Cell Signaling Pathways: Insulin Flashcards
What is a major metabolic fuel?
glucose
Circulating levels of glucose are tightly regulated through the opposing actions of principally:
insulin
glucagon
Insulin ___ glucose levels
reduces
Glucagon ____ glucose levels
raises
What does the mammalian brain depend upon as its primary/major source of energy?
glucose
Glucose is derived from what materials?
those ingested in the diet
Carbs exist as : (3)
polysaccharides
disaccharides
monosaccharides
starch and glycogen are:
polysaccharrides
sucrose, maltose, and lactose are:
disaccharides
galactose, glucose, and fructose are:
monosaccharides
What represents about 60% of the carb intake for Westerners?
starch
Carbs are broken down into what in the gut?
hexoses
Can hexoses pass freely through the cell membrane?
no
How are hexoses absorbed since they can’t pass freely though the CM?
absorbed via glucose transporters like GLUT4
Insulin released by Beta Islet cells when blood glucose is (low/high).
high
How is blood glucose regulated when it’s high?
high blood glucose –> insulin released by Beta Islet cells in pancreas (also inhibits glucagon release by Alpha Islet cells) –> increased uptake of glucose –> glucose converted into glycogen (muscle and liver) or triglycerides (adipocytes)–> normal blood glucose levels
Which organ releases insulin?
pancreas
How is blood glucose regulated when it’s low?
low blood glucose –> glucagon released by Alpha Islet cells in pancreas (also inhibits insulin release by Beta Islet cells) –> glycogen and triglycerides converted into glucose and fatty acids –> normal blood glucose levels
Type of post-translational modification that effects protein function:
phosphorylation
Is phosphorylation reversible?
yes
What can REVERSIBLY turn an enzyme or receptor on or off altering its function?
phosphorylation
What does reversible phosphorylation result in?
conformational change in structure of enzymes and receptors causing them to become activated or deactivated
The protein-phosphate bond is a (low/high) energy bond.
high
Where does phosphorylation occur?
specific side chains of enzymes or receptors: serine, threonine, tyrosine, histidine
enzyme catalyzing a phosphorylation reaction:
kinase
enzyme that uses a high energy source of phosphate; most commonly ATP
kinase
enzyme that removes phosphate residues (dephosphorylation):
phosphatase
Insulin can decrease blood glucose in 2 ways:
- dephosphorylates via protein phosphatase which activates glycogen synthase
- dephosphorylates via protein phosphatase which deactivates glycogen phosphorylase
* * both preventing conversion to glucose 1-phosphate but allowing conversion from glucose to glycogen and storage of glycogen
Glucagon/epinephrine can increase blood glucose in 2 ways:
- Activates cAMP which activates protein kinase A which phosphorylates and inhibits glycogen synthase
- Activates cAMP which activates phosphorylase kinase which phosphorylates and activates glycogen phosphorylase
* *both lead to conversion of glycogen to glucose 1-phosphate
What is the first molecule in insulin biosynthesis?
Proinsulin
Which molecules cleave proinsulin at specific sites?
prohormone convertase 2 and 3
The cleavage of proinsulin leads to the production of:
active insulin and C-peptide
Where is insulin stored?
granules in B-cells of pancreas
Which molecule activates insulin gene expression?
Ca2+
Ca2+ activates insulin gene expression via which protein?
Calcium Responsive Element Binding (CREB) Protein
Is the activation of insulin gene expression a slow or fast process?
slow
What causes K+ATP channels to close causing depolarization in the pancreas?
increased ATP:ADP ratio
The closing of K+ATP channels causing depolarization in the pancreas causes which channels to open and which molecule is released into the cell?
voltage-gated Ca2+ channels
Ca2+
The release of Ca2+ from voltage-gated Ca2+ channels
causes rapid:
exocytosis of stored insulin
What is the normal fast blood glucose:
70-130 mg/dL
Describe the overall kinetics of insulin release:
initial fast response followed by more prolonged phase
Is the first phase of insulin release kinetics fast or slow and why?
fast
rapid exocytosis of stored insulin granules
Is the second phase of insulin release kinetics fast or slow and why?
slow
insulin production via gene expression
Insulin is what type of hormone?
Protein/peptide hormone that has PM-bound receptor system
What is the insulin receptor composed of?
alpha and beta chains
What are the alpha and beta chains of the insulin receptor activated by?
insulin
IGF-I (insulin-like growth factor-1)
IGF-II (insulin-like growth factor-2)
The insulin receptor belong to what class of receptors?
tyrosine kinase receptors
Transmembrane receptor
Binding of ligand (insulin or IGF-II) to the alpha chains of the ectodomain induces what?
structural change (conformational change) in the receptor leading to autophosphorylation of tyrosine residues within the intracellular TK domain of the beta chain.
Insulin binding to ___ activates a _____ of ______ signaling.
IR-beta
cascade
intracellular
How many different glucose transporters?
13
What are the main glucose transporters?
GLUT1-5
What are 2 ways glucose uptake in cells can occur?
- facilitated (passive) diffusion = transport down concentration gradient via carrier protein
- active transport = energy requiring transport against concentration gradient
process of passive transport with transport aided by integral membrane channels or carrier proteins and causes a conformational change
facilitated diffusion
Describe the process of Na+ coupled sugar transport:
extracellular Na+ binds to protein channel in membrane causing conformational change which allows glucose to bind and get transported, along with Na+, into the intracellular side and when Na+ leaves, the protein returns to its normal state
Insulin increases the translocation of which GLUT receptor to the CM?
