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

ISLETS OFLANGERHANS

PANCREATICACINI

DUCTULESDUCTS

Pancreatic structures

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

α cells(Glucagon)

β cells(Insulin, Amylin)

D cells(Somatostatin)

F cells (PancreaticPolypeptide)

Pancreatic islets

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

α chain

β chain

C peptide

PROINSULININSULIN

Ca++

Insulin secretionInsulin secretion

β cell

F18-6

Enzyme phosphorylationProtein synthesisEFFECTGlucose synthesisFat synthesisGrowth and gene expressionGlucose transport

TK

α α

β β

TK

F18-7

GLYCOGEN

GLUCOSE-6-PHOSPHATE

TRIOSE PHOSPHATE

PHOSPHOENOLPYRUVATE

PYRUVATE

ACETYL-CoA

MALONYL-CoA

FFA

GLUCOSE-6 PHOSPHATASE

GLUCOSE

GLUCOKINASE

6-PHOSPHOFRUCTOKINASE

PYRUVATE KINASE

FATTY ACID SYNTHASE

ACETYL-CoA CARBOXYLASE

PHOSPHORYLASE

GLYCOGEN SYNTHASE

PYRUVATE DEHYDROGENASE

FRUCTOSE-1-,6-BIPHOSPHATEALDOLASE

F18-8

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

GLUCOSE

GLYCOGEN

GLUCOSE-6-PHOSPHATE

GLUCOSE

TCA

GLYCOGEN

GLUCOSE

GLUCOSE-6-PHOSPHATE

TCA (ENERGY)

GLUCOSE

FFA

GLUCOSEFFA

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

NORMOGLYCEMIA

βα αβ

INSULIN

GLUCAGON

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

α

βINSULIN

GLUCAGOND

SOMATOSTATIN

Pancreatic cell interaction

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– 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

– 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)