Parathyroid, Insulin Flashcards
Normal range for serum calcium
2.1-2.5 mmol/ L
Diagram calcium ingested into gut
1000 mg
300 mg initially absorbed
125 excreted into gut again
175 mg into blood/ecf
from diet–> feces calcium
825 mg via gut 700 mg initially + 125 re-excreted from blood
Percentages of calcium in ECF
40% - protein bound
10 % - complexed
50% - ionized
How is calcium also excreted apart from feces
Urine from kidneys
ECF Calcium excretion
10 000 mg into kidney
but 175 into urine
9825 mg reabsorbed into blood
from ECF –> Bone
500 mg back and forth
regulated by PTH and calcitonin
kidneys
PTH/Teriparatide function + homeostasis
Stimulus: Falling blood Ca++
Release from PT glands
1. Stimulate Ca++ release from bones
2. Stimulates Ca++ uptake in kidneys + PO4 excretion
3. Kidney activates vitamin D –> increases Ca++ intestine uptake
Blood Ca++ rises to homeostasis
Calcitonin + Homeostasis
Stimulus: high Ca++ level
Thyroid gland: calcitonin
1. Reduce Ca++ uptake in kidneys - increase excretion
2. Stimulates Ca++ deposition in bones
Result: blood Ca++ levels decline
Calcitonin vs Teriparatide
antagonistic drugs
Calcium in blood with age + in norm?
Mostly above the norm 2.62 —> lowers then incr. with age
Parathyroid hormone significant AA
First 34 most active
Rest of peptide has subtle effects in signalling
Calcium regulation of PTH pathways
activate beta-arrestin
binds AP2
internalizes receptor to endosome
sustains signal for MAPK
also GPCRi–> increase MAPK + lower cAMP
Gq = increased calcium
PTH glands sensing calcium –> response speed/intensity
Narrow sensitivity to level of EC calcium to determine PTH release
Ca + vitamin D in regulating PTH/ negative feedback
when high [Ca]
Increase Ca –> decreased PTH release
Gq –> PLC –> Calcium inside increases –> ERK + MAPK –> SP1 –> vitamin D receptor transcription occurs
Calcium, vitamin D and PTH regulation
When increased vitamin D
Decreases PTH release
Vitamin D receptor + vit D –> into nucleus –> downregulates PTH transcription –> low PTH
Common denominator between Ca, vit D and regulation of PTH
When high Ca/vitamin D, levels of PTH decrease
Familial hypocalciuric hypercalcemia overall pathology. treatment
- Autosomal dominant – inactivating mutation in calcium-sensor receptor gene
- Parathyroid gland less sensitive to Ca, higher Ca+ needed to reduce PTH
- Higher than normal blood Ca, low urinary Ca
- Not treated
- Chelator in emergencies
Autosomal dominant hypocalcemia
ADH type 1
- Autosomal dominant activating mutations in Ca-sense-receptor
- PT gland more sensitive to Ca, lower [Ca] required to reduce PTH
- Lower [Ca], high PO4, higher urinary [Ca]
- can cause seizures
Treating ADH
- Supplements - Ca + vit D
- Synthetic PTH –> increase Ca++ release and reuptake/kidney
- Calcilyitcs - CaSR antagonists – not approved in humans
Most common cause of hypercalcemia
Primary Hyperparathyoridism
Causes of primary hyperparathyroidism
Parathyroid:
hyperplasia, adenoma, carcinoma
Solution of primary hyperparathyroidism
Surgical removal
CaSR regulators
What are calcimimetics for
- Increase CaSR sensitivity to serum calcium
- Inhibit PTH release –> reduce [Ca] reuptake
- Treat primary + secondary hyperparathyroidism
What is secondary hyperparathyroidism from?
