Lecture 4: Insulin Signaling and Pathways

Question 1

Fasting Glucose + Sugary Snack Blood Glucose Level

Answer 1

140 mg/dL

Question 2

Diabetes Definition

Answer 2

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

Question 3

IGF1 ( cousin of insulin receptor)

Answer 3

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”

Question 4

IGF2 (cousin of insulin receptor)

Answer 4

Growth hormone during gestation

Receptor serves as inactive decoy

Question 5

Insulin Pathway

Answer 5

Insulin binds to IR –> Activates IRS1 –> Activates p13K complex –> Enhances glycogen synthase

Question 6

Insulin Receptor

Answer 6

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

Question 7

Insulin Pathway in a Hepatocyte

Answer 7

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

Question 8

GLUT 1

Answer 8

Found in most cells

High Capacity/Affinity

Question 9

GLUT 2

Answer 9

Liver, intestine, hypothalmus, beta cells

Low affinity

Question 10

GLUT 3

Answer 10

Neurons Placenta

Insulin Independent

Question 11

GLUT 4

Answer 11

Heart, Muscles, Fat

Activated by insulin

Question 12

GLUT 5

Answer 12

Mucosal Surface

Dietary Fructose

Question 13

GLUT 4 Membrane Pathway

Answer 13

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)

Question 14

Beta Cell Sensitivity

Answer 14

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

Question 15

Insulin Effects on Liver

Answer 15

Stimulates glucose oxidation
Promotes glucose storage as glycogen
Inhibits glycogenolysis and gluconeogenesis

Question 16

Insulin Effects on Muscle

Answer 16

Stimulates glucose uptake (GLUT4)
Promotes storage as glycogen
Inhibits muscle breakdown

Question 17

Insulin and Adipose Tissue

Answer 17

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

Question 18

Glucagon

Answer 18

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

Question 19

Epinephrine/Norepinephrine

Answer 19

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

Question 20

Growth Hormone/Cortisol

Answer 20

Initially can decrease glucose, but long term increase glucose

Question 21

Glucagon Like Peptide 1

Answer 21

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

Question 22

Glucose and Glucagon

Answer 22

Glucose decreases glucagon levels in minutes

Question 23

Alpha Cells Sensitivity

Answer 23

Alpha cell sensor has GLUT1 and glucokinase
High capacity, high affinity
Responsiveness to changes in blood glucose concentration in the LOW physiologic range

Question 24

Brain in Glucose Regulation

Answer 24

• Glial neuronal loop centrally senses hypoglycemia via GLUT2
• Promote glucagon secretion

Question 25

Brain Dead and Hyper/Hypoglycemia

Answer 25

Trauma/Stress causes hyperglycemia