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Endocrine Pancreas Adipose hormores Diabetes mellitus and hypoglycemia

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Presentation on theme: "Endocrine Pancreas Adipose hormores Diabetes mellitus and hypoglycemia"— Presentation transcript:

1 Endocrine Pancreas Adipose hormores Diabetes mellitus and hypoglycemia
นพ.ฐสิณัส ดิษยบุตร

2 Metabolic effects Metabolic effects
Structure Insulin Biosynthesis Regulation Glucagon Pancreas Somatostatis Action Receptor Metabolic effects Polypeptide Y Structure Leptin Biosynthesis Regulation Adiponectin Adipocyte Resistin Action Metabolic effects Receptor Others

3 Disorders of glucose homeostasis
Hypo glycemia Hyper glycemia Management Diabetes Etiology Complication Pathophysiology Classification Symptoms & Signs Risk factors

4 Islets of Langerhans 60% 25% 10%

5 Insulin Polypeptide hormone MW. = 5807 Dalton
Frederick G. Banting ( ) 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

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7 การสังเคราะห์และโครงสร้างของอินสุลิน

8 กลไกการควบคุมการหลั่งอินสุลิน
X

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11 Regulation of Secretion
Major Minor Glucose + Amino acids + Neural input (vagus n) + Gut hormones + (secretin, gastrin, CCK,GIP, GLP-1 glucagon) Epinephrine - Insulin -

12 ปริมาณการหลั่งอินสุลิน
Insulin Regulation of Secretion ระดับการหลั่ง insulin เมื่อมีการเปลี่ยนแปลง ระดับกลูโคสในเลือด การเพิ่มของระดับ insulin ในเลือด ภายหลังการเพิ่มของระดับน้ำตาล มากกว่าปกติ 2-3 เท่าอย่างรวดเร็ว ระดับกลูโคสในพลาสมา (mg/100mL) ปริมาณการหลั่งอินสุลิน (จำนวนเท่าของปกติ) 20 15 10 5 เวลา (นาที) ระดับอินสุลินในพลาสมา (mU/mL) 100 80 60 40 20

13 α unit (outer membrane)
Insulin receptor β unit (transmembrane)

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16 Insulin signaling and action
Insulin receptor Insulin binding activates receptor tyrosine kinase activity alpha beta Tyrosine beta Tyrosine- P Insulin-receptor complex Reversal of Glucagon- Stimulated phosphorylation Stimulation of glucose transport Protein kinases Protein kinases-P Phosphorylation Of proteins Insulin signaling and action Induction & Repression of Specific genes Biologic effects

17 Insulin internalization
Richard A Roth: Diabetes Mellitus: A Fundamental and Clinical Text, 3rd Edition

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19 Glucose transporters Active Facillitated transport transport Insulin
Glucose transporter (GLUT ) Insulin sensitive Most tissues eg. muscle , adipose Epithelium of intestinal , renal tubule , choroid plexus RBC , WBC lens of eye cornea , liver brain Insulin insensitive Glucose-Na co-transport

20 Glucose transporter (GLUT)
Tissue/Organ GLUT-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

21 insulin

22 Glucagon

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24 Glucose depletion Glucagon release

25 Glucagon Regulation of Secretion Major Minor Cortisol + Glucose -
Neural (stress) + Gut hormones + Epinephrine Glucose - Insulin - Amino acid + + = stimulates = inhibits

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27 glucagon

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32 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

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35 Somatostatin Secrete from delta cell of pancreas, stomach intestine and periventricular nucleus of hypothalamus

36 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

37 Somatostatin action

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40 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

41 Adiponectin  Adiponectin interacts with at least two known cellular receptors (ADIPOR1 and ADIPOR2). Activation of ADIPOR1 and/or ADIPOR2 by adiponectin stimulates the activation of peroxisome-proliferator-activated receptor- (PPAR), AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase33. Adiponectin regulates the expression of several pro- and anti-inflammatory cytokines. Its main anti-inflammatory function might be related to its capacity to suppress the synthesis of tumour-necrosis factor (TNF) and interferon- (IFN) and to induce the production of anti-inflammatory cytokines such as interleukin-10 (IL-10) and IL-1 receptor antagonist (IL-1RA). Activation of PPARs exerts anti-inflammatory effects through inhibition of the transcriptional activation of pro-inflammatory response genes. ACC, acetyl-CoA carboxylase; GLUT4, glucose transporter type 4; IKK, inhibitor of nuclear factor-B (IB) kinase; NF-B, nuclear factor-B; PPRE, peroxisome-proliferator response element; SREBP1C, sterol-regulatory-element-binding protein 1C; TNFR, TNF receptor. Herbert Tilg1 and Alexander R. Moschen. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nature Reviews Immunology 6, 

