Inhaled Formoterol Diminishes Insulin-Induced Hypoglycemia in Type 1 Diabetes

Abstract

OBJECTIVEHypoglycemia is one of the major factors limiting implementation of tight glycemic control in patients with type 1 diabetes and is associated with increased morbidity and mortality during intensive insulin treatment. β-2 Adrenergic receptor (AR) agonists have been reported to diminish nocturnal hypoglycemia; however, whether long-acting inhaled β-2 AR agonists could potentially be used to treat or prevent hypoglycemia has not been established.RESEARCH DESIGN AND METHODSSeven patients with type 1 diabetes and seven healthy control subjects received inhaled formoterol (48 μg), a highly specific β-2 AR agonist, or a placebo during a hyperinsulinemic-hypoglycemic clamp study to evaluate its capacity to antagonize the effect of insulin. In a second set of studies, five subjects with type 1 diabetes received inhaled formoterol to assess its effect as a preventive therapy for insulin-induced hypoglycemia.RESULTSDuring a hyperinsulinemic-hypoglycemic clamp, compared with placebo, inhaled formoterol decreased the glucose infusion rate required to maintain plasma glucose at a target level by 45–50% (P < 0.05). There was no significant effect on glucagon, epinephrine, cortisol, or growth hormone release (P = NS). Furthermore, in volunteers with type 1 diabetes 1 h after increasing basal insulin delivery twofold, glucose levels dropped to 58 ± 5 mg/dL, whereas hypoglycemia was prevented by inhaled formoterol (P < 0.001).CONCLUSIONSInhalation of the β-2 AR–specific agonist formoterol may be useful in the prevention or treatment of acute hypoglycemia and thus may help patients with type 1 diabetes achieve optimal glucose control more safely.

Anabolic and lipolytic actions of beta2‐agonists in humans and antidoping challenges

“…While muscle hypertrophy is scarcely explored for the inhaled route, daily inhalation of terbutaline at 4 mg (8 puffs from a 0.5 mg Turbohaler) for 4 weeks was recently shown to induce a 1 kg gain in lean mass in healthy young men . In addition, an inhaled dose of 54 μg formoterol (6 puffs from a 9 μg Turbohaler), a dose that lies within the current WADA threshold limit, induces skeletal muscle signalling and increases resting metabolic rate, fat oxidation, and peripheral glucose uptake . The same is the case for salbutamol, which via the inhaled route has been shown to induce lipolysis at therapeutic doses and to increase resting metabolic rate .…”

“…Because of their ability to increase metabolic rate, beta 2 ‐agonists are considered to be thermogenic substances and their effects on fat oxidation are well documented . Aside from inducing lipolysis in adipose tissue and pancreatic insulin production and release, beta 2 ‐agonists have a range of other systemic effects, including stimulation of hepatic glucose production and release, and epinephrine release, among other effects . Thus, the mechanisms underlying the changes in metabolism induced by beta 2 ‐agonists are complex and possibly involve several tissues.…”

Impaired hypoglycaemia awareness in type 1 diabetes: lessons from the lab

“…More recently, there has been significant interest in discovering how cytokine, purine, steroid, opiate, β 2 -adrenergic or serotonergic signalling may play roles in the development of IAH [22,[38][39][40][41][42]. These extracellular signals are able to modulate firing rates of glucose-sensing neurons.…”

“…This knowledge has been derived from laboratory-based research, which has enabled proof-of-concept clinical trials. For instance, the inhaled highly-selective β 2 -adrenoreceptor agonist formoterol fumerate was shown to amplify the CRR to hypoglycaemia in a small group of participants with type 1 diabetes [42], while oral dehydroepiandrostenedione (DHEA), which has both anti-corticosteroid and anti-GABA activity, blunted the suppressive effect of recurrent hypoglycaemia on subsequent hypoglycaemia CRR in individuals without diabetes [39]. It is interesting that many of these extracellular signals help coordinate the body's response to a wide variety of physiological stressors and play roles in both amplifying the acute response to a given stressor and initiating subsequent adaptive responses that are designed to protect cells during subsequent exposure to that stressor.…”

Evaluation of the counter‐regulatory responses to hypoglycaemia in patients with type 1 diabetes during opiate receptor blockade with naltrexone

“…[7][8][9] However, pharmacological treatments with beta2-agonists and opioid antagonists have also been tested for prevention and treatment of hypoglycaemia. [10][11][12][13] Nakao et al 14 reported that plasma beta-endorphins are released in response to insulin-induced hypoglycaemia. Subsequent studies found that an intravenous infusion of naloxone, an opiate receptor blocker, enhanced the counter-regulatory hormone response to hypoglycaemia in dogs, 15 as well as in healthy non-diabetic humans and in patients with T1DM.…”