Artificial Pancreas to Ease Diabetes Burden

Artificial Pancreas to Ease Diabetes Burden

  7:09:00 PM    Science Lover

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The 25.8 million Americans who have diabetes may soon be free of finger pricks and daily insulin dosing. Mayo Clinic endocrinologists Yogish Kudva, M.B.B.S., and Ananda Basu, M.B.B.S., M.D., are developing an artificial pancreas that will deliver insulin automatically and with an individualized precision never before possible.

Glucose level blood test. Researchers are 
developing an artificial pancreas that will 
deliver insulin automatically and with an 
individualized precision never before possible. 
(Credit: © evgenyb/ Fotolia)

As part of this effort, Drs. Kudva and Basu will present their latest findings on how the mundane movements of everyday life affect blood sugar to the American Diabetes Association meeting this month in San Diego.

"The effects of low-intensity physical activity, mimicking activities of daily living, measured with precise accelerometers on glucose variability in type 1 diabetes had not been examined," says Dr. Kudva.

Among his newest findings is that even basic physical activity after meals has a profound impact on blood sugar levels for people with type 1 diabetes. "You would expect this result, but we wanted to know to what extent this phenomena would happen in people with type 1 diabetes," Dr. Kudva says.

Diabetics who engaged in low-grade physical activity after eating had blood sugar levels close to those of people with fully functioning pancreases. Those who remained sedentary after their meal, however, had elevated blood sugars.

The researchers plan to incorporate these findings into an artificial pancreas being developed at Mayo Clinic. The "Closed Loop System" under development includes a blood sugar monitor, an automatic insulin pump, a set of activity monitors that attach to the body and a central processing unit.

Clinical trials of the artificial pancreases are likely to begin in November with a handful of inpatient volunteers. Study participants will follow strict diet, exercise and insulin-delivery regimens in Mayo's Clinical Research Unit. Data will then be fed into an insulin-delivery algorithm, which mimics the body's natural process of monitoring and responding to glucose levels in the bloodstream.

"Physical activity enhances insulin action, hence lowering blood glucose concentration," Dr. Kudva says. "Real-time detection of physical activity -- and modeling of its effect on glucose dynamics -- is vital to design an automatic insulin delivery system."

Dr. Kudva and other Mayo researchers have spent nearly 15 years working on various aspects of diabetes and obesity. They are collaborating on the artificial pancreas and developing an algorithm that will afford patients the peace of mind to eliminate their daily routine of diabetes maintenance.

Dr. Basu will present findings that blood sugar levels decrease faster in the mornings in healthy adults than at dinner time, suggesting a diurnal pattern to natural insulin action. He proposes further study of this phenomenon and possible incorporation into the algorithm that drives the Closed Loop System.

The research has been funded by grants from the National Institutes of Health.

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Could Diabetes Be in Your Bones?

Could Diabetes Be in Your Bones?

  8:54:00 PM    Science Lover

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Our bones have much greater influence on the rest of our bodies than they are often given credit for, according to two new studies in the July 23 issue of Cell, a Cell Press publication. Both studies offer new insights into the interplay between bone and blood sugar, based on signals sent via insulin and a bone-derived hormone known as osteocalcin.

Insulin signaling in bone favors whole-body glucose 
homeostasis by activating osteocalcin(1) Insulin signals 
osteoblasts, bone cells responsible for bone formation, 
which (2) tell osteoclasts, bone cells responsible for 
resorption, to destroy old bone. Next (3), the acidic 
(low pH) conditions created by the osteoclasts activates 
osteocalcin inside the bone. Finally (4), the active 
osteocalcin released from bone travels to the pancreas 
and stimulates the release of more insulin. (Credit: Image 
provided by Columbia University Medical Center)

Mice whose bones can't respond to insulin develop high blood sugar and insulin resistance, both hallmarks of diabetes. Those symptoms are tied to a drop in osteocalcin. The findings suggest that osteocalcin, or perhaps a drug that targets bone, might hold promise in fighting the global epidemic of type 2 diabetes, according to the researchers.

"Our study reveals a key molecular link between bone remodeling and metabolism," said Gerard Karsenty of Columbia University.

"Bone is an organ that has to pay attention to where calories are going," added Thomas Clemens of Johns Hopkins University School of Medicine. "It talks to muscle, fat, the pancreas. It's a player in energy metabolism."

And perhaps that makes a lot of sense, Karsenty said. The remodeling of bone relies on two cell types, bone-building osteoblasts and bone-resorbing osteoclasts, making bone the only organ with a cell type that is entirely focused on destroying host tissue. "On a daily basis, the formation of bone is expensive in terms of energy," he said.

In fact, the idea that the skeleton is much more than a reservoir for calcium and phosphate isn't entirely new, the researchers said. Earlier evidence by Karsenty's group had shown links between bone and the fat hormone leptin. (Obese adults are significantly less likely to develop osteoporosis.)

