Opioid Receptors May Curb Hypoglycemia in Diabetes

Novel pharmacologic approaches may prevent hypoglycemia and lead to safer intensive glycemic control in type 1 diabetes mellitus (DM) through activation of opioid receptors, according to a new study.

Intensive insulin therapy in type 1 DM reduces many DM-associated complications. “The standard of care in type 1 DM is to achieve as close to normal glucose levels as possible. However, we also know from the Diabetes Control and Complications Trial and other trials that intensive insulin therapy is associated with a 3-fold or higher risk of iatrogenic hypoglycemia. Recurrent episodes of hypoglycemia lead to hypoglycemia unawareness, which can make patients fearful of maintaining tight glycemic control, and hypoglycemic events themselves are associated with morbidity. Iatrogenic hypoglycemia, therefore, represents a major challenge to optimal management of type 1 DM,” Michelle Carey, MD, MPH, Fellow in Endocrinology, Diabetes and Metabolism at Albert Einstein College of Medicine, Bronx, New York, told ConsultantLive.

Previous studies at Albert Einstein demonstrated the importance of the opioid receptor pathway in hypoglycemia-associated autonomic failure (HAAF). “Opioid receptor blockade with naloxone can prevent the development of experimentally induced HAAF in nondiabetic subjects and can improve HAAF in subjects with type 1 DM,” said Dr Carey. “This makes the opioid receptor pathway a potentially key player in the development of HAAF.”

Dr Carey and colleagues set out to examine whether opioid receptor activation alone would induce HAAF. In a study presented by Dr Carey at the American Diabetes Association 74th Scientific Sessions in San Francisco (Abstract 148-OR), 7 healthy, nondiabetic subjects, median age 33 years, participated in 2 study protocols in random order over 2 consecutive days. On day 1, they received two 120-minute infusions of saline or morphine, separated by a 120-minute break. On day 2, they underwent stepped hypoglycemic clamps with evaluation of counter-regulation, endogenous glucose production, and hypoglycemic symptoms.

Compared with saline, morphine induced a blunted epinephrine response, a lower rate of endogenous glucose production, and fewer hypoglycemia-associated headaches on day 2. “These findings demonstrate for the first time in humans that opioid receptor activation induces HAAF,” Dr Carey said. “They show that stimulation of opioid receptors with morphine does indeed reduce the counter-regulatory hormonal response to hypoglycemia a full day after receiving morphine.”

Dr Carey added, “The most important goal of any research on hypoglycemia and HAAF is to identify clinical applications to improve the lives of patients with type 1 diabetes. We know that the opioid receptor pathway can be manipulated experimentally to impact HAAF, both through blockade with naloxone and now in our studies through activation with morphine.”

Clinical trials using naloxone or other more specific opioid receptor antagonists will be important to understand the therapeutic implications of the experimental findings. “It is exciting to think that we could prevent the development of HAAF and hypoglycemia unawareness in patients using these strategies,” Dr Carey said.

Michelle Hawkins, MD, Professor of Medicine at Albert Einstein, suggests that physicians “be alert to the risk of hypoglycemia or insulin in type 1 DM patients who are well controlled. Be vigilant and ask them about symptoms when their blood sugar goes low, for example, when they exercise.”