42 Herbert Tilg1 and Alexander R. Moschen
Herbert Tilg1 and Alexander R. Moschen. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nature Reviews Immunology 6, 

43 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

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45 Central resistin nullifies central leptin action, induces hyperinsulinemia, and prevents obesity.
Central resistin nullifies central leptin action, induces hyperinsulinemia, and prevents obesity. Left, Schematic representation of main physiological central leptin actions. When secreted by adipocytes, leptin (blue arrow) reaches the brain and inhibits β-cell function (red arrow) but increases muscle insulin sensitivity (green arrow). Right, Resistin (red arrow), when secreted by adipocytes, reaches the hypothalamus and inhibits central leptin signaling. Consequently, β-cell function is maintained (green arrow), and hyperinsulinemia is induced and prevents the occurrence of diabetes. In both cases, leptin and resistin prevent the occurrence of hyperglycemia. Burcelin R Endocrinology 2008;149:

46 Resistin

47 Effects of resistin Daniel R.  Human resistin: found in translation from mouse to man. Trend in Endo and Metabo: 22(7) 2011:

48 Adipose hormones in summary

49 Ana Bertha Zavalza-Gómez
Ana Bertha Zavalza-Gómez. Adipokines and insulin resistance during pregnancy. Diabetes Research and Clinical Practice: 80(1) 2008, 8–15

50 Tilg and Moschen Nature Reviews Immunology 6, 772–783 (October 2006) |
doi: /nri1937

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52 Diabetes mellitus Hypoglycemia

53 (beta-cell destruction, usually leading to absolute insulin deficiency
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

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55 Diabetes Mellitus

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60 DM Normal IFG IGT DM. Diagnosis 1. Symptoms
2. Risk factors : Family history obesity, hyperlipidemia etc. Normal IFG IGT DM. FPG (mg/dl) < >125 (2 times) 2-hr OGTT < >200+clinical Random PG < >200+clinical

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63 H2O Glucose Sorbitol Fructose [Sorbitol] Sorbitol Theory

64 หมู่ carbonyl อิสระของ glucose จะ ทำปฏิกิริยาอย่างช้า ๆ กับ
Non-Enzymatic Glycosylation of Protein (Glycation) หมู่ carbonyl อิสระของ glucose จะ ทำปฏิกิริยาอย่างช้า ๆ กับ หมู่ a amino ของ ปลาย N-terminal และ e-amino ของ lysine Val-NH2 ปลายอะมิโน ของสายโกลบิน O OH HO CH2OH กลูโคส Stable Ketoamine HbA1c Amadori rearrangement Unstable schiff base almidine pre-HbA1c Val- N H C H C OH HO C H Val- N H H2C C O

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66 Glycated hemoglobin HbA1C

67 Fructosamine

68 Insulin resistance

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70 Maintenance of Blood Glucose levels Fasting : 12 hrs
Glycogen Fasting : 12 hrs ( glycogenolysis ) Dietary CHO AA Glycerol Lactate Glucose Glucose Gut Brain RBC Other tissues Fed Glucose Glycerol Starved : 30 hrs ( gluconeogenesis ) AA Lactate

71 Glucoregulatory hormones
low blood glucose hypothalamic regulatory center pituitary ANS ACTH pancreas adrenal A cells cortisol epinephrine norepineprine glucagon Actions of the Glucoregulatory hormones

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73 Hypoglycemia Definition plasma glucose < 60 mg/dl
Symptomatic plasma glucose < 45 mg/dl

74 Symptoms Adrenergic overactivity Neuroglycopenia Acute neuroglycopenia
Subacute neuroglycopenia Chronic neuroglycopenia

75 Finish


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