Kidney disease
Minimal Ca intake
5 mmol/day
should be 1 gram/day
Net absorption of calcium + intake required
Net absorption above zero when intake above 5 mmol or 200 mg per day
Oral intake of calcium + absorption + age
Infants: 60%
15-20% adults lower with age
Optimal intake dose + Ca absorption
Absorption best with doses lower than 500 mg
Supplements vs dietary
Oral Ca supplements - therapy
Dietary Ca preferred
Most common Ca supplements
Calcium carbonate
Calcium citrate
Ca carbonate vs citrate
Calcium carbonate - cheapest, most absorbed with food, needs acidic environment
Calcium citrate- equally absorbed with and without food, absorbed with reduced stomach acid
Vitamin D and Ca+ absorption
Organ site
how influence each other
Calcium absorption primarily –> duodenum and jejunum
Vitamin D increases Ca binding protein - increase Ca uptake, cytoplasmic transport and basolateral membrane transfer
Vitamin D deficiency results in decreased Ca absorption
Factors influencing Ca excretion
PTH - regulates 10% renal reabsorption
Protein and Na levels increase calcium excretion
Thiazide diuretics – increase Ca reabsorption
Loop diuretics increase Ca excretion
Bone mineral density, how to prevent/treat
Ca and vitamin D
Biphosphonates
Denosumab
Parathyroid hormone
Romosozumab
Calcitonin
Prevalence of Age-related osteoporosis in Canada
1/4 woman >50 yrs
1/8 men > 50 yrs
Age-related bone loss, mineral and bone strength –> increased fracture risk
Calcium and vitamin D supplementation on PM women
Vitamin D supplements reduced the incidence of vertebral fractures
Antiresorptive example
Bisphosphonates
Bisphosphonate function + drugs
Supply osteoclast apoptosis
Drug embedded in bone –> inhibits osteoclast activity–> apoptosis
Drugs: Alendronate, Zolendronate
Bisphosphonate effect on bone mineral density
administration
pharmacokinetics
Injection iv or oral.
Rapid intake in bone mineral
Long-term depot
Side effect of bisphosphonates
Oral administration GI issues
need to be taken on empty stomach, upright for an hour
Long-term use, atypical fractures
Osteonecrosis of the jaw, rare, due to dental work
Antiresorptive, but antibody
Denosumab
Mechanism of Denosumab
Ab binds to RANKL, displacing RANK
RANK + RANKL usually bind osteoclast, promoting bone resorption
Now with mab, this is inhibited
Inhibited osteoclasts
Denosumab, Dosing, Pharmacokinetics and side effects
Dosing: 60 mg shot/ 6 months
Rapid onset, reversible
Side effects: ONJ/rare
Long term atypical fractures
PTH-Teriparatide mechanism of increasing BMD(2)
Anabolic - Intermittent low-dose PTH increases bone formation
However,
Continuous high-dose PTH increases osteoclast-mediated bone resorption
What is this odd PTH mechanism called?
Use dependent mechanism
Teriparatide name
Forteo
Teriparatide: administration
20 mcg/day s.c. injection
Teriparatide: PK and duration use
95% bioavailability from s.c. injection
half-life 5 mins
B-c metabolism non-spcific enzyme degradation
Excretion: renal
Duration: restricted to 2 years - potential osteosarcoma
Romosozumab mechanism of action
Anabolic
Wnt- stimulate osteoblast formation, cellular growth+differentiaion
Sclerostin - blocks Wnt signalling
Romosozumab - mab –> inhibits sclerostin
Efficacy of anabolic Romosozumab
same efficacy as PTH - efficient
Side effects of Romosozumab
Hypocalcemia - bone pain
CV- heart attack, stroke - incr risk
Should use Romosozumab if CV issues
No; better to switch to PTH
Calcitonin, organ + regulation
from thyroid gland, parafollicular cells
Increased synthesis + release when [Ca] and gastrin increase
Calcitonin Effects + pathway
Binds to GPCR + Gs –> AC –> cAMP
Decrease Ca gut uptake
Increase kidney Ca excretion
Inhibit bone resorption via osteoclasts
Calcitonin + for what + drug
Calcitonin has been used to treat osteoporosis
Salmon calcitonin is used as a nasal spray
Removed from Canadian and US markets for lack of evidence of efficacy in osteoporosis and potential risk of increased cancer incidence
Endocrine – pancreas and hormones
Alpha cells - glucagon, breakdown of glycogen
Beta cells - insulin, glucose uptake-utilization
Delta cells - somatostatin - inhibit insulin/glucagon release
Type 1 diabetes
Early life onset
Autoimmune destruction of pancreatic beta cells
Loss of insulin
Replacement therapy required
Type 2 diabetes
Later life onset
Assoc with obesity
insulin resistance in target tissue
Feedback increases insulin secretion
eventual hyperglycemia
Why diabetes is deadly
Not able to produce insulin in late stage
then insulin dependent
Up regulation of PKC signalling
Increase in inflammatory cytokines
CV disease
Renal disease
Blindness
Heart attack, stroke
Who has increased risk of diabetes
Asian indian
Lowest risk - europeans
Also BMI factor
Contributing factors in T2D
Energy expenditure
Caloric intake
Dietary nutrients
Microbiome
Epigenetics
Age
^^^ all environmental factors for obesity
What other than environment affect obesity –> what is result for both
Adiposity genes
result: beta-cell dysfunction
Type 2 diabetes
Diagnosis of diabetes
TBG - fasting blood glucose
HbA1c- glycosylated hemoglobin
OGTT - glucose tolerance test
FPG normal vs diabetic
<5.5 mmol/L
>7.0mmol/L
OGTT peak glucose normal vs diabetic
<7.8 mmol/L
>11.1 mmol/L
Treatment options for T2D
Lifestyle change
Insulin secretagogues
Insulin sensitizers
What are biguanides?
