Erythromycin, one of the most common macrolide antibiotics, has long been known to have side effects on the gastrointestinal tract, especially when it is introduced rapidly into the vein [1,2]. Erythromycin and its derivatives are now called motilides because they are specific agonists of motilin receptors, thereby mimicking motilin's stimulatory actions on gastrointestinal motility [1,2]. Erythromycin has been successfully shown to accelerate delayed gastric emptying associated with various conditions such as diabetes mellitus, cancer therapy, postvagotomy, and progressive systemic sclerosis [1,2]. In vivo studies in humans with the motilin agonist erythromycin have suggested that, at low concentrations, the effect of erythromycin is neurally mediated but the response at high concentrations reflects a direct muscular effect [3].Recently we found that motilin's actions are not limited to gastrointestinal motility [4±6]. Physiologi- Diabetologia (2000) Abstract Aims/hypothesis. Erythromycin mimics the effect of the gastrointestinal hormone motilin by binding to its receptor and acting as a motilin agonist. We recently found that motilin stimulates insulin secretion at lower doses than doses required to stimulate gastric contractile activity. We studied the effects of erythromycin on insulin secretion and glycaemic control in patients with diabetes mellitus. Methods. Inpatients (n = 34) with Type II (non-insulin-dependent) diabetes mellitus were randomly assigned to receive either erythromycin (400 mg orally three times a day, n = 19) or a placebo (n = 15) for 1 week (first study). Another 34 outpatients with Type II diabetes were also treated with erythromycin (200 mg orally three times a day, n = 17) or a placebo (n = 17) for 4 weeks (second study). Finally, nine inpatients with Type II diabetes and eight normal control subjects received intravenous erythromycin (10 mg × kg ±1 × h ±1 ) or saline infusion and insulin secretion was examined (third study).Results. Erythromycin lowered fasting blood glucose and fructosamine concentrations (p < 0.01) and increased basal as well as glucose-stimulated insulin secretion (p < 0.05±0.01) (first study). Low doses of erythromycin treatment for 4 weeks also significantly improved glycaemic control in Type II diabetic patients (second study). Erythromycin infusion significantly increased plasma insulin and decreased glucose concentrations in Type II diabetic and control subjects and greatly potentiated glucose-induced insulin secretion in the latter (third study). Conclusion/interpretation. These results indicate that erythromycin given orally has an antidiabetogenic effect and therefore erythromycin derivatives that lack the antibacterial activity could have a therapeutic value in Type II diabetic patients. [Diabetologia (2000) 43: 411±415]
Aims/hypothesis. We investigated the potential role of mosapride, a 5HT-4 receptor agonist, in glycaemic control in Type II (non-insulin-dependent) diabetic mellitus patients without autonomic neuropathy. Methods. Thirty-four inpatients with Type II diabetes mellitus were randomly assigned to receive either mosapride (5 mg orally three times a day, n=17) or a placebo (n=17) for 1 week (first study). Changes in blood glucose and insulin were determined basally as well as after intravenous glucose loading. Insulin sensitivity was evaluated during hyperinsulinaemic-normoglycaemic-clamp studies and by measuring the number of and the autophosphorylation of insulin receptors on the erythrocytes of patients (n=9). Sixtynine outpatients with Type II diabetes were similarly treated with mosapride or a placebo for 8 weeks (second study). Finally, tissue-specific expression of 5HT-4 receptors was examined by reverse transcriptase-polymerase chain reaction (RT-PCR (8.61±0.20 vs 7.67±0.19%, p<0.01) concentrations (second study). The RT-PCR analysis demonstrated specific expression of 5HT-4 receptors in the muscle, but not in the liver or fat tissues. Conclusions/interpretation. Mosapride could improve insulin action at muscle and glycaemic control in Type II diabetic patients. [Diabetologia (2002) 45:792-797]
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