Endocrine II: Diabetes and Pancreas / Calcium and Phosphate regulation Flashcards
Islet of Langerhans Cell Types and %
BAD
- Beta=insulin producing (75%)
- Alpha=glucagon producing (20%)
- Delta=somatostatin producing (5%)
what does somatostatin do?
inhibits insulin, glucagon and GH
how does insulin antagonize glucagons effect?
driving glucose uptake and thus decreasing blood sugar
how does glucagon antagonize insulins effect?
stimulating hepatic glucose release and increasing blood sugar
what is a normal blood sugar
4-6mM = 80-100mg/dL
what things stimulate insulin?
glucagon
glucose (hyperglycemia)
amino acids
incretins (GIP, GLP)
sulfonylurea drugs
what things inhibit insulin
somatostatin
NE/Epi and cortisol
fasting/exercise
what things stimulate glucagon?
glucose (hypoglycemia)
amino acids
NE/Epi and cortisol
exercise and fasting
what things inhibit glucagon?
incretins (GIP, GLP)
insulin
somatostatin
mechanism of action of glucose binding to beta cells releasing insulin
- glucose binds GLUT 2 R on pancreatic beta cell
- closes the K-ATP channel
- depolarizes beta cell
- opens Ca channel
- Ca binds to vesicles
- insulin is released
C-Peptide
Cleaved off when endongenous insulin is made. Exogenius injectable insulin does not have this peptide.
Sulfonylureas do what
directly block the K-Atp channel in Beta cells causing insulin release
Incretins do what and are broken down by what?
GIP and GLP
- Indirectly close the K-Atp channel in Beta cells causing insulin release
- This insulin release directly inhibtis Alpha cells release of glucagon
- Quickly broken down by DPP4
What maken incretins work better?
DPP4 antagonists
how does glucose control alpha cells in low glucose environments?
- Some glucose enters via the GLUT1
- Some ATP is still made inside cell
- Most of the K-Atp channels are closed
- Some depolerization occures
- Some VGCC open and Ca enters
- Ca binds to vesicles
- Some glucagon is released
how does glucose control alpha cells in high glucose environments?
- A ton of glucose enters via GLUT1
- A ton of ATP is made
- All K-Atp channels close
- Entire cell depolarized
- VDCC inactivated
- No Ca can enter and bind to vesicles
- No glucagon is released
What two things can inhibit glucagon release in the alpha cells?
- Insulin from Beta cells
- Somatostatin from Delta cells
What problems do diabetics have concerning alpha cells?
Insulin does not act upon them to inhibt glucagon release which increases resting blood sugar levels
is insulin anabolic or catabolic? and what does it cause in skeletal muscle, liver, and adipose tissue
anabolic
Skeletal muscle: increase glucose and AA uptake
Hepatic: supress glucose production
Adipose: inhibit lipolysis (breakdown of trigycerides into free fatty acids
is glucagon anabolic or catabolic? and what does it cause in skeletal muscle, liver, and adipose tissue
catabolic
Skeletal muscle: no effect
Hepatic: glycogen breakdown, sugar formation, ketone formation
Adipose: stimulates lipolysis = triglycerides into free fatty acids
what tissue is responsible for type 2 diabetes?
skeletal muscle, primary glucose storage
GLUT2
Glucose transporter in liver non-insulin dependent
Glucose transporter in Beta cell, glucose dependent
GLUT4
Insulin dependant transporter in muscle and fat cells
Myocytes and adipocytes
OGTT
oral glucose tolerance test
OGTT Levels
- Normal: After 2 hours less than 140 and never over 200
- Insulin Resistant: more upper limits of normal (slightly over or near 200 after 2 hours)
- Diabetes: Greater than 200 after 2 hours
What is T1D?
loss of beta cells due to autoimmune distruction (genetic factor)
triggered by environmental factor
What are some enviromental factors that can trigger T1D?
- Viruses like Mumps, Rubella, and Coxsackie
- Nutrients: cows milk
Babies>milk>antibodies for cow insulin>close to human insulin>autoimmune
Systemic effects of insulin deficiency problem 1
T1D issue
Decreased glucose uptake causes
* Hyperglycemia
* Glycosuria
* Osmotic diuresis
* Electrolyte depletion
Dehydration
acidosis
Coma
Death
Glucose is hydroscopic so it ends up in urine
Systemic effects of insulin deficiency problem 2
T1D issue
Increased protein catabolism
* Increased plasma amino acids
* Nitrogen lossed in urine
* Osmotic diuresis
Dehydration
Acidosis
Coma
Death
Systemic effects of insulin deficiency problem 3
T1D issue
Increased Lipolysis
* Increased plasma FFA
* Ketogenesis
* Ketouria
* Ketoemia
Dehydration
Acidosis
Coma
Death
What is insulin resistance?
loss of insulin receptor sensitivity in the GLUT4 transporter in skeletal muscle
Less transportation of glucose into the SK
How do we transport more glucose into skeletal muscle in an insulin resistant person?
