Endocrine Pancreas Adipose hormoresDiabetes mellitus and hypoglycemia

นพ.ฐสิ�ณั�สิ ดิ�ษยบุ ตร

Insulin

GlucagonSomatosta

tis

Polypeptide Y

Pancreas

Biosynthesis

Structure Regul

ation

Action

Receptor

Metabolic effects

Leptin

Adiponectin

Resistin

Others

Adipocyte

Biosynthesis

Structure Regul

ation

ActionRecep

tor

Metabolic effects

Disorders of glucose homeostasis

Diabetes

Hyper

glycemia

Hypoglycemia

Etiology

Classification Risk

factors

Symptoms & 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 TR

REAE

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

E

CC T S

IC

S L Y Q L E Y C

C- PEPTIDE

A- CHAIN

B- CHAIN

H2N

COOH

A1

A21

B1 B30

การสั�งเคราะห์�และโครงสัร�างของอ�นสั�ล�น

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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 (นาที�)

ระดิ�บุ

อิ�นสิ ล

�นในพ

ลาสิม

า (m

U/m

L)

100

80

60

40

20

0

การเพ��มขอิงระดิ�บุ insulin ในเล�อิดิภายหล�งการเพ��มขอิงระดิ�บุน!"าตาลมากกว#าปกต� - 23 เที#าอิย#างรวดิเร&ว

ระดิ�บุกล'โคสิในพลาสิมา(mg/100mL)

ปร�มา

ณักา

รหล� �ง

อิ�นสิ ล

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อิงปก

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0 100 200 300 400 500 600

20

15

10

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ระดิ�บุการหล��ง insulin เม��อิม�การเปล��ยนแปลงระดิ�บุกล'โคสิในเล�อิดิ

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 cells

GLUT-2 (bidirectional) Renal tubular cell, intestinal epithelial cell, liver, pancreas

GLUT-3 Neurons, placenta

GLUT-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 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 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 อิ�สิระขอิง g lucose จำะ ที!าปฏิ�ก�ร�ยาอิย#างช้.า ๆ ก�บุหม'# a amino ขอิง ปลาย N-terminal และ e-amino ขอิง lysine

Val-NH2

ปลายอิะม�โนขอิงสิายโกลบุ�น

O OH

OH

OH

HO

CH2OH

กล'โคสิStable 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 tissues

Glucose

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

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