METABOLIC DISEASE: Uncovering how the antidiabetic drug metformin really works

Metformin is the drug of choice for treating individuals with type 2 diabetes. It works primarily by suppressing the production of glucose by the liver. Recent data suggest that metformin suppresses glucose production by the liver by activating the protein AMPK. However, a team of researchers, led by Benoit Viollet and Marc Fortez, at Institut Cochin, Paris, has now found that metformin still suppresses glucose production by the liver in mice lacking AMPK. Further analysis revealed that metformin in fact elicits its antidiabetic effects in the liver by reducing intracellular levels of ATP (a molecular energy source). As noted by Morris Birnbaum and Russell Miller, in an accompanying commentary, these data have clinical implications because AMPK is considered an attractive target for the development of new drugs to treat type 2 diabetes.

Title: Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state

Title: An energetic tale of AMPK-independent effects of metformin

ONCOLOGY: Overcoming the toxic effects of anticancer radiation therapy

Severe side effects, in particular the destruction of blood cell precursors in the bone marrow, limit the efficacy of radiation therapy for the treatment of cancer. Researchers are therefore seeking to develop ways to protect healthy cells from the toxicity of radiation therapy. A team of researchers, led by Normal Sharpless, at the University of North Carolina School of Medicine, Chapel Hill, has now determined that small molecules that inhibit both CDK4 and CDK6 (proteins involved in regulating cell proliferation) mitigate the effects of radiation therapy on blood cell precursors in mice. Importantly, treating tumor-bearing mice with both a CDK4/6 inhibitor and radiation reduced the toxicity of radiation therapy without compromising its therapeutic effects. The authors and, in an accompanying commentary, Andrei Gudkov and Elena Komarova therefore suggest that CDK4/6 inhibitors might provide a way to improve the efficacy of radiation therapy for the treatment of patients with cancer.

Title: Mitigation of hematologic radiation toxicity in mice through pharmacological quiescence induced by CDK4/6 inhibition

Title: Radioprotection: smart games with death

TRANSPLANTATION: Noninvasive imaging of heart transplant rejection in mice

Despite the use of drugs that suppress the immune system, rates of graft rejection are high among recipients of heart transplants. Currently, the onset and progression of graft rejection in heart transplant recipients are monitored by serial biopsy. A noninvasive approach to monitor heart transplant recipients would be of tremendous benefit to physicians and patients. Ralph Weissleder, Matthias Nahrendorf, and colleagues, at Massachusetts General Hospital and Harvard Medical School, Boston, have now brought this a step closer to reality by developing a technique that enabled them to define and validate an imaging signature of heart graft rejection in mice. Specifically, they found that noninvasive imaging for the presence of the protein MPO, which is expressed at high levels in immune cells characterized by high levels of expression of the protein Ly-6C, was a signature of hearts that were rejected. The authors therefore suggest that MPO imaging might provide a noninvasive way to monitor heart transplant recipients and identify those likely to reject their grafts.

Title: Myeloperoxidase-rich Ly-6C+ myeloid cells infiltrate allografts and contribute to an imaging signature of organ rejection in mice

CARDIOVASCULAR DISEASE: Uncovering the causes of hardening of the arteries

Atherosclerosis, or hardening of the arteries, is a disease of the major arterial blood vessels that is a common cause of heart attack and stroke. It is one of the leading causes of death in developed countries. A team of researchers, led by Pek Yee Lum and Xia Yang, at Rosetta Inpharmatics LLC, Seattle, has now studied gene-disease causality relationships in mice susceptible to atherosclerosis. The team identified in the fat tissue and liver of the mice, 292 genes causal for a specific characteristic of atherosclerosis (aortic arch lesion size) and experimentally validated one of these candidate genes using a knockout mouse model. Of clinical significance, the candidates identified by the team were enriched for genes whose functional DNA variation has been shown previously to be associated with atherosclerosis disease risk in humans. The authors believe that further studies using this approach and the data they generate will provide insights into the mechanisms underlying the development of atherosclerosis, a key to developing new therapeutics and diagnostic biomarkers.

Title: Identification and validation of genes affecting aortic lesions in mice

HEPATOLOGY: Scar tissue in the liver: how to block its formation

Cirrhosis of the liver is a condition in which scar tissue (fibrotic tissue) slowly replaces healthy liver tissue due to chronic injury caused by any one of a number of insults, including persistent heavy alcohol consumption and infection with hepatitis B or C viruses. This causes the liver to slowly deteriorate and malfunction. A team of researchers, led by Vijay Shah and Sheng Cao, at the Mayo Clinic, Rochester, has now identified a molecular regulator of a key step in the development of liver fibrosis in rats, leading them to suggest that this molecule could be targeted for therapeutic purposes.

A key step in the development of liver fibrosis is the recruitment of cells known as hepatic stellate cells (HSCs). Their recruitment is dependent on the growth factor PDGF, but the molecular mechanisms that regulate the effects of PDGF have not been determined. The team found that the protein neuropilin-1 was central to the effects of PDGF on rat, mouse, and human HSC recruitment in vitro. Furthermore, blocking neuropilin-1 ameliorated recruitment of HSCs and blocked liver fibrosis in a rat model. The authors believe that these data have therapeutic implications because neuropilin-1 overexpression was observed in cirrhotic liver tissue from humans with disease caused by both hepatitis C virus infection and steatohepatitis.

Title: Neuropilin-1 promotes cirrhosis of the rodent and human liver by enhancing PDGF/TGF-beta signaling in hepatic stellate cells

Karen Honey
Journal of Clinical Investigation

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