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Endocrine Physiology-2pancreas & parathyroid glands
Milagros B. Rabe, M.D., M.S. Ph.D.
Department of Physiology
UERMMMC College of Medicine
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Endocrine pancreas
Alpha- glucagonBeta- insulinDelta somatostatinF cell pancreaticpolypeptide
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Regulation
of blood
glucose
levels
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Insulin synthesis
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Secretion of insulin
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Phases of insulin secretion
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Insulin Receptor
S-S S-Sa
b
ATP ADP
S-S
tyr
Heterotetrametric
protein
b chain has tyrosine
kinase activitya chain -recognition
site
**NIDDM - has more EX-11 (+) < affinity to insulin than Ex-11(-)Sesti (Pharmacogenomics, Feb 2000
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Insulin molecule
c c
c
1
5
6
1020
R
R
KG
7
1019
20
R
30
Porcine insulin = alanine @B30 (threonine in humans)
bovine insulin = alanine @B30 & A8 (threonine in humans); valine @A10 (isoleucine in humans)
A chain
B chain
NH2COOH
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Insulin signaling
Allosteric interactionautophosphorylation of tyrosine kinase
phosphorylation of IRS-1
GTPras
Stimulation of Raf kinase
activation of MAP kinasePhosphorylation of
regulatory genes
activation of enzymes
transcriptional activation
Biologic effects
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facilitated diffusion:fat & muscle
endocytosis
exocytosis
vesicle
*Exercise inc. receptor density not due to insulin action
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Regulators of insulin release
Stimulants glucose, mannose, leucine
vagal stimulation
sulfonylurea
amplifiers GIP, CCK, secretin, gastrin, GLP-1 & 2, b adrenergic
stimulation
inhibitors a adrenergic stimulation, somatostatin, diazoxide,
phenytoin
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Incretin Effect
0
50
100
150
200
250
300
0 30 60 90 120 240
IV glucose
oral glucose
G
l
u
c
o
s
e
mg/dl
Time (minutes)
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Incretin Effect
0
10
20
30
40
50
60
70
0 30 60 90 120 160plasmain
sulinxme
anfasting
level
oral glucose
IV glucose
Time (minutes)
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Incretin Effect
Intestinal hormones modulate insulin
secretion
glucointegrins (post prandial glucose
homeostasis)
GIP (gastric inhibitory peptide)
GLP-1 (glucagon like peptide 1)
Thorens, B (Diabetes Metab 1995 Dec 21:311-8)
Drucher, DJ (Diabetes 1998 Feb 47:159-69)
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What are the effects of insulin?
On muscle?
On adipose cells?
On the liver?
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Effects of Insulin
Adipose Cell increased facilitated diffusion of glucose (via GLUT 4)
increased TAG, FFA synthesis; decreased lipolysis
Muscle cells increased facilitated diffusion of glucose (via GLUT 4)
increased glycolysis & increased glycogen synthesis
increased amino acid uptake and protein synthesis
Liver increased glucose uptake by increased glucokinase activity
increased glycogen synthetase activity
increased lipogenesis
decreased phosphorylase & gluconeogenesis
decreased proteolysis
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Glucagon synthesis
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glucagon
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Effects of glucagon
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regulation
effects
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somatostatin
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Effects of somatostatin
Decreased gastric emptying
Decreased GIT blood flow
Decreased nutrient absorption in the GIT Decreased insulin and glucagon secretion
Decreased growth
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Regulation of calcium
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calcitonin
parafollicular cells; 32 aa
Regulators of secretion:
Stimulators
high serum calcium
gastrin (most potent), CCK, glucagon, secretin
inhibitors
low serum calcium
effects: decreased serum Ca++ by (-) bone resorption; (-) osteoclast activity
inc Ca++ excretion in urine
P th
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Parathormone
Linear polypeptide, 84 aa Effects mediated by interaction with G protein and inc cAMP
Effect: inc plasma Ca++ by : inc bone resorption (inc osteoclasts & activity)
inc reabsorption of Ca++ in kidney and inc excretion of PO4 inkidney
inc formation of 1,25 vit D3 --> aids Ca++ absorption in GIT Regulators of secretion:
Stimulators: low serum Ca; high serum phosphate; low serumMg++
inhibitors:1,25 vit D3; high serum Ca++
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Treatment of hypercalcemia
Assess hydration of patient and restore renal
function
intravenous bisphosphonates - inhibit osteoclast
activity in bone; 60-90 mg pamidronate IV over 4hours or 4 mg zoledronic acid IV over 15 min
calcitonin 4-8 IU/kg SC q 12 h if non responsive to
first 2 steps
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Hypocalcemia Causes:
hypoparathyroidism (surgical, idiopathic, genetic (Di Georgesyndrome= immune def., cardiac defects, hypoparathyroidism)
resistance to PTH action (pseudohypoparathyroidism)
vit D deficiency
Features: neuromuscular excitability (tetany, paresthesia, seizure);
prolonged QT interval on ECG, dry flaky skin and brittle nails
Chvosteks sign (tap facial nerve 2 cm anterior to earlobe;
contraction of facial muscles at angle of mouth);
Trousseaus sign = inflate BP 20 mm Hg above systolic BP for 3 minproduces carpal spasm
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Treatment of hypocalcemia
Acute hypocalcemia
IV calcium as calcium chloride 272 mg/10 ml;
calcium gluconate 90 mg/10 ml); oral calcium + vit
D3 preparation; caution Calcium irritating to veins;caution in px on digitalis meds
Chronic
calcium 1.5-3 gm oral + vitamin D3
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