Erythromycin improves glycaemic control in patients with Type II diabetes mellitus

Abstract

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]

Mosapride, a 5HT-4 receptor agonist, improves insulin sensitivity and glycaemic control in patients with Type II diabetes mellitus

“…*p < 0.05, **p< 0.01 between the two groups well as increased number of and the autophosphorylation of insulin receptors on the erythrocytes of patients after Mosapride treatment. Because erythromycin, domperidone, and metoclopramide all do not show such noticeable effects ( [12] and unpublished data), it is highly likely that Mosapride directly improves insulin sensitivity, apart from its gastroprokinetic effect.…”

“…The simultaneous fall in blood glucose and insulin concentrations, as well as stronger decrease in blood glucose response to insulin after Mosapride treatment (not shown), suggested an overall improvement in insulin action. This was clearly shown in the increased glucose utilisation in the hyperinsulinaemic-normoglycaemic-clamp studies, as of insulin-sensitizing agents with no major side effects such as liver dysfunction as with troglitazone [27] and lactic acidosis as with metformin, and could be especially useful for patients with delayed gastric emptying [10,11,12].…”

“…In addition to its well known gastroprokinetic effect [11], orally administered erythromycin significantly stimulated insulin secretion and improved glycaemic control in patients with Type II diabetes mellitus [12]. Because cisapride, which acts as an agonist of both 5HT-3 and 5HT-4 receptors [6,13], might also have stimulatory effects on the endocrine pancreas in humans ( [14] and our unpublished data), in this study we examined mosapride, a specific 5HT-4 receptor agonist, to see if it has beneficial effects on glycaemic control in patients with Type II diabetes mellitus.…”

Expression of motilin in the hypothalamus and the effect of central erythromycin on gastric motility in diabetic rats

“…Prokinetic agents, such as erythromycin (EM), are regularly used for the treatment of diabetic gastroparesis [7] . EM mimics the effect of gastrointestinal hormone motilin by binding to its receptor and acting as a motilin receptor agonist [8,9] . It has been demonstrated in some in vitro experiments that EM may act directly on smooth muscles, and it exhibits the similar animal and tissue specificity as motilin does [7] .…”

“…It has been demonstrated in some in vitro experiments that EM may act directly on smooth muscles, and it exhibits the similar animal and tissue specificity as motilin does [7] . Peripheral administration of motilin or EM (or other motilin mimetics) has a direct effect on the contractility of gastric smooth muscles and improves the gastric motility in diabetic gastroparesis [8,[10][11][12] . Central nervous system is probably also involved in this peripheral effect of EM.…”