Abstract
AimAdministration of N‐acetyl cysteine (NAC) during hypoglycaemia will preserve the counterregulatory response to subsequent hypoglycaemia in healthy humans.MethodsThis was a randomized double‐blind cross over study where humans were given either a 60‐minute infusion of NAC (150 mg/kg) followed by a 4‐hour infusion of NAC (50 mg/kg) or saline starting 30 minutes before the initiation of a 2‐hour hypoglycaemic (HG) clamp at 8 am. After rest at euglycaemia for ~2 hours, subjects were exposed to a 2nd HG clamp at 2 pm and discharged home in euglycaemia. They returned the following day for a 3rd HG clamp at 8 am.ResultsTwenty‐two subjects were enrolled. Eighteen subjects completed the entire protocol. The epinephrine response during clamp 3 (171 ± 247 pg/mL) following clamp 1 NAC infusion was lower than the response during the clamp 1 NAC infusion (538 ± 392 pg/mL) (clamp 3 to clamp 1 NAC: P = .0013). The symptom response during clamp 3 (7 ± 5) following clamp 1 NAC infusion was lower than the response during the clamp 1 NAC infusion (16 ± 10) (clamp 3 to clamp 1 NAC: P = .0003). Nine subjects experienced rash, pruritus or nausea during NAC infusion.ConclusionWe found no difference in the hormone and symptom response to experimental hypoglycaemia measured in subjects who were administered NAC as opposed to saline the day before. This observation suggests that further development of NAC as a therapy for impaired awareness of hypoglycaemia in patients with diabetes may be unwarranted.
Highlights
Hypoglycaemia occurs frequently in the lives of patients with type 1 diabetes
In this proof of principle study, we found no difference in the counterregulatory hormone and symptom response to experimental hypoglycaemia measured in subjects who were administered N-acetyl cysteine (NAC) as opposed to saline the day before
This observation suggests that further development of NAC as a therapy for impaired awareness of hypoglycaemia in patients with diabetes may be unwarranted, because we found adverse events to be more frequent in our study than in the package insert despite pretreatment with diphenhydramine
Summary
Hypoglycaemia occurs frequently in the lives of patients with type 1 diabetes. Recurrent hypoglycaemia episodes closely spaced in time leads to impaired awareness of hypoglycaemia in which the counterregulatory response to hypoglycaemia is markedly reduced, and the first sign of a low blood sugar is neuroglycopenia.[1]. Investigators have used information obtained in experimental studies designed to identify the pathways that link the detection of a single episode of hypoglycaemia to the blunting of the counterregulatory response during hypoglycaemia experienced in subsequent days Such investigation has revealed the importance of opioid signalling during the first episode of hypoglycaemia and has demonstrated that blockade of opioid signalling using an intravenous administration of a drug during this first episode will preserve the counterregulatory response to hypoglycaemia the subsequent day.[4] acute oral administration of the opioid antagonist naltrexone did not have an impact on the counterregulatory responses in subjects with well-controlled type 1 diabetes[5] and 4 weeks of oral naltrexone therapy did not restore the counterregulatory response in patients with type 1 diabetes and impaired awareness of hypoglycaemia.[6] Future work will need to determine if the failure of naltrexone to restore the response was due to inadequate dosing or selection of patients who may be refractory to such restoration
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