A new study from the Joslin Diabetes Center has identified insulin resistance in the liver as a key factor in the cause of metabolic syndrome and its associated atherosclerosis, which puts millions of people worldwide at high risk of cardiovascular disease.
Metabolic syndrome describes the clustering of factors, including dyslipidemia, glucose intolerance and hypertension with central adiposity, which result in an increased risk of atherosclerosis, the build up of plaque in the coronary arteries that leads to heart attack and stroke. Metabolic syndrome is increasing in worldwide occurrence as a consequence of increasing obesity prevalence. It is likely to have a marked impact on the prevalence of cardiovascular disease and Type 2 diabetes worldwide in the next two decades. In the USA, surveys estimate that as many as one in four adults has metabolic syndrome and UK research suggests a similar number of sufferers; certain ethnic groups, such as Asian and Afro-Caribbean people, and women with polycystic ovary syndrome, are most at risk.
The study, published in the February issue of Cell Metabolism, provides not only an understanding of how metabolic syndrome occurs, but also pinpoints a target for treatment of the condition.
“This is one of the first true insights into the role of the liver in the metabolic syndrome and provides guidance for future therapies,” said senior investigator Ronald Kahn, Head of the Joslin Research Section on Obesity and Hormone Action and an internationally recognized researcher in diabetes and metabolism. “Showing this connection between atherosclerosis and insulin resistance is one of the most dramatic findings I’ve seen in 35 years.”
“This study clearly indicates that metabolic syndrome is not merely a collection of abnormalities that should be considered and treated independently, as some experts have advocated,” said Kahn and his team of researchers. “Rather, it appears that metabolic syndrome is truly a group of closely linked disturbances in glucose and cholesterol metabolism that stem from a defect in insulin signaling in the liver.”
The research was funded in part by grants from the National Institutes of Health and The Iacocca Foundation. Joslin Diabetes Center is the world’s largest diabetes clinic, diabetes research center and provider of diabetes education.
Source: Biddinger SB, Hernandez-Ono A, Rask-Madsen C et al. Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis. Cell Metab. 7, 125–134 (2008).
Obesity drug prescriptions in Britain rise eightfold
The number of drug prescriptions written by doctors to treat obesity has exceeded 1 million in a year for the first time, eight-times more than in 1999, recent government statistics showed.
The NHS said 1.06 million prescriptions of the two main obesity drugs orlistat (marketed as xenical), which prevents the absorption of some fat in the intestine, and sibutramine (Reductil®), which affects the chemical messages that control how a person thinks about food, were issued in 2006, at a cost of GB£47.5 million.
The NHS data showed that 24% of adults were classified as obese, a 50% rise in the last 10 years, while one in six children aged 2–15 years are classified as obese, a figure that has risen from one in ten.
The report comes a week after the government launched a GB£372 million strategy aimed at cutting levels of obesity in England. It includes GB£75 million for a marketing campaign to promote healthy living to parents of young children.
The shadow health secretary, Andrew Lansley, said: “The burden obesity is placing on our already overstretched NHS is becoming more and more unmanageable.
“Drug treatments are a short-term solution from a government that can’t see beyond the short term. They’ve missed and scrapped obesity targets, slashed budgets for preventative measures and cut specialist staff. What we need to do is help people make healthy choices so they don’t become obese in the first place,” he commented.
Denise Armstrong from Heart Research UK, said: “Obesity is a complex condition that cannot always be reversed through diet and exercise alone. However, a healthy lifestyle programme including increased physical activity should go hand in hand with any drug therapy.”
Type 2 diabetes treatment drug Galvus® approved in EU
Drug: Vildagliptin
Tradename: Galvus®
Manufacturer: Novartis International AG, Basel, Switzerland
Indication: Once-daily oral treatment for Type 2 diabetes mellitus
EU health authorities have approved Galvus® (vildagliptin) as a new oral treatment for Type 2 diabetes patients, paving the way for launches in Europe. Galvus is a much anticipated medication that may offer new benefits to millions of people with diabetes.
This regulatory approval applies in all 27 EU member states as well as in Norway and Iceland, and comes after changes updating the EU label were proposed by Novartis regarding the administration of Galvus.
As a member of the new class of Dipeptidyl peptidase 4 inhibitors, Galvus works through a novel mechanism of action by targeting the dysfunction in the pancreatic islets that causes high blood sugar levels in patients with Type 2 diabetes by producing more insulin.
Over 20,000 patients have participated in the Galvus clinical trial program to date, including nearly 13,000 treated with Galvus. When studied in combination with the most widely prescribed Type 2 diabetes medicines, Galvus delivered significant blood sugar reductions with a positive tolerability profile in a broad range of patients. The overall incidence of side effects was similar to placebo, with the most frequent being stuffy nose, headaches, dizziness and upper respiratory tract infection.
In the USA, there are concerns that Galvus may never come to market; the FDA has requested further clinical trial data from its manufacturer Novartis. Novartis may discontinue its work to have Galvus approved, citing the immense financial burden that additional research would entail.
