Features | Partner Sites | Information | LinkXpress
Sign In
GLOBETECH PUBLISHING
GLOBETECH PUBLISHING
JIB

Metabolic Pathway Discovered Has Implications for Diabetes, Obesity, Cancer Therapy

By BiotechDaily International staff writers
Posted on 18 Oct 2012
A newly discovered hedgehog-signaling pathway has been found to be a primary regulator of cellular energy metabolism and to include insulin-independent glucose uptake.

Scientists from the Max Planck Institute of Immunobiology and Epigenetics in Freiburg (Freiburg, Germany) and the Medical University of Vienna (Vienna, Austria) together with an international research team have jointly resolved this pathway, which also involves the known activation of Smo upon binding of Sonig Hedgehog (Shh) to its membrane receptor Patched (Ptch). Smo controls the previously known hedgehog pathway through transcription factors, whereas it controls the newly discovered, must faster, alternative hedgehog pathway through calcium-dependent activation of an AMP-kinase. This rewires metabolism so that the cell can now rapidly absorb large quantities of glucose, rebalancing anabolism and catabolism. Further, rather than promoting efficient energy metabolism through mitochondria, this pathway promotes the much less efficient lactic acid fermentation, the process cancer cells use to acquire their energy anaerobically, as in the Warburg effect.

The US Food and Drug Administration approved the first hedgehog inhibitor, Vismodegib, for treatment of cancer this year. There are presently at least six further agents being tested in clinical studies. Surprisingly, the first patient cohorts receiving Vismodegib have shown serious side effects, such as weight loss and muscle cramps, to the extent that more than half of the participants discontinued use. “Activation of the AMP-kinase and increased catabolism could explain the exaggerated weight loss of the participants in the clinical studies. More importantly though, the influx of calcium into muscle cells leads to instant contraction, and must be triggering the cramps,” explained Prof. Andrew Pospisilik from the Max Planck Institute in Freiburg. Hedgehog inhibitors do not have to lead to these side effects. “We targeted the Smo protein with various substances and found out that there are inhibitors that do not evoke an increase in calcium or glucose values, and, critically, these same inhibitors fail to cause muscle cells to contract in culture," said Prof. Pospisilik.

The scientists also found that cultured fat cells dramatically increase the glucose quantity they can absorb – without relying on insulin. This finding was confirmed by glucose-tolerance tests on mice treated with the classic hedgehog inhibitor cyclopamine, which showed correspondingly lower blood glucose than untreated mice. “Agents that only activate the Smo-calcium/AMP-kinase hedgehog signaling pathway are therefore candidates as medications for treating excess body weight, as well as type-1 and type-2 diabetes. Similar to the broad hedgehog inhibitors, they possess the potential to induce muscle cramps. Thanks to our findings, we now know that a new agent must first be tested on muscle cells before it is used on humans,” said Prof. Harald Esterbauer of the Medical University of Vienna.

The study was published October 12, 2012, in the journal Cell.


Related Links:
Max Planck Institute of Immunobiology and Epigenetics in Freiburg
Medical University of Vienna


comments powered by Disqus

Channels

Genomics/Proteomics

view channel
Image: This micrograph depicts the presence of aerobic Gram-negative Neisseria meningitidis diplococcal bacteria; magnification 1150x (Photo courtesy of the CDC - US Centers for Disease Control and Prevention).

Infection by Meningitis Bacteria Depends on Dimerization State of Certain Host Cell Proteins

A team of molecular microbiologists has untangled the complex three-way interaction between the non-integrin laminin receptor (LAMR1), galectin-3 (Gal-2), and the pathogenic bacterium Neisseria meningitidis.... Read more

Drug Discovery

view channel

Molecule in Green Tea Used as Carrier for Anticancer Proteins

A molecule that is a key ingredient in green tea can be employed as a carrier for anticancer proteins, forming a stable and effective therapeutic nanocomplex. This new discovery could help to construct better drug-delivery systems. Some cancer treatments depend on medication comprising the therapeutic drug and a carrier... Read more

Lab Technologies

view channel
Image: The UC Santa Cruz Ebola Genome Portal contains links to the newly created Ebola browser and to scientific literature on the deadly virus (Photo courtesy of UCSC).

Ebola Genome Browser Now Online to Help Scientists’ Respond to Crisis

A US genomics institute has just released a new Ebola genome browser to help international researchers develop a vaccine and antiserum to help stop the spread of the Ebolavirus. The investigators led... Read more

Business

view channel

Interest in Commercial Applications for Proteomics Continues to Grow

Increasing interest in the field of proteomics has led to a series of agreements between private proteomic companies and academic institutions as well as deals between pharmaceutical companies and novel proteomics innovator biotech companies. Proteomics is the study of the structure and function of proteins.... Read more
 
Copyright © 2000-2014 Globetech Media. All rights reserved.