Finding Could Lead to New Treatments for Better Blood Glucose Control

Researchers at the Joslin Diabetes Center have shown for the first time that insulin plays a key role in suppressing levels of glucagon, a hormone involved in carbohydrate metabolism and regulating blood glucose levels.

The study helps in the understanding of why those with diabetes have high blood glucose levels and could lead to development of a drug aimed at targeting glucagon levels.

“This is a very important finding because until now scientists have only speculated that insulin may be involved in keeping glucagon levels in check,” said Rohit N. Kulkarni, M.D., Ph.D., Principal Investigator in the Joslin Section on Cellular and Molecular Physiology and senior author of the study published today in the April issue of Cell Metabolism.

Produced by the alpha cells in the pancreas, glucagon acts on the liver to help raise blood glucose when it becomes low. It has the opposite effect on the liver as insulin, which is released from pancreatic beta cells to lower blood glucose when it is high. In a healthy individual, the two counter each other to keep blood glucose levels balanced. In individuals with long-standing type 1 or type 2 diabetes, inappropriate glucagon secretion can increase the chances of hypoglycemia (low blood glucose levels) and can interfere with insulin therapy.

The finding suggests that for people with either type 1 or type 2 diabetes, a therapeutic approach could be developed to target insulin receptors or proteins in alpha cells in order to suppress glucagon secretion.

In addition, the research may also help in the understanding of why patients with type 1 diabetes in particular, who are required to inject insulin on a regular basis, are at risk for hypoglycemia. It was thought that this increased risk was linked in some way to insulin receptors in the alpha cells, an idea that today’s study suggests is in fact the case, Dr. Kulkarni explained.

“This gives us some insight into the cause of hypoglycemia, the most common complication in patients with type 1 diabetes,” he said. “Injecting insulin leads to a decrease in blood glucose.  If it starts to go too low, glucagon normally kicks in to prevent hypoglycemia. But, what happens in diabetes is the alpha cells become desensitized by repeated insulin injections over many years and they start to behave abnormally. We believe this is linked to insulin receptor function.”

In the study, Dr. Kulkarni and his team created a genetically engineered mouse model in which pancreatic alpha cells – those that secrete glucagon – were modified so that they did not contain insulin receptors. The idea was to explore the role of insulin in regulating glucagon secretion.

The modified mice exhibited elevated glucagon levels and also showed impaired glucose tolerance, as is seen in diabetes.

“This is the first genetic model wherein we provide definitive proof that insulin is able to suppress glucagon in mammals,” Dr. Kulkarni said.  “The next step is to identify the specific proteins in alpha cells that could be targeted to suppress glucagon secretion.”

The paper concludes that the findings indicate there is a significant role for insulin signaling in the regulation of alpha cell functioning in both normal and hypoglycemic conditions and provide direct genetic evidence for a key role for insulin receptors in the modulation of pancreatic alpha cell function.

The study was funded in part by the American Diabetes Association, the Swiss National Science Foundation, the National Institutes of Health and the European Union.

Also contributing to the research were Dan Kawamori, Amarnath J. Kurpad, Jiang Hu, Chong Wee Liew and Judy L. Shih, all of Joslin; Eric L. Ford and Kenneth S. Polonsky, both of Washington University School of Medicine; Pedro L. Herrera, University of Geneva Medical School; and Owen P. McGuinness, Vanderbilt University School of Medicine.

Source: Joslin Diabetes Center

Research examines middle-aged and older populations; waist size found to be a risk factor even when body mass index falls within normal range

Adding to the growing evidence that a person’s waist size is an important indicator of heart health, a study led by investigators at Beth Israel Deaconess Medical Center (BIDMC) has found that larger waist circumference is associated with increased risk of heart failure in middle-aged and older populations of men and women. 

