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

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Presentation on theme: "Endocrine Pancreas Adipose hormores Diabetes mellitus and hypoglycemia นพ. ฐสิณัส ดิษยบุตร."— Presentation transcript:

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

2 Insulin Glucagon Somatostatis Polypeptide Y Pancreas Biosyn thesis Structu re Regula tion Action Recept or Metabolic effects Leptin Adiponectin Resistin Others Adipocyte Biosyn thesis Structu re Regula tion Action Recept or Metabolic effects

3 Disorders of glucose homeostasis Diabe tes Hyper glyce mia Hypo glyce mia Etiology Classific ation Risk factors Symptoms & Signs Pathophy siology Complic ation Manage ment

4 Islets of Langerhans 60% 25% 10%

5 Insulin 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 การสังเคราะห์และโครงสร้าง ของอินสุลิน

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 Insulin เวลา ( นาที ) ระดับอินสุลินในพลาสมา ( m U/mL) การเพิ่มของระดับ insulin ในเลือด ภายหลังการเพิ่มของระดับน้ำตาล มากกว่าปกติ 2-3 เท่าอย่างรวดเร็ว ระดับกลูโคสในพลาสมา (mg/100mL) ปริมาณการหลั่งอินสุลิน ( จำนวนเท่าของปกติ ) ระดับการหลั่ง insulin เมื่อมีการเปลี่ยนแปลง ระดับกลูโคสในเลือด Regulation of Secretion

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

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

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

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

20 Glucose transporter (GLUT) GLUTTissue/Organ GLUT-1RBC, endothelial cells and other cells GLUT-2(bidirectional) Renal tubular cell, intestinal epithelial cell, liver, pancreas GLUT-3Neurons, placenta GLUT-4Adipose tissue, striated muscle

21 insulin

22 Glucagon

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24 Glucose depletion Glucagon release

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

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27 gluca gon

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32 EnzymeActivity 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 Insulin and glucagon effect on carbohydrate metabolism

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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 Herbert Tilg 1 and Alexander R. Moschen. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nature Reviews Immunology 6,

42 Herbert Tilg 1 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. Burcelin R Endocrinology 2008;149:

46 Resistin

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

48 Adipose hormones in summary

49 Ana Bertha Zavalza-GómezAna Bertha Zavalza-Gómez. Adipokines and insulin resistance during pregnancy. Diabetes Research and Clinical Practice: 80(1) 2008, 8–15Diabetes Research and Clinical Practice80(1)

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

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52 Diabetes mellitus Hypoglycemia

53 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 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 Sorbitol Theory Glucose Sorbitol Fructose [Sorbitol] H2OH2O

64 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-NH 2 ปลายอะมิโน ของสายโกลบิน O OH HO CH 2 OH กลูโคส Stable Ketoamine HbA1c Amadori rearrangement Unstable schiff base almidine pre-HbA1c Val- N H C H C OH HO C H H C OH CH 2 OH Val- N H H 2 C C O HO C H H C OH CH 2 OH

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66 Glycated hemoglobin Hb A1C

67 Fructosamine

68 Insulin resistance

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

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

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

74 Symptoms 1.Adrenergic overactivity 2.Neuroglycopenia Acute neuroglycopenia Subacute neuroglycopenia Chronic neuroglycopenia

75 Finish


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