin has 2 peptide chains A and B that are linked together by 2 disulfide bonds
Insulin has totally three disulfide bonds
Two disulfide bonds connect Chain A and Chain B. One disulfide bond is an inter chain bond in chain A
The C-peptide enables correct disulfide bond formations
Endogenous insulin synthesis leads to increased blood levels of:
- Insulin (high)
- C-peptide (high)
- Pro-insulin (small measurable amount)
C-peptide has a longer half-life (30 mins) than insulin( 5 min) and is measured in a C-peptide test which represents endogenous insulin synthesis
What does insulin forms in blood?
Insulin forms in the blood first dimers and then hexamers with zinc in the center.
The hexamer separates into the single insulin monomers before binding to the insulin receptor
Describe the insulin receptor - location , structure
The insulin receptor is found in the plasma membranes of many cells
It contains alpha and beta subunits bound together by disulfide bonds
Alpha chains: binding domain of insulin outside
Beta chains: tyrosine kinase domain inside the cell
How does insulin react to insulin-receptors?
- Binding of insulin to the alpha-chains activates the tyrosine kinase activity of the B-chains
- Auto phosphorylation on a critical tyrosine residue
- Phosphorylations of tyrosine residue of target proteins
What are the functions of insulin and glucagon inn homeostasis?
- They regulate fuel storage and mobilization
- their blood levels are continuously fluctuating
- Their plasma half-lives is in the range of minutes
- They are both released and stimulated by arginine to assure that both hormones are present in blood
It is the ratio of serum insulin-to-glucagon that determines a metabolic change
Describe the structure of glucagon
Peptide hormone with 29 amino acids in a single polypeptide chain
Summarize glucagon formation
Pro glucagon is first formed and this large protein precursor is tissue specifically modified
- In alpha cells of pancreas proglucagon is converted mainly to glucagon by selective proteolytic cleavages in the secretory granules
Explain the stimulation of glucagon secretion
- The primary stimulus is the decrease in blood glucose
- Alanine and arginine enhance glucagon secretion
- Epinephrine stimulates glucagon release as it signals physiologic stress. This overrides the effects of circulating substrates
How can glucagon secretion be inhibited?
Inhibition of glucagon secretion by:
- Elevated blood glucose level
- Insulin
Where are glucagon receptors found?
Found in hepatocytes and renal cortex cells
How does glucagon interact with glucogan receptors?
- glucogan binds to high-affinity G protein-coupled receptors(GCPR) and acts via the cAMP-messenger system
- Glucagon activates glycogen degradation and gluconeogenesis I in liver at the same time. It activates gluconeogenesis in the kidney
What are the Normal blood glucose levels?
-fasting: 70-110 mg/dL(3.8 - 6.1 mmol/L)
2 hrs postrprandial:less than 120 mg/dL (<6.6 mmol/L)
What is hypoglycemia?
Blood glucose level below 55 mg/dL (< 3.0 mmol/L ) with adrenergic or neuroglycopenia symptoms
What is the special role of glucose metabolism ?
Many cells depend on glucose for their metabolism (RBC, brain, retina as example)
- Insulin and glucagon are the main hormonal regulators of blood glucose levels and the release of insulin or glucagon responds directly to glucose molecules in the blood.
- Glucagon, epinephrine, cortisol and growth hormone are often grouped as insulin counter regulatory hormones and are released to prevent low blood glucose levels
Explain the response to low blood glucose levels
1. Less than 70 mg/dL:
Increased release of:
Epinephrine
Glucagon
Growth hormone
Cortisol
- Less than 55 mg/dL
Begin of adrenergic and neuroglycopenia
- Transient hypoglycemia can lead to cerebral dysfunction
- Severe prolonged hypoglycemican cause coma and death
What are adrenergic symptoms?
Adrenergic symptoms usually occcur when the blood glucose level falls abruptly and epinephrine release is stimulated.
Symptoms: anxiety, palpitation, tremors, sweating
What are Neuroglycopenia symptoms?
Neuroglycopenia symptoms usually occur from a gradual decline in blood glucose often below 40 mg/dL. The slow decline deprives the brain of glucose but fails to trigger the epinephrine response
Symptoms: headache, confusion, slurred speech, and coma which can lead to death in prolonged hypoglycemia
Low blood glucose leads to release of insulin counterregulatory hormones. Explain this
These hormones are released by two overlapping glucose-regulatory
- Glucagon is directly release by alpha-cells
- Hypothalamic glucose receptors can trigger:
2a. The release of ACTH and growth hormones from the anterior pituitary gland. ACTH stimulates cortisol release which leads to epinephrine secretion from the medulla
2b. The secretion of Catecholamines using the sympathetic autonomic nervous system
How can hypoglycemia be treated?
Hypoglycemia is an acute danger
Conscious patient: Oral consumption of glucose
Unconscious patient: injection of glucagon or epinephrine to activate hepatic glycogen degradation and release of glucose into the blood
What can lead to hypoglycemia?
- Due to insulinoma
- Very high abnormal levels of insulin
- Deficient gluconeogenesis
Explain hypoglycemia due to insulinoma
Insulinoma is a tumor of the pancreatic islet cells that releases insulin
- severe hypoglycemia may result in patients with an insulinoma due to excessive uptake of blood glucose into skeletal muscle and fat cells by GLUT 4
- abnormal high level of serum insulin blocks the action of the insulin counterregulatory hormones
- The blood contains high levels of insulin and C-peptide and elevated amounts of proinsulin
Explain how very high levels of insulin may lead to hypoglycemia
a. Insulin rejection can cause hypoglycemia which is frequently found in diabetic patients
b. Reactive postprandial hypoglycemia is transient and can occur after a carbohydrate rich meal
How can a deficiency of gluconeogenesis lead to hypoglycemia?
a. Hereditary diseases can cause hypoglycemia which needs specific treatment. Often onset in childhood
b. High alcohol intake can cause hypoglycemia due to abnormal high NADH/NAD+ ratio from ethanol metabolism
