DM Endocrine Pharmacology - Leid Flashcards
What is the preferred energy source for the body?
Carbohydrates
What are the end products of carbohydrate digestion?
Monosaccharides
What are the three most common monosaccharides?
Glucose
Fructose
Galactose
All three are C6H12O6
Which monosaccharide is the one that others are broken down into?
Galactose and fructose are both broken down into glucose in the liver and released into the blood.
Glucose is broken down into ATP inside the cell.
The cellular energy preference is glucose>fat>protein
What is contained in each disaccharide:
- sucrose
- lactose
- maltose
Sucrose: glucose-fructose
Lactose: galactose-glucose
Maltose: glucose-glucose
How much ATP is generated from each energy storage form?
- Triglycerides
- Glycogen
- Amino Acids
Triglycerides - 300-400 ATP
Glycogen - 36 ATP/glucose molecule (produces 38, uses 2)
Proteins - 3-34 ATP/AA
The preferred storage form of glucose is fatty acids, because the yield of ATP is so great when B-oxidation occurs in Kreb’s cycle.
What is the path of glycogen in Kreb’s cycle?
Glycogen -> Glucose -> Pyruvic Acid -> Acetyl CoA -> TCA Cycle -> Electron Transport Chain -> ATP
What is the path of Triglycerides through Kreb’s cycle?
Triglycerides -> Glycerol -> Pyruvic Acid -> Acetyl CoA -> TCA cycle -> ETC -> ATP
Also, Triglycerides can go to fatty acids which enter at the Acetyl CoA part of the process.
What is the path of proteins through Kreb’s cycle?
Proteins -> AA -> Pyruvic Acid
- > Acetyl CoA
- > TCA cycle - >ETC -> ATP
What is the path of ketone bodies to produce ATP?
Ketone bodies are formed when liver stores of carbohydrates are exhausted. It is a means of transferring energy from the liver to the brain and heart. When insulin is not used to cause glucose to be stored, then there is a lot of glucose in the blood. The ketone bodies make the blood more acidic, and if there is no bicarbonate to buffer then ketoacidosis can occur, which can be very dangerous.
What is acetyl CoA an intermediate of?
- Protein catabolism
- Glucose breakdown
- Storage as fatty acid, or fatty acid breakdown
- Formation of triglycerides, phospholipids, eicosanoids, ATP
- Ketone body formation or breakdown
- Formation of cholesterol and subsequent bile acid or steroid hormone synthesis
What is the euglycemic range?
From 70-100
What tissues do not require insulin for glucose uptake?
brain, liver, beta cells
What tissues do require insulin for glucose uptake?
skeletal muscle (the biggest reservoir), heart, and adipose tissue
What hormones help maintain the balance of glucose levels in the blood?
cortisol
insulin
glucagon
somatostatin
What are the 3 primary inputs of glucose?
- Dietary intake of carbs
- Hepatic synthesis
- Glycogen breakdown (in muscle, liver)
What are the 3 primary outputs of glucose?
- Uptake by insulin-sensitive tissues (storage, utilization)
- Uptake by non-insulin sensitive tissue (utilization)
- Renal excretion
What hormone does each cell produce:
- alpha cells
- beta cells
- delta cells
- alpha cells produce glucagon
- beta cells produce insulin delta cells
- produce somatostatin (which suppresses secretion of glucagon and insulin)
Where are alpha, beta, and delta cells located?
IN the endocrine pancreas
What secretes digestive juices into the duodenum?
The acini, or exocrine pancreas.
What secretes hormones directly into the blood?
The endocrine pancreas secretes insulin, glucagon, and somatostatin directly into the bloodstream.
What percentage of the pancreas do Islets of Langerhans encompass?
This is the endocrine pancreas - only 1%
What does glucagon do?
It increases glycogenolysis and gluconeogenesis. Basically puts glucose back into the bloodstream as an opposite hormone to insulin.
What does insulin do?
It allows insulin-sensitize tissues to take up and store glucose.
What does somatostatin do?
It decreases secretions of alpha and beta cells.
What does the exocrine pancreas secrete?