Scientists also had evidence that osteoblasts might respond to insulin in important ways. Osteoblasts bear insulin receptors and when treated with insulin show signs of collagen synthesis and take up more glucose, Clemens' team notes. People with type 1 diabetes due to a lack of insulin can also develop weakened bones.

Karsenty's team describes bone as a multitasker. It has mechanical, hematopoietic (blood-producing) and metabolic functions. It also acts as an endocrine organ through the release of osteocalcin hormone, which favors glucose metabolism when in its active form.

Still, Clemens said he was surprised by what they saw after developing a mouse lacking insulin receptors only in their osteoblasts. "The mice started to get fat," he said. They showed changes in their biochemistry that were consistent with insulin resistance. They also had low osteocalcin levels and fewer osteoblasts to produce less bone.

With age, the animals became even fatter and developed more marked high blood sugar accompanied by severe glucose intolerance and insulin resistance. Those symptoms improved with osteocalcin treatment.

Karsenty's group presents independent evidence for the important role of insulin in bone for keeping glucose in check through osteocalcin, in what he refers to as a "feed-forward loop." But his group goes a step further to suggest that bone-resorbing osteoclasts (not just osteoblasts) have a place in this too.

Karsenty explains that bone-building osteoblasts actually control bone resorption by osteoclasts, a process that takes place under very acidic conditions. Those conditions would also favor the chemical modification necessary to produce active osteocalcin, which can escape bone to act as a hormone.

That could be important to those who take osteoporosis drugs designed to block bone resorption, Karsenty suggests. "It's a red flag," he said. "Osteoporotic patients treated with [bone resorption inhibitors] may be at risk of glucose intolerance."

The researchers include Mathieu Ferron, Columbia University, New York, NY; Jianwen Wei, Columbia University, New York, NY; Tatsuya Yoshizawa, Columbia University, New York, NY; Andrea Del Fattore, University of L'Aquila, L'Aquila, Italy; Ronald A. DePinho, Harvard Medical School, Boston, MA; Anna Teti, University of L'Aquila, L'Aquila, Italy; Patricia Ducy, Columbia University, New York, NY; and Gerard Karsenty, Columbia University, New York, NY.

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Gene Therapy Reverses Type 1 Diabetes in Mice

Gene Therapy Reverses Type 1 Diabetes in Mice

  9:35:00 PM    Science Lover

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Researchers have developed an experimental cure for Type 1 diabetes, a disease that affects about one in every 400 to 600 children and adolescents.

In a new study using gene therapy in mice, researchers 
say they have developed an experimental cure for 
Type 1 diabetes. (Credit: iStockphoto)

Results of the research in a mouse model of Type 1 diabetes are being presented at The Endocrine Society's 92nd Annual Meeting in San Diego.

Using gene therapy, the team from Baylor College of Medicine in Houston tried to counter the two defects that cause Type 1 diabetes: autoimmune attack and destruction of the insulin-producing beta cells. They used nonobese diabetic mice, which spontaneously develop diabetes due to autoimmunity, just as humans do with Type 1 diabetes.

"A single treatment cured about 50 percent of the diabetic mice, restoring their blood sugar to normal so that they no longer need insulin injections," said study co-author Lawrence Chan, MD, DSc, chief of Baylor's diabetes, endocrinology and metabolism division.

Type 1 diabetes occurs when the body's immune system attacks and destroys the beta cells in the pancreas, the insulin "factory" of the body. The resulting near-complete deficiency of insulin -- the hormone that controls blood sugar -- leads to a buildup of high blood sugar and thus diabetes.

In past studies of their original gene therapy, Chan's group was able to stimulate new formation of beta cells in the liver and restore insulin production and normal blood sugar levels in more than 100 mice with chemically induced diabetes. However, in nonobese diabetic mice the treatment failed to reverse Type 1 diabetes because the mouse's immune system killed the newly formed beta cells, he said.

In this research, which was funded by the National Institute of Diabetes, Kidney and Digestive Diseases, Chan said they "added to the original gene therapy approach a protective gene that shields the newly formed beta cells from autoimmune attack." The added gene was for interleukin-10, an important regulator of the immune system. Past studies showed that interleukin-10 can prevent diabetes development in mice but cannot reverse the disease once it has developed because of the lack of beta cells.

However, when the researchers combined the gene therapy with interleukin-10 into a single intravenous injection, the treatment showed a complete reversal of diabetes in half of the mice during more than 20 months' follow-up. Although the therapy did not reverse autoimmunity throughout the body, it protected the new beta cells from the local destructive effect of autoimmunity, Chan explained.

"We developed a protective 'moat' around the new beta cells," he said. "We are now developing other strategies to try to fortify the newly formed beta cells and give them better weapons in addition to the moat, in order to increase the treatment's cure rate."

Why the gene therapy did not work in all the mice is unclear. However, Chan said the treated mice that did not have improvements in their blood sugar did gain weight and lived a little longer than untreated mice.

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