We increase insulin levels which is a right shift on the insulin effectiveness curve
how do we develop type 2 diabetes?
insulin resistance (inactivity and genetics)
obesity
beta cell hyperplasia (normal glucose/high insulin)
beta cell fatigue (high glucose/ high insulin)[last place to reverse damage]
beta cell failure (high glucose/ low insulin)
how do we know that insulin resistance (inactivity and genetics) precede obesity for type 2 diabetes?
research shows that from just two weeks of inactivity insulin and glucose levels increased
HbA1C
glucose that is covalently bound to hemoglobin and a test for diabetes
HbA1C levels
- 6% / 114 / Normal
- 6-7.5% / 115-164 / Good
- 7.6-9 / 167-214 / Poor
- > 9 / >214 / Very Poor
% / Mean blood Glucose / Range
what does elevated HbA1C increased the risk of
Morbidity and mortality
retinoplasty / neuropathy
CVD / Stroke / ESRD
* Specific for anesthesia
* Reduced lung function
* Glycosylation of joints (harder to move neck for DL)
How to calculate Mean Plasma Glucose?
(33.3 x HbA1c)-86
(33.3 x 7)-86=147 (Good range)
what does HbA1C predict preoperativly in non diabetic pts?
mortality
acute kidney injury
Getting good glycemic control before surgeries decreasces these
what is the leading cause of CKD and ESRD?
diabetes
DKA
diabetic ketoacidosis
ketones (blood acids elevated)
sugar elevated
dehydration and coma
Quick Rundown: Insulin
Inhibits glucose production in liver
Promotes glucose uptake in SK and adipose
Lowers blood sugar
Promotes Glucose production in Liver
T3/T4
Glucagon
Catecholamines
Cortisol
GH
Inhibits glucose uptake in SK and adipose
Cortisol
GH/IGF-1
Surgery and Anesthesia increase stress hormones
T3/T4
Glucagon
Catecholamines
Cortisol
GH/IGF-1
GH
Anterior Pituitary hormone
Increases liver glucose production
Bind to receptors on the liver to produce another hormone - IGF-1
GH/IGF-1
makes muscle and adipose tissue more insulin resistant
Increased GH usually more diabetic
what is the major storage site for calcium and phosphate?
bone as hydroxyapatite (HA)
free calcium vs protein bound calcium vs complex calcium
free 50%
PB 40%
complex 10%
free phosphate vs protein bound phosphate vs complex phosphate
free 80%
PB 10%
complex 10%
Ca2+ and PO4- are in dynamic equalibrium
Calcium excreted in feces 900 mg/d
Phosphate excreted in urine 900 mg/d
how does thyroid regulate Calcium?
c cells release calcitonin and lowers calcium
how does parathyroid regulate phosphate and calcium?
chief cells release parathyroid hormone and increase phosphate and calcium
By bone breakdown
how do the skin, liver and kidney regulate phosphate and calcium?
skin intakes Vit D
liver converts to 25OHVitD3
kidney converts to active VitD3
how does the bone regulate phosphate?
osteocytes secrete FGF23 that regulate phosphate
what is the normal blood calcium level?
10mg/100mL
what is used theraputically to prevent bone loss? shows no clinical symptoms when deficient.
calcitonin
what activates PTH?
hypocalcemia
hyperphosptemia
what decreases PTH?
hypercalcemia
increases in Vit D and FGF23
What is 1,25(OH)2?
1 25 hydroxy vitamin d
AKA Calcitrol
Pathway for Activated Vit D
AKA Calcitrol
Skin/Sun
ProD3
PreD3
Vitamin D3 (we get this from diet)[aka Cholecaliferol]
Liver converts to: Calcifediol(25(OH) Vit D)
Kidney converts to: Calcitrol (1,25 (OH)2D2) via 1-alpha hydroxylase
1-alpha hydroxylase is activated by what?
PTH
What does PTH do?
If calcium levels drop it has 3 rapid and 2 slow ways to increase Ca2+ uptake
If phosphate levels increase it helps lower them
3 rapid ways PTH increases Ca2+
- Wastes phosphate via kidney
- Increases kidney Ca2+ reabsporbtion
- Breakdown bone via osteoprogenerin cells
2 slow ways PTH increases Ca2+
- Osteoclastic bone reabsorption
- Increase gut absorption
How does PTH decrease high phosphate levels?
PTH increases calcitrol synthesis
Promotes renal excretion
Calcitrol is incresed by what
PTH via 1-alpha hydroxylase
Calcitrol is decreased by what
Increased Ca2+
Increased Calcitrol
Increased FGF23
Breadown of what controls Ca2+
Thyroid: Calcitonin = lowers Ca2+
Parathyroid: PTH = raises Ca2+
Vit D: helps raise Ca2+
Breakdown of what controls Phosphate
Parathyroid: PTH = Increases PO4-
Bone: FGF23 = lowers PO4-
Vit D: increases PO4-
FGF23 is increased by
Increased PO4-
Increased PTH
Increased Calcitrol
FGF23 is decreased by
Decreased PO4-
Decreased PTH
Decreased Calcitrol
How to remember Osterocyte types
B and C
OsteoBlasts = Build Bone
OsteroClasts = Consume Bone
Difference between OPG and RANKL?
OPG = Maintaine bone
RANKL = Bone breakdown
Osteolysis steps
7
- PTH>Vit D> osteoblasts
- Stimulated osteoblasts release RANKL and M-CSF
- Osteoblasts stop OPG production (allows for more osteoclast formation)
- M-CSF binds to stem cells = osteoclast precurser formation
- RANKL binds to precursers making pre-osteoclasts
- The pre-osteoclast group merge into mature osteoclasts
- Osteoclast attach to bone and begin breakdown
M-CSF: Macrophage-colony stimulating factor
