Article pubs.acs.org/JAFC
Cite This: J. Agric. Food Chem. 2017, 65, 9266-9274
Gastro-Resistant Insulin Receptor-Binding Peptide from Momordica charantia Improved the Glucose Tolerance in Streptozotocin-Induced Diabetic Mice via Insulin Receptor Signaling Pathway Hsin-Yi Lo,† Chia-Cheng Li,† Feng-Yuan Chen,† Jaw-Chyun Chen,§ Chien-Yun Hsiang,*,‡ and Tin-Yun Ho*,⊥
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Graduate Institute of Chinese Medicine and ‡Department of Microbiology, China Medical University, Taichung 404, Taiwan § Department of Medicinal Botany and Healthcare, Da-Yeh University, Changhua 515, Taiwan ⊥ Department of Health and Nutrition Biotechnology, Asia University, Taichung 413, Taiwan ABSTRACT: Momordica charantia is a commonly used food and has been used for the management of diabetes. Our previous study has identified an insulin receptor (IR)-binding protein (mcIRBP) from Momordica charantia. Here we identified the gastroresistant hypoglycemic bioactive peptides from protease-digested mcIRBP. By in vitro digestion and IR kinase activity assay, we found that a 9-amino-acid-residue peptide, mcIRBP-9, was a gastro-resistant peptide that enhanced IR kinase activities. mcIRBP-9 activated IR signaling transduction pathway, which resulted in the phosphorylation of IR, the translocation of glucose transporter 4, and the uptake of glucose in cells. Intraperitoneal and oral administration of mcIRBP-9 stimulated the glucose clearance by 30.91 ± 0.39% and 32.09 ± 0.38%, respectively, in streptozotocin-induced diabetic mice. Moreover, a pilot study showed that daily ingestion of mcIRBP-9 for 30 days decreased the fasting blood glucose levels and glycated hemoglobin (HbA1c) levels by 23.62 ± 6.14% and 24.06 ± 1.53%, respectively. In conclusion, mcIRBP-9 is a unique gastro-resistant bioactive peptide generated after the digestion of mcIRBP. Furthermore, oral administration of mcIRBP-9 improves both the glucose tolerance and the HbA1c levels in diabetic mice via targeting IR signaling transduction pathway. KEYWORDS: diabetes, gastro-resistant peptide, hypoglycemia, insulin receptor, Momordica charantia
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INTRODUCTION Diabetes and its complications are severe global health problems.1 In 2015, there were 415 million people with diabetes worldwide and five million people died because of diabetes. The estimated number of diabetic patients will increase by 55% and reach 642 million patients by 2040. Furthermore, the global health cost due to diabetes was USD 673 billion worldwide in 2015 and will reach USD 802 billion by 2040.2 Diabetes is characterized by hyperglycemia, which is caused by defective insulin secretion, resistance to insulin action, or a combination of both.1 Some foods have showed functional activities on the regulation of blood glucose. For example, jaboticaba (Myrciaria jaboticaba) is rich in polyphenols with antioxidative activities.3 Intake of jaboticaba peels decreases glucose and insulin levels after the second meal, suggesting that jaboticaba improves the insulin sensitivity in healthy adults.4 Single oral administration of 1-deoxynojirimycin-enriched mulberry powder significantly suppresses the elevation of postprandial blood glucose and the secretion of insulin, suggesting that mulberry powder can be used as a dietary supplement for the prevention of diabetes in healthy subjects.5 Furthermore, daily administration of Ginkgo biloba L. leaf dry extract improves the glycemic control in patients with type 2 diabetes.6 Three-month supplementation of ginger (Zingiber off icinale) improves glycemic indices in type 2 diabetic patients. Moreover, daily supplementation with fermented red ginseng lowers postprandial glucose levels in subjects with impaired fasting glucose or type 2 diabetes.7 In addition of food extracts, © 2017 American Chemical Society
intake of soy proteins significantly improves the glucose homeostasis in women with gestational diabetes.8 Conglutin gamma protein from Lupinus albus seeds has a relevant postprandial hypoglycemic effect in humans, suggesting that it could potentially be used to manage patients with impaired glucose metabolism.9 Additionally, oral administration of insulin-like protein from Costus igneus significantly reduces the blood glucose levels in streptozotocin (STZ)-induced diabetic Swiss mice via insulin signaling pathway.10 These studies therefore promise the beneficial effects of foods and food-derived peptides on the regulation of blood glucose. Bitter melon (Momordica charantia L.) is a commonly used vegetable and has been widely used in traditional medicine for the treatment of diabetes in Asia. Daily intake of bitter melon for 4 weeks shows hypoglycemic effects in patients with type 2 diabetes.11 Bitter melon decreases fasting blood glucose levels and lowers 2-h plasma glucose levels after oral glucose tolerance test in type 2 diabetic patients. However, no patient experiences a symptomatic hypoglycemic event or has a documented blood glucose level 20%, 6−20%, 3−5%, and
