New insight on diabetes

Missing sugar molecule raises diabetes risk in humans

February 24th, 2011

Researchers at the University of California, San Diego School of Medicine and Rady Children's Hospital-San Diego say an evolutionary gene mutation that occurred in human millions of years ago and our subsequent inability to produce a specific kind of sugar molecule appears to make people more vulnerable to developing type 2 diabetes, especially if they're overweight. The findings are published in the Feb. 24 online edition of The FASEB Journal, a publication of the Federation of American Societies of Experimental Biology. Corresponding study author, Jane J. Kim is an assistant professor in the UCSD Department of Pediatrics and a member of the Pediatric Diabetes Research Center and Rady Children's Hospital-San Diego, a research and teaching affiliate of the UCSD School of Medicine. Kim said the findings represent the first documented evidence linking the sugar production to insulin and glucose metabolism problems associated with diabetes. "It opens up a new perspective in understanding the causes of diabetes," said Kim. "Given the global epidemic of obesity and diabetes, we think that these findings suggest that evolutionary changes may have influenced our metabolism and perhaps increased our risk of the disease." Type 2 diabetes is caused by both genetic and environmental factors, such as a fatty diet and lack of exercise, that result in progressively dysfunctional pancreatic beta cells, elevated blood sugar levels due to insulin resistance and eventual health complications, sometimes fatally so. Diabetes is an expanding problem, nationally and globally. In the United States, more than 25 million adults and children � almost nine percent of the population - have diabetes, according to the American Diabetes Association. Another 79 million Americans are estimated to be prediabetic. Worldwide, roughly 285 million people are believed to have the disease. Sialic acids are sugar molecules found on the surfaces of all animal cells, where they act as vital contact points for interaction with other cells and with their surrounding environment. Virtually all mammals produce two types: N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc). Humans are the exception. For reasons lost in the mists of evolution, a mutation in a gene called CMAH occurred 2 to 3 million years ago, inactivating an enzyme in humans that catalyzes production of Neu5Gc by adding a single oxygen atom to Neu5Ac. Researchers compared two groups of mice: one with a functional CMAH gene, the other with an altered CMAH gene similar to the human mutation. Both groups of mice were fed a high-fat diet. Mice in both groups became obese and developed insulin resistance. However, only mice with the CMAH gene mutation experienced pancreatic beta cell failure � the cells that make and release insulin, a hormone that controls blood sugar levels. Kim said the findings help refine understanding of why obese humans appear to be particularly vulnerable to type 2 diabetes, and also suggest that current animal models used to study diabetes may not accurately mirror the human condition. In clinical terms, she said further research to determine how sialic acid composition affects pancreatic beta cell function may reveal new strategies to preserve the cells, improve insulin production and prevent diabetes. Co-authors of the study are Sarah Kavaler and Alice Jih, UCSD Department of Pediatrics and Rady Children's Hospital-San Diego; Hidetaka Morinaga and WuQuiang Fan, UCSD Department of Medicine; Maria Hedlund and Ajit Varki, UCSD departments of Medicine, Cellular and Molecular Medicine and UCSD Glycobiology Research and Training Center. Funding support was provided by the National Institutes of Health Source: UC San Diego Credit: Eurekalert

BONES AND MALE FERTILITY

Skeleton regulates male fertility

February 17, 2011

Researchers at Columbia University Medical Center have discovered that the skeleton acts as a regulator of fertility in male mice through a hormone released by bone, known as osteocalcin.

