An oral treatment for metabolic syndrome and diabetes is a step closer after researchers published a paper in the Oct. 31 issue of Nature detailing a new candidate compound which approaches the disease from a different angle than traditional injectable insulin therapies.
A research team led by University of Tokyo professor Takashi Kadowaki, an expert on diabetes and metabolic medicine, aim to begin clinical trials of the drug, called AdipoRon, within five years.
Diabetes is a burgeoning problem in a progressively more obese and sedentary world. Both obesity and a more sedentary lifestyle reduce the cells ability to utilise glucose for energy production. The hormone insulin, which is produced in the pancreas, is well recognised as an integral part of this process, however, research over the past decade has identified other hormones and substances which play an equally important role in glucose metabolism. The hormone adiponectin, which is secreted by fat cells, is one such substance. It is secreted by fat cells, and helps to regulate glucose and increase the effectiveness of insulin, but levels decrease as body fat increases.
In conditions such as Type 2 diabetes, obesity, polycystic ovarian syndrome or excessively reduced body fat, cells can become resistant to the effects of insulin through a mechanism that is not yet clear. A compound that was able to reverse the effects of insulin resistance would therefore be useful in these conditions. In 1995, scientists discovered such a compound – adiponectin, however the molecular structure of the compound was complicated and it was destroyed by the digestive system if taken orally.
Exercise increases levels of adiponectin, as does calorie restriction. A deficiency of this hormone has been implicated as a factor in the development of not only diabetes and metabolic syndrome, but also cancer, heart disease, liver disease and Alzheimer’s disease. The hormone has been found to be plentiful in people who attain an age of 100 years or more.
All of this research set scientists to wonder whether adiponectin could be useful in the treatment or prevention of these diseases, however, the molecular structure was complicated and researchers struggled to find a way in which it could be effectively produced and administered. After several hundred failed attempts to synthesise a compound similar to adiponectin that could be efficiently mass-produced and administered orally without being destroyed by the gastro-intestinal system, researchers have successfully identified such a molecule, with a function similar to adiponectin.
The researchers verified the effects of this substance by administering it to mice who were fed either a high fat diet in order to induce diabetes, or to mice who had reduced levels of body fat (lipoatrophy) which can also induce insulin resistance.
They found that the hormone improved insulin resistance and lowered blood glucose levels in both sets of mice. They further discovered that adiponectin works by reducing triglyceride levels in skeletal muscle.
The amount of food the mice ate and their weight did not change, but their blood sugar levels and neutral fat levels decreased. A considerable effect to stop the loss of muscle strength due to obesity was also confirmed, according to the team.
When one group of mice were continuously fed a diet high in fat, 70 percent of them died within 120 days. When the adiponectin-like substance was given to the mice along with a high-fat diet, however, the death rate was just 30 percent under the same conditions.
“Physical exercise and diet therapy are basic treatments for diabetes and metabolic syndrome at present. We hope the desired medicine will contribute to the treatment of people who cannot do physical exercise due to heart or joint conditions,” a member of the team said.
“This is a great result that offers hope for diabetes patients,”
said Yuji Matsuzawa, director of Sumitomo Hospital in Osaka, who discovered adiponectin in 1995.
“We look forward to seeing whether the effects of the substance translate over from mice to humans,”
the expert on endocrinology and metabolism added.
Because of its ability to lower blood glucose levels in the fact of insulin resistance, Kadowaki’s team conclude that “adiponectin has potential as an anti-diabetic drug.”
Nishimura, Satoshi. (2013-10–1) Adipose Natural Regulatory B Cells Negatively Control Adipose Tissue Inflammation. . DOI: 10.1016/j.cmet.2013.09.017
Okada-Iwabu, Miki. (2013-10-30) A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. . DOI: 10.1038/nature12656