Review
20 January 2025
State Key Laboratory of Food Nutrition and Safety, Food Biotechnology Engineering Research Center of Ministry of Education, College of Food Science and Engineering, Tianjin University of Science & Technology, Tianjin 300457, China
School of Ocean and Environment, Tianjin University of Science & Technology, Tianjin 300457, China
*Author to whom correspondence should be addressed.
Type II diabetes mellitus (T2DM) is a prevalent, long-standing metabolic condition marked by the body’s reduced response to insulin and inadequate insulin production, impacting a significant portion of the global population. Research has demonstrated that bioactive peptides play a crucial role in reducing blood sugar levels, enhancing insulin sensitivity, balancing lipid metabolism, and combating inflammation. These peptides also contribute to the enhancement of pancreatic islet function, lowering systemic inflammation by influencing various molecular signaling pathways. This paper provides an overview of recent advancements and potential applications of bioactive peptides in addressing T2DM. It highlights the diverse impacts of bioactive peptides sourced from different origins in combating diabetes. This comprehensive review offers theoretical substantiation and novel insights to support the future clinical utilization and exploration of bioactive peptides for T2DM management.
Diabetes mellitus is a complex, long-term condition influenced by a combination of genetic and environmental elements. The global prevalence of diabetes has been on the rise in the 21st century, with an estimated 537 million individuals worldwide diagnosed with diabetes in 2021. This number is projected to surge by 46% to reach 783 million by 2045, and the onset of diabetes is occurring at progressively younger ages [1]. T2DM is a metabolic disorder distinguished by prolonged high blood sugar levels and elevated insulin levels stemming from compromised insulin function, secretion, or both factors [1]. The global incidence of T2DM is on the upswing across nations, largely attributed to sedentary habits and a widespread rise in obesity rates [2,3,4]. Currently, the primary treatment modalities for T2DM include insulin injections and oral anti-diabetic medications; however, many of these medications are associated with side effects, adverse reactions, and the development of drug resistance [5,6,7,8,9]. Noteworthy side effects of diabetes medications encompass heightened risk of hypoglycemia, skin rashes, drug-induced skin conditions, gastrointestinal disturbances, swelling, weight increase, and susceptibility to urinary tract infections among diabetic individuals [10,11,12,13,14]. Standard treatment approaches fail to address the personalized requirements of patients, leading to variations in the effectiveness of blood sugar regulation and an inability to prevent the progression of complications associated with the disease [11].
As research progresses, bioactive peptides have emerged as a focal point in enhancing T2DM management because of their natural, safe, and efficient attributes. Bioactive peptides from food are short amino acid sequences found in proteins that exhibit biological effects. Typically consisting of 2–20 amino acid residues, they are more readily digested and absorbed by the body compared to larger molecules [15]. Research indicates that incorporating grains, fruits, vegetables, fish, meat, eggs, milk, and other foods into the daily diet positively influences blood sugar control. Furthermore, bioactive peptides derived from natural sources, characterized by their small size, easy absorption, and adaptable structure, can effectively intervene and manage T2DM through various mechanisms [15,16,17,18,19,20,21,22]. Currently, the exploration of innovative food-derived bioactive peptides with enhanced biological potency, specificity, and bioavailability for preventing and treating metabolic conditions like T2DM is gaining momentum as a burgeoning research area.
Bioactive peptides sourced from food have the potential to enhance the management of T2DM through multiple mechanisms. Firstly, they can modulate energy metabolism and enhance glucose processing through uncoupling mechanisms. Specific bioactive peptides from food exhibit α-glucosidase inhibitory properties, slowing carbohydrate digestion and absorption to lower post-meal blood glucose levels [23]. Additionally, these peptides can boost glucose metabolism effectiveness, contributing to improved glucose processing efficiency. For instance, studies highlight that β-glucan-rich, low-starch bread enhances metabolic regulation and diminishes blood glucose levels in individuals with T2DM [24]. Conversely, bioactive peptides can enhance insulin sensitivity by influencing the PI3K/AKT and MAPK pathways [24]. Insulin plays a vital role in blood glucose regulation, and heightened insulin sensitivity facilitates improved cellular absorption and utilization of glucose, aiding in blood glucose management [25]. Furthermore, these peptides can be targeted to obstruct metabolic enzymes related to T2DM, including inhibiting α-glucosidase to delay carbohydrate absorption, reducing the rate of amylenzymatic hydrolysis to glucose, and impeding the escalation of blood glucose levels [26].
Currently, the prevalent techniques for creating bioactive peptides involve enzymatic and fermentation methods. By carefully selecting suitable proteases, refining the reaction parameters, and employing intricate enzymatic breakdown, highly potent small peptides can be synthesized [27]. Additionally, bioactive peptides find utility in crafting functional foods like whey protein and its associated bioactive peptides, known for their role in modulating blood glucose levels. These compounds exhibit diverse biological functions that can combat diet-induced obesity, improve glucose tolerance, and postpone the emergence of T2DM [28,29,30]. The advancement of functional foods enriched with bioactive peptides holds substantial importance in supporting the supplemental management of T2DM and elevating the nutritional worth of food products.
