In the paper, lead author Dr. Michael W. Schwartz, 91±¬ÁĎ professor of medicine and director of the Diabetes and Obesity Center of Excellence, and his colleagues from the universities of Cincinnati, Michigan, and Munich,  note that the brain was originally thought to play an important role in maintaining normal glucose metabolism  With the discovery of insulin in the 1920s, the focus of research and diabetes care shifted to almost exclusively to insulin. Today, almost all treatments for diabetes seek to either increase insulin levels or increase the body’s sensitivity to insulin.

“These drugs,” the researchers write, “enjoy wide use and are effective in controlling hyperglycemia [high blood sugar levels], the hallmark of type 2 diabetes, but they address the consequence of diabetes more than the underlying causes, and thus control rather than cure the disease.”

New research, they write, suggests that normal glucose regulation depends on a partnership between the insulin-producing cells of the pancreas, the pancreatic islet cells, and neuronal circuits in the hypothalamus and other brain areas that are intimately involved in maintaining normal glucose levels. The development of diabetes type 2, the authors argue, requires a failure of both the islet-cell system and this brain-centered system for regulating blood sugar levels .

In their paper, the researchers review both animal and human studies that indicate the powerful effect this brain-centered regulatory system has on blood glucose levels independent of the action of insulin. One such mechanism by which the system promotes glucose uptake by tissues is by stimulating what is called “glucose effectiveness.” As this process accounts for almost 50 percent of normal glucose uptake, it rivals the impact of insulin-dependent mechanisms driven by the islet cells in the pancreas.

The findings lead the researchers to propose a two-system model of regulating blood sugar levels composed of the islet-cell system, which responds to a rise in glucose levels by primarily by releasing insulin, and the brain-centered system that enhances insulin-mediated glucose metabolism while also stimulating glucose effectiveness.

The development of type 2 diabetes appears to involve the failure of both systems, the researchers say. Impairment of the brain-centered system is common, and it places an increased burden on the islet-centered system. For a time, the islet-centered system can compensate, but if it begins to fail, the brain-centered system may decompensate further, causing a vicious cycle that ends in diabetes.

Boosting insulin levels alone will lower glucose levels, but only addresses half the problem. To restore normal glucose regulation requires addressing the failures of the brain-centered system as well. Approaches that target both systems may not only achieve better blood glucose control, but could actually cause diabetes to go into remission, they write.

In addition to Schwartz, the authors of the Nature paper “Cooperation between brain and islet in glucose homeostasis and diabetes” are  Randy J. Seeley, Matthias H. Tscho, Stephen C. Woods, Gregory J. Morton, Martin G. Myers,  and David D’Alessio.

This work was partly funded by National Institutes of Health grants DK083042, DK093848 and DK089053, and the 91±¬ÁĎ Nutrition Obesity Research Center and Diabetes Research Center, and the Helmholtz Alliance  for Imaging and Curing Environmental Metabolic Diseases, through the Initiative and Networking Fund of the Helmholtz Association.

A clinical trial at the Veterans Affairs Puget Sound Health Care System and the 91±¬ÁĎ will address new approaches to prevent the development of type 2 diabetes or slow its progression. Participants will be treated with medications normally used for people who have had diabetes for at least one year. The study will enroll individuals who have prediabetes or have been recently diagnosed with diabetes, but who are not taking medications to treat the condition.

The will examine the effects of three such medication regimens.  Each will be administered for 12 months. The three regimens are: liraglutide plus metformin for 12 months; insulin for three months followed by metformin for nine months; and metformin alone for 12 months. The expectation is that the use of these medications before diabetes has developed will preserve or enhance the body’s ability to produce insulin, the hormone that is crucial to maintain normal blood sugar levels.

Thestudyis a nationwide program looking at the effects of various treatments to preserve insulin secretion and thereby prevent the development of diabetes or its progression early in the disease. The 91±¬ÁĎ and VA diabetes research group in Seattle is one of three recruiting adult patients for the medication trial, along with the University of Chicago and Indiana University in Indianapolis.

, professor of medicine, Division of Metabolism, Endocrinology and Nutrition, at the 91±¬ÁĎ,  leads the Seattle clinical trial and is also chairs the national study.

“We hope to identify people who are at high risk of developing diabetes as they have mild elevations in their blood glucose as well as individuals who have had diabetes for less than a year and have not required medications,” Kahn said.

“The purpose of the study,” he explained, “is to determine whether aggressively treating such patients with medications used in diabetes can slow the disease process and prevent the loss of the ability of the pancreas to make and release insulin.”

The study, sponsored by the National Institutes of Health, is currently recruiting patients. To be eligible, patients must be between 20 and 65 years old, have prediabetes or self-reported type 2 diabetes for less than one year, and must not have taken any medications to treat diabetes in the past. Participants also must be considered overweight or obese. The investigators aim to enroll 85 patients who will participate in the trial for 21 months.

More details are available at the National Institute of Health’s clinical trials , identifier: NCT01779362.

To participate in the study, call 206-764-2768.

Patients with diabetes who are depressed are much more likely to develop episodes of dangerously low blood sugars, or hypoglycemia, than are those who are not depressed, a new study has found.

These episodes typically occur when the drugs used to control high blood sugars drive down blood sugar levels too low.

“Severe hypoglycemia can be very dangerous for these patients. Symptoms can vary. Patients may feel shaky, sweaty and anxious. But very low blood sugar can cause loss of consciousness even coma and death and repeated episodes can lead to cognitive impairment over time,” said lead author Dr. Wayne J. Katon, professor of psychiatry and behavioral sciences at the 91±¬ÁĎ School of Medicine. The episodes are also costly to the health-care system. They account for one in four emergency room visits or hospitalizations in the United States due to adverse drug reactions, he said.

In the study, researchers at the 91±¬ÁĎ and the Group Health Research Institute in Seattle tracked more than 4,100 patients with diabetes for five years. At the beginning of the study all the participants filled out a psychological screening questionnaire that identified those who had signs of major depression.

After analyzing data at the end of the five-year study, the researchers found that those participants who had met the criteria for major depression were 42 percent more likely to have low blood sugar episode severe enough that it required a trip to the emergency room or admission to the hospital than were participants who were not depressed..

The depressed patients were also 34 percent more likely to have a greater number of hypoglycemic episodes.

It’s not surprising that depression makes it more likely for people with diabetes to have episodes of hypoglycemia, Katon said.  Patients with diabetes have to juggle three or four diseasecontrol medications, test their blood sugar levels regularly and adjust their medication doses based on these results, and stick to special diets. “When you’re depressed, it can be very hard to do all those things,” he said.

Depression is common among people with diabete; it affects up to one in five. That’s why it’s important for health-care providers to screen their patients for depression and for patients to call it to their physician’s attention, Katon said.

“The good news is that depression is something that can be treated effectively with either psychotherapy or with antidepressant medication,” said Katon. “But it’s important that it be recognized and treated because it significantly increases the patient’s risk of this serious complication.

The study, “Association of Depression With Increased Risk of Severe Hypoglycemic Episodes in Patients With Diabetes,” appears the May/June issue of the Annals of Family Medicine.

The project was supported by funding from the National Institute of Mental Health, grant numbers: MH069741 and MH073686.

This story was written by Michael McCarthy for 91±¬ÁĎ Health Sciences/91±¬ÁĎ Medicine.