Abstract
Diabetes mellitus (DM) is a group of metabolic diseases, and there is an urgent need to develop new therapeutic DM oral drugs with fewer side effects and sound therapeutic efficacy. In this study, a β cell expansion factor A (BefA) production strain of Escherichia coli (BL21-pet 28C-BefA) was constructed, and the antidiabetes effect of BefA was evaluated using type 1 DM (T1DM) and type 2 DM (T2DM) mice models. The T1DM mice results indicated that BefA significantly reduced blood glucose levels; exerted a protective effect on islet β cell morphology; downregulated the expressions of TLR-4, p-NFκB/NFκB, and Bax/Bcl-2, and the secretion levels of IL-1β and TNF-α; increased the expression of PDX-1 protein and insulin secretion in a concentration-dependent manner; and restored the disturbed microbial diversity to normal levels. Similarly with the T1DM mice, BefA obviously increased islet β cells and reduced the inflammatory reaction and apoptosis in T2DM mice, as well as improved liver lipid metabolism by downregulating the expressions of CEBP-α, ACC, and Fasn; inhibited the synthesis of triglycerides; and induced Cpt-1, Hmgcs2, and Pparα in a concentration-dependent manner. In conclusion, BefA alleviates diabetes via increasing the number of islet β cells, reducing the inflammatory reaction and apoptosis, improving liver lipid metabolism, and restoring microbial diversity to normal levels, which provides a new strategy for a DM oral drug.
Highlights
Diabetes mellitus (DM) is a group of complex metabolic disorders characterized by abnormally elevated blood glucose concentrations secondary to either insufficient insulin secretion, insulin resistance, or both [1, 2].Studies show that acute complications can be caused by elevated blood glucose, which eventually cause damage to the liver, heart, cerebrovascular, and other organs and even lead to death [3, 4].The global mortality rate of DM is as high as 10.7%, and it is estimated that there will be 693 million people with DM worldwide by 2045 [5]
Insulin-dependent type 1 diabetes mellitus (T1DM) and insulin-independent type 2 diabetes mellitus (T2DM) are the main types of diabetes, among which T1DM results from the specific deficiency of insulin-producing pancreatic β cells from autoimmune destruction [8] and T2DM is an agerelated disease characterized by the dysfunction of glucose metabolism representing insulin-resistant states that is accompanied by a destruction of β cells [9]
As no work was done to verify the increasing effect of orally administered BefA on the number of mammalian islet β cells, newborn germ-free (GF) mice and specific pathogen-free (SPF) mice were used in the present study to confirm the antidiabetes effect of BefA for the first time, and our results indicated that BefA could markedly increase the number of β cells compared among the SPF mice and GF mice (Figure 1(c)), which is consistent with previous work in zebrafish [19]
Summary
Diabetes mellitus (DM) is a group of complex metabolic disorders characterized by abnormally elevated blood glucose concentrations secondary to either insufficient insulin secretion, insulin resistance, or both [1, 2].Studies show that acute complications (e.g., hyperosmolar coma and diabetic ketoacidosis) can be caused by elevated blood glucose, which eventually cause damage to the liver, heart, cerebrovascular, and other organs and even lead to death [3, 4].The global mortality rate of DM is as high as 10.7%, and it is estimated that there will be 693 million people with DM worldwide by 2045 [5]. Based on the disadvantages of the above treatment strategies, it is of great importance to develop new therapeutic drugs for both T1DM and T2DM with fewer side effects and better therapeutic efficacy. Both impaired pancreatic β cell function and insulin secretion have been demonstrated in both T1DM and T2DM,while treatments targeting pancreatic β cell proliferation are currently lacking [17, 18]
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