18. pancreatic function and metabolism
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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 PresentationTRANSCRIPT
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18. Pancreatic function and metabolism
V BS 122 2012
Luis A. Bate
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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)
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Reading
Chapter 78
Guyton
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ISLETS OFLANGERHANS
PANCREATICACINI
DUCTULESDUCTS
Pancreatic structures
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Pancreatic islets
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Pancreatic secretions
• In addition to the digestive enzymes the pancreas serves an important endocrine role
• Produces – Insulin– Glucagon– Pancreatic polypeptide– Somatostatin– Amylin
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α cells(Glucagon)
β cells(Insulin, Amylin)
D cells(Somatostatin)
F cells (PancreaticPolypeptide)
Pancreatic islets
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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
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α chain
β chain
C peptide
PROINSULININSULIN
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Ca++
Insulin secretionInsulin secretion
β cell
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Enzyme phosphorylationProtein synthesisEFFECTGlucose synthesisFat synthesisGrowth and gene expressionGlucose transport
TK
α α
β β
TK
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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
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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
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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
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GLUCOSE
GLYCOGEN
GLUCOSE-6-PHOSPHATE
GLUCOSE
TCA
GLYCOGEN
GLUCOSE
GLUCOSE-6-PHOSPHATE
TCA (ENERGY)
GLUCOSE
FFA
GLUCOSEFFA
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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
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Role of insulin
• Lowers the circulatory concentrations of glucose, fatty acids and amino acids
• Enhances storage of these in large molecules– Glycogen– Triglycerides– Proteins
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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
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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
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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)
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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
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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
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Glucagon
• 29 amino acid protein• Produced by alpha cells• Released when circulatory glucose is low• Contributes to elevation of circulatory
glucose
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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
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Regulation of circulatory glucose
HYPERGLYCEMIA HYPOGLYCEMIA
NORMOGLYCEMIA
βα αβ
INSULIN
GLUCAGON
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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
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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
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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
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α
βINSULIN
GLUCAGOND
SOMATOSTATIN
Pancreatic cell interaction
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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
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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
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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
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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
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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)
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