Lupanine Improves Glucose Homeostasis by Influencing KATP Channels and Insulin Gene Expression.
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(2+) action potentials. Determination of the current through ATP-dependent K⁺ channels (KATP channels) revealed that lupanine directly inhibited the 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.
Dept. of Pharmaceutical and Medicinal Chemistry, Münster University, Corrensstraße 48, 48149 Münster, Germany. matswiedemann@uni-muenster.de.
Mats
M
Wiedemann
Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, 44340 Guadalajara, Jalisco, Mexico. carmenhpv@yahoo.de.
Carmen M
CM
Gurrola-Díaz
Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, 44340 Guadalajara, Jalisco, Mexico. bevargro@hotmail.com.
Belinda
B
Vargas-Guerrero
Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg 69120, Germany. Wink@uni-heidelberg.de.
Michael
M
Wink
Departamento de Botánica y Zoología, Centro Universitario de Ciencias Biológicas y Agropecuarias, Universidad de Guadalajara, 45110 Guadalajara, Jalisco, Mexico. pgarcia@cucba.udg.mx.
Pedro M
PM
García-López
Dept. of Pharmaceutical and Medicinal Chemistry, Münster University, Corrensstraße 48, 48149 Münster, Germany. martina.duefer@uni-muenster.de.
Martina
M
Düfer
D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000494:pharmacology; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D054086:KATP Channels / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D013034:Sparteine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D013311:Streptozocin
D001786:Blood Glucose; D007328:Insulin; D054086:KATP Channels; C008298:lupanine; D013034:Sparteine; D013311:Streptozocin; D001120:Arginine
KATP channel; Lupinus; beta-cell; glucose tolerance; insulin secretion; lupanine; membrane potential; quinolizidine alkaloids; streptozotocin; type-2 diabetes mellitus