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Mechanism For Sulfonylurea Treatment Failure In Type 2’s

In a set of mouse experiments, scientists attempt to learn more about why sulfonylureas eventually fail in the treatment of patients with type 2 diabetes. They may be more likely to keep working if they are used in moderation and stopped for a period of time.

Type 2 diabetes is often treated using sulfonylurea drugs such as glibencalmide. These medications inhibit the ATP-driven potassium channels in pancreatic beta cells, pushing calcium to enter the beta cells, inducing them to release insulin in a process known as depolarization. This insulin causes blood glucose levels to fall temporarily, but long-term treatment with these types of medications eventually fails through an unknown mechanism.

To investigate this mechanism, Maria Remedi and Colin Nichols from the Washington University School of Medicine examined the pancreatic beta cells in mice treated with sulfonylureas. In their results, they displayed that the treatment does not cause death of pancreatic beta cells, but rather causes them to become permanently depolarized across the cell’s channels. They additionally showed that, after being treated by slow-release sulfonylureas, this beta cell failure is actually reversible if the treatment is removed.

"Why this happens isn’t clear yet, but we’ve found what may be cause for hope," says senior author Colin G. Nichols, Ph.D., the Carl F. Cori Professor and professor of cell biology and physiology. "We’ve shown in a mouse model that whatever causes this shutdown doesn’t kill the insulin-making beta cells of the pancreas or stop them from making insulin. Instead, it somehow stops them from secreting insulin."

When they stopped receiving the drug, beta cells began secreting insulin again hours later. Nichols and co-author Maria Sara Remedi, Ph.D., instructor of cell biology and physiology, report the findings in Public Library of Science Medicine.

"I find these experimental observations very exciting," says Alan Permutt, M.D., professor of medicine and of cell biology and physiology. "But I’m very cautious that patients understand that the relevance of this model to human diabetes and its treatment still needs to be tested."

If human beta cells also survive and can continue to produce insulin after long-term sulfonylurea exposure, it may be possible to rethink treatment strategies, Nichols suggests.

"Doctors now prescribe new long-acting sulfonylureas to establish a chronic presence of the drug in the bloodstream," he says. "But it may be beneficial to use the older drugs that go away more quickly, allowing the beta cells time to recover."

Another potential option would be alternating periods of drug treatment with periods when the patient’s symptoms are managed by insulin injection, Nichols suggests.

Type 2 diabetes accounts for 90 percent to 95 percent of the estimated 16 million Americans with diabetes. Patients with the disorder develop resistance to insulin, a hormone that helps the body control blood sugar levels. In many cases, their beta cells also make less insulin. Physicians typically treat the condition with a sulfonylurea and metformin, a drug that increases insulin sensitivity.

Nichols and Remedi saw an important opportunity to learn about the long-term failure of sulfonylureas with the availability of an implantable time-release capsule form of one of the drugs, glibenclamide. They implanted the capsules in the necks of mice. As expected, the drugs initially caused mouse beta cells to release more insulin and blood sugar levels dropped rapidly. Within a few days, though, the response to the drug reversed: Insulin secretion levels dropped, and blood sugar levels rose dramatically.

Examination of the pancreas showed that the animals’ beta cells were still alive and contained normal levels of insulin.

"The problem seems to lie somewhere between the trigger for secreting insulin, which was hyperactivated while they were on the medication, and the actual mechanisms that release insulin," Nichols says. "The insulin is there, it’s just not ready to release."

Nichols and Remedi are currently seeking further insight into the causes of this breakdown.

If applicable to the human model, these findings have strong implications for sulfonylurea dosing. For instance, further investigation should be made into the use of low-dose or pulsed dose treatments, which could help prevent treatment failure. This evaluation should first be more fully evaluated in animals before it reaches any clinical stages.

Erik Renstrom and colleagues from Lund University contributed an accompanying perspective in which they discuss the implications of this study.

Chronic antidiabetic sulfonylureas in vivo: Reversible effects on mouse pancreatic b-cells. Remedi MS, Nichols CG PLoS Med 5(10):e206.   doi:10.1371/journal.pmed.0050206

Click Here for Full Length Article

Why treatment fails in type 2 diabetes. 
Rosengren A, Jing X, Eliasson L, Renström E
PLoS Med 5(10): e215. doi:10.1371/journal.pmed.0050215
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