the endocrine pancreas - education.med.imperial.ac.uk
TRANSCRIPT
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Worldwide, there are 170 million people with diabetes mellitus
• This prevalence will double before 2030 • 2.7 million with diabetes mellitus in UK • 3.2 million deaths annually directly attributable to diabetes • Commonest cause of end stage renal failure, blindness and non-traumatic amputations
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• Aims: – To explain the endocrine pancreas and how it
regulates carbohydrate, lipid and protein metabolism
• Learning outcomes: – Know the anatomy, embryology and physiology of
the endocrine pancreas – Be able to describe functioning of alpha and beta
cells ie regulation of insulin and glucagon secretion – Describe glucose sensing by the beta cell – List the principal actions of insulin and glucagon – Integrate the actions of insulin on intermediary
metabolism
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Pancreas - Anatomy
β cell - insulin α cell - glucagon δ cell - somatostatin • Autonomic innervation
• Islets = 2% of pancreatic mass, but receive 15% of perfusion
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Pancreas - Embryology
• Develops from two buds from the primitive gut
• Buds grow, branch and fuse
• Islet cells differentiate from cells adjacent to buds
• Endocrine function from 10–15 weeks
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Pancreas - Physiology
[Glucose] (mmol/L)
[Insulin]
4 6
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Pancreas - Physiology
[Glucose] (mmol/L)
[Insulin]
4 6
↑Glucose
↑Insulin
Glucose uptake Liver, adipose, muscle
Eat
↓Glucose
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Pancreas - Physiology
[Glucose] (mmol/L)
[Insulin]
4 6
[Glucose] (mmol/L)
[Glucagon]
4 6
↑Glucose
↑Insulin
Glucose uptake Liver, adipose, muscle
Eat
↓Glucose
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Pancreas - Physiology
[Glucose] (mmol/L)
[Insulin]
4 6
[Glucose] (mmol/L)
[Glucagon]
4 6
↑Glucose
↑Insulin
Glucose uptake Liver, adipose, muscle
Eat
↓Glucose
↓Glucose
↑Glucagon
Stimulate Glucose release from liver
Fast
↑Glucose
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Pancreas - Physiology
[Glucose] (mmol/L)
[Insulin]
4 6
[Glucose] (mmol/L)
[Glucagon]
4 6
↑Glucose
↑Insulin
Glucose uptake Liver, adipose, muscle
Eat
↓Glucose
↓Glucose Fast
↑Glucose
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Banting/Best/Collip Isolate Insulin in 1920
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Insulin Synthesis and Secretion • 50 AA peptide, 3 intramolecular disulphide bridges, 5808 kDa • Synthesised as preproinsulin • Peptidases cleave C-peptide off • Half life of insulin in the circulation = 6 minutes
Physiological Insulin Profile:
[ ]
Time
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Insulin Release
β cell
éGlucose
Amino acids
Gut hormones
Glucagon
β receptors
Insulin
+ve effects -ve effects
Somatostatin
α receptors
êGlucose
Parasympathetic
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Biphasic insulin release Phase 1
Phase 2
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Glucose sensor in beta cells
éGlucose via Glut2
Shuts K+ channel
glucokinase (glycolysis)
Opens Ca2+ channel s;mulates
G-‐6-‐P ATP
Insulin release
increased Ca2+ depolarisa;on
nega;ve feedback
Rate of conversion propor;onal to ambient [gluc]
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Glucagon-like peptide 1 (GLP-1) is an incretin
• Stimulates Insulin secretion • Inhibits Glucagon secretion • Inhibits Gastric emptying • Inhibits Appetite • Stimulates Nausea
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Inflammatory basis of insulin resistance
Glucose
Molecular Basis of Insulin Action
Glucose
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Intermediary Metabolism
All reactions concerned with storing and generating metabolic energy. Using that energy in cellular processes
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Intermediary Metabolism Made Easy
Glucose
Acetyl CoA
GLYCOLYSIS
KREBS CYCLE
OXIDATIVE PHOSPHORYLATION
Fatty Acyl CoA Fatty Acids
Triglycerides
Glycerol
Amino acids
ADP + O2
ATP + CO2
β OXIDATION
FATTY ACID BIOSYNTHESIS
Acetoacetate 3-OH butyrate Acetone
KETOGENESIS
CHO
GLUCONEOGENESIS
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Insulin & Intermediary Metabolism Eat ↑Glc ↑Insulin Pancreas
Glc
Glycogen
Glc
Glycerol
Fatty acids
Trigs
VLDL
Fatty acids Triglycerides
LPL
Glc Glut4 Glut4
Hexokinase
P-FructoKinase
Glycogen synthase
Glut2
HSL
Glycogen
Aa Protein
Fatty acids
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Actions of Insulin
• Carbohydrate – Glucose
uptake – Glycogenesis – Inhibit
glycogenolysis – Inhibit
gluconeogenesis
• Lipid – Inhibit HSL – Hepatic fatty
acid synthesis
– Suppress ketone body production
• Protein – Aa uptake – Anabolic
• Others – K+ uptake – H2O retention
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Glucagon • 29 Aa peptide hormone from alpha cells • Synthesised from preproglucagon
• Released in response to low blood glucose • Stimulates glycogenolysis and
gluconeogenesis • Disordered secretion also occurs in diabetes
mellitus
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Insulin & Intermediary Metabolism Fast ↓Glc ↓Insulin Pancreas
Glc
Glycogen
Glc
Glycerol
Fatty acids Trigs
VLDL
Fatty acids Triglycerides
LPL
Hexokinase
P-FructoKinase
Glycogen synthase
HSL
Gluconeogenesis
éHep Glc output
Fatty acids
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GCG & Intermediary Metabolism Fast ↓Glc ↓Insulin Pancreas
Glc
Glycogen
Glc
Glycerol
Fatty acids Triglycerides
LPL
HSL
Gluconeogenesis
↑Glucagon
Glycogenolysis
éHep Glc output
Fatty acids Trigs
VLDL
LPL Fatty acids
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Ketogenesis
TG FFA
Insulin -ve
Liver
β oxidation
Acetyl-CoA Ketogenesis
3-OH butyrate Acetocetate Acetone
Hormone Sensitive lipase
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N.B. • Islets do secrete other hormones
– Pancreatic Polypeptide – Vasoactive Intestinal Polypeptide – Ghrelin – Gastrin – Somatostatin
• Rarely functional endocrine tumours of the pancreas release these hormones
• This can occur in genetic diseases such as multiple endocrine neoplasia type 1
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Summary • The endocrine pancreas mainly secretes insulin (β cells)
and glucagon (α cells) • They have opposing effects on blood glucose (insulin↓,
glucagon↑) • Insulin controls much more than just carbohydrate
metabolism (lipids and protein, K) • The principal insulin-responsive tissues are liver, adipose
and muscle • Diabetes mellitus, the commonest endocrinopathy is
caused by a lack of insulin action and excessive glucagon • Neuroendocrine tumours of the pancreas are rare but
important (especially at Hammersmith Hospital!)