Pt Endocrine Lecture 2- 2013

7/30/2019 Pt Endocrine Lecture 2- 2013

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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

Pt Endocrine Lecture 2- 2013

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