Oral sericin ameliorates type 2 diabetes through passive intestinal and bypass transport into the systemic circulation

Jun Zhang; Fuping Wang; Hailing Zhong; Jin Pi; Guobao Chen; Zhongmin Chen

doi:10.1016/j.jep.2024.118342

Oral sericin ameliorates type 2 diabetes through passive intestinal and bypass transport into the systemic circulation

J Ethnopharmacol. 2024 May 13:118342. doi: 10.1016/j.jep.2024.118342. Online ahead of print.

Authors

Jun Zhang¹, Fuping Wang¹, Hailing Zhong², Jin Pi¹, Guobao Chen¹, Zhongmin Chen³

Affiliations

¹ School of pharmacy and bioengineering, Chongqing University of Technology, 69 Hongguang Avenue, Chongqing, 400054, China.
² Chongqing University Cancer Hospital, 181 Hanyu Road, Shapingba District, Chongqing, 400030, China.
³ School of pharmacy and bioengineering, Chongqing University of Technology, 69 Hongguang Avenue, Chongqing, 400054, China; The Center Affiliated Hospital of Chongqing university of Technology, Intersection of Lishi Road and Mawangping Main Street, Banan District, Chongqing, 400054, China. Electronic address: chenzhongmin@cqut.edu.cn.

PMID: 38750984
DOI: 10.1016/j.jep.2024.118342

Abstract

Ethnopharmacological relevance: Boiled silkworm cocoons have been used to treat 'Xiaoke disease' (diabetes mellitus) recorded in Chinese medicine for over 800 years. In recent years, it has been found that the active substance silk sericin (SS) has therapeutic benefits in treating type 2 diabetes mellitus (T2DM). SS promotes pancreatic islet signalling, the proliferation of pancreatic islet cells, and insulin secretion. It is inferred that SS enters the bloodstream after oral administration and plays a role in the body's circulation. As a natural protein, SS needs to resist digestion by proteases in the gastrointestinal tract and cross the gastrointestinal barrier after oral administration. It is currently unclear how SS crosses the gastrointestinal barrier and whether it exerts therapeutic effects on T2DM by entering the circulation.

Aim of the study: To study how SS crosses the gastrointestinal barrier and whether it enters the body circulation to exert a therapeutic effect on T2DM.

Materials and methods: SS was extracted from silkworm cocoons using an alkaline method with sodium carbonate. The antidigestive capacity of SS was detected using SDS-PAGE gel electrophoresis experiments. The mode of uptake and translocation of orally consumed SS in vivo was analysed using the AP-side to BL-side and BL-side-AP-side translocations, apparent Permeability coefficient(Papp), and Exocytosis rates(ER). The study compared the differences between the adSS group and the adSS+EDTA group by using Ethylenediaminetetraacetic acid(EDTA) to separate the tight junctions between Caco-2 cells. The aim was to analyse whether the transport mode of oral filaggrin proteins in vivo could be absorbed by bypass transport. By administering SS through oral and intraperitoneal injection to type 2 diabetic mice, we measured its concentration in the blood, as well as blood glucose and insulin levels, to determine its effectiveness in treating diabetes and its ability to enter the body's circulation for treatment.

Results: The molecular weight of SS decreased from 10k∼25kDa to 10k∼15kDa after in vitro simulated gastrointestinal fluid digestion, indicating its good antidigestive properties. The apparent Papp was greater than 1×10^-6 cm·s^-1 , and the ER was between 0.5 and 1.5, indicating that adSS was well-absorbed and mainly passively transported. The Caco-2 cell model showed that the addition of EDTA promoted the transport of adSS, resulting in significantly larger Papp and ER values, indicating that adSS was absorbed by bypass transport. After oral administration of SS, the concentration of SS in the blood was lower than after intraperitoneal injection, which is 60% of intraperitoneal administration. Mice with a T2DM model who were administered SS for 5 weeks showed significant improvement in insulin resistance and glucose tolerance. Additionally, the pancreatic tissue appeared more regular. In the treatment of T2DM, injections of SS have been shown to be more effective than oral administration. Both oral and intraperitoneal injections have been partially involved in the circulation.

Conclusions: SS is enzymatically cleaved by proteolytic enzymes in the gastrointestinal tract. The smaller molecules are partially absorbed into the body's circulation through passive and paracrine transport, exerting a therapeutic effect on T2DM.