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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 - PowerPoint PPT Presentation
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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)