A single overactive enzyme worsens the two core defects of diabetes - impaired insulin sensitivity and overproduction of glucose - suggesting that a drug targeting the enzyme could help correct both at once, according to mouse studies done by researchers at Columbia University Medical Center. The findings were published today in the online edition of Cell Metabolism.
A drug that inhibits the enzyme, MK2, eventually could be added to metformin - the current first-line treatment for type 2 diabetes - to achieve better control over insulin and glucose levels than is possible with either drug alone, said the researchers.
“MK2’s compatibility with metformin makes it a very exciting potential drug target,” said Ira Tabas, MD, PhD, Richard J. Stock Professor and Vice Chair of Research in the Department of Medicine and professor of anatomy & cell biology (in physiology and cellular biophysics), who led the study with Lale Ozcan, PhD, associate research scientist.
“The one clear leader among drugs currently available for type 2 diabetes is metformin, which does a pretty good job of attacking both problems. But because metformin is often not enough, we need drugs that can be added to metformin—or used in patients who cannot tolerate metformin,” Dr. Tabas said. “If you take an obese, diabetic mouse and give it metformin, you get a partial improvement. If you give it an MK2-inhibitor, you also get a partial improvement. However, if you give both, the benefit is additive, which is consistent with our data that metformin and MK2 work through different biochemical pathways.”
The researchers’ earlier findings, on MK2’s effects on glucose, were published last year in the same journal.
Though both papers report the biochemical details of how MK2 works in mice, Drs. Tabas and Ozcan, working with CUMC surgeons Marc Bessler, MD, and Beth Schrope, MD, PhD, also have recent unpublished data suggesting that MK2 is overactive in obese people, including those with pre-diabetes, but not in lean people. Moreover, the MK2 pathway is active in human liver cells, and, according to a large human genetic study called DIAGRAM, a key component of the pathway that activates MK2 is associated with diabetes.
About 25.8 million people in the U.S. and 347 people worldwide have diabetes (mostly type 2). According to the Centers for Disease Control and Prevention, each year, about 6 percent of people with pre-diabetes develop type 2 diabetes; unless they make lifestyle changes, about 15 to 30 percent will develop diabetes within five years. “In addition to improving insulin sensitivity and glucose levels, our data suggest to us that a drug that inhibits MK2 could prevent the progression of pre-diabetes to full diabetes,” Dr. Tabas said.
Such a drug could protect the cells that produce insulin. “As the disease progresses, the insulin-producing cells have to put out more and more insulin to deal with the ever-increasing amounts of glucose in the bloodstream. Eventually, they burn out and the patient must use insulin,” Dr. Tabas said. “If we can protect the pancreas’s beta cells from the stress of dealing with high glucose, we may be able to prevent or delay progression to full diabetes.”
Globally, the prevalence of chronic, noncommunicable diseases is increasing at an alarming rate. About 18 million people die every year from cardiovascular disease, for which diabetes and hypertension are major predisposing factors. Propelling the upsurge in cases of diabetes and hypertension is the growing prevalence of overweight and obesity - which have, during the past decade, joined underweight, malnutrition, and infectious diseases as major health problems threatening the developing world.1 Today, more than 1.1 billion adults worldwide are overweight, and 312 million of them are obese. In addition, at least 155 million children worldwide are overweight or obese, according to the International Obesity Task Force. This task force and the World Health Organization (WHO) have revised the definition of obesity to adjust for ethnic differences, and this broader definition may reflect an even higher prevalence - with 1.7 billion people classified as overweight worldwide.
In the past 20 years, the rates of obesity have tripled in developing countries that have been adopting a Western lifestyle involving decreased physical activity and overconsumption of cheap, energy-dense food. Such lifestyle changes are also affecting children in these countries; the prevalence of overweight among them ranges from 10 to 25%, and the prevalence of obesity ranges from 2 to 10%. The Middle East, Pacific Islands, Southeast Asia, and China face the greatest threat. The relationship between obesity and poverty is complex: being poor in one of the world’s poorest countries (i.e., in countries with a per capita gross national product [GNP] of less than $800 per year) is associated with underweight and malnutrition, whereas being poor in a middle-income country (with a per capita GNP of about $3,000 per year) is associated with an increased risk of obesity. Some developing countries face the paradox of families in which the children are underweight and the adults are overweight. This combination has been attributed by some people to intrauterine growth retardation and resulting low birth weight, which apparently confer a predisposition to obesity later in life through the acquisition of a “thrifty” phenotype that, when accompanied by rapid childhood weight gain, is conducive to the development of insulin resistance and the metabolic syndrome.
The human and financial costs of obesity are also mounting: a higher body-mass index (the weight in kilograms divided by the square of height in meters) has been shown to account for up to 16% of the global burden of disease, expressed as a percentage of disability-adjusted life-years. In the developed world, 2 to 7% of total health care costs are attributable to obesity. In the United States alone, the combined direct and indirect costs of obesity were estimated to be $123 billion in 2001. In 2004 in the Pacific Islands, the economic consequences of noncommunicable diseases, mainly obesity and diabetes, amounted to $1.95 million - almost 60% of the health care budget of Tonga.
Drs. Tabas and Ozcan are planning to test this hypothesis with pre-diabetic mice.
Inhibiting MK2 also reduces cholesterol
Unpublished data from Drs. Tabas and Ozcan also suggest that MK2 inhibitors may not carry the cardiovascular risks associated with several newer diabetes drugs. Because of these risks, the FDA will not approve a new diabetes drug unless it has been found to be safe in large clinical trials designed to detect cardiovascular risk.
The Columbia researchers’ mouse studies show that MK2 inhibition reduces cholesterol, and other researchers have found that MK2 deficiency in mice protects against atherosclerosis. “A drug that inhibits MK2 may not just be heart-safe, but may actually be cardio-protective,” Dr. Tabas said.
He and Dr. Ozcan have created a company to develop compounds able to inhibit MK2.
“As with all drug development, it’s a long shot, but we think MK2 is less of a long shot than most.”
Drs. Tabas’ and Ozcan’s paper is titled, “Activation of Calcium/Calmodulin-Dependent Protein Kinase II in Obesity Mediates Suppression of Hepatic Insulin Signaling.”
This work was supported by NIH grants HL087123 and HL075662; American Heart Association Scientist Development Grant 11SDG5300022; NYONRC Pilot and Feasibility Grant DK26687; FAPESP/BEPE 2012/21290-4; German Center for Cardiovascular Research; the German Ministry of Education and Research; Deutsche Forschungsgemeinschaft BA 2258/2-1; European Commission FP7-Health-2010; and MEDIA-261409. The basic science at the foundation of this work is part of a large NIH-sponsored program undertaken with two other CUMC professors, Domenico Accili, MD, and Alan Tall, MD, who have provided valuable guidance throughout these studies.
Drs. Ozcan and Tabas are among the co-founders of Tabomedex Biosciences LLC, which is developing inhibitors of the pathway described above for treatment of type 2 diabetes. The authors declare no additional financial or other conflicts of interest.
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