Endocrine Pancreas Adipose hormores Diabetes mellitus and hypoglycemia

1. Endocrine Pancreas Adipose hormoresDiabetes mellitus and hypoglycemia นพ.ฐสิณัส ดิษยบุตร

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

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

4. Islets of Langerhans 60% 10% 25%

5. Insulin 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 Frederick G. Banting (1891-1941) Charles Best

7. การสังเคราะห์และโครงสร้างของอินสุลินการสังเคราะห์และโครงสร้างของอินสุลิน

8. กลไกการควบคุมการหลั่งอินสุลินกลไกการควบคุมการหลั่งอินสุลิน X

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

12. 20 15 10 5 0 100 80 60 40 20 0 ปริมาณการหลั่งอินสุลิน (จำนวนเท่าของปกติ) ระดับอินสุลินในพลาสมา (mU/mL) -10 0 10 20 30 40 50 60 70 80 0 100 200 300 400 500 600 เวลา (นาที) ระดับกลูโคสในพลาสมา (mg/100mL) Insulin Regulation of Secretion ระดับการหลั่ง insulin เมื่อมีการเปลี่ยนแปลง ระดับกลูโคสในเลือด การเพิ่มของระดับ insulin ในเลือด ภายหลังการเพิ่มของระดับน้ำตาล มากกว่าปกติ 2-3 เท่าอย่างรวดเร็ว

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

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

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

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

20. Glucose transporter (GLUT)

21. insulin

22. Glucagon

24. Glucose depletion Glucagon release

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

27. glucagon

32. Insulin and glucagon effect on carbohydrate metabolism Enzyme Activity InsulinGlucagon Gluconeogenesis and glucose export Glucose-6-phosphatase Fructose-1,6-bisphosphatase PEPCK Pyruvate Glucokinase 6-phosphofructo-1-kinase Pyruvate kinase Glycolysis and glucose oxidation

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

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 Tilg1 and Alexander R. Moschen.Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nature Reviews Immunology6, 772-783

42. Herbert Tilg1 and Alexander R. Moschen.Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nature Reviews Immunology6, 772-783

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

45. Central resistin nullifies central leptin action, induces hyperinsulinemia, and prevents obesity. Burcelin R Endocrinology 2008;149:443-444

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: 259-265

48. Adipose hormones in summary

49. 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 Immunology6, 772–783 (October 2006) | doi:10.1038/nri1937