Lecture 4: Insulin Signaling and Pathways Flashcards
(25 cards)
Fasting Glucose + Sugary Snack Blood Glucose Level
140 mg/dL
Diabetes Definition
Fasting Glucose level @ or above 120 mg/dL
A1c (level of glucose attachment to hemoglobin) > 6.5%
Oral Value Glucose Tolerance Test- above 200 mg/dL
Random or casual plasma glucose concentration> 200 mg/dL plus other symptoms
IGF1 ( cousin of insulin receptor)
Made by the liver in response to growth hormone from the pituitary
Activates insulin receptor at 1/10 potency of insulin
Used therapeutically for growth failure called “IGF1 deficiency”
IGF2 (cousin of insulin receptor)
Growth hormone during gestation
Receptor serves as inactive decoy
Insulin Pathway
Insulin binds to IR –> Activates IRS1 –> Activates p13K complex –> Enhances glycogen synthase
Insulin Receptor
Tyrosine Kinase receptor/enzyme
Has an alpha and beta subunit
Covalently dimerizes to undergo autophosphorylation
Catalyzes IRS family proteins, Shc, and Cbl
Proteins interact in other signaling pathways through their SH2 domains
P1(3)K, Cbl/CAP, ras, and MAP kinase cascade
Insulin Pathway in a Hepatocyte
Insulin stimulates utilization and storage of glucose as a lipid and glycogen
Represses glucose synthesis and release
Regulates enzymes like glycogen synthase and citric lyase through phosphorylation
Mediated by Hepatic Nuclear Factor (HNF)-4, Forkhead protein family (Fox), sterol regulatory element binding protein (SREBP)-1
GLUT 1
Found in most cells
High Capacity/Affinity
GLUT 2
Liver, intestine, hypothalmus, beta cells
Low affinity
GLUT 3
Neurons Placenta
Insulin Independent
GLUT 4
Heart, Muscles, Fat
Activated by insulin
GLUT 5
Mucosal Surface
Dietary Fructose
GLUT 4 Membrane Pathway
GLUT 4 bound to the Golgi Apparatus
Insulin causes exocytosis of the GLUT 4 to the membrane to intake glucose
When insulin decreases, endocytosis removes some of these receptors back to the Golgi apparatus
GLUT 4 movement can also be caused by environmental signals (aka exercise)
Beta Cell Sensitivity
Glucose enters beta cells through GLUT 2, which has a low capacity
Glucokinase has a lower capacity for glucose than other hexokinases. Glucose is not inhibited by its product G6P, allowing for the cell to sense blood glucose levels
Oxidative Phosphorylation increases ATP/ADP ratio
ATP closes the ATP gated K+ channel and depolarizes the membrane
Depolarization opens the Ca channel, lets Ca+ enter the beta cell and allows for secretion of insulin
Insulin Effects on Liver
Stimulates glucose oxidation
Promotes glucose storage as glycogen
Inhibits glycogenolysis and gluconeogenesis
Insulin Effects on Muscle
Stimulates glucose uptake (GLUT4)
Promotes storage as glycogen
Inhibits muscle breakdown
Insulin and Adipose Tissue
Stimulates glucose transport into adipocytes
Promotes the conversion of glucose into triglycerides and fatty acids
Glucose enters both through passive diffusion and facilitated transport- insulin stimulates facilitated transport
May have an effect on lipogenic enzymes
Glucagon
Major catabolic agent that increases blood sugar
Alpha cells of the pancreas
Released in response to hypoglycemia, stress, trauma, infection, starvation
Decreases glycolysis, increases gluconeogenesis
Increases ketone production in liver
Initially thought to be a contaminant in pancreatic extracts
Signals through cyclic Adenosine Monophosphate
Epinephrine/Norepinephrine
Increase in hepatic glucose production, limits glucose through adrenergic receptors
Glycogenolysis, gluconeogenesis, glucose release from liver
Stimulates glycolysis in muscle tissue
Lipolysis in adipose tissue
Decrease in insulin secretion
Increases glucagon secretion
Effect mediated through the hypothalmus in reponse to low blood glucose levels
Released from adrenal medulla, after stimulation of adrenal medulla
Growth Hormone/Cortisol
Initially can decrease glucose, but long term increase glucose
Glucagon Like Peptide 1
Encoded by glucagon gene
Produced by intestine as an incretin- increases insulin in blood even before blood glucose elevates
(Effects in anticipation of increase in blood sugar)
Brain: Increases neuroprotection and decreases appetite
Stomach: Decreases gastric emptying
Pancreas: Increases insulin secretion and beta cell neogenesis, Decreases beta cell apoptosis and glucagon secretion
Muscle: Increases glucose uptake
Liver: Decrease in glucose production
Heart: Increases cardioprotection, increases cardio output
Glucose and Glucagon
Glucose decreases glucagon levels in minutes
Alpha Cells Sensitivity
Alpha cell sensor has GLUT1 and glucokinase
High capacity, high affinity
Responsiveness to changes in blood glucose concentration in the LOW physiologic range
Brain in Glucose Regulation
- Glial neuronal loop centrally senses hypoglycemia via GLUT2
- Promote glucagon secretion