Digestive juices Proteases (Trysinogen) Lipases (PLA2) Other enzymes (Amylase) Bicarbonate ions
What types of chains are in insulin and pro-insulin?
Pro-insulin has an A chain, C chain, and B chain. Disulfide bonds link the A and B chains together.
Mature insulin has had the C chain cleaved out, leaving just the A and B chains with the disulfide linkages. Insulin is 51 aa’s long. Half-life in circulation is only 3-5 minutes.
When insulin is prone to dimerization, what occurs?
The monomer form of insulin is active, so a dimer increases the half-life and makes the formulation ER. Modifying the B chain to make it more or less prone to oligomerization can make the insulin release more quickly or slowly.
What transports glucose inside a pancreatic B cell? Does this transporter need insulin to transport this glucose?
GLUT1 and GLUT2
No insulin is needed to transport this glucose
When glucose is brought into a beta cell, what is it broken down to?
TO Fructose 1,6BP by a glucokinase (which phosphorylates twice and then isomerizes)
Inside a beta cell, what is fructose 1,6 BP metabolized to?
TO Phosphoenolpyruvate, which is further broken down to pyruvate.
Once glucose is broken down to pyruvate in the beta cell, where does pyruvate go?
It is metabolized to Acetyl CoA, which enters Kreb’s cycle and the ETC, to produce 36 ATP
What does the ATP produced from ECT and Kreb’s do in the beta cell?
It blocks inward-rectifying potassium channels.
Normally, inward-rectifying K channels leak K to maintain hyper polarization of the membrane potential.
When this channel is blocked, K cannot leak out and so the membrane becomes depolarized as the membrane potential goes up.
When ATP blocks the inward-rectifying K channels in a beta cell, what occurs next?
- Membrane potential goes up, causing initial depolarization
- Voltage-gated Ca channels open, causing further depolarization
What are the sources of calcium in a beta cell?
- Depolarization causes Ca channel to open, giving an influx of calcium
- DAG from the ETC/Kreb’s yields calcium
- M3 muscarinic receptor triggered by ACh (uses DAG, IP3)
What does the influx of calcium in a beta cell trigger?
It triggers both insulin synthesis and insulin secretion out of the cell into the blood stream.
What is needed for insulin production and secretion in a beta cell besides calcium?
A GLP-1 receptor agonist is needed. It binds to its receptor, which is a Gs receptor that stimulates the production of cAMP that assists the insulin pathway.
What do melatonin, NE, and EPI do in a beta cell?
They bind to their receptor, which is a Gi receptor. This inhibits cAMP production to inhibit insulin production and secretion.
What are two different mechanisms that we currently utilize with drugs to achieve insulin production and secretion?
GLP-1 agonists
DPP IV inhibitors
Sulfonylureas
Meglitinides
So what can stimulate insulin release?
Glucose
leucine (aa)
vagal stimulation, ACh
Sulfonylureas, meglitinides
What are some amplifiers of glucose-induced insulin release?
Enteric hormones: - GLP-1, GIP, cholecystokinin, gastrin, secretin B-adrenergic effect of catecholamines Arginine GLP-1 agonists
What are some inhibitors of insulin release?
a-adrenergic effect of catecholamines
Somatostatin
Diazoxide, thiazides, B-blockers, clonidine, phenytoin, vinblastine, colchicine
When glucose is consumed, what is the response of insulin?
There is an initial spike of insulin about 1 minute after the glucose enters the bloodstream, which dissipates within 3-5 minutes. This is phase 1.
After phase 1 comes phase 2, which is a more gradual release of insulin over the next 50 minutes or so, that dissipates when the glucose infusion stops.
Which phase do pre-diabetics usually lose first?
phase 1 response
What is the pathway of activation in an insulin-sensitive tissue?
- autophosphorylation occurs on the 4-subunit insulin receptor (alpha and beta subunits)
- insulin may now dock at the receptor
- several pathways are activated, including one that leads to IRS proteins
- With help, GLUT4 translocates from the cytosol to the membrane, where it functions as a glucose uptaker
