EXAM3_L28_Insulin_Glucagon Flashcards
What is diabetes fasting glucose levels?
> 126mg/dL
7mmol/L
1 hour postprandial Normal blood glucose
up to 145 mg/dL
8mmol/L
Normal Fasting blood glucose?
70-110mg/dL
3.9-6.1mmol/L
Symptomatic Hypoglycemia
What are the responsibilities of the Pancreas?
What 3 cell types of the pancreas?
DIGESTION GLUCOSE HOMEOSTASIS (insulin/glucagon)
Exocrine, Endocrine, ductal cell types
What 4 cell types in the islets of langerhans of the endocrine pancreas?
- Alpha- glucagon (15-20%)
- Beta- INSULIN (60-80%)
- Gamma- Somatostatin (5-10%)
- PP-cells - Pancreatic polypeptide (15-20%)
3 beta cell functions
synthesize, store, regulate INSULIN
Synthesis of Insulin
Describe the 6 steps of how its made
from transcription->prepro>pro>insulin + c pep
Where it happens and what is modified
1st. Beta cell gene for insulin is transcribed into mRNA in the nucleus
2. mRNA code for insulin is transported to RER in Cytosol
3. N-terminal signal penetrates RER and insulin is made/injected into the lumen of RER as pre-pro-insulin
4. Pre-pro-insulin is cleaved and now Pro-insulin
5. Pro-insulin is transported to the golgi where it is cleaved and forms Insulin and C-Peptide
6. Insulin and C peptide are secreted in secretory vessicles via exocytosis
What does PDI & Chaperone do? (Protein Disulfide Isomerase)
Helps correct folding of pro-insulin and forms the disulfide bonds in the RER
so that it can be transported to the Cis golgi for cleavage into insulin and Cpeptide
Where is 3 places glucagon made?
Alpha cells of the endocrine pancreas (outside perimeter)
AND
L-Cells of Intestines
(some in brain too)
What are incretins? Where are they synthesized?
GI hormones released in response to meal w/ carbs
Insulin-secretion-stimulating agents
made during the post-translational processing of
pro-glucagon
(when it is made by intestinal L-Cells)
What is GLP-1?
Where does it come from?
GLP1 is created during post-translational processing of the glucagon from LCELLS.
L-Cells secrete glucagon in the small intestines (colon-ilium)
undergo post-processing and incretins are made as a result.
What does GLP-1 do?
LOWERS BLOOD GLUCOSE LEVELS by:
Stimulating insulin and inhibiting Glucagon release
Increases the IG ratio
What is GLP-1 degraded by? how fast?
-GLP1 degraded by DPP-4 (dipeptidyl peptidase-4) within minutes
What is responsible for increasing the IG ratio after a carbohydrate rich meal?
INCRETIN GLP1 released by the L-cells of the small intestines (colon and ilium) minutes after eating a meal
prepares the pancreas for the nutrient load to enter the blood
What type of drugs are used to treat diabetes mellitus?
Incretin mimetic drugs:
EXENATIDE (Byetta)- GLP-1 mimetic, resists degradation by DPP-4 w/ long half life (12 hours).
Mimetic drugs resemble incretins- which are decreased in diabetes mellitus patients
What is Exenatide (Byetta)?
GLP-1 Incretin mimetic drug used to treat diabetes mellitus
-long half-life (12 hours) by resisting degradation by DPP-4
What are secretagogues?
Insulin is stored in secretory granules and secretagogues initiate release of insulin upon being signaled
What does Glucokinase do?
Converts Glucose to G6P inside the cell.
Once G6p, glucose is STUCK inside the cell
Describe how beta cells Detect blood glucose
Increased [Glucose] > increased ATP/ADP ratio
ATP inhibits (atp sensitive K channel) > DEPOLARIZATION
depolarization> CamKinase2 > Exocytosis of INSULIN
What is Sulfonylurea? What does it target?
Overall Function?