GLUT4
Which transporter mediates intestinal absorption of glucose from the diet on the luminal side of the intestinal enterocyte?
Sodium-Glucose co-Transporter 1 (SGLT1)
Which transporter is important in the basolateral efflux of glucose into the blood stream?
GLUT2
Which transporter is important in the glucose-mediated secretion of incretin hormones, GIP and GLP-1?
SGLT1
Gut hormones released after eating that stimulate the secretion of insulin by the beta-cells of the pancreas:
incretin hormones
Major incretin hormones:
glucagon-like peptide-1 (GLP-1)
gastric inhibitory peptide (GIP)
Both GLP-1 and GIP are inactivated by the enzyme ____________.
dipeptidyl peptidase-4 (DPP-4)
Where is dipeptidyl peptidase-4 (DPP-4) released from?
endothelial cells of blood vessels
Lead to increased insulin secretion and decreased glucagon levels and consequently improvement in hyperglycemia:
DPP-4 inhibitors
Ex. of DPP-4 inhibitor
serine protease
First DPP-4 inhibitor agent approved by FDA in 2006:
Sitagliptin
hormone lowers blood glucose by stimulating cellular uptake and glycogen synthesis:
insulin
example of insulin
Humalin R (T1 diabetes)
Insulin action on rat adipocytes shows as insulin increases, glucose uptake ____ and lipolysis _____.
increases
decreases
What is the storage form of glucose?
Glycogen
What are the 2 fates of glucose once it’s converted in glucose-6-phosphate?
- stored as glycogen
- enters glycolysis to form pyruvate which has multiple fates
Where is glucagon produced?
Alpha cells of pancreas
Where is insulin produced?
Beta cells of pancreas
Insulin regulates changes in metabolic pathways regulating fatty acid synthesis and glycogen synthesis primarily by altering the ________ statues of key enzymes on these pathways.
Phosphorylation
What type of process is insulin release by the pancreas?
Biphasic: slow and fast
In the rapid release of insulin by the pancreas, what is contained in the stored vesicles that get exocytosed?
Active insulin and C-peptide
During insulin release by the pancreas, the _____ transporter transports glucose into the cell where it is converted into ___ via _____ and _____. This causes the ________ ratio to increase and consequently closes __ channel causing _________. This causes _______ channels to open which releases _____ into the cell causing rapid _____ of stored insulin and activates insulin ____ _______ via _____ which is a slow process.
GLUT2 ATP Glycolysis and Krebs ATP:ADP ratio Katp Depolarization Voltage-gated Ca2+ channels Ca2+ Exocytosis Gene expression CREB
The affinity (Kd) of the insulin receptors (IRA & IRB) for insulin is ____ and ____ for IGFs, so in order to get IGF binding to insulin receptor, they need to be at (lower/higher) concentrations.
High
Low
Higher
IGF1 & IGF2 bind to their receptors in addition to which insulin HOMOdimer?
IRA (insulin receptor alpha)
Signaling via the insulin receptor involves a series of adaptor proteins (___ & ___) which transduce the signal via ___ and ___ kinases to effect changes in key metabolic activities and gene expression within the nucleus.
IRS1 & IRS2
AKT
MAP
How does insulin. Increase the translocation of GLUT4 to the cm?
Insulin binds to a receptor on the CM —> causes signaling transduction cascade -> GLUT4 secretory vesicles in the cytoplasm move to the CM via exocytosis -> exocytosis leaves the GLUT4 behind on the cell which increases the number of receptors on the membrane —> increases glucose uptake in the cell
What occurs during the transport of glucose in the gut?
Gathered is a high concentration of glucose in the intestinal lumen (gut). The SGLT1 protein transporter on the micro Billie of the lumen transports glucose and Na+ from the gut into the enterocyte (epithelial cell) which starts to raise the glucose concentration in the enterocyte. GLUT2 on the basolateral membrane can move glucose down its concentration gradient into the bloodstream. At the same time, Na+ concentration is high so Na+ need to be moved out on the basolateral membrane through Na+/K+ ATPase
What do GLP1 receptor agonists do?
Stimulate incretin receptor in absence of GLP1
Ex of GLP1 receptor agonist
Trulicity
Inhibitor that increases incretin levels
DPP4 inhibitors
Blocks reabsorption of glucose by the kidney
SGLT2 (Farxiga)
How does insulin affect lipolysis?
Insulin binds to insulin receptor on adipocyte which activates tyrosine kinase cascade and leads to phosphorylation of PDE3B which converts cAMP to AMP (cAMP leads to release of FFA) (inhibits cAMP). When cAMP is inhibited by the phosphorylation cascade, it converts to AMP and doesn’t allow free fatty acid release since we don’t want FFA dumped into blood when there are high levels of circulating glucose.
Insulin activates ______ via dephosphorylation which converts acetyl-CoA into ______ which promotes synthesis of fatty acids in the cytoplasm.
ACC
Malonyl-CoA
Glucagon deactivates ACC via __________ which does not produce malonyl-CoA.
Phosphorylation
Insulin is a characteristic of the “___ state”
Fed
