Diabetes, an issue with glucose homeostasis

Wei Guo

University of Pennsylvania

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10/24/2015

Blood Glucose Homeostasis

http://themedicalbiochemistrypage.org

meal

Blood glucose level (mg/dl)

Insulin and Glucose Homeostasis

Diabetes�-Type I (lack of insulin)� -Type II (lack of response to insulin)

Glucose Transporters

(GLut4, etc.)

How is the glucose level in the blood controlled?

Plasma membrane

Exocytosis

Blood glucose homeostasis is maintained

by insulin-regulated GLUT4 exocytosis

Vesicle

GLUT4

Glucose

uptake

Low glucose

High glucose

Insulin

receptor

Skeletal muscles or adipocytes

Insulin

Insulin and Glut4 Transport

High blood glucose level

Glut4 transport to the plasma membrane to mediate glucose uptake

Insulin release from pancreatic β cells

Medical Relevance of �GLUT4 Translocation

• 18,000,000 Americans have Type II diabetes
• Type II diabetes is characterized by insulin resistance of muscle, fat, liver.
• Type II diabetic patients have normal levels of GLUT4 in muscle, but not well incorporated to the cell membrane.
• Transgenic overexpression of GLUT4 in mouse models of type II diabetes normalizes blood glucose levels
• Exercise elicits muscle GLUT4 translocation and increases muscle GLUT4 expression in humans, and lowers blood glucose in type II diabetic patients

Membrane Trafficking in Eukaryotic Cell

Alberts et al., Molecular Biology of the Cell, 4^th edition

Exocytosis and Endocytosis:

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http://www.youtube.com/watch?v=K7yku3sa4Y8&feature=related

Exocytosis

Protein incorporation to the plasma membrane

Glucose

GLUT4 storage vesicles

Endosomes

Plasma membrane

Insulin-Stimulated GLUT4 Translocation

Budding

Transport

Docking,

Fusion

GLUT4 storage vesicles

Endosomes

Plasma membrane

Insulin-Stimulated GLUT4 Translocation

Insulin

Budding

Moving

Docking,

Fusing

Glucose

Glucose

So what are wrong in diabetes patients?

Insulin signaling is impaired.

Insulin and Glut4 Transport

High blood glucose level

Glut4 transport to the plasma membrane to mediate glucose uptake

Insulin release from pancreatic β cells

Insulin and Glut4 Transport

High blood glucose level

Glut4 transport to the plasma membrane to mediate glucose uptake from the blood.

Insulin release from pancreatic β cells

Harrison's principles of internal medicine. Vol. 2. New York: McGraw-Hill Medical, 2008.

Adapted from James, D. E. J. Clin. Invest. 2005;115:219-221

The Rab GTPase Activating Protein (GAP) AS160 and Its Substrate Rab10 in GLUT4 Translocation

Beyond Diabetes……

Neuron Synaptic Transmission

Figure 13-68 Molecular Biology of the Cell (© Garland Science 2008)

Mast Cell Exocytosis: histamine release

What happens at the PM?

Vesicle docking and fusion