The hormone insulin keeps blood sugar (glucose) levels within a narrow range in people who don’t have diabetes. People with Type 2 diabetes are either resistant to insulin or do not produce enough insulin to maintain normal blood sugar levels.

Onglyza is in a class of drugs known as dipeptidyl peptidase-4 (DPP-4) inhibitors which stimulate the pancreas to make more insulin after eating a meal.

“Keeping blood sugar levels in adequate control is essential to the good health of the 24 million people in the United States with Type 2 diabetes,” said Mary Parks, M.D., director of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research. “High blood sugar levels can cause blurry vision and excessive urination and eventually result in such serious conditions as kidney and eye disease.”

The most common side effects observed with Onglyza are upper respiratory tract infection, urinary tract infection, and headache. Other side effects include allergic-like reactions such as rash and hives.

Approval of Onglyza was primarily based on the results of eight clinical trials. The application seeking FDA approval was submitted before December 2008 when the agency recommended that manufacturers of new diabetes drugs carefully design and evaluate their clinical trials for cardiovascular safety. Although Onglyza was not associated with an increased risk for cardiovascular events in patients who were mainly at low risk for these events, the FDA is requiring a postmarket study that will specifically evaluate cardiovascular safety in a higher risk population.

Onglyza is manufactured by Bristol-Myers Squibb Co. of Princeton, N.J., and marketed by Bristol-Myers and AstraZeneca Pharmaceuticals LP, of Wilmington, Del.

Source: FDA, July 31, 2009

Some studies have suggested several mechanisms through which adiponectin may decrease the risk of type 2 diabetes, although the strength and consistency of the relation between plasma adiponectin and risk of type 2 diabetes has been unclear, according to background information in the article.

Shanshan Li, M.D., M.Sc., of the Harvard School of Public Health, Boston, and colleagues conducted a review and meta-analysis to assess the consistency of the association of adiponectin levels and risk of type 2 diabetes. The researchers identified thirteen studies with a total of 14,598 participants and 2,623 new cases of type 2 diabetes that met criteria for inclusion in the meta-analysis.

The authors found that higher adiponectin levels were associated with a lower risk of type 2 diabetes. This inverse association was consistently observed in whites, East Asians, Asian Indians, African Americans and Native Americans. The results did not differ substantially by method of diabetes ascertainment, study size, follow-up duration, body mass index or proportions of men and women.

“Although these epidemiologic studies cannot establish causality, the consistency of the association across diverse populations, the dose-response relationship, and the supportive findings in mechanistic studies indicate that adiponectin is a promising target for the reduction of risk of type 2 diabetes,” the authors write.

The researchers add that recent studies have shown that adiponectin levels can be increased through pharmaceutical and lifestyle interventions. “In addition, adiponectin levels may be useful for identifying persons likely to benefit most from interventions to treat ‘dysfunctional adipose tissue’ and its metabolic complications. Future studies should also evaluate whether adiponectin is useful for prediction of type 2 diabetes in addition to established risk factors using statistical techniques appropriate for prognostic analyses.”

Source: JAMA. 2009;302[2]:179-188

“Obesity is occurring at epidemic rates in the U.S. and worldwide and that impacts the risk and prognosis of many diseases,” said Yu-Hua Tseng, Ph.D. an Assistant Investigator in the Joslin Section on Obesity and Hormone Action and lead author of the paper published in the August 21 issue of Nature. “We hope this study can be translated into applications to help treat or prevent obesity.”

Dr. Teng cited obesity as a major risk factor for type 2 diabetes, and its close relationship to the metabolic syndrome, a group of medical problems associated with insulin resistance that can increase the risk of atherosclerosis.

Dr. Teng states that there are 2 main types of fat cells, white and brown. In laboratory studies of mouse cells, she and her colleagues found that a bone-producing protein called BMP-7 drives precursor cells giving rise to mature brown fat cells.

“White fat cells are the ‘conventional’ form of fat designed to store energy. By contrast, the main role of brown fat is to burn calories by generating heat. Brown fat cells largely disappear by adulthood in humans, but their precursors still remain in the body,” Tseng explained.

An earlier (2005) Joslin study by Dr. Teng and colleagues discovered genes that control the creation of the precursor cells of brown fat. A later (2007) Joslin study by C. Ronald Kahn, M.D., head of the Joslin Section on Obesity and Hormone Action and also a co-author of the current Nature study, found clusters of brown fat cells dispersed between bundles of muscle fibers in an obesity-resistant strain of mice.

The study identified BMP-7 as the protein capable of inducing the formation and function of brown fat cells.Delivery of BMP-7 into mice using adenovirus as a vector resulted in an increase in the development of brown fat tissue. In one of the experiments, the mice that developed brown fat tissue gained less weight than those that did not. In another experiment, mice that received injections of progenitor cells—similar to stem cells—that had been pre-treated with BMP-7 also developed additional brown fat tissue.

