endocrine pancreas adipose hormores diabetes mellitus and hypoglycemia
DESCRIPTION
Endocrine Pancreas Adipose hormores Diabetes mellitus and hypoglycemia. นพ.ฐสิณัส ดิษยบุตร. Structure. Insulin. Biosynthesis. Regulation. Pancreas. Somatostatis. Glucagon. Action. Metabolic effects. Receptor. Polypeptide Y. Structure. Leptin. Biosynthesis. Regulation. Adipocyte. - PowerPoint PPT PresentationTRANSCRIPT
Endocrine Pancreas Adipose hormoresDiabetes mellitus and hypoglycemia
นพ.ฐสณส ดษยบตร
Insulin
Glucagon Somatostatis
Polypeptide Y
Pancreas
Biosynthesis
Structure Regul
ation
ActionRecep
torMetabolic
effects
LeptinAdiponecti
n Resistin
Others
Adipocyte
Biosynthesis
Structure Regul
ationActionRecep
tor
Metabolic effects
Disorders of glucose homeostasis
Diabetes
Hyper
glycemia
Hypoglycemia
Etiology
Classification Risk
factorsSymptoms & Signs
Pathophysiology
Complication
Management
Islets of Langerhans
60% 25% 10%
InsulinFrederick G. Banting
(1891-1941)
Polypeptide hormone MW. = 5807 Dalton 51 amino acids arranged in 2 polypeptides chains ( A=21 , B=30 ) Produced by B-cells of islets of Langerhans
Charles Best
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 RREAE
G
DLQV
NV
NQ
GRK Q L S G E L A L P Q L S G A G P G G G L E V Q
I
ECC T S
IC
S L Y Q L E Y C
C- PEPTIDE
A- CHAIN
B- CHAI NH2N
COOH
A1
A21
B1 B30
การสงเคราะหและโครงสรางของอนสลน
กลไกการควบคมการหลงอนสลน
X
Regulation of Secretion
Major Minor
Glucose + Amino acids + Neural input (vagus n) + Gut hormones + (secretin, gastrin, CCK,GIP, GLP-1 glucagon) Epinephrine - Insulin -
Insulin
-10 0 10 20 30 40 50 60 70 80เวลา (นาท)
ระดบ
อนสล
นในพ
ลาสม
า (m
U/m
L)
100
80
60
40
20
0
การเพมของระดบ insulin ในเลอดภายหลงการเพมของระดบนำ"าตาลมากกวาปกต - 23 เทาอยางรวดเรว
ระดบกลโคสในพลาสมา(mg/100mL)
ปรมา
ณกา
รหลง
อนสล
น(จ
ำานวน
เทาข
องปก
ต)
0 100 200 300 400 500 600
20
15
10
5
0
ระดบการหลง insulin เมอมการเปลยนแปลงระดบกลโคสในเลอด
Regulation of Secretion
Insulin receptorα unit (outer membrane)
β unit (transmembrane)
Insulin Insulin receptor
alpha
beta
Tyrosine
Insulin binding activatesreceptor tyrosine kinase activity
Biologic effects
Protein kinases
Protein kinases-P
beta
Tyrosine- P
Insulin-receptor complex
Induction &Repression ofSpecific genes
Reversal ofGlucagon-Stimulatedphosphorylation
Stimulation of glucose transport
PhosphorylationOf proteinsInsulin signaling and action
Insulin internalization
Richard A Roth: Diabetes Mellitus: A Fundamental and Clinical Text, 3rd Edition
Glucose transporters
Active transport
Facillitatedtransport
Insulinsensitive
Insulininsensitive
Most tissueseg. muscle , adipose
Epithelium of intestinal ,renal tubule ,choroid plexus
RBC , WBClens of eyecornea , liverbrain
Glucose transporter (GLUT )
Glucose-Na co-transport
Glucose transporter (GLUT)
GLUT Tissue/OrganGLUT-1 RBC, endothelial cells and other cellsGLUT-2 (bidirectional) Renal tubular cell, intestinal
epithelial cell, liver, pancreasGLUT-3 Neurons, placentaGLUT-4 Adipose tissue, striated muscle
insulin
Glucagon
Glucose
depletion
Glucagon release
GlucagonRegulation of Secretion
Major Minor
Glucose -Insulin -Amino acid +
Cortisol + Neural (stress) + Gut hormones + Epinephrine +
+ = stimulates - = inhibits
glucagon
Enzyme Activity Insulin Glucagon
Gluconeogenesis and glucose exportGlucose-6-phosphataseFructose-1,6-bisphosphatasePEPCK
PyruvateGlucokinase6-phosphofructo-1-kinasePyruvate kinase
Glycolysis and glucose oxidation
Insulin and glucagon effect on carbohydrate metabolism
Somatostatin
Secrete from delta cell of pancreas, stomach intestine and periventricular nucleus of hypothalamus
Somatostatin actionInhibitory 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 ebeta-oxidation 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, NF-kB)
• 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
Daniel R. Human resistin: found in translation from mouse to man. Trend in Endo and Metabo: 22(7) 2011: 259-265
Effects of resistin
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 diabetesImpaired 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. Symptoms2. Risk factors : Family history obesity, hyperlipidemia etc.
Normal IFG IGT DM.
FPG (mg/dl) <110 110-125 >125 (2 times)
2-hr OGTT <140 140-200 >200+clinical
Random PG <160 >200+clinical
Sorbitol Theory
Glucose Glucose Sorbitol Fructose
[Sorbitol]
H2O
Non-Enzymatic Glycosylation of Protein (Glycation)
หม carbonyl อสระของ g lucose จะ ทำาปฏกรยาอยางชา ๆ กบหม a amino ของ ปลาย N-terminal และ e-amino ของ lysine
Val-NH2
ปลายอะมโนของสายโกลบน
O OH
OH
OH
HO
CH2OH
กลโคสStable KetoamineHbA1c
Amadorirearrangement
Unstable schiff basealmidine pre-HbA1c
Val- N H C H C OH HO C H H C OH H C OH CH2OH
Val- N H H2C C O HO C H H C OH H C OH CH2OH
Glycated hemoglobin
HbA1C
Fructosamine
Insulin resistance
Maintenance of Blood Glucose levels
Fed
Gut
Dietary CHO
Glucose
Fasting : 12 hrs( glycogenolysis )
Glycogen
GlycerolAA
Lactate Glucose
BrainRBCOther tissuesGlucose
GlycerolAALactate
Starved : 30 hrs( gluconeogenesis )
Glucoregulatory hormones
low blood glucose
hypothalamic regulatorycenter
pituitary
ACTH
adrenal
Actions of the cortisol epinephrine norepineprine glucagon
ANS
pancreas
A cells
HypoglycemiaDefinition plasma glucose < 60 mg/dl
Symptomatic plasma glucose < 45 mg/dl
Symptoms
1. Adrenergic overactivity
2. Neuroglycopenia
• Acute neuroglycopenia
• Subacute neuroglycopenia
• Chronic neuroglycopenia
Finish