Alteration of the intestinal barrier and GLP2 secretion in Berberine-treated type 2 diabetic rats

Abstract

For centuries, Berberine has been used in the treatment of enteritis in China, and it is also known to have anti-hyperglycemic effects in type 2 diabetic patients. However, as Berberine is insoluble and rarely absorbed in gastrointestinal tract, the mechanism by which it works is unclear. We hypothesized that it may act locally by ameliorating intestinal barrier abnormalities and endotoxemia. A high-fat diet combined with low-dose streptozotocin was used to induce type 2 diabetes in male Sprague Dawley rats. Berberine (100 mg/kg) was administered by lavage to diabetic rats for 2 weeks and saline was given to controls. Hyperinsulinemia and insulin resistance improved in the Berberine group, although there was no significant decrease in blood glucose. Berberine treatment also led to a notable restoration of intestinal villi/mucosa structure and less infiltration of inflammatory cells, along with a decrease in plasma lipopolysaccharide (LPS) level. Tight junction protein zonula occludens 1 (ZO1) was also decreased in diabetic rats but was restored by Berberine treatment. Glutamine-induced glucagon-like peptide 2 (GLP2) secretion from ileal tissue decreased dramatically in the diabetic group but was restored by Berberine treatment. Fasting insulin, insulin resistance index, plasma LPS level, and ZO1 expression were significantly correlated with GLP2 level. In type 2 diabetic rats, Berberine treatment not only augments GLP2 secretion and improves diabetes but is also effective in repairing the damaged intestinal mucosa, restoring intestinal permeability, and improving endotoxemia. Whether these effects are mechanistically related will require further studies, but they certainly support the hypothesis that Berberine acts via modulation of intestinal function.

GLP2: an underestimated signal for improving glycaemic control and insulin sensitivity

“…It is well accepted that GLP2 is involved in modulation of intestinal permeability (Moran et al 2012). In diabetic rats, plasma lipopolysaccharide, zonulin 1 expression, insulin level and insulin-resistant index are closely related to GLP2 levels (Shan et al 2013). On the basis of these observations, the authors advanced the very suggestive hypothesis that impaired GLP2 in prediabetic subjects may predispose these patients to T2D by increasing intestinal permeability and endotoxemia-related inflammation.…”

“…However, prospective studies in humans are needed. They found that glutamine-induced GLP2 secretion is decreased in rats with streptozotocin-induced experimental diabetes (Shan et al 2013). Impaired GLP1 secretion is a characteristic of the prediabetic situation such as impaired glucose tolerance and gestational diabetic mellitus (Lim & Brubaker 2006) and likely also GLP2 secretion from the same L-cells is impaired.…”

“…Therefore, GLP2 could be responsible for glycaemic improvement after bariatric surgery and can be considered as a key signal to drive intestinal reprogramming of glucose metabolism (Saeidi et al 2013). In addition, animal studies have shown that GLP2 secretion from ileal tissue is decreased in diabetic conditions (Shan et al 2013), and reduced numbers of L-cells have been detected in the intestinal tissue from HFD-fed mice compared with intestinal tissue from mice receiving a control diet (Kappe et al 2014). Therefore, GLP2-decreased production might lead to T2D.…”

Uncoupling protein‐2 mediates the protective action of berberine against oxidative stress in rat insulinoma INS‐1E cells and in diabetic mouse islets

“…Hyperglycaemia causes excessive ROS formation, particularly superoxide anions (Jay et al, 2006), and ROS overproduction is involved in the development of beta cell dysfunction (Malin et al, 2014). Both clinical and experimental studies show that berberine is effective in treating the metabolic syndrome, correcting hyperinsulinaemia, increasing insulin sensitivity and stimulating insulin secretion through mechanisms including triglyceride reduction, augmented secretion of glucagon-like peptide (GLP)-2 and increased release of GLP-1 (Lu et al, 2009;Yu et al, 2010;Perez-Rubio et al, 2013;Shan et al, 2013). The berberine analogue, 8,8-dimethyldihydroberberine, improved glucose tolerance and alleviates insulin resistance in db/db mice (Cheng et al, 2010).…”

Glucagon-like peptides 1 and 2

“…Shan et al [81] showed that the plant alkaloid berberine, which is an L-cell secretagogue, increased the expression of the tight junction protein zonula occludens-1 in a diabetic rat model with increased intestinal permeability [82]. In a study in obese mice on a high-fat diet that enhances intestinal permeability, a negative correlation was found between the plasma GLP-2 concentration and the gut permeability to fluorescein isothiocyanatedextran and lipopolysaccharide, suggesting that the peptide positively affects gut barrier integrity [83].…”