glucose transport and glucose metabolism in diabetes and cancer xiaozhuo chen, october 8, 2015
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Glucose transport and glucose metabolism in diabetes and cancer
Xiaozhuo Chen, October 8, 2015
2008
Age-adjusted Percentage of U.S. Adults Who Were Obese or Who Had Diagnosed Diabetes
Obesity (BMI ≥30 kg/m2)
Diabetes
1994
1994
2000
2000
<14.0% 14.0-17.9% 18.0-21.9% 22.0-25.9% >26.0%
<4.5% 4.5-5.9% 6.0-7.4% 7.5-8.9% >9.0%
CDC’s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics
2008
Center for Disease Control and Prevention (CDC) Predicts that about 1/3 of children born in 2000 in the US will develop type 2 diabetes.
Predicted break-down statistics: Hispanics - females 53%, Hispanic males 45%, Blacks - females 49%, males 40%, Whites – females 31%, males 27%
Numbers of people with diabetes (in millions) for 2000 and 2010 (top and middle values, respectively), and the percentage increase.
Zimmet et al. Nature 414:782-787 (2001)
The prevalence of type 2 diabetes mellitus among Chinese in Hong Kong, Singapore, Taiwan and Mauritius, compared with that in the People's Republic of China6
Zimmet et al. Nature 414:782-787 (2001)
Moller D. Nature414:821-827 (2001)
Organs involved in glucose metabolism and in diabetes
Positive and negative regulations (signals) in glucose metabolism between tissues
Adipose (fat) tissue is now considered as an endocrine organ
Type 2 diabetes
Lingapa & Farley, Physiological Medicine, 2000
Type 2 diabetes
Comparison of normal glucose metabolism with glucose metabolism in diabetes
Why Insulin and Insulin Signaling Pathway are Needed?
Reality: Unpredictable cycle of feeding and then starvation that ensues between meals
Solution: Store nutrients in the forms that can be used as energy sources during periods of fasting – glucose, amino acids and fatty acids as nutrients, and glycogen, protein, and lipids as storage macromolecules
Insulin: Master hormone that regulates the energy homoestasis
Most potent anabolic hormone known
-Pancreatic Islet Cells are the Source of Insulin
-cells with insulin
-cells with glucagon
Pancreatic islet
How Relatively Stable Blood Glucose Concentration is Maintained ?
HepatocytesLiver
After a meal Before a meal
The idealized diagram shows the fluctuation of blood sugar (red) and the sugar-lowering hormone insulin (blue) in humans during the course of a day containing three meals. In addition, the effect of a sugar-rich versus a starch-rich meal is highlighted.
Fast actions
Slow actions
Insulin Actions
Human Proinsulin
Insulin undergoes extensive posttranslational modification along the production pathway. Production and secretion are largely independent; prepared insulin is stored awaiting secretion. Both C-peptide and mature insulin are biologically active. Cell components and proteins in this image are not to scale.
Computer-generated image of six insulin molecules assembled in a hexamer, highlighting the threefold symmetry, the zinc ions holding it together, and the histidine residues involved in zinc binding. Insulin is stored in the body as a hexamer, while the active form is the monomer.
Insulin release from pancreas oscillates with a period of 3–6 minutes
Structure of Insulin Receptor
Pierre De Meyts and Jonathan Whittaker
Insulin binding domain
Transmembranedomain
Intracellular tyrosine kinase domain
Insulin
P IRS
PI3K
Akt P
IR
Glut4
Insulin-mediated glucose transport signaling pathway
Glucose Uptake AssayInsulin
P IRS
PI3K
Akt P
IR
glucose
Insulin-mediated glucose transport signaling pathway
GLUT4 translocation
Insulin
P IRS
PI3K
Akt P
IR
Glut4
Insulin-mediated glucose transport signaling pathway
Glucose Uptake AssayInsulin
P IRS
PI3K
Akt P
IR
glucose
Insulin-mediated glucose transport signaling pathway
Insulin-mediated signaling pathwayInsulin
P IRS
PI3K
Akt P
IR
glucose
Glucose uptake assay
2 deoxy-D-[3H]-glucose
Glut4
Glucose transporters
Structural model of the major insulin-responsive glucose transporter GLUT4
Signal transduction in insulin action
Alternative (supplementary) glucose transport pathway
Current known insulin receptor mediated signaling pathways
Three steps that provide functional divergence for insulin signaling
PI-3 Kinase
1. Type 1A PI-3K in adipocytes
2. Heterodimer – p85 regulatory subunit and a p110 catalytic subunit
3. IRS1 and/or IRS2 bind PI-3K via SH-2 domain on p85, which then activates p110
4. 6 isoforms of p85 regulatory subunits – tissue specific expression
5. Function of PI-3K is to convert phosphotidylinositol 4,5-bisphosphate (PIP2) to PI 3,4,5-triphosphate (PIP3)
6. Activates three Ser/Thr kinases – Akt/PKB, atypical PKC isoforms and phosphoinositide-dependent kinases (PDK-1 and PDK-2)
Three steps that provide functional divergence for insulin signaling
Akt / PKB (Protein kinase B)
1. 3 isoforms, Akt-2 is most highly expressed in adipocytes
2. Phosphorylation and activation of Akt involve 3’ phosphoinositides and the action of PDK
3. Contains PH domain
4. The downstream targets of Akt/PTB have not been identified.
5. Required for insulin-mediated glucose transport
6. Involved in multiple other insulin responses
7. Represents an important mechanism for “cross-talk” between PI-3K pathway and other pathways regulating gene transcription and mitogenic effects.