The research, led by Gerard Karsenty, M.D., Ph.D., chair of the Department of Genetics and Development at Columbia University Medical Center, is slated to appear online on February 17 in Cell, ahead of the journal's print edition, scheduled for March 4.
Until now, interactions between bone and the reproductive system have focused only on the influence of gonads on the build-up of bone mass.
"Since communication between two organs in the body is rarely one-way, the fact that the gonads regulate bone really begs the question: Does bone regulate the gonads?" said Dr. Karsenty.
Dr. Karsenty and his team found their first clue to an answer in thereproductive success of their lab mice. Previously, the researchers had observed that males whose skeletons did not secrete a hormone called osteocalcin were poor breeders.
The investigators then did several experiments that show that osteocalcin enhances the production of testosterone, a sex steroid hormone controlling male fertility. As they added osteocalcin to cells that, when in our body produce testosterone, its synthesis increased. Similarly, when they injected osteocalcin into male mice, circulating levels of testosterone also went up.
Conversely, when osteocalcin is not present, testosterone levels drop, which causes a decline in sperm count, the researchers found. When osteocalcin-deficient male mice were bred with normal female mice, the pairs only produced half the number of litters as did pairs with normal males, along with a decrease in the number of pups per litter.
Though the findings have not yet been confirmed in humans, Dr. Karsenty expects to find similar characteristics in humans, based on other similarities between mouse and human hormones.
If osteocalcin also promotes testosterone production in men, low osteocalcin levels may be the reason why some infertile men have unexplained low levels of testosterone.
Skeleton Regulates Male Fertility, But Not Female
Remarkably, although the new findings stemmed from an observation about estrogen and bone mass, the researchers could not find any evidence that theskeleton influences female reproduction.
Estrogen is considered one of the most powerful hormones that control bone; when ovaries stop producing estrogen in women after menopause, bone mass rapidly declines and can lead to osteoporosis.
Sex hormones, namely estrogen in women and testosterone in men, have been known to affect skeletal growth, but until now, studies of the interaction between bone and the reproductive system have focused only on how sex hormones affect the skeleton.
"We do not know why the skeleton regulates male fertility, and not female. However, if you want to propagate the species, it's probably easier to do this by facilitating the reproductive ability of males," said Dr. Karsenty. "This is the only rationale I can think of to explain why osteocalcin regulates reproduction in male and not in female mice."
Other Novel Functions of Osteocalcin Reported Earlier
The unexpected connection between the skeleton and male fertility is one of a string of surprising findings in the past few years regarding the skeleton. In previous papers, Dr. Karsenty has found that osteocalcin helps control insulin secretion, glucose metabolism and body weight.
"What this work shows is that we know so little physiology, that by asking apparently naïve questions, we can make important discoveries," Dr. Karsenty says. "It also shows that bone exerts an important array of functions all affected during the aging process. As such, these findings suggest that bone is not just a victim of the aging process, but that it may be an active determinant of aging as well."
Next Steps and Potential Drug Development
Next, the researchers plan to determine the signaling pathways used by osteocalcin to enhance testosterone production.
And as for potential drug development, since the researchers have also identified a receptor of osteocalcin, more flexibility in designing a drug that mimics the effect of osteocalcin is expected.
Whether it's for glucose metabolism or fertility, says Dr. Karsenty, knowing the receptor will make it easier for chemists to develop a compound that will bind to it.
"This study expands the physiological repertoire of osteocalcin, and provides the first evidence that the skeleton is a regulator of reproduction," said Dr. Karsenty.

Provided by Columbia University Medical Center

anti TB drug

2 in 1: Multi-tasking protein provides new approaches for anti-tuberculosis drugs

February 15, 2011

In a paper published today in PNAS, scientists from the European Molecular Biology Laboratory (EMBL) in Hamburg, Germany, reveal new insights into the workings of enzymes from a group of bacteria including Mycobacterium tuberculosis, the bacterium that causes tuberculosis. The new findings present possible new opportunities for developing organism-specific drugs, which target the pathogen but leave other microorganisms, which are beneficial to us, untouched.

Tuberculosis remains one of the largest threats to human health worldwide, and one of the most frequent causes of death in HIV patients. With the increasing emergence of strains of Mycobacterium tuberculosis that are hyper-resistant to drugs, it becomes ever more urgent that novel treatments be developed, and the search for novel strategies for drug development is an important step in this process.
In the current study, Matthias Wilmanns and his group at EMBL identified a multi-tasking enzyme from Mycobacterium tuberculosis that catalyses reactions on two different molecules, or substrates. In most organisms, cells need two specific enzymes, known as HisA and TrpF, in order to produce two essential amino acids – histidine and tryptophan. However, in Mycobacterium tuberculosis, the encoding gene for TrpF is missing, and the two reactions are instead catalysed by a single enzyme, which is able to recognize and bind to two different substrates. This enzyme is known as PriA.
Using the Mycobacterium tuberculosis version of the PriA enzyme as a model, the researchers were able to unravel the hitherto unknown mechanism of bi-substrate specific binding observed in this group of bacteria.
"When we solved the three-dimensional structure of PriA, we found that it has the unique ability to form two different substrate-specific active sites," Wilmanns says: "it can form a reaction-specific active site, or undergo what we call 'substrate-induced metamorphosis' to form a different active site."
To further verify these observations, Wilmanns and colleagues screened 20,000 small molecule compounds, and identified a handful which inhibited both PriA-catalysed reactions but had no effect on TrpF activity.
"We believe that this ability for bi-substrate catalysis in Mycobacterium tuberculosis could be a new opportunity for future drug development," Wilmanns concludes: "This organism-specific reaction process could be exploited, since only the pathogen but none of the other bacteria living in or on humans, many of which are important for our well being, would be targeted."

Provided by European Molecular Biology Laboratory