The purpose of the study was to determine what controls the development of fat depots, a central question in adipocyte biology. BMPs are a family of proteins known to regulate organ formation during embryonic development. Dr. Teng and associates suggested that different members of BMPs determine brown versus white fat cell fate. Scientists hope that improved knowledge of fat development will lead to new drugs or therapeutic approaches to fight obesity.

“Diet and exercise are still the best approaches for weight reduction in the general population,” Tseng said. “However, for people who are genetically predisposed to obesity, these approaches may have very little effect.” As we learn more about the controls of brown fat development, medical interventions to increase energy expenditure by brown fat inducing agents, such as BMP-7, may provide hope to these individuals in losing weight and preventing the metabolic disorders associated with obesity,” she said.

Source: Nature, August 21, 2008

Low incidence of type 1 diabetes was noted in people living in equatorial regions, while higher incidence was noted in populations at higher latitudes where sunlight was scarcer.

Photosynthesis of vitamin D3 is set in motion by ultraviolet exposure, while this form of vitamin D is also available through diet and supplements. "This is the first study, to our knowledge, to show that higher serum levels of vitamin D are associated with reduced incidence rates of type 1 diabetes worldwide," said Cedric F. Garland, Dr. P.H., professor of Family and Preventive Medicine in the UCSD School of Medicine, and a member of the Moores UCSD Cancer Center.

About 1.5 million Americans cope with type 12 diabetes every day, and type 1 diabetes ranks second only to asthma as the most chronic disease among children. Type 1 diabetes is diagnosed in some 15,000 Americans each year, and causes blindness and kidney failure in youth and middle age.

"This research suggests that childhood type 1 diabetes may be preventable with a modest intake of vitamin D3 (1000 IU/day) for children, ideally with 5 to 10 minutes of sunlight around noontime, when good weather allows," said Garland. "Infants less than a year old should not be given more than 400 IU per day without consulting a doctor. Hats and dark glasses are a good idea to wear when in the sun at any age, and can be used if the child will tolerate them."

Even after allowing for the fact that equatorial regions will have lower per capita healthcare expenditures than more developed countries, the association of UVB irradiance to incidence of type 1 diabetes remained strong. The researchers created a graph with a vertical axis for diabetes incidence rates, and a horizontal axis for latitude. The latitudes range from -60 for the southern hemisphere, to zero for the equator, to +70 for the northern hemisphere. They then plotted incidence rates for 51 regions according to latitude. The resulting chart was a parabolic curve that looks like a smile.

In the paper the researchers call for public health action to address widespread vitamin D inadequacy in U.S. children.

"This study presents strong epidemiological evidence to suggest that we may be able to prevent new cases of type 1 diabetes," said Garland. "By preventing this disease, we would prevent its many devastating consequences."

The study was published June 5, 2008 in the online version of the scientific journal Diabetologia.

The WARNINGS section of the product has been updated to include a BOXED WARNING and a description of the epidemiologic data that is the basis for the revised label. These data come from a retrospective study that compared cancer incidence and cancer mortality among 1,622 patients exposed to Regranex to 2,809 otherwise similar patients who were not exposed. The results were consistent with no overall increase in cancer incidence among the patients exposed to Regranex. However, there was a five-fold increased risk of cancer mortality in the group exposed to three or more tubes of Regranex.

"In announcing this label change, FDA still cautions health care professionals to carefully weigh the risks and benefits of treating patients with Regranex," said Susan Walker, M.D., director of the Division of Dermatological and Dental Products. "Regranex is not recommended for patients with known malignancies."

In late March, 2008 the FDA issued an Ongoing Safety Review Communication on Regranex notifying the public that it was conducting a safety review. This follow-up communication is in keeping with FDA’s commitment to notify the public of any regulatory changes with this FDA approved product.

Regranex is a medicine that is a recombinant form of human platelet-derived growth factor which is applied directly to diabetic foot and leg ulcers that are not healing. The recombinant form of platelet growth factor has a biologic activity that is much like that produced naturally by the body. Growth factors cause cells to divide more rapidly. It is for this reason that the manufacturer continued to monitor studies begun before Regranex was approved in December 1997 for any evidence of adverse effects such as increased numbers of cancers. In a long term safety study completed in 2001, there were more deaths from cancer in people who used Regranex than in those who did not use it.

Following the report of the study completed in 2001, an additional study was performed using a health insurance database that covered the period from January, 1998 through June, 2003. This study used the database to identify two groups of patients with similar diagnoses, drug use, and use of health services, one of which used Regranex and one group that did not. The results of this study showed that deaths from cancer were higher for patients who were given three or more prescriptions for treatment with Regranex than those who were not treated with Regranex. No single type of cancer was identified, but rather deaths from all types of cancer, combined were observed.

