Whey proteins show strongest human evidence for muscle and glycemic effects, review finds

Whey proteins have long been prized as a rich source of indispensable amino acids, but a new narrative review argues that their relevance to clinical nutrition extends well beyond basic protein supply. The review, published in Frontiers in Nutrition, synthesizes clinical, preclinical and mechanistic literature to assess how whey’s rapid digestion, leucine content, sulfur-containing amino acids and bioactive fractions might inform the formulation of Foods for Special Medical Purposes, or FSMPs—strictly regulated products used in enteral nutrition for patients who cannot meet their needs through ordinary food.

The authors, from the Faculty of Pharmacy at the University of VIZJA in Warsaw, searched PubMed, Scopus and Web of Science for peer-reviewed articles published between 2000 and 2025 in English or Polish. The search strategy identified 289 articles, and after removal of duplicates, screening of titles and abstracts, and manual checking of reference lists, 82 articles were assessed at the full-text stage. Because the included studies varied widely in populations, whey preparations, interventions and outcomes, the authors performed no quantitative meta-analysis and no formal risk-of-bias assessment, instead distinguishing human clinical evidence from animal, in vitro and mechanistic findings when interpreting results.

The most consistent human evidence, according to the review, concerns three areas: rapid postprandial aminoacidemia, stimulation of muscle protein synthesis, and acute modulation of postprandial glycemia. Whey proteins are digested and absorbed quickly in the small intestine, in contrast to casein, which forms gastric clots and digests more slowly. This produces a pronounced rise in plasma amino acids that is closely associated with strong stimulation of muscle protein synthesis. Whey contains roughly 14 percent leucine, one of the richest known protein sources of this amino acid, which acts as a nutrient signal activating the mTORC1 pathway that drives muscle protein synthesis.

Experimental and human studies indicate that whey protein preparations, including whey protein isolate, can stimulate muscle protein synthesis more effectively than casein or soy under selected conditions, an effect attributed to rapid amino acid availability and high leucine content. The effect appears particularly relevant in older adults, in whom anabolic resistance reduces the efficiency of muscle protein synthesis; whey has been shown to enhance postprandial muscle protein accretion more effectively than slower-digesting proteins in this group. In studies of older adults, per-meal protein doses of approximately 25 to 30 grams, delivering about 2.5 to 3 grams of leucine, have often been used or proposed to overcome anabolic resistance, although the review stresses these are population- and context-dependent targets rather than universal dosing recommendations.

Evidence for longer-term functional outcomes is less uniform. In older adults with sarcopenia or at risk of muscle loss, improvements have been reported with formulations combining whey protein with additional leucine and vitamin D. The review is explicit that in such combined interventions the observed effects cannot be attributed to whey protein alone and should be read as evidence for the potential benefit of the overall nutrition formulation. A whey-, leucine- and vitamin D-enriched supplement also helped preserve muscle mass in obese older adults undergoing intentional weight loss. These findings are population-specific, the authors caution, and should not be extrapolated automatically to critically ill, renally impaired or oncological patients.

The second strong area of human evidence is metabolic. Clinical studies indicate that consuming whey protein, either as a preload before a meal or as part of a meal, increases circulating levels of the incretin hormones GLP-1 and GIP, leading to enhanced insulin secretion and attenuated postprandial glucose excursions in both healthy individuals and patients with type 2 diabetes. Whey preloads have been shown to reduce the area under the glucose curve and improve early-phase insulin response after carbohydrate intake. Leucine itself activates mTOR signaling in pancreatic beta cells, promoting glucose-stimulated insulin secretion, and the amino acids delivered by rapid whey digestion stimulate pancreatic insulin secretion both directly and through incretin-mediated pathways. Similar effects have been observed in individuals with impaired glucose tolerance, where whey intake has been associated with improved glycemic control and additional cardiometabolic benefits.

