Lupanine Improves Glucose Homeostasis by Influencing KATP Channels and Insulin Gene Expression

Abstract

Abstract:The glucose-lowering effects of lupin seeds involve the combined action of several components. The present study investigates the influence of one of the main quinolizidine alkaloids, lupanine, on pancreatic beta cells and in an animal model of type-2 diabetes mellitus. In vitro studies were performed with insulin-secreting INS-1E cells or islets of C57BL/6 mice. In the in vivo experiments, hyperglycemia was induced in rats by injecting streptozotocin (65 mg/kg body weight). In the presence of 15 mmol/L glucose, insulin secretion was significantly elevated by 0.5 mmol/L lupanine, whereas the alkaloid did not stimulate insulin release with lower glucose concentrations. In islets treated with L-arginine, the potentiating effect of lupanine already occurred at 8 mmol/L glucose. Lupanine increased the expression of the Ins-1 gene. The potentiating effect on secretion was correlated to membrane depolarization and an increase in the frequency of Ca channel. The effect was dose-dependent but, even with a high lupanine concentration of 1 mmol/L or after a prolonged exposure time (12 h), the KATP channel block was incomplete. Oral administration of lupanine did not induce hypoglycemia. By contrast, lupanine improved glycemic control in response to an oral glucose tolerance test in streptozotocin-diabetic rats. In summary, lupanine acts as a positive modulator of insulin release obviously without a risk for hypoglycemic episodes.

Preclinical characterization of 55P0251, a novel compound that amplifies glucose‐stimulated insulin secretion and counteracts hyperglycaemia in rodents

“…An example of the delineated approach has emanated from the traditional use of lupins for treatment of diabetes mellitus in the Mediterranean area . Lupins are rich in quinolizidine alkaloids such as lupanines, sparteine and multiflorine, which are believed to serve the plants as a defence against infections and herbivores, but also have been associated with insulinotropic effects on isolated pancreatic islets and with lowering of blood glucose . More than a decade ago, acute improvement of glucose tolerance in mice by a single dose of (−)–multiflorine inspired Kubo et al to design derivatives with pronounced anti‐hyperglycaemic activities …”

“…3 Lupins are rich in quinolizidine alkaloids such as lupanines, sparteine and multiflorine, which are believed to serve the plants as a defence against infections and herbivores, 4,5 but also have been associated with insulinotropic effects on isolated pancreatic islets and with lowering of blood glucose. [6][7][8][9][10][11][12] More than a decade ago, acute improvement of glucose tolerance in mice by a single dose of (−)-multiflorine inspired Kubo et al to design derivatives with pronounced anti-hyperglycaemic activities. 11,12 We have resumed this effort and exploited one of the described multiflorine derivatives as the molecular blueprint for a more extensive derivatization program directed towards the discovery of novel anti-diabetic agents.…”

Bioactive Variability and In Vitro and In Vivo Antioxidant Activity of Unprocessed and Processed Flour of Nine Cultivars of Australian lupin Species: A Comprehensive Substantiation

“…These six common compounds were reported to have several biological activities by many researchers. Lupanine was reported to possess antioxidant (inhibition of lipid peroxidation), anti-cholinergic as well as antidiabetic activity by improving glucose homeostasis along with stimulating insulin secretion [41][42][43][44][45]. Researchers reported n-Hexadecanoic acid to have antioxidant, anti-inflammatory, hypocholesterolemic and cancer prevention activities [33], 9,12-octadecandionoic acid to have anti-inflammatory, antibacterial, hypocholesterolemic and hepatoprotective activities, 11-octadecenoic acid, methyl ester to have antioxidant and antimicrobial properties [46], methyl stearate to have anti-inflammatory, intestinal lipid metabolism regulation, nematicidal, antinociceptive, antioxidant and antifungal activities and 13-docosenamide to have antimicrobial activity [47,48].…”

Evidence that the multiflorine‐derived substituted quinazolidine 55P0251 augments insulin secretion and lowers blood glucose via antagonism at α2‐adrenoceptors in mice

“…In the Mediterranean area, lupins have traditionally been used for the treatment of diabetes mellitus . They are rich in quinolizidine alkaloids, such as lupanines, sparteine and multiflorine, which among other actions have been associated with insulinotropic effects on isolated pancreatic islets as well as with lowering of blood glucose …”

“…3 They are rich in quinolizidine alkaloids, such as lupanines, sparteine and multiflorine, which among other actions have been associated with insulinotropic effects on isolated pancreatic islets as well as with lowering of blood glucose. [4][5][6][7][8][9][10] Based on work from Kubo et al, 9,10 who described multiflorine derivatives with antidiabetic properties in mice, we used a molecular scaffold derived from (−)-multiflorine as the starting point for an extensive derivatization programme. In line with the idea of building on bioactivity in vivo, we used glucose tolerance tests in orally dosed mice for structural optimization and discovered a novel class of fully synthetic substituted quinazolidines with distinct anti-hyperglycaemic activity.…”