Abstract
Lupinus mutabilis (LM) is a legume part of Bolivian traditional diet that has a nutraceutical property reducing blood glucose levels. The prevalence of type 2 diabetes is increasing worldwide thus; the search for novel anti-diabetic drugs is needed. Based on its traditional use, we evaluated the anti-diabetic effect of LM in the spontaneously diabetic Goto-Kakizaki (GK) rat, a model of type 2 diabetes and in Wistar (W) rats as healthy control. LM seeds hydroethanolic extract, analyzed by gas chromatography-mass spectrometry and high-performance liquid chromatography-high resolution mass spectrometry, is a complex mixture of volatile and non-volatile components. A single oral administration of LM extract (2000 mg/kg b.w.) improved glucose tolerance during the oral glucose tolerance test (OGTT) (30–120 min) in GK and W rats (p < 0.0001). The long-term treatment with LM (1000 mg/kg b.w.), for 21 days, improved the area under the curve (AUC) of glucose during OGTT at day 20, in both GK (p < 0.01) and W rats (p < 0.01). The HbA1c (GK rats, p < 0.05 and W rats, p < 0.0001) and the non-fasting glucose (GK rats, p < 0.05) were also reduced. LM increased both serum insulin levels (2.4-fold in GK rats and 2.5-fold W rats), and the glucose-induced (16.7 mM glucose) insulin release in isolated islets from treated animals (6.7-fold in GK rats, and 6.6-fold in W rats). Moreover, LM (10 mg/mL) stimulated in vitro glucose induced (16.7 mM glucose) insulin release in batch incubated GK and W rat islets (p < 0.0001). In perifused GK rat islets, insulin release in 16.7 mM glucose was increased 95.3-fold compared to untreated islets (p < 0.0001), while no significant differences were found in perifused W rat islets. The LM mechanism of action, evaluated using inhibitory compounds of the insulin secretion pathway, showed that LM-dependent insulin secretion was reduced 42% by diazoxide (p < 0.001), 70% by nifedipine (p < 0.001), 86.7% by H89 (p < 0.0001), 70.8% by calphostine-C (p < 0.0001) and 93% by pertussis toxin (p < 0.0001). A similar effect was observed in W rats islets. Our findings provide evidence that LM has an anti-diabetic effect through stimulation of insulin release. The effect is-dependent on L-type calcium channel, protein kinase A and C systems, and G protein-coupled exocytosis and is partially mediated by K-ATP channels.
Highlights
Diabetes Mellitus Type 2 (T2DM) is a health problem that has been increased worldwide and its prevalence, according to the International Diabetes Federation (IDF), is estimated to reach 642 million people by 2040 [1]
The fragmentation pattern of the eluting peaks was compared against the Wiley 275 mass spectral library, which indicated that Lupinus mutabilis (LM) extract could tentatively be assigned to contain sparteine, palmitic acid, linoleic acid, oleic acid, lupanine, nuttalline, oxylupanine, and 11,12-dehydrolupanine
Pancreatic islets isolated from GK rats and 30 min during the oral glucose tolerance test (OGTT); GK rats (C) and W rats (D) (n = 6)
Summary
Diabetes Mellitus Type 2 (T2DM) is a health problem that has been increased worldwide and its prevalence, according to the International Diabetes Federation (IDF), is estimated to reach 642 million people by 2040 [1]. T2DM is a metabolic disorder with chronic hyperglycemia due to impaired insulin secretion and decreased insulin sensitivity of multiple etiologies [2,3,4]. The chronic hyperglycemia can lead to the development of diabetes complications i.e., nephropathy, retinopathy, neuropathy, and macrovascular damage [5,6]. Natural sources have offered anti-diabetic non-toxic alternatives with less or lack of side effects [5,7,8,9]. Based on the Bolivian traditional use, we selected the Lupinus mutabilis (LM) seeds to evaluate its anti-diabetic effect
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