Transcript Endocrine Pancreas & Adipokine

Endocrine Pancreas
Adipose hormores
Diabetes mellitus
and hypoglycemia
นพ.ฐสิณสั ดิษยบุตร
Structure
Biosynthesis
Glucagon
Insulin
Regulation
Pancreas
Somatostatis
Action
Receptor
Polypeptide Y
Metabolic effects
Structure
Biosynthesis
Adiponectin
Receptor
Leptin
Regulation
Adipocyte
Resistin
Action
Others
Metabolic effects
Disorders of glucose
homeostasis
Hyper
glycemia
Hypo
glycemia
Management
Diabetes
Etiology
Classification
Risk factors
Complication
Pathophysiology
Symptoms & Signs
Islets of Langerhans
60%
25%
10%
Insulin
Polypeptide hormone
Charles Best Frederick G. Banting
MW. = 5807 Dalton
(1891-1941)
51 amino acids arranged in
2 polypeptides chains ( A=21 , B=30 )
Produced by B-cells of
islets of Langerhans
การสังเคราะห์และโครงสร้างของอินสุ ลิน
C-PEPTIDE
A1 G
I
V
E
Q
C
Q L S G E L A L P Q L S G A G P G G G L E V Q
K
G
R
C T
S
C
I
A-CHAIN
A21
S L Y Q L E N Y C N COOH
V
Q
L
D
E
A
E
R
R
H2N F V N Q H L C G S H L V E A L Y L V C G E R G F F Y T P K T
B1
B30
B-CHAIN
กลไกการควบคุมการหลัง่ อินสุ ลิน
X
Regulation of Secretion
Major
Glucose +
Minor
Amino acids +
Neural input (vagus n) +
Gut hormones +
(secretin, gastrin, CCK,GIP, GLP-1
glucagon)
Epinephrine Insulin -
Insulin
Regulation of
Secretion
ระดับการหลั่ง insulin
เมื่อมีการเปลี่ยนแปลง
ระดับกลูโคสในเลือด
ระดับอินส ุลินในพลาสมา (mU/mL)
การเพิ่มของระดับ insulin ในเลือด
ภายหลังการเพิ่มของระดับนา้ ตาล
มากกว่ าปกติ 2-3 เท่ าอย่ างรวดเร็ว
20
ปริมาณการหลัง่ อินส ุลิน
(จานวนเท่าของปกติ)
100
15
80
60
10
40
20
0
-10
0
10
20
30 40 50
เวลา (นาที)
60
70
80
5
0
0
100
200
300
400
ระดับกล ูโคสในพลาสมา
(mg/100mL)
500
600
α unit (outer membrane)
Insulin receptor
β unit (transmembrane)
Insulin
alpha
beta
Tyrosine
Stimulation of
glucose transport
Insulin receptor
Insulin binding activates
receptor tyrosine kinase activity
Reversal of
Glucagonbeta
Stimulated
phosphorylation
Phosphorylation
Of proteins
Induction &
Insulin
signaling
of
and action Repression
Specific genes
Insulin-receptor
complex
Tyrosine- P
Protein Protein kinases-P
kinases
Biologic effects
Insulin internalization
Richard A Roth: Diabetes Mellitus: A Fundamental and Clinical Text, 3rd Edition
Glucose transporters
Active
transport
Glucose transporter (GLUT )
Insulin
sensitive
Insulin
insensitive
Facillitated
transport
Most tissues
eg. muscle , adipose
Epithelium of
intestinal ,
renal tubule ,
choroid plexus
Glucose-Na co-transport
RBC , WBC
lens of eye
cornea , liver
brain
Glucose transporter (GLUT)
GLUT
Tissue/Organ
GLUT-1
RBC, endothelial cells and other cells
GLUT-2
(bidirectional) Renal tubular cell, intestinal
epithelial cell, liver, pancreas
Neurons, placenta
GLUT-3
GLUT-4
Adipose tissue, striated muscle
insulin
Glucagon
Glucose
depletion
Glucagon release
Glucagon
Regulation of Secretion
Major
Glucose Insulin Amino acid +
Minor
Cortisol +
Neural (stress) +
Gut hormones +
Epinephrine +
+ = stimulates
- = inhibits
glucagon
Insulin and glucagon effect on carbohydrate metabolism
Enzyme
Activity
Insulin
Glucagon
Gluconeogenesis and glucose export
Glucose-6-phosphatase
Fructose-1,6-bisphosphatase
PEPCK
Pyruvate
Glucokinase
6-phosphofructo-1-kinase
Pyruvate kinase
Glycolysis and glucose oxidation
Somatostatin
Secrete from delta cell of
pancreas, stomach intestine
and periventricular nucleus
of hypothalamus
Somatostatin action
Inhibitory hormone
Brain (anterior pituitary)
- Inhibit Growth hormone release
- Inhibit TSH
Gastrointestinal tract
- Suppress the release of gastrin, cholecystokinin, motilin,
secretin, vasoactive intestinal peptide, gastric inhibitory
peptide
- Inhibit both insulin and glucagon release
- Suppress pancreatic enzyme release
- Decrease gastric emptying rate, reduce GI muscle
contraction and blood flow
Somatostatin action
Adiponectin
Energy metabolism
• Adiponectin level
inversely correlate with
adipose tissue percentage
