Macroalgal protein hydrolysates from Palmaria palmata influence the ‘incretin effect’ in vitro via DPP-4 inhibition and upregulation of insulin, GLP-1 and GIP secretion

Abstract

Purpose This study investigated metabolic benefits of protein hydrolysates from the macroalgae Palmaria palmata, previously shown to inhibit dipeptidylpeptidase-4 (DPP-4) activity in vitro. Methods Previously, Alcalase/Flavourzyme-produced P. palmata protein hydrolysate (PPPH) improved glycaemia and insulin production in streptozotocin-induced diabetic mice. Here the PPPH, was compared to alternative Alcalase, bromelain and Promod-derived hydrolysates and an unhydrolysed control. All PPPH’s underwent simulated gastrointestinal digestion (SGID) to establish oral bioavailability. PPPH’s and their SGID counterparts were tested in pancreatic, clonal BRIN-BD11 cells to assess their insulinotropic effect and associated intracellular mechanisms. PPPH actions on the incretin effect were assessed via measurement of DPP-4 activity, coupled with GLP-1 and GIP release from GLUTag and STC-1 cells, respectively. Acute in vivo effects of Alcalase/Flavourzyme PPPH administration on glucose tolerance and satiety were assessed in overnight-fasted mice. Results PPPH’s (0.02–2.5 mg/ml) elicited varying insulinotropic effects (p < 0.05–0.001). SGID of the unhydrolysed protein control, bromelain and Promod PPPH’s retained, or improved, bioactivity regarding insulin secretion, DPP-4 inhibition and GIP release. Insulinotropic effects were retained for all SGID-hydrolysates at higher PPPH concentrations. DPP-4 inhibitory effects were confirmed for all PPPH’s and SGID counterparts (p < 0.05–0.001). PPPH’s were shown to directly influence the incretin effect via upregulated GLP-1 and GIP (p < 0.01–0.001) secretion in vitro, largely retained after SGID. Alcalase/Flavourzyme PPPH produced the greatest elevation in cAMP (p < 0.001, 1.7-fold), which was fully retained post-SGID. This hydrolysate elicited elevations in intracellular calcium (p < 0.01) and membrane potential (p < 0.001). In acute in vivo settings, Alcalase/Flavourzyme PPPH improved glucose tolerance (p < 0.01–0.001) and satiety (p < 0.05–0.001). Conclusion Bioavailable PPPH peptides may be useful for the management of T2DM and obesity.

Seaweed-Derived Proteins and Peptides: Promising Marine Bioactives

“…An increase in calcium transmembrane mobilization, as well as an upregulation of cyclic adenosine monophosphate (cAMP) was found liable for the overall incretin effect. When testing these effects in vivo with mice (100 mg/kg body weight), it was found an improved glucose tolerance, as well as satiety response after 90 min of oral administration, which would indicate a positive increase in GLP-1 and other incretin upregulation [ 129 ].…”

“…Seaweed BAPs may also act as α-glucosidase inhibitors, reducing gut glucose absorption and subsequent glycemic levels [ 54 ]. Given that these effects have been described in animal models, there is a great potential for these peptides as dietary supplements for diabetes and/or obesity management [ 128 , 129 ]. The anti-inflammatory or antitumoral properties of seaweed BAPs have also been highlighted.…”

Seaweeds as a Source of Functional Proteins

“…Alcalase, bromelain, and Promod-derived hydrolysates dipeptidyl peptidase IV (DPP-IV) inhibitory activities, [111] Alcalase/Flavourzyme hydrolysates Antihyperglycemic/antidiabetic potential [112] Peptides: ILAP, LLAP, MAGVDHI DPP-IV inhibitory activities [113] Papain hydrolysates: NIGK Platelet-activating factor acetyl-hydrolase (PAF-AH) inhibitory peptides [114] IRLIIVLMPILMA…”

“…demonstrated activity against Seaweeds can be a natural source of DPP-IV inhibitors. Studies have reported that protein hydrolysates of P. palmata have DPP-IV inhibitory activities that are useful for the management of T2DM [111,144] and obesity [111]. Oral administration of P. palmata protein hydrolysate derived from Alcalase and Flavourzyme reduced food intake by streptozotocininduced diabetic mice and showed antihyperglycemic effects [112].…”

Seaweed Protein Hydrolysates and Bioactive Peptides: Extraction, Purification, and Applications

“…For example, P. palmata, was used to obtain a protein hydrolysate with the ability of improving glycemia and insulin production when assessed in vivo, as the specific Alcalase/Flavourzyme protein hydrolysate enhanced the glucose tolerance and satiety. Thus, these P. palmata protein hydrolysates were suggested as potential molecules for managing two chronic diseases with a worldwide increasing prevalence: obesity and type-2 diabetes mellitus [19]. Another work based on proteins extracted from the same species proved their antiproliferative capacity against five human cancer cell lines derived from breast (MCF-7), liver (HepG-2), gastric (SGC-7901), lung (A549), and colon cancers (HT-29), with half inhibitory concentrations (IC 50 ) ranging between 192 and 317 µg/mL [20].…”