Study suggests obesity may be wired into the brain
A predisposition for obesity may be hard-wired into the brain from birth, suggests a new US study published in the February issue of Cell Metabolism. The study showed that obese rats had faulty brain wiring that impaired their response to the hunger-suppressing hormone leptin.
Rats selectively bred to be diet-induced obese (DIO) showed abnormalities in a part of the brain critical for appetite control, the researchers found. Specifically, the obese rats were shown to harbor defects in neurons of the arcuate nucleus (ARH) of the hypothalamus, which leaves their brains less responsive to the hunger-suppressing hormone leptin. Produced by fat tissue, leptin plays a central role in fat metabolism, acting as a signal to the brain regarding the body’s energy status.
“The neurodevelopmental differences in these animals can be seen as early as the first week,” said lead researcher Sebastien Bouret, an Assistant Professor of neuroscience at the University of Southern California (CA, USA). “The results show that obesity can be wired into the brain from early life. The three-million-dollar question now is how to get around this problem.”
Previous research had suggested that the brains of DIO rats are insensitive to leptin, the researchers added, who looked for brain abnormalities that could explain this. They found defects in the brain circuits that relay leptin signals throughout the hypothalamus.
In the new study, the researchers examined the DIO rats for signs of abnormal brain development and found fewer neural projections from the ARH, a deficiency that persisted into adulthood. Those projections are needed to relay the leptin signal received by the ARH to other parts of the hypothalamus, Bouret said.
The researchers found further evidence that those changes in brain wiring stem from a reduced responsiveness of the brain to leptin’s action during development.
“Surprisingly, this deficiency developed very early in life, before the animals became obese, and appeared to extend into adulthood. Somehow, these animals are programmed to become obese. The obesity is hard-wired into the brain,” said Bouret.
While their condition might be ameliorated by exercising and eating right, he added, the findings suggest that the propensity to gain weight canot be reversed.
If the findings are replicated in humans, then those individuals who are genetically predisposed to obesity because of the way their brains are configured would have to be very careful about “diet and energy balance,” said Richard Simerly, co-researcher and Director of the neuroscience program at the Saban Research Institute at the University of Southern California.
“The study was conducted in rats, not humans, and yet it could ultimately lead to novel obesity treatments. It is not just about drugs that modify short-term appetite, there may be drugs that stimulate development of the appropriate neural pathways. So, it is an exciting, but very early, time in this field,” said Philip Smith, Director of the Office of Obesity Research, at the National Institute of Diabetes and Digestive and Kidney Diseases.
Source: Bouret SG, Gorski JN, Patterson CM. Hypothalamic neural projections are permanently disrupted in diet-induced obese rats. Cell Metab. 7, 179–185 (2008).
Inexpensive anti-inflammatory drug to treat Type 2 diabetes
In a new US study, researchers from Harvard Medical School’s Joslin Diabetes Center found that salsalate, an inexpensive anti-inflammatory drug similar to asprin, had a positive impact on blood glucose levels and inflammation in obese young adults at risk for developing Type 2 diabetes.
The double-masked, placebo-controlled study, which appears in the February issue of Diabetes Care, included obese people in their 20s treated with either 4 g of salsalate or placebo daily. Glucose levels were assessed at study entry and after a month of treatment, as was a key marker of inflammation.
Compared with placebo, salsalate was associated with a 13% reduction in fasting glucose levels and a 20% reduction in blood sugar response to an oral glucose-tolerance test, which measures the body’s ability to control glucose after a patient consumes a specific amount of glucose. Treatment with the anti-inflammatory drug was also associated with a 34% reduction in circulating levels of the inflammation marker C-reactive protein.
The proof-of-principal study concludes that salsalate reduces glycemia and may improve inflammatory cardiovascular risk indexes in the obese. The findings support the hypothesis that chronic inflammation contributes to obesity-related abnormal blood glucose and suggests that targeting inflammation may provide a therapy for diabetes prevention.
“This is exciting because salsalate has a good safety profile after many years of use, is inexpensive to make and appears to have the potential to lower blood glucose,” said Allison Goldfine, lead researcher of the study, Director of Clinical Research at Joslin and Assistant Professor at Harvard Medical School. “It may be useful in preventing diabetes.”
Results of the clinical trial have prompted the National Institutes of Health to fund a much larger trial designed to examine the safety and effectiveness of salsalate as a treatment for diabetes by lowering blood glucose, slowing the progression of coronary artery disease in those with metabolic syndrome and perhaps preventing diabetes in those at high risk. The 3-year trial is now underway at 16 diabetes centers across the USA.
Joslin researcher Steven Shoelson states that if early findings are confirmed, salsalate could prove to be even more beneficial than the widely prescribed diabetes drug metformin. The generically available drug would also be much cheaper for patients than most other drugs used in the treatment of diabetes. “If we establish that this drug works, it could be the second metformin, with the added benefit of possibly lowering the risk of cardiovascular disease”, he says.
Source: Fleischman A, Shoelson SE, Bernier R et al. Salsalate improves glycemia and inflammatory parameters in obese young adults. Diabetes Care 31, 289–294 (2008).