Insulin and the regulation of plasma glucose

1. Insulin and the regulation of plasma glucose Guo Xiaosun guoxiaosun@126.com Shandong University

2. Part 1 Introduction Circulating glucose level are maintained within tight limits, which requires a complex control system.

3. Importance of Glucose Regulation • Too little – Brain problems • Too much • Osmotic water loss (cellular and systemic) • Damages blood vessels fluorodeoxyglucose-positron-emission tomography, FDG-PET

4. Glucose in urine

5. Anatomy of the pancreas

7. The functions of pancreas • 1.Exocrine function: pancreatic juice • 2. Endocrine function: hormones

8. The endocrine pancreas

9. Hormones of endocrine pancreas 胰岛激素与血糖 （＋） （－）

10. Part 2 Insulin and the response to high blood glucose levels

11. Insulin discovered byFrederick Banting and Charles Best in 1921. Leonard Thompson first patient successfully treated. 1965/9/17it is the first protein synthesized by Chinese scientists . Leonard Thompson (1908–1935) Before and after receiving insulin (McCormick)

12. 51 amino acids • 2 chains linked by disulfide bonds • 5800 Dalton molecular weight

13. Synthesis and secretion

14. Insulin in blood • 1. No specific carrier • 2. Half life:3-5 min • 3. Normal fasting level is within a tight range • 4. Changed in response to food intake.

15. Effects of Insulin • Nearly all cells (80%) increase glucose uptake (seconds) • Active transport • Primarily affects liver and muscle • Brain tissue is excepted • Alters phosphorylation of many key intracellular metabolic enzymes (minutes) • Alters protein synthesis and gene transcription (hours)

18. Insulin Affects Tissues Differently • Muscle • Uptake of glucose and immediate use (exercise) or storage as glycogen (Exercising muscles can take up glucose without insulin) • Inhibits glycogen breakdown • Liver • Uptake of glucose and storage as glycogen. • Inhibits glycogen breakdown • Inhibits gluconeogenesis. • Adipose Tissue • Promotes glucose uptake and conversion to glycerol for fat production

19. Insulin and Fat Metabolism • Liver cells store glycogen only up to 5-6% • Remaining glucose metabolized to fat • Triglycerides are synthesized and release into blood • Inhibits breakdown of fatty acids to ketones. • Adipose cells store fat • Inhibits breakdown of triglycerides • Stimulates uptake and use of glucose to form glycerol • Stimulates fatty acid uptake and conversion to triglycerides • Lack of insulin • Free fatty acids build up in blood • Liver metabolizes to produce phospholipids and cholesterol • Can lead to excess acetoacetic acid production and buildup of acetone (acidosis, which can lead to blindness and coma)

20. Insulin and Protein Metabolism • Promotes • Transport of amino acids • Protein synthesis • Gene transcription • Inhibits protein degradation • Prevents glucose synthesis in liver • Inhibits breakdown of amino acids to form glucose. • Decreases urea formation • Lack of insulin causes elimination of protein stores

21. Most Cells  Protein synthesis Insulin Control  amino acids Muscle  Glucose uptake  Glycogen synthesis Gastrointestinal hormones • Adipose • Glucose uptake • Glycerol production • Triglyceride breakdown •  Triglyceride synthesis  triglycerides Amino acids Pancreas Beta cells  Insulin • Liver •  Glucose uptake • Glycogen synthesis • Fatty acid synthesis • Glucose synthesis Bloodglucose  glucose Brain No effect Feedback

22. Regulation of insulin secretion 1. Plasma glucose concentration 2. Others: Ach, bombesin, GLP1

25. Part 3 Hormones that act to raise blood glucose levels Glucagon Other hormones

26. Glucagon 1. α cell 2. 29-amino-acid peptide 3. Response to low glucose levels 4. Effects: on liver, blood glucose↑ (1)Increase glycogenolysis (2)Stimulate gluconeogenesis (3)stimulate lipolysis (4)cell uptake Glu and amino ↓ Glycolysis ↓

28. Glucagon Control • Adipose • Triglyceride breakdown • Triglyceride storage  Fatty acids Exercise Amino acids Pancreas Alpha cells • Liver •  Glycogen breakdown • Glucose synthesis •  Glucose release  Blood glucose Epinephrine (stress) Brain No effect Feedback

29. Other hormones that act to raise blood glucose 1. Growth hormone 2. Glucocorticiods 3. Catecholamine

30. Regulation of hormones on blood glucose

31. Importance of Glucose Regulation • Too little – Brain problems • Too much • Osmotic water loss (cellular and systemic) • Damages blood vessels

32. Part 4 Disorders of bloodglucose regulation: Diabetes mellitus

33. case • Robert ,male,18y. • tired, large volume of urine, thirst, losing weight, his breath smelled ketotic. • PE: W 60kg, H 1.75m, pulse 90b.p.m, BP 115/75mmHg • Lab: Urine: glucose +++, ketones++

34. DM (diabetes mellitus) Characteristics: Chronic hyperglycemia Metabolism disturbance Main symptoms: • Polydipsia • Continuous hunger • Polyuria • Weight loss Cause: inadequate production and/or action of insulin

35. 全球糖尿病流行趋势2000--2025

36. Classification of Diabetes Mellitus（ADA 1997） • Type 1 diabetes • A. Immune mediated • B. Idiopathic • Type 2 diabetes • Other specific types • Gestational diabetes mellitus

38. Oral glucose tolerance test Aim: to confirm DM. Method: to measure how the body deals with glucose load.

39. 7.0 6.1 5.6 7.8 11.1 FPG (mmol/l) CH IFH I-IFG IFG+IGT IPH I-IGT 2hr PPG(mmol/l)

40. IFG（impaired fasting glucose） • IGT（impaired glucose tolerance）

41. Type1 diabetes: insulin deficiency

42. Cause of type1 diabetes • Β cell destruction • (1) Genetic predisposition: HLA gene • (2) Environmental challenge: inflammation of B cell and attacked by immune system

44. Results of type1 diatebes • Hyperglycemia • The body response as hypoglycemia • Glycosuria • Ketone bodies↑ • Kussmaul’s respiration • May lead to ketoacidosis • Growth Failure in children

45. 胰 岛 素↓ 葡 萄 糖 利 用↓ 蛋白质分解↑ 脂肪分解↑ 糖氧化↓ 血 糖↑ 酮体生成↑ 能量不足 ＞肾糖阈 脱水 酮血症 饥饿感 高渗性利尿 酮 尿 酸中毒 昏 迷 多尿 (尿糖) 口渴 体重↓ 多食 多饮

46. Complications of type1 diatebes Diabetic ketoacidosis

47. Complications of type1 diatebes Hypoglycemic coma • Cause • Prevention • Treatment

48. Laboratory Examinations • blood • Glucose • ketone body • HbA1c • FIM • Insulin、Cpeptide、insulin autoantibody • Oral glucose tolerance test ， • IVGTT • C peptide release test • Urine • glucose • ketone body • trace protein

49. Comprehensive Diabetes Management Plan • Diet • Exercise • Pharmacologic therapy • Monitoring of Blood Glucese • Patient Education

50. Management of type1 diatebes Appropriate diet • (1) several small regular meal than one large meal • (2) low in fat and simple carbohydrates • carbohydrates 50-60%， fat 20-25%，protein15-20% • (3) high vegetables and fruits • (4) avoid alcohol Appropriate Exercise • Walk is safe.