Bioactive peptides are available from a variety of sources due to their low molecular weight and flexible structure compared to macromolecular proteins. Bioactive peptides have a high degree of structural diversity, which allows them to play specific roles against different biological targets (Table 1). For example, antimicrobial peptides (AMPs) can be extracted from a variety of sources, such as plants, animals, and micro-organisms, and have different structures and functions [31]. Pushpanathan et al. [31] also showed that certain AMPs can be used as antitumor, contraceptives, or drug delivery vehicles. This indicates that bioactive peptides not only have antibacterial activity but can also be used as signaling molecules, immunomodulators, growth factors, and other biological functions. Through 3D-QSAR analysis, specific physicochemical properties were found to be the key factors determining the antimicrobial activity and selectivity of AMPs [32]. This study demonstrates that bioactive peptides are often highly selective and specific for specific micro-organisms or cell types. This selectivity is primarily determined by the physicochemical interaction between the peptide and the cell membrane of interest. The molecular flexibility of bioactive peptides is critical to their biological activity. The flexibility of a molecule can enhance its ability to interact with the target molecule by altering its structural characteristics. Bioactive peptides of marine biological origin have antimicrobial activity and are able to inhibit microbial growth, which may help reduce the risk of infection in diabetes management [33].
Table 1. Functions of bioactive peptides.
Bioactive peptides can be obtained from many different organisms, including animals, plants, micro-organisms, and marine organisms (Table 2). Bioactive peptides extracted from non-traditional food sources, such as those prepared from protein-rich non-traditional food sources such as Bellamya bengalensis, using enzymatic technology, have shown therapeutic functions, such as antihypertensive [39]. In addition, micro-organisms are also important sources of bioactive peptides, and many micro-organisms, such as bacteria, fungi, actinomycetes, and microalgae, are capable of synthesizing peptides with different biological activities [31]. It has been shown that marine plants, such as Sicilian marine fennel (Crithmum maritimum), have also been found to contain bioactive metabolites [39].
Table 2. Comparison of common preparation methods for bioactive peptides.
BIOPEP-UWM currently lists 62 different feature categories, 4 of which are described below. These four categories were selected because they are important and representative in the field of biological functions. Antimicrobial peptides are related to biological defense and antimicrobial resistance. Plant growth promoting peptides help the green development of agriculture. Regulatory peptides regulate physiological activities in organisms. Growth factors promote biological growth, tissue repair, and medical regeneration.
Antimicrobial Peptides (AMPs)
Antimicrobial peptides are a class of short-chain polypeptides with broad-spectrum antimicrobial activity, which are widely found in nature, including plants, animals, and micro-organisms. These peptides inhibit or kill micro-organisms by interacting with their cell membranes and disrupting the integrity of their cell membranes [45]. Antimicrobial peptides are diverse in variety and structure, and their common feature is that they have cationic properties and are able to interact with negatively charged microbial cell membranes [41].
The mechanism of action of antimicrobial peptides is mainly to directly damage the cell membrane of micro-organisms and interfere with their internal structure. Some antimicrobial peptides are able to form transmembrane pores that cause cell contents to leak, thereby killing micro-organisms [46]. In addition, antimicrobial peptides can further inhibit microbial growth by binding to their DNA and interfering with their replication and transcription processes [43]. Antimicrobial peptides have also shown toxic effects on certain cancer cells, suggesting that they may also have potential applications in anticancer treatments.
Bioactive Peptides of Plant Origin
Plant-derived bioactive peptides have some potential to improve T2DM. Studies have shown [44] that natural peptides in legume seeds, such as aglycin, vglycin, and soymorphin-5, have been reported to have an effect on lowering blood glucose levels, improving insulin sensitivity, and glucose tolerance. These natural peptides promote β-cell proliferation and insulin secretion through their interaction with insulin and its receptors and therefore have a potential therapeutic effect on T2DM [44]. Studies have shown that plant-derived bioactive peptides have also been studied as potential drugs for the treatment of diabetes, playing a role in regulating immune responses, inhibiting tumor growth, and promoting apoptosis, showing promising applications in the treatment of diabetes [47].
Regulatory Peptides
Regulatory peptides are a class of small molecule peptides that have the function of regulating various physiological processes in living organisms. Regulatory peptides play an important role in improving T2DM through multiple pathways. On the one hand, they enhance insulin sensitivity and promote insulin secretion, thereby regulating blood glucose levels [48]. On the other hand, regulatory peptides can improve insulin resistance, reduce gluconeogenesis, and improve the body’s uptake and utilization of glucose. In addition, regulatory peptides can also regulate fat metabolism, reduce blood lipids, reduce fat accumulation, and alleviate the effects of obesity on diabetes [44]. At the same time, regulatory peptides also play an active role in regulating intestinal hormones and protecting pancreatic islet cells, improving the body’s metabolic function in an all-round way and providing new ideas and methods for the control and treatment of T2DM [49].
Growth Factors
Growth factors are a class of polypeptides with a variety of physiological functions that were originally described for their activity to promote cell division. These peptides not only play a role in cell division but are also involved in a variety of biological roles, such as regulating tissue morphology, differentiation, motility, and functional activity. Growth factors function through autocrine or paracrine mechanisms, and they function by binding to specific receptors on cell membranes, some of which also have kinase activity [50]. Together with hormones and neurotransmitters, growth factors play a fundamental role in cell-to-cell communication, with key functions including controlling the cell cycle, initiating mitosis, maintaining cell proliferation and survival, migration, differentiation, and apoptosis [51]. Growth factors play an important role in key events, such as follicular development, early embryogenesis, and implantation in reproductive activities, and although their mechanism of action and synergistic effects with other hormones are known, their full role has not been fully elucidated [52].
The bioactive peptides in whey protein directly promote insulin secretion and enhance insulin sensitivity. Melnik et al. [53] showed that branched-chain amino acids (BCAAs) in whey protein, such as leucine, isoleucine, and valine, can activate the mTORC1 signaling pathway in β cells and promote β-cell proliferation, insulin synthesis, and secretion. In addition, whey protein increases the secretion of glucose-dependent insulin-stimulated polypeptides (GIPs), thereby reducing postprandial blood glucose levels [54].
Whey protein can also improve glycemic control by modulating other metabolic pathways, and certain amino acid combinations (e.g., leucine, isoleucine, and valine) can mimic the insulin-boosting
