Pancreatic Hormones. Aims ส ว ฒณ ค ปต ว ฒ ต กจ ฑาธ ช ห อง 111

Transcription

1 Pancreatic Hormones ส ว ฒณ ค ปต ว ฒ ต กจ ฑาธ ช ห อง 111 Aims Pancreatic hormones Insulin Glucagon Describe the fundamental physiological mechanisms controlling of the secretion of insulin and glucagon into the blood stream. Understand the effects of insulin and glucagon on glucose, fatty acid, and amino acid metabolism in the various body tissues. 1

2 Anatomy and histological of pancreas Exocrine gland: enzymes Islet of langerhans: Insulin, Glucagon Islet of Langerhans Parasympathetic fibers A, α % Glucagon B, β 60-80% Insulin B cells Sympathetic fibers D, σ 8% Somatostatin D cells A cells F 2% Pancreatic polypeptide 2

3 Chain A: 21 aa Disulfide bridge Chain B: 30 aa Insulin Peptide hormone MW

4 Rough ER Vesicle Preproinsulin Proinsulin Insulin processing Insulin : C peptide 1:1 Golgi Processing in vesicles Cleavage of proinsulin Insulin secretion Insulin C peptide Clinical Application Hemoglobin A1C (HbA1C) Glycosylated hemoglobin Glucose Hemoglobin HbA1C HbA1C lives for 8-12 wks Normal value for HbA1C = mm 4

5 Controlled diabetes, not much glucose, not much glycosylated haemoglobin Uncontrolled diabetes, more glucose, much more glycosylated haemoglobin Factor affecting insulin secretion Glucose Amino acids GI hormones Mixed meal Diabetogenic H Parasympathetic β cells Sympathetic Insulin Somatostatin Insulin 5

6 Normal blood glucose 100 mg/dl (3-5 mm) Basal plasma insulin concentration microu/ml Glucose 1 st phase Meals 2 nd phase Insulin Glucose 6

7 Glucose- induced insulin secretion G ATP Ca 2+ Ca 2+ Ca 2+ Insulin secretion ATP dependent Non ATP dependent 7

8 Insulin secretion GLP-1 M2 receptor NEFA GRP40 Incretin effect Incretins: GLP-1, GIP B-cells + Glucose Insulin secretion 8

9 Insulin transport Insulin (peptide hormone) Dissolve in blood plasma Half life of insulin is less than 10 minutes Insulin Action on Cells: Dominates in Fed State Metabolism 9

10 Insulin signaling α subunit β subunit containing tyrosine kinase Insulin Insulin receptor Glucose transport Protein synthesis Lipid synthesis glycogen synthesis Growth and Gene expression Metabolic effect Glucose uptake Carbohydrate Insulin actions Facilitates glucose transport into muscle, adipose and many other tissues but not brain Stimulates glycogen production (glycogen synthesis) and inhibits glycogen breakdown (glycogenolysis) in liver and skeletal muscle Glucose usage Glycolysis 10

11 Insulin actions inhibits glucose synthesis (gluconeogenesis) in liver Protein Facilitates amino acids into muscle and other tissues Stimulates protein synthesis and inhibits protein breakdown Lipid Promotes formation of fatty acids and glycerol from glucose Insulin actions Facilitates free fatty acids into cells ( lipoprotein lipase) Promotes synthesis of triglyceride and inhibits their breakdown ( hormone sensitive lipase) 11

12 Insulin actions Growth Promotes growth of the fetus Promotes postnatal growth by inhibiting protein degradation Needed for promotion of IGFs Insulin actions Protein Amino acid uptake & protein synthesis Amino acid output & amino acid oxidation CHO Glycogen synthesis Glycogenolysis Gluconeogenesis Hepatic glucose production Lipid Triglyceride synthesis Lipolysis 12

13 Insulin deficit Diabetes Mellitus Absolute: Insulin dependent diabetes mellitus (IDDM)/ Type I 5-10% Relative: Non insulin dependent diabetes mellitus (NIDDM)/ Type II 90-95% 95% Defect in insulin secretion Insulin resistance Receptor Postreceptor Diagnosis Diabetes Millitus ADA: American Diabetes Association A A casual plasma glucose level (taken at any time of day) of 200 mg/dl or greater when the symptoms of diabetes are present. A A fasting plasma glucose value of 126 mg/dl or greater. An OGTT value in the blood of 200 mg/dl or greater measured at the 2-hour 2 interval. 13

14 Insulin deficiency Glucose uptake Glycogenolysis Gluconeogenesis Protein breakdown Change in blood Change in urine Sign and symptoms Plasma glucose (hyperglycemia) Glucose in urine (glycosuria) Osmotic diuresis Frequency of urination (polyurea) Dehydration, Thirst (polydipsia) Food consumption (polyphagia) Weight loss Insulin deficiency Lipolysis Change in blood Change in urine Plasma lipid used as fuel Ketosis Ketones in the urine (ketonurea) 14

15 Signs and symptoms of diabetes mellitus Hyperglycemia Glucosuria (Osmotic diuresis) Hyperlipidemia Ketonemia Protein wasting Weight loss Insulin excess Over dose insulin Insulinoma Hypoglycemia Neuroglycopenia Hunger Dizziness Coma Cathecolamine: anxiety, sweating, tachycardia 15

16 Glucagon 29 amino acids identical to enteroglucagon Glucagon act by binding to its receptor and activated G protein which cause an increase in camp. Glucagon has the effect of increasing blood glucose levels (opposite( effect of insulin) 16

17 Enteroglucagon Factor affecting glucagon secretion 17

18 Glucagon actions Metabolic effect Carbohydrate Stimulates breakdown of glycogen stored in the Liver and inhibits glycogen synthesis Stimulates gluconeogenesis in the liver Glucagon actions Protein Stimulates amino acids uptake in the liver Stimulates protein breakdown and inhibits protein synthesis 18

19 Glucagon actions Lipid Stimulates lipolysis in fat and liver Stimulates ketone formation in the liver Glucagon actions CHO Glycogen synthesis Glycogenolysis Lipid Lipolysis Gluconeogenesis Hepatic glucose production 19

20 Insulin & Glucagon Regulate Metabolism Fed state insulin dominates Insulin & Glucagon Regulate Metabolism Fast state glucagon dominates 20

21 Low blood glucose High blood glucose Glucagon released by A cells of pancreas Insulin released by B cells of pancreas Liver releases Glucose into blood Fat cells take in glucose from blood Achieve Normal blood Glucose levels 21

22 Insulin and glucagon cause the tight control of blood glucose concentration Catecholamines Corticosteroids Growth H Counter regulatory hormone Glucagon excess and deficit are rare Glucagon excess: cancer of alpha cells (glucagonomas) There is no report of glucagon deficit. 22

23 Somatostatin Somatotrophin-release inhibiting factor (SRIF) Also found in nerve terminals and other tissues. Somatostatin is a local inhibitor of insulin and glucagon secretion. Also function as a neurotransmitter/ neuromodulator in the control of moter activity and cognitive functions. Pancreatic polypeptide (PP) 36 amino acids Secretion of PP is mainly under autonomic control. PP is released following feeding or during hypoglycaemia Role of PP is still not understood. 23