The science of hypoglycemia has been significantly enhanced by federal funding and its unique emphasis on communication between diabetes experts and neurology researchers. Moreover, advances in continuous glucose monitoring have renewed hope that an artificial pancreas can be developed. Funding for hypoglycemia research will require a modest increase over the next 5 years to support basic research on the brain responses to low glucose, clinical research on new behavioral strategies to avoid or reduce the impact of hypoglycemia, and clinical trials to validate new technologies in "real world" settings in both children and adults with type 1 diabetes.

OPPORTUNITIES IN HYPOGLYCEMIA
Fear of hypoglycemia is a major reason why people with type 1 diabetes do not always maintain their blood glucose levels as tightly as technically possible, despite undeniable evidence that tight control can reduce the long-term complications of diabetes. Discovering how the brain reacts to hypoglycemia will enable investigators to develop new ways for patients to protect themselves from low blood sugar.

The brain relies almost exclusively on glucose for fuel, yet the amount of glucose in brain tissue is only one quarter as much as in the blood. This lower glucose supply makes the brain extremely sensitive to injury during hypoglycemia. An important research goal is to develop a "neuroprotective" drug that can prevent permanent injury to the brain when glucose levels drop too far.

Hypoglycemia damages the brain's ability to defend itself from future episodes of low glucose, setting up a vicious cycle in which each episode of hypoglycemia increases the risk of another episode. By identifying the defects in the brain's mechanisms for defending itself against low glucose, it may be possible to design drugs that restore these defenses in type 1 diabetes patients and break the cycle of recurrent hypoglycemia.

Some individuals are more prone to hypoglycemia than others. Genetic screening of high-risk patients could lead to a better understanding of the mechanisms of hypoglycemia and the development of targeted prevention strategies.

Devices such as continuous glucose monitors and an artificial, closed-loop pancreas have the potential to prevent hypoglycemia by helping type 1 diabetes patients maintain optimal glucose regulation.

BENEFITS OF THIS RESEARCH
Hypoglycemia is a serious medical consequence of type 1 diabetes that severely impacts quality of life. Patients and their caregivers must constantly choose between intensively managing their diabetes to reduce the risk of long-term complications of the eyes, kidneys, nerves, and heart or exposing their health and life to the short-term, but very real, threat of hypoglycemia. Finding new strategies to reduce the risk of hypoglycemia or developing drugs that shield the brain from injury during low-glucose conditions would protect the health and well-being of all patients with type 1 diabetes. However, the benefits of hypoglycemia research go far beyond type 1 diabetes. Drugs that prevent hypoglycemia or reverse its effects might also be useful in other diseases that can trigger low glucose, such as certain types of tumors or hormone deficiencies. Research to understand how the brain senses and uses glucose and other nutrients may have applications in the treatment of obesity or type 2 diabetes.


OPPORTUNITIES IN ARTIFICIAL PANCREAS TECHNOLOGY
The potential of artificial pancreas technology to improve the health of type 1 diabetes patients compels an accelerated research agenda to: "close the loop" between glucose measurement and insulin delivery in real time; validate new technologies in real world settings; and ensure accessibility of the devices to all patients.

Sophisticated computer algorithms must be developed to convert the stream of data on minute-to-minute changes in glucose levels into accurate and safe insulin doses. Too much insulin at one time could increase the acute risk of hypoglycemia, but chronic under-delivery of insulin raises the chance of long-term complications.

Functional algorithms that link data from the glucose sensor to the insulin pump must be tested in a variety of "real world" situations to validate and optimize their impact on diabetes care. Federal funding has enabled the establishment of the Diabetes Research in Children Network (DirecNet) to investigate the utility of technological advances for disease management in children and adolescents with type 1 diabetes.

Current glucose monitoring or insulin delivery devices must be worn on the outside of the body and require re-calibration or a new injection site every few days. A prime research goal is to develop an artificial pancreas that can be implanted into a patient's body and maintain normal physiological glucose control over long periods of time (up to months or even years) with minimal maintenance.

BENEFITS OF THIS RESEARCH
An artificial pancreas that precisely senses changes in blood glucose levels and modulates insulin delivery in response would allow patients to maintain tight glucose control while minimizing the risk of hypoglycemia. Such technology would immediately benefit type 1 diabetes patients, as well as individuals with type 2 diabetes who have become insulin dependent, by reducing the daily burden of disease and improving health outcomes. Importantly, an artificial pancreas could be used by type 1 diabetes patients who are not eligible for islet transplantation or as a stopgap measure to improve diabetes management until islet transplantation becomes a routine therapy for type 1 diabetes. To maximize the benefits of this research, it is critical that these new devices become available to all patients who can benefit from them and that the technology is suitable for use in children.