16-Islets and disease Flashcards
Glucose Uptake and Metabolism
Beta cell takes up and metabolizes glucose.
Membrane potential changes due to potassium channel closure.
Membrane depolarizes
Calcium-Induced Insulin Release
Calcium enters the cell near the plasma membrane.
Calcium-induced insulin release from secretory granules via calcium-dependent exocytosis (triggering mechanism).
Granules are pre-packaged with insulin
Incretins
Prime the pancreas and enhance the response to glucose loading
Released from enteroendocrine cells of the GI tract
Deactivated by DPP-4 (Dipeptidyl Peptidase-4)
DPP-4 found in epithelial cell
Receptors on Beta Cells
Beta cells express receptors for GLP-1 (Glucagon-Like Peptide-1) and GIP (Glucose-Dependent Insulinotropic Polypeptide)
Glucose Toxicity Effects
Key tissues become sensitive to glucose toxicity.
Mobilization of glucose through alternative metabolic pathways.
Glucotoxicity affects capillary endothelial cells, mesangial cells, neurons, and Schwann cells.
Consequences include glaucoma, cataracts, microvascular damage to kidneys, CNS, and blood vessels of the heart
Signaling Pathways of incretins
Receptors coupled to adenylate cyclase.
Presence of GLP-1 and/or GIP increases cyclic AMP levels.
Triggers protein kinase A, enhancing exocytosis of insulin.
Cyclic AMP also activates EPAC2 (Exchange Protein Activated by cAMP), a novel signal transduction mechanism that enhances insulin exocytosis.
GLP-1 and GIP close potassium channels and open calcium channels in beta cells
Beta Cell Mass Decline
In healthy individuals, beta cell mass remains constant after expansion post-birth.
Cell mass declines in diabetes, and this decline is irreversible.
Genetic Predisposition
Susceptibility to type 1 diabetes is genetically predetermined.
Requires exposure to external pathogens, likely viral infection.
Combination of genetic predisposition and external events leads to autoimmune processes and destruction of beta cells.
Insulin Therapy
Insulin therapy is the gold standard for type 1 diabetes.
Transitioned from animal insulins to human insulins and synthetic insulin analogs.
Inhaled insulins are available but not widely used clinically.
Glucagon Need
Over time, glucagon-secreting alpha cells become damaged or destroyed
Characteristics of type 2
Beta cell dysfunction and impaired insulin sensitivity in target tissues.
Influence of the microbiome and intrauterine development as risk factors.
Pancreatic Islet Response:
Unhealthy diet leads to increased insulin release from pancreatic islets via exocytosis.
Maintains inhibition of lipolysis and glucose uptake.
Insulin output decreases due to beta cell damage
Insulin Sensitizers
Metformin:
Elevates AMP by inhibiting mitochondria complex 1, activating AMPK.
Enhances insulin signaling, increases hepatic insulin sensitivity, and glucose uptake.
Decreases hepatic glucose production and inhibits gluconeogenesis.
Activates AMPK, switching cells to a catabolic state, restoring energy balance.
Thiazolidinediones:
Acts on liver, muscle, and adipocytes.
Activates receptors, improves insulin sensitivity, and changes gene transcription.
Suppresses alternative sources of energy, leading to glucose utilization.
KATP Channel Inhibitor
Secretagogues:
Inhibit ATP-sensitive potassium channels, depolarize membranes.
Mimic the action of glucose.
Sulfonylureas:
Cause KATP channels to close, allowing opening of VG Ca channels.
Increase insulin release.
Incretin Mimetic Secretagogues
GLP-1 Agonists (e.g., Semaglutide):
Act directly on beta cells and also used for weight management.
Contraindicated in diabetic ketoacidosis and pregnancy.
Orally delivered semaglutide has 0.8% bioavailability.
DPP-4 Inhibitors:
Increase half-life of GLP-1 and GIP.
Enhance insulin release, increase glucose uptake, suppress glucagon secretion, and decrease glucose output for glycemic control.
SGLT2 Inhibitors
Inhibit glucose reabsorption in the kidney tubule.
Result in glucose excretion in the urine, lowering blood glucose levels