• Impair adipocyte
differentiation
• Increase energy
expenditure
• Increase fatty acid ebetaoxidation and reduce fat
mass
• Inhibit hepatic
gluconeogenesis
Anti-inflammatory response
• Inversely correlate with
inflammatory cytokines
• Suppress DM, obesity,
atherosclerosis. NASH
• Reduce insulin resistance
Adiponectin
Herbert Tilg1 and Alexander R. Moschen. Adipocytokines: mediators linking adipose
tissue, inflammation and immunity. Nature Reviews Immunology 6, 772-783
Herbert Tilg1 and Alexander R. Moschen. Adipocytokines: mediators linking
adipose tissue, inflammation and immunity. Nature Reviews
Immunology 6, 772-783
Resistin
Inflammatory response
• Increase inflammatory
cytokine production (IL-1,
IL-6, IL-12, TNF-α, NFkB)
• Up-regulate adhesion
molecule (ICAM1,
VCAM1)
• Correlate with chronic
inflammation
Inflammatory response
• Strongly correlate with
obesity
• Associates with insulin
resistance
• Central resistin increases
glucose-induced insulin
secretion and beta-cell mass,
leading to hyperinsulinemia,
insulin resistance and allow
body to adapt for obesity,
while maintaining normal
glucose level in DM
Central resistin nullifies central leptin action, induces hyperinsulinemia, and prevents
obesity.
Burcelin R Endocrinology 2008;149:443-444
Resistin
Effects of resistin
Daniel R. Human resistin: found in translation from mouse to
man. Trend in Endo and Metabo: 22(7) 2011: 259-265
Adipose hormones in summary
Ana Bertha Zavalza-Gómez. Adipokines and insulin resistance during
pregnancy. Diabetes Research and Clinical Practice: 80(1) 2008, 8–15
Tilg and Moschen Nature Reviews Immunology 6, 772–783 (October 2006) |
doi:10.1038/nri1937
Diabetes mellitus
Hypoglycemia
Type 1
(beta-cell destruction, usually leading to absolute insulin deficiency
Autoimmune
Idiopathic
Type 2
(may range from predominantly insulin resistance with relative insulin
deficiency to a predominantly secretory defect with or without insulin
resistance)
Other specific types : Genetic defects of beta-cell function
Genetic defects in insulin action
Diseases of the exocrine pancreas
Endocrinopathies
Drug- or chemical-induced
Uncommon forms of immune-mediated diabetes
Infections
Other genetic syndromes sometimes associated with diabetes
Gestational diabetes
Impaired Fasting glucose and Impaired glucose tolerance
The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus*, Report of the Expert
Committee on the Diagnosis and Classification of Diabetes Mellitus
Diabetes Mellitus
DM
Diagnosis
1. Symptoms
2. Risk factors : Family history
obesity, hyperlipidemia etc.
FPG (mg/dl)
Normal
IFG
<110
110-125
2-hr OGTT
<140
Random PG
<160
IGT
DM.
>125 (2 times)
140-200
>200+clinical
>200+clinical
H2O
Glucose
Glucose
Sorbitol
[Sorbitol]
Sorbitol
Theory
Fructose
Non-Enzymatic Glycosylation of Protein (Glycation)
หมู่ carbonyl อิสระของ glucose จะ ทาปฏิกิริยาอย่ างช้ า ๆ กับ
หมู่ a amino ของ ปลาย N-terminal และ e-amino ของ lysine
ปลายอะมิโน
ของสายโกลบิน
Val-NH2
CH2OH
O OH
OH
HO
OH
กลูโคส
Val- N
H C
H C OH
HO C H
H C OH
H C OH
CH2OH
Unstable schiff base
almidine pre-HbA1c
Amadori
rearrangement
Val- N H
H2 C
C O
HO C H
H C OH
H C OH
CH2OH
Stable Ketoamine
HbA1c
Glycated hemoglobin
HbA1C
Fructosamine
Insulin resistance
Maintenance of
Blood Glucose levels
Glycogen
AA
Glycerol
Lactate
Dietary CHO
Fasting : 12 hrs
( glycogenolysis )
Glucose
Glucose
Gut
Fed
Glucose
Glycerol
AA
Lactate
Brain
RBC
Other tissues
Starved : 30 hrs
( gluconeogenesis )
low blood glucose
pituitary
ACTH
hypothalamic
regulatory
center
ANS
pancreas
adrenal
A cells
cortisol epinephrine norepineprine
glucagon
Actions of the
Glucoregulatory hormones
Hypoglycemia
Definition plasma glucose < 60 mg/dl
Symptomatic plasma glucose < 45 mg/dl
Symptoms
1. Adrenergic overactivity
2. Neuroglycopenia
•
Acute neuroglycopenia
•
Subacute neuroglycopenia
•
Chronic neuroglycopenia
Finish