“This has been a clinical problem for a very long time, and we see it all the time. A patient comes into my clinic, the nurses check their blood sugar, it’s 50 mg/dL, and they’re just sitting there without any symptoms,” said lead investigator Sandra Aleksic, MD, of the Albert Einstein College of Medicine, New York.
As blood glucose in the brain drops, people get confused, and their behavioral defenses are compromised. They might crash if they’re driving. “If you have HAAF, it makes you prone to more hypoglycemia, which blunts your response even more. It’s a vicious cycle,” she said at the annual scientific sessions of the American Diabetes Association.
Endogenous opioids are at least partly to blame. Hypoglycemia induces release of beta-endorphin, which in turn inhibits production of epinephrine. Einstein investigators have shown in previous small studies with healthy subjects that morphine blunts the response to induced hypoglycemia, and intravenous naloxone – an opioid blocker – prevents HAAF ().
Intravenous naloxone, however, isn’t practical for outpatients, so the team wanted to see whether intranasal naloxone also prevented HAAF. The“are very promising, but this is preliminary.” If it pans out, though, patients may one day carry intranasal naloxone along with their glucose pills and glucagon to treat hypoglycemia. “Any time they are getting low, they would take the spray,” Dr. Aleksic said.
The team used hypoglycemic, hyperinsulinemic clamps to drop blood glucose levels in seven healthy subjects down to 54 mg/dL for 2 hours twice in one day and gave them hourly sprays of either intranasal saline or 4 mg of intranasal naloxone; hypoglycemia was induced again for 2 hours the following day. The 2-day experiment was repeated 5 weeks later.
Overall, there was no difference in peak epinephrine levels between the first hypoglycemic episode on day 1 and the third episode on day 2 in subjects randomized to naloxone (942 pg/mL plus or minus 190 versus 857 pg/mL plus or minus 134; P = .4). The third episode, meanwhile, placed placebo subjects into HAAF (first hypoglycemic episode 1,375 pg/mL plus or minus 182 versus 858 pg/mL plus or minus 235; P = .004). There was also a trend toward higher hepatic glucose production in the naloxone group.
“These findings suggest that HAAF can be prevented by acute blockade of opioid receptors during hypoglycemia. ... Acute self-administration of intranasal naloxone could be an effective and feasible real-world approach to ameliorate HAAF in type 1 diabetes,” the investigators concluded. A trial in patients with T1DM is being considered.
Dr. Aleksic estimated that patients with T1DM drop blood glucose below 54 mg/dL maybe three or four times a month, on average, depending on how well they manage the condition. For now, it’s unknown how long protection from naloxone would last.