Source: FDA, June 6, 2008

Diabetic retinopathy (PDR) is the most common cause of legal blindness in working-aged adults in the United States, accounting for 10% of new cases of blindness. Diabetes is also the leading cause of kidney disease, called end-stage renal disease (ESRD), in the U.S. and the Western world.

While researchers have known that these conditions in diabetic patients can be hereditary, the actual genese involved have been relatively unknown until now.

Researchers discovered the involvement of the EPO gene in a study of 1,618 people with diabetic retinopathy and end-stage renal disease, and 954 diabetes patients without any eye or kidney disease in three separate populations. Their studies demonstrate that if a person has a copy of the mutant EPO gene, they have an increased risk of developing PDR and ESRD during their lifetime.

According to Dr. Dean Li from the Program in Human Molecular Biology and Genetics at the University of Utah, while there is no proven pharmacologic treatment for diabetic vascular eye diseases, "inhibiting the growth of unwanted blood vessel growth using antibodies directed against vascular endothelial growth factor (anti-VEGF therapy) has been advocated. This genetic study suggests that future therapeutic strategies need to consider blunting the effects of erythropoietin in addition or as an alternative to an anti-VEGF strategy."

The study was led by Kang Zhang M.D., Ph.D., Director of the Division of Ophthalmic Genetics at the Moran Eye Center and Associate Professor of Ophthalmology and Visual Sciences at the University of Utah, and was published in the journal Proceedings of National Academy of Sciences.

The class of drugs is a relatively new and effective class of oral antidiabetic agents that have gained wide use in clinical conditions characterized by insulin resistance, the study authors note. Other recent studies have suggested that these therapies may have unfavorable effects on bone, resulting in slower bone formation and faster bone loss.

According to the study, individuals who were currently taking rosiglitazone and pioglitazone had approximately 2x or 3x the likelihood of hip and other non-spine fractures than those who did not take these drugs. The odds for fracture were increased among patients who took the drugs for approximately 12 to 18 months and the risk was highest for those with two or more years of therapy.

Source: Archives of Internal Medicine, April 28, 2008

In a recent paper, researchers from the Joslin Diabetes Center note that Insulin inhibits a master gene regulator protein called SKN-1, whose activity increases lifespan. SKN-1 also controls what is called the Phase 2 detoxification pathway, a network of genes that defends cells and tissue against oxidative stress—damage caused by elevated levels of free radicals (byproducts of metabolism)—and various environmental toxins. This new research result was validated in experiments on the digestive system of C.elegans, a microscopic worm often used as a model organism.

"We’ve found something new that insulin does and it has to be considered when we think about how insulin is affecting our cells and bodies," said Dr. T. Keith Blackwell, senior investigator at Joslin and author of the paper. "This has implications for basic biology since under some circumstances insulin may reduce defense against the damaging effects of oxidative stress more than we realize."

Enhancing the activity of SKN-1 may lead to increased resistance to chronic diseases and influence longevity, said Dr. Keith, and the work could be important as it relates to diabetes and the many problems associated with the disease, particularly vascular and renal complications.

"The major implication is that we have found something new that affects lifespan and aging, and an important new effect that insulin and/or a related hormone called insulin-like growth factor-1 may have in some tissues," said Blackwell. "The implications go far beyond diabetes."

A gene regulator protein called FOXO is important in diabetes metabolism, tumor suppression and stem cell maintenance, a fact known since the 1990’s. FOXO controls a number of genes involved in stress resistance, and studies in C.elegans demonstrated that diminished insulin signaling increased activity of a FOXO protein called DAF-16, leading to greater stress resistance and longer life.

The Joselin research adds to knowledge about insulin and its effects on gene pathways, while putting SKN-1 next to FOXO as a second master gene regulator that is inhibited by insulin signaling. According to the paper, insulin’s effect on SKN-1 occurs independently of its effect on DAF-16.

The paper was published in the March 21, 2008 issue of Cell.

"Although the American Diabetes Association recommends that all children with diabetes be cared for by a pediatric endocrinologist as part of a diabetes team, there is a current shortage of pediatric endocrinologists in this country," says study lead author Joyce Lee, M.D., MPH, a pediatric endocrinologist and member of the Child Health Evaluation and Research (CHEAR) Unit in the U-M Division of General Pediatrics. "This problem will likely only worsen due to the recent epidemic of childhood obesity."

