ERS38 Physiology Of Insulin And Glucagon Flashcards
Pancreas
Upper abdominal cavity behind stomach
Blood supply:
- Head: **Superior mesenteric artery + **Pancreaticoduodenal artery (both between duodenum and pancreas)
- Tail, Body, Neck: ***Splenic artery branches
2 main functions:
- Exocrine: ***Acinar cells + Ducts —> Digestive enzymes into pancreatic duct —> Duodenum
- Endocrine: ***Islets of Langerhans (scattered among acini, 1-2% pancreatic mass) —> Hormones that regulate blood sugar (Insulin, Glucagon) into circulation
Islets of Langerhans
Each islet contain 3000-4000 cells
- Alpha (α) cells (30-45%)
- Glucagon
- ***periphery surrounding β cells - Beta (β) cells (majority: 45-60%)
- Insulin
- ***located in centre of islet - Delta (δ) cells (3-10%)
- Somatostatin
Richly vascularised —> allow hormone readily secreted into circulation / rapid sensing of blood glucose level
***Feedback system of pancreatic islets
Autocrine / Paracrine
- based on activation + inhibition of islet cells by endocrine hormones produced in islets
- Insulin (***升Insulin跌Glucagon) —> activate β + inhibits α —> ↑ Insulin + ↓ Glucagon
- Glucagon (***兩個都升) —> activate α —> ↑ Glucagon —> activate β + δ —> ↑ Insulin + ↑ Somatostatin
(Glucagon receptors on β cells: too much Glucagon —> secrete Insulin to counteract) - Somatostatin (***兩個都跌) —> inhibit α + β —> ↓ Insulin + ↓ Glucagon
Insulin: Synthesis
Mature insulin molecule
- **2 polypeptide chain A + B (generated by proteolytic processing of a larger precursor molecule (Preproinsulin))
- joined by
—> **2 pairs of Disulfide bonds between A/B
—> ***1 intramolecular Disulfide bond in A chain
- a.a. sequence highly conserved among vertebrates
**Preproinsulin (with signal peptide to guide it into ER)
(—> signal peptide lost after entering ER)
—> **Proinsulin
(—> removal of ***C chain)
—> Insulin
**Equimolar amounts of C-peptide + Insulin are stored in secretory granules of β cells
—> both eventually released into circulation
—> measuring level of C-peptide
—> determine **natural Insulin level
—> determine β cell function + determine Type 1/2 DM (low C-peptide —> Type 1)
Insulin: Secretion
Insulin secretion:
- ***Pulsatile
- stimulated by High blood glucose level, inhibited by Low blood glucose level
β cell:
Glucose enter β cell by diffusion via Glucose transporter ***GLUT2 (on cell membrane)
—> Glycolysis + TCA cycle
—> ATP (act as 2nd messenger)
Unstimulated state (No ATP produced): Open of β cell ATP-sensitive K channel (inwardly-rectifying) —> resting membrane potential ~ -60mV
Stimulated state (High glucose —> ATP produced): ***Closure of ATP-sensitive K channel —> no K efflux —> ***+ve charge accumulate —> ***Depolarisation of membrane —> ***Opening of Voltage-dependent Ca channel —> ↑ cytosolic Ca —> ↑ cAMP —> ***Insulin exocytosis
Medication:
1. **Meglitinide
2. **Sulfonylurea
—> ↑ Insulin secretion by blocking ATP-sensitive K channel (after binding to Sulfonylurea receptor on channel)
Insulin receptor
Insulin receptor:
- ***Tyrosine kinase-linked receptors
- Tyrosine kinase: transmembrane signalling protein
Structure:
Heterotetramer (2 α + 2 β)
—> linked by disulfide bond into tetramer (in absence of ligand)
—> functionally dimeric protein complex
1. α-subunit —> ligand binding
2. β-subunit (Tyrosine kinase) —> protein kinase that catalyses phosphorylation of proteins
Insulin binding onto α-subunit
—> Activate Tyrosine kinase in β-subunit
—> Auto-Phosphorylation of β-subunit (Tyrosine residues)
—> Amplification of kinase activity
—> Phosphorylation of **Insulin receptor substrate 1 (IRS-1)
—> IRS-1: docking centre for **recruitment + activation of other enzymes
—> ultimately mediate insulin’s effects
2 features distinguishing Insulin receptor from other enzyme-linked receptors:
- Covalent tetramer after dimerisation (本身係dimer) (other receptor only form dimer after ligand binding)
- Phosphorylation of IRS-1 first instead of binding to signalling protein directly
Insulin signaling pathway
Insulin receptor substrate 1 (IRS-1) —>
-
**PI3K/AKT pathway
- **Metabolic effects of insulin
AKT: linking ***insulin-dependent GLUT4 to insulin signaling pathway
—> activate GLUT4
—> move to cell surface
—> transport glucose into cell
Shc protein —>
- Ras/ERK pathway
- ***Cell growth + differentiation induced by insulin (by controlling gene expression)
***Physiological effects of insulin
↓ [Glucose] in blood
- Glucose storage and uptake
- Muscle / Adipose tissue: **↑ Glucose uptake into cells by insertion of GLUT4 onto membrane
- Muscle / Liver: **↑ Glycogenesis
(by indirectly inhibit GSK3 + PKA —> preventing inhibition of Glycogen synthase)
- Liver: **↓ Gluconeogenesis (from a.a., fatty acids) + **↓ Glycogenolysis - Lipid synthesis
- Liver: **↑ Lipogenesis (Fatty acid synthesis from Glucose after Glycogen level high —> TAG synthesis)
- Adipose tissue: **↓ Lipolysis (TAG synthesis)
***Summary of Insulin action in 3 tissues
Liver:
- ↑ Glucose uptake but NOT utilisation, ↓ Gluconeogenesis
- ↑ Glycogenesis, ↓ Glycogenolysis
- ↑ Lipogenesis (Fatty acid)
Muscle:
- ↑ Glucose uptake + utilisation
- ↑ Glycogenesis
Adipose tissue:
- ↑ Glucose uptake + utilisation
- ↓ Lipolysis (TAG synthesis)
***Glucagon: Synthesis and Secretion
Glucagon:
- ***linear peptide (29 a.a.)