A further proposed mechanism involves inhibition of dipeptidyl peptidase IV, the enzyme that rapidly degrades incretin hormones. Peptides generated from hydrolyzed whey protein, including beta-lactoglobulin-rich whey protein concentrates, have demonstrated DPP-IV inhibitory activity in vitro, and the activity appears more pronounced in hydrolyzed forms than in native preparations. The review, however, is firm that enzyme-assay activity should not be interpreted as evidence of clinically meaningful glycemic improvement; the potential contribution of DPP-IV inhibition remains primarily mechanistic and requires confirmation in well-controlled human studies, since detection of activity in an assay does not establish that an effective peptide concentration is achieved in human plasma or target tissues after oral ingestion.

Beyond these two well-supported areas, the evidence base thins considerably. Whey proteins contain relatively high levels of sulfur-containing amino acids, particularly cysteine, which serves as a precursor for glutathione, the most abundant intracellular antioxidant. Available clinical and preclinical evidence suggests whey supplementation may increase glutathione levels and improve oxidative status in various populations, with associated reductions in pro-inflammatory cytokines including IL-1 beta, IL-6 and TNF-alpha, and increases in the anti-inflammatory mediator IL-10. Bioactive components such as lactoferrin and beta-lactoglobulin fragments have shown antimicrobial activity, modulation of phagocyte function and regulation of inflammatory signaling. Yet the review classifies antioxidant and immunomodulatory effects as supported mainly by preclinical data and selected clinical evidence, with clinical effects varying by population, dose and formulation.

Wound healing, gut microbiota modulation and anticancer activity receive even weaker support. Preclinical data suggest whey supplementation may accelerate wound healing through reduced inflammatory infiltration, enhanced granulation tissue formation and re-epithelialization, but dedicated clinical trials are still needed. Both clinical and preclinical studies indicate whey proteins and their hydrolysates may promote beneficial bacterial genera such as Bifidobacterium and Lactobacillus and modulate short-chain fatty acid production, though this remains an emerging area with limited clinical validation. Most strikingly, protein-lipid complexes such as HAMLET, formed by alpha-lactalbumin and oleic acid, and related complexes including BAMLET and BLAGLET, have shown selective cytotoxicity against tumor cell lines in vitro and, in animal models, oral HAMLET administration has been associated with delayed tumor progression and improved survival without systemic toxicity. The authors emphasize these findings cannot currently be translated into clinical recommendations for cancer prevention or treatment.

For FSMP formulation, the review argues that design should start with the clinical purpose of the product rather than an assumption that more whey is universally better. Whey concentrate, isolate and hydrolysate are not interchangeable: they may differ in protein purity, residual lactose and fat, peptide profile, osmolality, taste, allergenic potential, digestion kinetics, processing stability and cost. Hydrolysis may facilitate digestion in selected contexts but does not guarantee superior clinical effectiveness and may increase bitterness or alter osmolality. The contribution of co-formulated casein, plant protein, collagen, leucine, vitamin D, carbohydrate, fat and fiber must also be weighed, and product-specific clinical evidence preferred over assumptions based on the protein source’s name. Overall, the authors conclude that whey proteins should be regarded as high-quality protein sources with potentially relevant biofunctional properties rather than established therapeutic agents, and that adequately powered comparative randomized trials are needed to define formulation-specific effects, dose-response relationships, long-term efficacy and safety in vulnerable patient populations.

Subject of Research: Biofunctional properties of whey proteins and their potential use in foods for special medical purposes

Article Title: Whey proteins revisited: from an amino acid source to therapeutic potential—a narrative review

Article References: Perliński, M., Banasiak, S., & Tenderenda, K. (2026). Whey proteins revisited: from an amino acid source to therapeutic potential—a narrative review. Frontiers in Nutrition, 13, Article 1933363. https://doi.org/10.3389/fnut.2026.1933363

Image Credits: AI Generated

DOI: 10.3389/fnut.2026.1933363

Keywords: whey protein, FSMP, muscle protein synthesis, glycemic control, leucine, incretin hormones, glutathione, DPP-IV inhibition, HAMLET, gut microbiota, wound healing, narrative review