The findings, published online in the April 7 Rapid Access Report of the journal Circulation: Heart Failure, showed that increased waist size was a predictor of heart failure even when measurements of body mass index (BMI) fell within the normal range. 
“Currently, 66 percent of adults in the United States are overweight or obese,” explains Emily Levitan, ScD, the study’s first author and a Research Fellow in the Cardiovascular Epidemiology Research Unit at BIDMC. “Knowing that the prevalence of heart failure increased between 1989 and 1999, we wanted to better understand if and how this increase in obesity was contributing to these rising figures.” 
A life-threatening condition that develops when the heart can no longer pump enough blood to meet the body’s needs, heart failure (also known as congestive heart failure) is usually caused by existing cardiac conditions, including high blood pressure and coronary artery disease. Heart failure is the leading cause of hospitalization among patients 65 and older, and is characterized by such symptoms as fatigue and weakness, difficulty walking, rapid or irregular heartbeat, and persistent cough or wheezing. 
The researchers examined two Swedish population-based studies, the Swedish Mammography Cohort (made up of 36,873 women aged 48 to 83) and the Cohort of Swedish Men (43,487 men aged 45 to 79) who responded to questionnaires asking for information about their height, weight and waist circumference. Over a seven-year period between January 1998 and December 2004 the researchers reported 382 first-time heart-failure events among the women (including 357 hospital admissions and 25 deaths) and 718 first-time heart-failure events among men (accounting for 679 hospital admissions and 39 deaths.) 
Their analysis found that based on the answers provided by the study participants, 34 percent of the women were overweight and 11 percent were obese, while 46 percent of the men were overweight and 10 percent were obese. 
“By any measure – BMI, waist circumference, waist to hip ratio or waist to height ratio –our findings showed that excess body weight was associated with higher rates of heart failure,” explains Levitan. 
Further breakdown of the numbers showed that among the women with a BMI of 25 (within the normal range), a 10-centimeter higher waist measurement was associated with a 15 percent higher heart failure rate; women with a BMI of 30 had an 18 percent increased heart failure rate. In men with a BMI of 25, a 10-centimeter higher waist circumference was associated with a 16 percent higher heart failure rate; the rate increased to 18 percent when men’s BMI increased to 30. 
Furthermore, adds Levitan, among the men, each one-unit increase in BMI was associated with a four percent higher heart failure rate, no matter what the man’s waist size. In women, she adds, BMI was only associated with increased heart failure rates among the subjects with the largest waists. Finally, the authors found that the association between BMI and heart-failure events declined with age, suggesting that the younger the person, the greater the impact of weight to heart health. 
“This study reinforces the importance of maintaining a healthy weight,” says Levitan. “Previous research has looked at various types of heart disease and related health issues, and no matter the particulars of the study, they’ve all been pretty consistent in determining that excess body weight increases a person’s risk of heart disease.” 
Study coauthors include BIDMC investigators Murray A. Mittleman, MD, DrPH (senior author), Amy Z. Yang, BA and Alicja Wok, DrMedSci. 
The study was supported by grants from the National Institutes of Health, the Swedish Research Council and the Swedish Foundation for International Cooperation in Research and Higher Education. 
Beth Israel Deaconess Medical Center is a patient care, research and teaching affiliate of Harvard Medical School and consistently ranks in the top four in National Institutes of Health funding among independent hospitals nationwide. BIDMC is a clinical partner of the Joslin Diabetes Center and a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox.

Source: Beth Israel Deaconess Medical Center

Gluten-free bread, which is suitable for patients with celiac disease, has been supplemented to resemble French bread in terms of texture and color, according to a study in the Journal of Food Science, published by the Institute of Food Technologists (IFT). The study was sponsored by the Commission of the European Communities.

Celiac disease is a digestive disease that damages the small intestine and interferes with absorption of nutrients from food. According to the National Institutes of Health, more than two million people who have celiac disease cannot tolerate gluten, a protein in wheat, rye, and barley. From a food science perspective, proteins play a key role in the unique baking quality of wheat by providing elasticity and cohesiveness to dough. Since bread is prepared mainly from wheat flour containing proteins implicated as the cause of the disease, celiac patients must avoid bread in many countries.

The ingredients added to gluten-free bread include guar gum, buckwheat flour, whole egg powder, and whey proteins. Breads with guar gum had color characteristics similar to French bread. Bread prepared with buckwheat flour had improved quality and softer texture similar to regular French bread and contained dietary fiber.

“Buckwheat flour in the actual base of ingredients was found to have interesting improving effects on the quality attributes of the bread,” according to lead researcher Marie de Lamballerie. “Sensory analysis is now underway to evaluate the acceptance of this formulation by a panel of consumers.”

To read the article, titled “Optimization of Gluten-Free Formulations for French-Style Breads,” visit http://www3.interscience.wiley.com/cgi-bin/fulltext/122267411/PDFSTART

Source: Journal of Food Science/Institute of Food Technologist