Glucagon like peptide-2 (GLP-2) is a
gastrointestinal hormone released in response to dietary nutrients, which acts through a specific receptor, the
GLP-2 receptor (GLP-2R). The physiological effects of GLP-2 are multiple, involving also the intestinal adaptation to high fat diet (HFD). In consideration of the well-known relationship between chronic HFD and impaired
glucose metabolism, in the present study we examined if the blocking of the GLP-2 signaling by chronic treatment with the GLP-2R antagonist,
GLP-2 (3-33), leads to functional consequences in the regulation of
glucose metabolism in HFD-fed mice. Compared with animals fed standard diet (STD), mice at the 10th week of HFD showed hyperglycaemia,
glucose intolerance, high plasma
insulin level after
glucose load, increased pancreas weight and β cell expansion, but not
insulin resistance. In HFD fed mice,
GLP-2 (3-33) treatment for 4 weeks (from the 6th to the 10th week of diet) did not affect fasting glycaemia, but it significantly increased the
glucose intolerance, both fasting and
glucose-induced
insulin levels, and reduced the sensitivity to
insulin leading to
insulin-resistance. In GLP-2 (3-33)-treated HFD mice pancreas was significantly heavier and displayed a significant increase in β-cell mass in comparison with vehicle-treated HFD mice. In STD mice, the
GLP-2 (3-33) treatment did not affect fasted or
glucose-stimulated glycemia,
insulin,
insulin sensitivity, pancreas weight and beta cell mass. The present study suggests that endogenous GLP-2 may act as a protective factor against the dysregulation of the
glucose metabolism that occurs in HFD mice, because
GLP-2 (3-33) worsens
glucose metabolism disorders.