Bitter melon triterpenes work as insulin sensitizers and insulin substitutes in insulin-resistant cells

• The bitter melon triterpenes DHM and THC act as insulin sensitizers.
• DHM and THC inhibit protein-tyrosine phosphatase-1B.
• DHM and THC have insulin substitution function.
• The insulin substitution function likely involves AMP-activated protein kinase.

The triterpenes 3β,25-dihydroxy-7β-methoxycucurbita-5,23(E)-diene (DHM) and 3β,7β,25-trihydroxycucurbita-5,23(E)-dien-19-al (THC) were previously isolated from Momordica charantia (bitter melon) and identified as hypoglycaemic principles. This study further investigated their hypoglycaemic mechanisms. FL83B cells were treated with tumour necrosis factor-α to result in insulin resistance, a feature of type 2 diabetes. DHM and THC increased the tyrosine phosphorylation of insulin receptor substrate isoform 1 and the phosphorylation of Akt only in the presence of insulin in insulin-resistant cells, suggesting that they are insulin sensitizers. However, they enhanced the phosphorylation of AS160 (Akt substrate of 160 kDa), the migration of glucose transporter-4 and the glucose uptake of insulin-resistant cells in the absence of insulin, suggesting that they can substitute for insulin to promote glucose clearance. The insulin substitution function was blocked by an AMP-activated protein kinase (AMPK) inhibitor, whereas the insulin-sensitizing function may involve the inhibition of protein-tyrosine phosphatase-1B (PTP-1B). The IC50 of DHM and THC to PTP-1B is 92.84 µM and 25.42 µM, respectively. In summary, DHM and THC have insulin-sensitizing and insulin-substitution functions, which are likely correlated with their effects on inhibiting PTP-1B and activating AMPK, respectively.