Previously, we reported that orally administered erythromycin, an agonist of the gastrointestinal hormone motilin (1,2), decreased fasting blood glucose and HbA1c levels and increased the early phase of insulin secretion in type 2 diabetic patients; this was determined by intravenous glucose tolerance test. Intravenous infusion of erythromycin also elevated insulin secretion and lowered blood glucose during infusion in type 2 diabetic patients and in normal control subjects. The enhancement of glucose-stimulated early insulin secretion, which is important in maintaining postprandial glucose levels within limits, could lead to the improvement of glycemic control (3). The gastrointestinal motor effect of motilin seems to take action through cholinergic mechanisms during the interdigestive state, and the insulin secretagogue action of motilin and erythromycin is thought to be mediated by vagal-cholinergic muscarinic pathways (4,5). This time we investigated whether erythromycin could stimulate basal insulin release and improve glycemic control when administered at 400 mg before sleep in 30 type 2 diabetic patients. After 1 month of treatment using this method, we found that there was a significant increase in fasting insulin level (34.0 ± 5.8 vs. 42.0 ± 5.8 pmol/l, P < 0.01), although this significant change in insulin had not been observed with the administration of 200 mg three times per day in the previous study (3). We also found a more significantly marked decrease in fasting blood glucose when using this method (11.0 ± 0.6 vs. 8.2 ± 0.5 mmol/l, P < 0.0001) rather than when administering erythromycin 200 mg three times per day (11.2 ± 0.8 vs. 9.7 ± 0.5 mmol/l, P < 0.05).

The improved value of fasting blood glucose was almost twice as much as the value in the previous study (3). HbA1c levels were also significantly improved compared with the control subjects (erythromycin 8.3 ± 0.2 vs. 7.8 ± 0.2%, P < 0.0001, and control subjects 8.4 ± 0.3 vs. 8.3 ± 0.2%). Interestingly, in most of the patients (25 of 30 patients, 83.3%), there was an improvement in bowel movements and/or constipation by taking erythromycin before sleep. There were two patients who had hypoglycemic attacks early in the morning, but no other side effects, such as liver dysfunction, were observed. It was reported that erythromycin improved impaired gastric emptying with severe diabetic gastroparesis (6). When administered before sleep, erythromycin may enhance cholinergic tone in the interdigestive state and increase the frequency of bowel movements while influencing insulin secretion.

Surprisingly, the administration of erythromycin before sleep initiated reduced fasting blood glucose, perhaps because of the stimulation of the basal insulin level and the improvement of bowel movements. Taking erythromycin four times per day, including before sleep, would be a more effective way to improve glycemic control and constipation that may be caused by diabetic autonomic neuropathy.

With this additional data, we should consider erythromycin derivatives that lack antibacterial activity not only as gastroprokinetic agents, but also as antidiabetogenic agents.

Table 1 —

Clinical characteristics and effects of erythromycin (400 mg before sleep) or a placebo on glycemic control in type 2 diabetic patients

Erythromycin
Placebo
Before1 month afterBefore1 month after
Age (years) 55.5 ± 2.4 54.0 ± 2.8 
Sex (M/F) 12/18 10/12 
Duration of diabetes (years) 8.0 ± 1.0 7.0 ± 1.0 
Oral hypoglycemic agents (yes/no) 30/0 2/10 
BMI (kg/m224.5 ± 1.2 24.2 ± 1.0 24.7 ± 1.2 24.5 ± 1.4 
HbA1c (%) (range 4.3–5.8) 8.3 ± 0.2 7.8 ± 0.2* 8.4 ± 0.3 8.3 ± 0.2 
Fasting blood glucose (mmol/l) 11.0 ± 0.6 8.2 ± 0.5* 10.7 ± 0.4 11.0 ± 0.5 
Fasting serum insulin (pmol/l) 34.0 ± 5.8 42.0 ± 5.8 32.4 ± 5.5 31.9 ± 4.6 
Erythromycin
Placebo
Before1 month afterBefore1 month after
Age (years) 55.5 ± 2.4 54.0 ± 2.8 
Sex (M/F) 12/18 10/12 
Duration of diabetes (years) 8.0 ± 1.0 7.0 ± 1.0 
Oral hypoglycemic agents (yes/no) 30/0 2/10 
BMI (kg/m224.5 ± 1.2 24.2 ± 1.0 24.7 ± 1.2 24.5 ± 1.4 
HbA1c (%) (range 4.3–5.8) 8.3 ± 0.2 7.8 ± 0.2* 8.4 ± 0.3 8.3 ± 0.2 
Fasting blood glucose (mmol/l) 11.0 ± 0.6 8.2 ± 0.5* 10.7 ± 0.4 11.0 ± 0.5 
Fasting serum insulin (pmol/l) 34.0 ± 5.8 42.0 ± 5.8 32.4 ± 5.5 31.9 ± 4.6 

Data are means ± SD or n.

*

P < 0.0001 vs. pretreatment values;

P < 0.01.

This work was supported in part by Grants-in-Aid for Scientific Research (A) 08559012 and Grant (C) 09671057 from the Ministry of Education, Science, Sports and Culture of Japan (to A.I.).

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Address correspondence to Akio Inui, Second Department of Internal Medicine, Kobe University School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. E-mail: inui@med.kobe-u.ac.jp.