Sulfonylurea is a secretagogue of insulin release
Targets the atp-sensitive K+ channel
LOWERS BLOOD GLUCOSE LEVELS
(risk of hypoglycemia b/c they act independent of existing blood glucose levels)
Type II diabetes (mellitus) can be treated with what drug that acts on atp-sensitive K+ Channels?
Sulfonylurea
blocks K+ channel causing a depolarization and release of insulin (independent of current blood glucose levels)
What is the first pass effect?
Blood pancreas to portal vein into liver (50-60% IG) metabolized before hitting systemic circulation.
how long is half life of IG?
Why?
3-5 minutes
50-60% metabolized in liver (first pass effect)
Kidney degrades 1/2 of systemic IG
Proteases destroy IG in systemic circulation
If IG has such a short half-life, its unreliable to use as a determining factor of diabetes. What Should you measure to determine levels of Beta-cell activity?
C-Peptide (secreted 1:1 ratio w/ insulin)
- not degraded by liver or other organs
- HL ~30 min
What REGULATES Insulin release?
looking for 1 major and 3 minor regulators
GLUCOSE! (almost entirely regulated by glucose)
- Epinephrine (stress hormone)- Inhibits Insulin Release
- incretins help release insulin (GLP1)
- AA’s stimulate insulin in absence of glucose
What is a counter-regulatory hormone?
What 4 are the counter-regulatory hormones ?
Hormones that oppose the action of insulin on glucose:
Glucagon, Epinephrine, Cortisol, growth hormone
How does epinephrine affect Pancreatic Beta Cells?
- promotes fuel mobilization during stress, exercise, and fasting)
Epinephrine (stress hormone) DECREASES/Inhibits INSULIN
How does epinephrine affect Pancreatic Alpha Cells?
Alpha cells produce GLUCAGON (increase blood glucose)
Epinephrine (stress hormone) INCREASES Glucagon and blood glucose
How do Dietary amino acids affect alpha and beta pancreatic cells?
CAN INCREASE BOTH insulin and glucagon secretion… ?
Why?
If there is no carbs in the diet, (PROTEIN ONLY DIET- ATKINs) - we use AA’s to make glucose
Glucose uptake is insulin-dependent in many tissues of the body (brain, RBC, intestine, cornea, kidney, liver)
What tissues REQUIRE Insulin/Glucagon for glucose uptake?
What transporter expressed on these cells?
MUSCLE & ADIPOSE
Insulin-dependent GLUT-4 TRANSPORTER
Muscle and Adipose are unique in that they require Glucose transporters to take up glucose.
Describe what signals initiate what transporters to get glucose into the cell.
- Insulin stimulates endosome to release GLUT4 transporter
- GLUT4 fuses with cell membrane of muscle/adipose and glucose is taken into the cell
- GLUT4 reabsorbed into endosome when insulin levels fall
General Fed state (charging mode)
High IG
Fuel storage (make TAGs, glycogen, proteins)
Use Glucose as energy source
Glucose uptake (GLUT4)
General Fasting State (battery mode)
- Low IG
- Battery Power (TAGs, Glycogen, Proteins)
- Use FA’s and Ketone Bodies for energy (except RBC and Brain- Always use glucose)
- Glucose synthesis in liver for export (for brain & RBC)
Where does Lipolysis Take Place?
Where does Beta Oxidation take Place?
ADIPOSE TISSUE_ NOT THE LIVER!!!!
Beta oxidation takes place in the liver
How much glucose does the brain require per day?
How much required for total body per day?
Brain requires 130grams glucose/ day
Total body requires 180grams glucose /day
72% of total required glucose is used by the BRAIN!!!
If we eat atkins Protein only Diet
where does glucose come from?
Low IG ratio:
small insulin release prevents muscle protein degradation, but not the rest of fasting responses
Synthesize glucose from scratch but uses dietary AA’s
LONG TERM FASTING
Muscles degrade to make glucose from scratch
What type of cell does glp1 work on?
Beta cell - helps release insulin
Which does what? Insulin/Glucagon phosphorylate/dephosphorylate target enzymes?
INSULIN- Dephosphorylates target enzymes
GLUCAGON- phosphorylates target enzymes
