18. Pancreatic function and metabolism V BS 122 2012 Luis A. Bate

Objectives To understand the role of the pancreas in the regulation of carbohydrate metabolism To learn in depth about insulin and glucagon actions To identify tha main pathophysiologies associated with these systems (Diabetes)

Reading Chapter 78 Guyton

Pancreatic structures ISLETS OF LANGERHANS DUCTULES DUCTS PANCREATIC ACINI F18-1

Pancreatic islets F18-2

Pancreatic secretions In addition to the digestive enzymes the pancreas serves an important endocrine role Produces Insulin Glucagon Pancreatic polypeptide Somatostatin Amylin F18-3

Pancreatic islets α cells (Glucagon) β cells (Insulin, Amylin) D cells (Somatostatin) F cells (Pancreatic Polypeptide) F18-4

INSULIN Traditionally associated with carbohydrate metabolism It also affects fat and protein metabolism, specially under disease conditions Circulates in an unbound form Half-life of 6 minutes Circulating for 10 minutes after release F18-5

PROINSULIN INSULIN α chain β chain C peptide

Insulin secretion β cell Ca++ F18-6

Enzyme phosphorylation Growth and gene expression Glucose transport α α β β TK TK Enzyme phosphorylation Growth and gene expression Glucose transport Fat synthesis Glucose synthesis Protein synthesis EFFECT F18-7

GLYCOGEN PHOSPHORYLASE GLUCOSE-6 PHOSPHATASE GLYCOGEN SYNTHASE GLUCOSE GLUCOSE-6-PHOSPHATE GLUCOKINASE 6-PHOSPHOFRUCTOKINASE FRUCTOSE-1-,6-BIPHOSPHATE ALDOLASE TRIOSE PHOSPHATE PHOSPHOENOLPYRUVATE PYRUVATE KINASE PYRUVATE DEHYDROGENASE PYRUVATE ACETYL-CoA ACETYL-CoA CARBOXYLASE MALONYL-CoA FATTY ACID SYNTHASE F18-8 FFA

Use of glucose Brain tissue can only use glucose as a fuel Brain can uptake glucose from circulation independently of insulin Only few types of cells permit free transport of glucose onto themselves Brain Liver Erythrocytes F18-9

Metabolic pathways of glucose in muscle Once inside a cell, glucose is phosphorilated by the enzyme glucokinase Once phosphorilated glucose cannot cross the cell membrane (leave the cell) Unlike the liver, muscle tissues lacks glucose-6-phosphatase Cannot release glucose into circulation Can only use it for its own metabolism Storage Energy F18-10

GLYCOGEN GLUCOSE-6-PHOSPHATE GLYCOGEN GLUCOSE GLUCOSE-6-PHOSPHATE TCA GLUCOSE GLUCOSE GLUCOSE FFA GLUCOSE TCA (ENERGY) FFA F18-11

Sequence of events following insulin elevation After seconds of attachment Increased glucose uptake by cells Muscle and adipose cells not on neurons Glucose is phosphorylated Enters metabolic pathway Permeability to aa increases After 10-15 minutes Increases internal enzymes After hours or days Increases translation of mRNA F18-12

Role of insulin Lowers the circulatory concentrations of glucose, fatty acids and amino acids Enhances storage of these in large molecules Glycogen Triglycerides Proteins F18-13

Effect of insulin on carbohydrates Muscle absorption of glucose Conversion of glucose to glycogen for storage Liver uptake of glucose Conversion of glucose to glycogen for short storage Inhibition of gluconeogenesis in the liver F18-14

Effect of insulin on fat metabolism After the deposit of glycogen is full (6% liver weight) it promotes the synthesis of fat in the liver Exported to circulation as VLDL Uptake by adipose tissue Stored as fat Inhibit hormone-sensitive lipase (no FFA release from adipocytes) Promotes glucose uptake in adipocytes Synthesis of glycerol and FFA F18-15

Effect of insulin on protein metabolism Promotes protein synthesis and storage Increases uptake of amino acids Increases translation of mRNA Turns on ribosomal assembly Inhibits catabolism In liver reduces gluconeogenesis (amino acid sparing) F18-16

Effect of the lack of insulin on protein metabolism Protein storage stops Increases plasma amino acids concentration Used for gluconeogenesis Convertion to urea and excreted Overall protein wastage Causes weakness Organ malfunction F18-17

Insulin catabolism Takes place in the liver and kidney Enzyme insulinase Disulfide bonds are reduced Peptide enzymes chop chains into small peptides and amino acids F18-18

Glucagon 29 amino acid protein Produced by alpha cells Released when circulatory glucose is low Contributes to elevation of circulatory glucose F18-19

Effect of glucagon on glucose metabolism Promotes glycogenolysis Through a complex enzymatic cascade Increases gluconeogenesis in the liver Promotes amino acid uptake Convert them to glucose F18-20

Regulation of circulatory glucose HYPERGLYCEMIA HYPOGLYCEMIA α β α β INSULIN GLUCAGON NORMOGLYCEMIA F18-21

Regulation of glucagon secretion High circulatory glucose inhibits secretion Low concentration enhances secretion Increased circulating amino acids increase secretion Permits conversion to glucose Exercise increases glucagon secretion F18-22

Other effects of glucagon Activates adipose cell lipase Makes available fatty acids for energy Inhibits storage of triglycerides in the liver Enhances heart strength Increases irrigation of kidney Enhances bile secretion Inhibits gastric secretion F18-23

Somatostatin inhibits both glucagon and insulin Acts locally in islets SS decreases stomach, duodenum and gallbladder motility SS inhibits secretion and absorption by the GIT Amylin is a protein produced by the pancreas which selectively inhibits insulin stimulated glucose utilization and glycogen deposition in muscle Amylin does not affect adipocyte glucose metabolism F18-24

Pancreatic cell interaction β INSULIN α D GLUCAGON SOMATOSTATIN F18-25

Pathophysiology Diabetes Mellitus Type I diabetes (Insulin-dependent) Due to lack of insulin production Juvenile diabetes mellitus Type II diabetes (non insulin-dependent) Due to decrease sensitivity of tissue to insulin (insulin resistance) Adult-onset diabetes F18-26

Type I diabetes Damage of B cells High glucose concentration Viral infection, autoimmune disorder, genetic predisposition Appears at a young age Very rapidly High glucose concentration Loss of glucose in urine Osmotic diuresis (dehydration) Polyurea F18-27

Cont . . . Structural changes in tissue Switch to use of fats Malfunction of blood vessels Risk of heart attack, stroke, kidney disease, retinopathy and blindness, ischemia and gangrene of limbs Also neurological problems Switch to use of fats Causes metabolic acidosis Diabetic coma... Death F18-27

Type II diabetes Accounts for 80-90% of cases Manifest at mature age (adult onset diabetes) Increased plasma insulin Many metabolic abnormalities Except ketosis Patients usually obese Can be managed through diet F18-28

Summary Reviewed the role of the pancreas in the regulation of carbohydrate metabolism Identified the functions of insulin and glucagon Pointed out the most common pathophysiologies associated with these systems (Diabetes)