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

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: Blocking the activity of HSP101 may imprison the malaria parasite inside its protective vacuole within the red blood cell. In the electron micrograph, the malaria parasites appear in blue and uninfected red blood cells are shown in red (Photo courtesy of the [US] National Institute of Allergy and Infectious Diseases).

Heat Shock Protein Plays Critical Role in Malaria Parasite Protein Trafficking

A pair of recent papers described the molecular operators that enable the malaria parasite Plasmodium falciparum to export a large variety of proteins across the parasitophorous vacuolar membrane (PVM)... Read more

Drug Discovery

view channel
Image: Molecular rendering of the crystal structure of parkin (Photo courtesy of Wikimedia Commons).

Cinnamon Feeding Blocks Development of Parkinson's Disease in Mouse Model

A team of neurological researchers has identified a molecular mechanism by which cinnamon acts to protect neurons from damage caused by Parkinson's disease (PD) in a mouse model of the syndrome.... Read more

Therapeutics

view channel
Image: This type of electronic pacemaker could become obsolete if induction of biological pacemaker cells by gene therapy proves successful (Photo courtesy of Wikimedia Commons).

Gene Therapy Induces Functional Pacemaker Cells in Pig Heart Failure Model

Cardiovascular disease researchers working with a porcine heart failure model have demonstrated the practicality of using gene therapy to replace implanted electronic pacemakers to regulate heartbeat.... Read more

Lab Technologies

view channel
Image: A one-year-old baby sits in a brain scanner, called magnetoencephalography (MEG)—a noninvasive approach to measuring brain activity. The baby listens to speech sounds such as “da” and “ta” played over headphones while researchers record her brain responses (Photo courtesy of the Institute for Learning & Brain Sciences at the University of Washington).

Brain Scanner Shows Infants’ Brains Rehearse Speech Sounds Months Before Their First Words

New research in 7- and 11-month-old infants revealed that speech sounds stimulate brain regions that coordinate and plan motor movements for speech. The new study suggests that babies’ brains begin establishing... Read more

Business

view channel

Cancer Immunotherapy Sector Predicted to Surge to USD 9 Billion Across Major Pharma Through 2022

The immunotherapy market will experience substantial growth through 2022, increasing from USD 1.1 billion in 2012 to nearly USD 9 billion in 2022 (corresponding to 23.8% annual growth) in the United Kingdom, United States, France, Germany, Italy, Spain, and Japan, according to recent market research. This notable growth... Read more
 
Copyright © 2000-2014 Globetech Media. All rights reserved.