The 16.5% of American children aged 6 to 19 who are obese are at risk for ‘adult’ diseases such as type 2 diabetes, elevated blood pressure and high cholesterol. As a result more children than ever are being referred to pediatric endocrinologists for screening, evaluation and management. "But even if just a small fraction of obese children are referred to a pediatric endocrinologist for evaluation", says Lee, " the overall ratio of one pediatric endocrinologist to 17,000 obese children makes providing the necessary care extremely challenging." Dr. Lee is assistant professor in the Department of Pediatrics and Communicable Diseases at the U-M Medical School.

Available pediatric endocrinologists are so few in relation to the number of children at risk that they cannot see even a fraction of the children with diabetes or at risk for the disease. "The epidemic of childhood obesity has undoubtedly created new challenges for our health care, and we need to reassess the current system to ensure children with diabetes or at risk for diabetes receive appropriate care," Lee notes.

Pediatric endocrinologists currently do not have the capabilities to see even a fraction of the large number of children with diabetes or at risk for diabetes. "The epidemic of childhood obesity has undoubtedly created new challenges for our health care, and we need to reassess the current system to ensure children with diabetes or at risk for diabetes receive appropriate care," Lee notes.

Using data from the American Board of Pediatrics and the National Survey of Children’s Health, Lee and her colleagues compared the number of board certified pediatric endocrinologists by region to obese children and children with diabetes in those same areas.

Their research revealed that there are an estimated 229,249 children with diabetes, and only 790 board-certified pediatric endocrinologists in the country. And, in two states—Montana and Wyoming—there are no board-certified pediatric endocrinologists.

The study was published in the March issue of The Journal of Pediatrics.

In that capacity he will guide the scientific direction of Burnham’s Orlando facility by forming several research programs related to diabetes, obesity, metabolism and heart disease. In addition, Dr. Kelly will be responsible for faculty recruitment for the Orlando site, which is situated in Lake Nona’s “medical city,” a newly developed science and technology park with several university and clinical partners.

“I was attracted by the excitement of building a unique world-class research effort focused on the immense problem of diabetes and its complications,” said Dr. Kelly. “The power of interdisciplinary research can be harnessed in a single institute by bringing together scientists across many different fields. I look forward to assembling a team that capitalizes on the current strengths of the Burnham organization, while adding talented new scientists that drive our research mission forward. Linking discovery science to health care delivery by working with our clinical partners in the context of the developing medical city will change the future of health care.”

Dr. Kelly will officially join Burnham on July 1, 2008. He is currently the Tobias and Hortense Lewin Professor, Director of the Center for Cardiovascular Research, and Chief of the Cardiovascular Division in the Department of Medicine at Washington University School of Medicine in St. Louis, Missouri. Dr. Kelly joined the Washington University School of Medicine faculty in 1989 after obtaining his M.D. from the University of Illinois College of Medicine in Chicago in 1982 and completing a medicine residency followed by Postdoctoral Fellowships in the Biological Chemistry and Clinical Cardiology departments at Washington University School of Medicine. He moved up the ranks from Instructor of Medicine to tenured Professor of Medicine, Molecular Biology and Pharmacology, and Pediatrics at Washington University.

Dr. Kelly’s scientific interests include fundamental and translational research in cellular energy metabolism relevant to common diseases such as heart failure and diabetes, especially diabetic heart disease. He is the author of more than 100 peer-reviewed original research papers focusing on these areas.

“We are proud that Dr. Kelly is joining the Burnham team to lead expansion of our medical research programs in Florida, and to launch a new research center devoted to diabetes and obesity research,” said John C. Reed, M.D., Ph.D., President and CEO, Professor and Donald Bren Presidential Chair. “Our organization and our collaborators will benefit significantly from Dr. Kelly’s scientific vision, impressive leadership qualities and strong track record of success in building world-class research programs.”

About Burnham Institute for Medical Research
Burnham Institute for Medical Research conducts world-class collaborative research dedicated to finding cures for human disease, improving quality of life, and thus creating a legacy for its employees, donors, and community. The Institute is headquartered in La Jolla, CA where it was established as a nonprofit, public benefit corporation in 1976 and is now home to four major centers: a National Cancer Institute-designated Cancer Center; the Del E. Webb Center for Neurosciences, Aging and Stem Cell Research; the Infectious and Inflammatory Disease Center; and the Sanford Children’s Health Research Center. In 2006, Burnham established a center for bionanotechnology research at the University of California, Santa Barbara. Burnham is currently establishing a campus at Lake Nona in Orlando, Florida that will focus on diabetes and obesity research and will expand the Institute’s drug discovery capabilities. Today, Burnham employs more than 800 people and ranks consistently among the world’s top 25 organizations for its research impact and among the top four research institutes nationally for NIH grant funding. For additional information about Burnham and to learn about ways to support its research, visit www.burnham.org.