Research Breakthrough Of Essential Molecule Reveals Important Targets In Diabetes And Obesity

Insulin is the most potent physiological anabolic agent for tissue-building and energy storage, promoting the storage and synthesis of lipids, protein and carbohydrates, and inhibiting their breakdown and release into the circulatory system. It also plays a major role in stimulating glucose entry into muscle tissue, where the glucose is metabolized and removed from the blood following meals. But gaps exist in understanding the precise molecular mechanisms by which insulin regulates glucose uptake in fat and muscle cells.

A research team led by Assia Shisheva, Ph.D., professor of physiology in Wayne State University's School of Medicine, has made breakthrough advancements on a molecule that may provide more answers to this mystery.

The conserved phospholipid enzyme, PIKfyve, was discovered in Shisheva's lab in 1999. Based on studies in cultured cells, the lab has implicated PIKfyve in the insulin-regulated glucose transport activation, which led to the development of a unique mouse model with PIKfyve ablation, or removal, in muscle (MPlfKO), the tissue responsible for the majority of postprandial glucose disposal.

In Shisheva's recent paper, "Muscle-specific PIKfyve gene distribution causes glucose intolerance, insulin resistance, adiposity and hyperinsulinemia but not muscle fiber-type switching," published online in the American Journal of Physiology - Endocrinology and Metabolism, Shisheva and her research team characterize whether this new model exhibits metabolic defects.

"Our team found a striking metabolic phenotype in the MPIfKO mice consisting of glucose intolerance and insulin resistance at an early age and on a normal diet," said Shisheva, a resident of Royal Oak. "We also revealed that PIKfyve is essential for normal insulin signaling to GLUT4/glucose transport in muscle and provided the first in vivo evidence for the central role of PIKfyve in the mechanisms regulating healthy blood glucose levels, or glucose homeostasis."

In addition, the research team found that these metabolic disturbances were followed by increased animal fat (adiposity) and elevated levels of insulin (hyperinsulinemia), but not abnormal amounts of lipids or cholesterol in the blood (dyslipidemia).

"The combined phenotype manifested by the MPlfKO mouse closely recapitulates the cluster of typical features in human prediabetes including systemic glucose intolerance and insulin resistance, hyperinsulinemia and increased visceral obesity without dyslipidemia," said Shisheva.

"Therefore, our mouse model, in addition to providing novel mechanisms of insulin resistance, represents a valuable tool for exploring new preclinical strategies to improve treatments in individuals with prediabetes."

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New Tool To Measure Sugar Consumption

Scientists at the University of Alaska Fairbanks identified a new tool that can dramatically improve the notoriously inaccurate surveys of what and how much an individual eats and drinks. Their research is published in the June 2013 issue of the Journal of Nutrition.

Conventional wisdom says that consumption of sugar-sweetened beverages such as soda and fruit juice is a significant contributor to obesity and chronic disease risk, but the science surrounding this issue is inconclusive. Part of the problem is that in a typical diet survey few people accurately and consistently recall what they consumed. The problem becomes exaggerated when people underreport foods they know are less healthy for them, like sugars.

"We were looking for an objective biomarker that could accurately measure long-term sugar intake from a single blood or hair sample" said Diane O'Brien, project leader and biologist with the UAF Center for Alaska Native Health Research at the Institute of Arctic Biology.

The biomarker O'Brien and her CANHR research group pilot-tested was the ratio of two different carbon atoms (heavy carbon 13 and light carbon 12) which are incorporated into plants during photosynthesis. The ratio, called an isotopic signature, is distinct in corn and sugar cane, which are the sources of nearly all of the sugars found in sugar-sweetened beverages.

"We used the isotopic signature of alanine an amino acid and building block of protein that essentially traps the carbon from dietary sugar so that it can be measured in the protein component of hair or blood," O'Brien said.

Even after foods and beverages are consumed, metabolized, transported in blood and stored in body tissues, these isotopic signatures remain largely intact. The more sugar-sweetened beverages an individual consumes, the greater alanine's carbon isotope ratio will be. Importantly, O'Brien's group found that alanine was uncorrelated with other foods that can contribute to elevated carbon ratios.

Although the use of isotope signatures to study food webs and diet is not new, previous efforts to accurately measure sweetener intake have not been particularly successful. The use of alanine and the technique employed by O'Brien's group makes their findings particularly exciting.

"Even for validated and well-accepted biomarkers of diet, associations with self-reported intake are generally very weak. Our biomarker was able to explain almost half of the variation in self-reported sugar-sweetened beverage intake, which in this field is a very high level of explanatory power," said O'Brien.

The scientists' findings are also being used in other health and diet-related research.

"Diane's research program has provided CANHR with incredibly valuable objectively measured biomarkers of food intake," said CANHR Director Bert Boyer. "These biomarkers are currently being used to help us understand the role polyunsaturated fatty acids play in disease prevention, including the modification of genetic risk."

The tool is not without its drawbacks, caution the authors.

"The gas chromatography-combustion-isotope ratio mass spectrometry process we used isn't inexpensive and or widely available," O'Brien said. "We expect that our findings will be most useful as a calibration tool, either for self-reported dietary data or more high-throughput biomarkers of sweetener intake."

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Helping Prevent Obesity Among Children Via Community-Based Programs

When it comes to confronting childhood obesity, researchers at the Johns Hopkins Bloomberg School of Public Health conclude that community-based approaches are important. A systematic review of childhood obesity prevention programs found that community-based intervention programs that incorporate schools and focus on both diet and physical activity are more effective at preventing obesity in children. The results of the study appear online in Pediatrics.

"In measuring the effectiveness of community-based programs that impact childhood obesity - more comprehensive interventions are definitely better," said Sara Bleich, PhD, associate professor inof Health Policy and Management and lead author on the paper. "The research shows that in order to help prevent obesity among children, we must focus on both diet and exercise in the communities where children live and go to school since the environment is a key contributor to obesity risk. Focusing on the community is especially important for children since they generally have little or no control over their environment."

This shift toward a stronger community focus is echoed in a recent Institute of Medicine (IOM) report, Accelerating Progress in Obesity Prevention, which recommends a comprehensive approach to childhood obesity prevention that includes the community.

Researchers examined nine studies that featured community-based interventions and found that, among those, the two interventions that included a school component effectively prevented obesity or overweight in children. Common characteristics found across most of the nine studies included the use of multiple intervention components (e.g., health education and family outreach), the inclusion of settings other than just the community (e.g., school, home, primary care, child care), and a focus on children at middle school age or younger.

"While additional research is needed to assess the full impact of community-based interventions on the prevention of childhood obesity, our conclusions indicate that more comprehensive approaches, which attempt to modify diet and exercise in the community with engagement from the schools, weigh in everyone's favor," said Bleich.

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