TGR5, a G protein-coupled receptor expressed in brown adipose tissue and muscle, may be a novel therapeutic target for Type 2 diabetes and obesity or “diabesity,” research indicates.

In preclinical and in vitro studies, a pharmacologic selective TGR5 activator brought about an increase in muscle energy expenditure, a property with “therapeutic potential,” according to the study authors.

The work was undertaken by Johan Auwerx (Ecole Polytechnique Federale de Lausanne, Switzerland) and international collaborators and focused on the protein TGR5, which upon activation by bile acids triggers an increase in energy expenditure and attenuates diet-induced obesity.

Through a combination of pharmacological and genetic gain- and loss-of-function studies, the researchers found that TGR5 controls the secretion of glucagon-like peptide (GLP)-1 from enteroendocrine cells in the gut.

The therapeutic relevance of GLP-1 is well-established, say the researchers, and several drugs exploiting the properties of this hormone are already in advanced clinical development.

When administered to obesity-prone mice, TGR5 resulted in improved liver and pancreatic function as well as enhanced glucose tolerance, Auwerx et al report in Cell Metabolism.

Most importantly, administration of a specific TGR5 agonist, INT-777, induced GLP-1 release as well as leading to an increase in the intracellular ADP/ATP ratio and a rise in intracellular calcium mobilization.

Taken together, the results indicate that TGR5 activation “counteracts the metabolic dysfunction associated with diabesity,” say the researchers, through an increase in energy expenditure and incretin secretion.

“This leads us to conclude that TGR5 agonists could represent potential promising agents for the management of diabesity, along with associated disorders such as nonalcoholic steatohepatitis.” MedWire Diabetes, lipidology AstraZeneca Global v2 - Cardiovascular News Medical Disease_group: diabetes mellitus, dyslipidemia Drug provider: none Baylor: lipid

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

Free abstract

Just as some people like to believe their current circumstances were preordained in a previous life, or in an alternate reality, scientifically-minded folks may feel certain that their genetic makeup is responsible for their struggles with weight control and diabetes. No doubt our genetics have a dramatic influence on our physical and psychological makeup, but genes are not simple, immutable masters of our realm. Genes respond to their environment, and a gene can be expressed differently at different times throughout an individual’s life.

A critical function of our genes is the issuing of instructions to make important proteins. The genetic instructions change according to the presence of epigenetic marks - chemicals that can be attached to a gene and thus change the rate that it produces a particular protein, or even stop its production altogether. Understanding proteins and their production is a huge and barely tapped area of investigation; how genes influence protein production may offer important clues in understanding, and perhaps even preventing, disease.

Juleen Zierath and her research team at the Karolinska Institute in Sweden are trying to discover how people develop insulin resistance (a precursor to type 2 diabetes). Epigenetic marks seem to play an important role, and their research, published in Cell Metabolism, indicates that these chemical markers are affected by the dietary substances they are subjected to.

In type 1 diabetes, an individual fails to produce sufficient quantities of insulin to control sugar levels in the blood. This is usually because of the failure of the pancreatic cells that should make it. In the case of insulin resistance or type 2 diabetes, however, insulin is being produced but the body has begun to ignore it. As a result, the insulin is ineffective at moving sugar out of the blood.

Dr. Zeirath’s group used muscle biopsies from a small group of type 2 diabetics plus individuals with early signs of insulin resistance, and compared them to biopsies from healthy participants. It turned out that hundreds of genes differed in ways that matched the different types of patients being examined. For this study, they narrowed their research down to one gene (PGC-alpha) that is involved with the development of the mitochondria - the power plants of a cell.

The researchers found extra epigenetic marks on the genes of diabetics and pre-diabetics, which resulted in the production of fewer and smaller mitochondria than normal. Since a poor diet and lack of exercise is strongly associated with insulin resistance, the researchers tested the idea that these circumstances could be causing the extra epigenetic marks on the genes. In their lab, they exposed cells to a bath of glucose, fat and cytokines (proteins that cause inflammation - found at high levels in the obese). It turned out that both fats and cytokines caused the appearance of more epigenetic marks in the PCG-alpha genes. In other words, our diet and lifestyle can actually damage our genes.

Dr. Zierath also tested an inhibiting chemical that was able to prevent the genetic changes. Sadly, perhaps, this could lead to the development of another drug to treat what is foremost a lifestyle disease. So many of us are, after all, ever hopeful for a pill that will undo the abuse we inflict upon bodies through our lifestyle choices. Unfortunately, the quick fix is never as good as preventing the damage in the first place. Here we have more evidence to dump upon the existing pile that our bodies, and many of our diseases, are deeply affected according to the care we give them. As Dr. Zierath concludes, “we are not victims of our genes. If anything, our genes are victims of us.”