Synthesis:
- Proglucagon —> Proteolytic processing in ER —> Mature Glucagon
Secretion:
- α is ~ to β
- similar glucose transport, metabolism, **inhibition of ATP-sensitive K channel upon high glucose level
—> but **opposite secretory response
α cell:
- ***Na channel (tetrodotoxin-sensitive: activate at -30mV)
- Mixture of Ca channel subtypes with different roles:
- **Low voltage-activated T-type channel (open ~ -60mV) —> pacemakers in initiation of AP
- **High voltage-activated L+N-type channel (open when membrane potential > -40/30mV)
Low glucose level:
ATP-sensitive K channel open
—> makes membrane potential ~-60mV
—> **Low voltage-activated T-type Ca channel open (already operating)
—> depolarise membrane potential to where Na channel activated (-30mV)
—> **Na channel activated
—> AP
—> **Ca entry through High voltage-activated N-type Ca channel
—> ↑ cytosolic Ca
—> Glucagon secretion
(i.e. α cell **electrically active in absence of glucose)
(Additionally, lack of Insulin remove suppression on α cells)
High glucose level:
Glucose enter α cell
—> ATP generation
—> **ATP-sensitive K channel close
—> High voltage achieved initially
—> **Inactivation of T-type Ca channel + Na channel
—> No Glucagon secretion
—> **Additional effect: Insulin secretion from β cell bind to α cell to inhibit Glucagon secretion (Paracrine effect)
—> **Overall 2 effects: Intrinsic effect (by all channels) + Paracrine effect —> 缺一不可
Physiological effects of Glucagon
Counteract hypoglycaemia by opposing Insulin actions
—> ↑ [Glucose] in blood
Glucagon receptor: ***GPCR receptor
- Liver: (via cAMP/PKA pathway)
- Inactivate **Glycogen synthase (directly via GSK3) —> **↓ Glycogenesis
- Activate **Glycogen phosphorylase —> **↑ Glycogenolysis
- Induce expression of Gluconeogenesis genes —> ***↑ Gluconeogenesis (75% of glucose production in fasting state) (Metformin ↓ Gluconeogenesis) - Adipose tissue: (via cAMP/PKA pathway)
- Activate **hormone-sensitive lipase (HSL) —> mobilise stored fats —> **↑ Lipolysis
(—> ↑ fatty acids in plasma for Gluconeogenesis)
Insulin
Only peptide hormone ↓ blood glucose level
whereas Glucagon, Cortisol, Epinephrine all ↑ blood glucose level
Diabetes mellitus
- Insulin levels insufficient
- Responsiveness of tissues to Insulin insufficient
—> unable to maintain normal blood glucose level
3 types:
- Type 1 diabetes (Juvenile diabetes)
- Insulin-dependent
- Inability to synthesise Insulin
- **Autoimmune destruction of β cells (irreversible)
- **C-peptide level low
- more often in children, young adult (but can occur at any age) - Type 2 diabetes (Progressive)
- Non-insulin dependent
- **Target tissues resistant to Insulin (i.e. higher level of Insulin required to maintain normoglycaemia)
- Associated with:
—> **Defects in Insulin signaling pathway
—> ***Over-nutrition causing ↑ lipid metabolite concentrations (e.g. DAG) —> lipid-induced Insulin resistance
(—> Abnormalities in Insulin secretion
—> Excessive production of glucose by liver (fasting hyperglycaemia)) - Gestational diabetes
- during pregnancy when placental hormones reprogram maternal physiology to meet fetal needs (block insulin action on mother’s body)
- more common in 2nd / 3rd trimester (> 13 week)
- **resolves after delivery
- uncontrolled can hurt mother / baby
- problems:
—> **↑ risk for obesity in offspring (C-section is needed)
—> ***Hypoglycaemia in offspring after birth (extra insulin made by baby during pregnancy) - Other causes of DM
- Acromegaly (too much GH —> antagonise insulin effect)
- Cushing’s syndrome (too much cortisol)
- Thyrotoxicosis (too much Thyroid hormone)
***Symptoms of DM
Hyperosmolarity of filtrate —> ***↓ reabsorption of water
- Polyuria
- Polydipsia
- Unexplained weight loss (∵ cannot utilise glucose)
- ↑ Appetite (∵ cannot utilise glucose)
- Fatigue (∵ cannot utilise glucose)
- Blurred vision (∵ Sorbitol formation —> Fluid influx —> Osmotic damage —> Cataract)
- Diabetic Neuropathy
- Diabetic Nephropathy
- Ketoacidosis
- Poor healing (∵ viscosity of blood —> slow blood flow)
Summary
Insulin:
Tyrosine kinase receptor
Liver:
- ↑ Glucose uptake but NOT utilisation, ↓ Gluconeogenesis
- ↑ Glycogenesis, ↓ Glycogenolysis
- ↑ Lipogenesis (Fatty acid)
Muscle:
- ↑ Glucose uptake + utilisation
- ↑ Glycogenesis
Adipose tissue:
- ↑ Glucose uptake + utilisation
- ↓ Lipolysis (TAG synthesis)
Glucagon:
GPCR
Liver:
- ↓ Glycogenesis, ↑ Glycogenolysis
- ↑ Gluconeogenesis
Adipose tissue:
- ↑ Lipolysis