Insulin sensitizers
Metformin
Metformin mechanisms
Antihyperglycemic
Lower elevated hepatic gluc outpu
Inhibit gluconeogenesis
Inhibit glucose 6 phosphatase activity–> glycogen sparing
Lower insulin resistance
Mechanism of metformin
Activation of 5 amp activated protein kinase AMPK
in hepatocytes and muscles
Do not increase insulin secretion, therefore not hypoglycemic, even at high doses
Thiazolidinediones - site of action + effect
PPAR
Nuclear hormone receptor
Expressed in fat–> adipocyte differentiation
Glitazones activate PPAR
Effect:
increase adipose tissues
increase storage
decreased bone density
weight gain
Example glitazone
Rosiglitazone
Newer T2D drugs
Pramlintide
Colesevelam
Liraglutide
Sitagliptin
Dapagliflozin, Canagliflozin
Pramlintide - site of action, effects
GI tract
Amylin analogue
Amylin release from beta cells with insulin, multiple effects
Inject before each meal subcutaneous
Pramlintide - mechanism
Brain –hunger inhibits
Slows gastric emptying - slower carb uptake
Inhibit glucagon release
Result : lower plasma glucose, body weight loss
Colesevelam effect
Bile acid binding resin - lower cholesterol
Inhibit gluconeogenesis
Improve plasma glucose
Colesevelam mechanism
May be attributed on affecting incretins release from gut
What are incretins
Group of hormones gut-released after eating
Regulate insulin amount released
Maintain beta cells
2 Regulators of incretin and receptors
Liraglutide
Sitagliptin
Liraglutide mechanism
GLP-1 receptor agonist
Sitagliptin mechanism
DPP-4 dipeptidyl peptidase-4 inhibitor - blocks GLP-1 degradation
Liraglutide effect
Duration of action 24 hours
Increase insulin, glucose dependent
Improve beta cells
Slow gastric emptying
Weight loss
Inhibit glucagon secretion
Liraglutide administration
Subcutaneous injection 1x/d
Thigh, stomach, upper arm
What is SGLT 2
Na-glucose reuptake transporter
In proximal convoluted tubule of nephron
Reabsorption of glucose usually
SGLT inhibitor
Dapagliflozin, Canagliflozin
Positive and negative effects fo D and C- flozin
+ - decreases plasma [glu]
decrease weight and BP
Diuretic
Decrease heart failure CV system
- tive
5x mycotic infection in urinary tract due to glucose in urine-bacteria?
Combination therapies
Multisensitizers: Metformin + Rosiglitazone
Insulin secretagog+ sensitizer: Glumepriride + Rosiglitazone
Insulin sensitizer and DPP4 inhibitor: Metformin + Sitaglimptin/linagliptin/saxagliptin
SGLT2 inhibitor + DPP4 inhibitor: Empagliflozin and Linagliptin
Which comb. treatment is safest + effective
SGLT2 inhibitor and DPP4 inhibitor
