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Glucagon
- Source: α-cells (pancreas)
- Target: Liver (adipose, skeletal muscle)
- Action: Promotes gluconeogenesis and glycogenolysis in liver
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Insulin
- Source: β-cells (pancreas)
- Target: Liver (adipose, skeletal muscle)
- Action: Promotes uptake of glucose, amino acids, and fatty acids from blood into cells for storage as glycogen, protein and triglyceride
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Somatostatin: "body stay the same"
- Source: δ-cells (pancreas)
- Target: Other islet cells, GI tract, brain and pituitary gland
- Action: Decrease release of insulin and glucagon, decrease GI tract motility, and decrease hormone secretion
- Single gene, highly conserved in nature
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Epinephrine
- Source: adrenal medulla
- Target: many
- Action: Promotes glycogenolysis in liver, and lipolytic via hormone-sensitive lipase
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Cortisol
- Source: adrenal cortex
- Target: many
- Action: Antagonizes insulin action
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GLP-1: "incretins"
- Source: Ileum
- Target: Pancreas, stomach, brain, heart
- Action: Increase β-cell mass and insulin secretion; delays gastric emptying, decreases food intake and glucagon secretion
- Most effective when eating
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Leptin
- Source: adipocytes
- Target: CNS (basomedial hypothalamus)
- Action: Signals adequacy of food stores, decreasing food intake
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Islet of Langerhans: cellular
- β cells predominate (60-80%)
- Cells linked by tight junctions; regulated entry of small molecules
- Blood flows from β to α & δ cells, so Insulin is the primary hormone!
- β cell is primary glucose sensor
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Structure of Insulin
- Acts as a monomer, but travels in polymer form: dimeric, hexameric, N-lithocholyl
- Signal peptidase cleaves the leader from preproinsulin
- Protease cleaves the connecting sequence from proinsulin
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Regulation of Insulin Secretion: Autonomic Control
- Adrenergic and cholinergic innervation of Islets
- α2 and activation of the sympathetic branch = ⇩ insulin secretion
- β2 and cholinergic receptors = ⇧ insulin secretion
- Therefore, β2 antagonists decrease basal insulin levels
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Chemical regulation of Insulin Release
- Glucose is the major stimulus for insulin release
- Other stimulants- gastrin, secretin, cholecystokinin, VIP, and enteroglucagon
- Insulin secretion is continuous, but increases after carbohydrate consumption (ingestion > IV nutrition)
- Insulin response to glucose is biphasic: short lived peak in 1-2 minutes, then released over hours
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MoA Glucose regulation of Insulin Release
- Glucose enters β-cell via GLUT2
- Glucose undergoes glycolysis to G6P, then eventually pyruvate
- This increases in ATP/ADP ratio, inhibiting the ATP-K+ channel (which normally pushes K+ out of the cell)
- K+ accumulating in the cell leads to depolarization, which triggers entry of Ca2+ through the voltage dependent Ca2+ channel
- Ca2+ increases cAMP signaling, which eventually activate the release of secretory granules containing insulin and peptide C
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cAMP Effects in β-cells
- Stimulate Phospholipase C to increase free Ca2+
- Gs linked receptors: glucagon, GIP, GLP-1
- Gi linked receptors: somatostatin, α2 agonists
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ATP-Sensitive Potassium Channel
- Open channel = hyperpolarization of β-cells
- Close channel = insulin secretion
- Allosteric inhibitors: Sulfonylurea/meglitinide, ATP
- Allosteric activators: Diazoxide, Mg2+, ADP
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MoA Glucose regulation of Insulin Production
- Translational > Transcriptional control
- Without glucose, eIF-4F Complex (essential for translation of proinsulin mRNA) is inhibited by eIF-4EBPs
- With glucose, eIF-4EBPs is phosphorylated, freeing up the eIF-4E piece of the essential complex ♡
- Without glucose, eIF-2α is phosphorylated and cannot form the essential Ternary Met tRNA complex.
- With glucose, phosphorylation of eIF-2α is decreased ♡
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Distribution of Insulin
- Insulin half-life: 5-6 min
- Proinsulin half-life: 17 min
- Normally, proinsulin ~10% of plasma insulin; if higher, then = marker of insulinoma
- Since C peptide is secreted with insulin but not metabolized as rapidly, = measure of acute insulin secretion
- After insulin binds to a receptor, it is internalized and degraded (50% liver)
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Insulin Receptor
- Dimerization regulated tyrosine kinase
- Insulin recognition at cysteine-rich area of alpha chain
- Binds to all members of IGF-family signaling molecules
- Binding is the key determinant of potency
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Glycogen Synthetase
- Essential for glycogenesis
- Insulin: activates
- Glucagon: inhibits
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Glycogen Phosphorylase
- Essential for glycogenolysis
- Insulin: inhibits
- Glucagon: activates
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Increased cAMP Effects in Liver cells
- Stimulates glycogen breakdown (activates glycogen phosphorylase)
- Inhibits glycogen synthesis (phosphorylates, and thus inhibits, glycogen synthase)
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α-Glucosidase inhibitors (Acarbose, Miglitol)
Prevent digestion of carbohydrates, and thus limits absorption of dietary glucose
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Thiazolidinediones
- PPARγ agonists
- Promote conversion of glucose to triglycerides in adipose tissue
- Thus increases glucose uptake by adipose tissue
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Biguanides
Inhibit gluconeogenesis
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Diabetic Ketosis
- Type I Diabetes
- Low insulin levels = high levels of free fatty acids
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