Negative regulations of insulin signaling
What is Insulin Resistance?
1. Impaired insulin-mediated glucose uptake in peripheral cells
2. Impaired suppression of gluconeogenesis by the
liver
3. Impaired suppression of lipolysis in adipocytes
Summary
Insulin receptor (IR) is a pre-formed tetrameric transmembrane protein with two and two subunits linked by disulfide bonds.
Extracellular -subunits of IR form the insulin binding site and intracellular subunits possess tyrosine kinase activity
Insulin binding to the a subunits of IR triggers a conformational change in the subunits and activates the tyrosine kinase activity of the subunits. Each -subunit trans-phosphorylates Tyr residues on the other -subunit (autophosphorylation).
Activated IR phosphorylates insulin receptor substrate proteins (IRSs)
Summary II
Phosphorylated tyrosine on IRS serves as docking site for PI-3K, and moves PI-3K from cytosol to the inner side of plasma membrane
PI-3K converts PIP2 into PIP3 by phosphorylation
PIP3 moves Akt (PKB) next to membrane bound protein kinases and protein kinases phosphorylates and activates Akt
Akt indirectly activates GLUT4, inducing the translocation of GLUT4 from cytoplasm to the plasma membrane and triggering transport of glucose into the adipocyte (also muscle) cells
Summary III (Common themes in signal transduction)
Tyrosine kinase receptors for most growth factors
Docking (often SH2 domain to phosphorylated Tyr) for protein-protein interaction near receptor
Multiple protein factors (often kinases) for signal amplification and potential crosstalk with other regulatory pathways
May have alternative pathway(s) for further fine tuning for the signal
Signal inhibitors and attenuators such as phosphatases and/or serine/threonine kinases coexist with activators
Temporal and spatial regulation of signal
II. Glucose transport and glucose metabolism in cancer
Positron Emission Tomography (PET) Scan
Esophageal cancer
Tracer: Glucose analogue – 18F-fluorodeoxyglucose
Hallmarks of cancer 2000
Oncogenic signaling
Loss of tumor suppression
Invasion and metastasis
Telomere and telomerase
New blood vessel formation
Resistance of apoptosis
Cell 2000; 100:57-70.
Hallmarks of cancer - 2010
Immuno-evasion
Inflammation
Cancer metabolism
Cancer genomics
Cell 2011;144:646-74
http://en.wikipedia.org/wiki/Positron_emission_tomographyhttp://en.wikipedia.org/wiki/File:PET-MIPS-anim.gifhttp://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=4237470
(18)F-FDG ((18)F-fluoro-2-deoxyglucose) uptake on positron emission tomography (PET)
More than 90% of all cancers show increased glucose uptake and glucose metabolism
Liver metastases of a colorectal tumor
Used for diagnosis, prognosis
Glucose metabolism and the Warburg effect
Warburg effect – Upregulated aerobic glycolysis and lactate production even in the presence of O2 in cancer cells.
Gatenby, et al. Nat. Rev. Cancer 2004; 4, 891-899.
Otto H. Warburg
German Biochemist
(1883-1970)http://www.nobelprize.org/nobel_prizes/medicine/laureates/1931/#
O2
O2
Nature Reviews Cancer 4, 891-899, 2004
Glucose metabolism and the Warburg effect
Warburg effect – Upregulated aerobic glycolysis and lactate production even in the presence of O2 in cancer cells.
Tumor cell
Normal cell
Molecular mechanisms driving the Warburg effect.
Cairns, et al., Nat. Rev. Cancer 11, 85-89 (2011).
ATP synthesis under normoxia and hypoxia conditions
What are the purposes of the Warburg effect?
1.For ATP synthesis? (Is there a shortage of ATP in cancer?)
2.For biosynthesis of other important biomass?
3.For ROS?
Cancer Metabolism: pathways and regulators
Science 324, 1029 (2009)
Therapeutic Targeting of Hallmarks of Cancer
Hanahan and Weinberg. Cell 144, 646-674 (2011).
Study guide
1.Insulin signaling pathway – key protein factors in the pathway
2. How and where is Insulin produced and how its secretion regulated?
3.How insulin induces Glut4 translocation and glucose transport?
4.Type 2 diabetes and insulin resistance
5.Glucose transporters relevant to cancer (Glut1 – 3)
6.What is the Warburg effect?
7.How the Warburg effect regulated?
8.How to inhibit the Warburg effect to block cancer growth?
The Glucose Transporter Gene Family
Glucose
Glut1 inhibitor
?Out
In
Inhibitors targeting glucose metabolism
Modified from Oncogene (2006) 25, 4633–4646
mitochondrion
Cell membrane
D