The insulinogenic effect of whey protein is partially mediated by a direct effect of amino acids and GIP on β-cells

Abstract

Background: Whey protein increases postprandial serum insulin levels. This has been associated with increased serum levels of leucine, isoleucine, valine, lysine, threonine and the incretin hormone glucose-dependent insulinotropic polypeptide (GIP). We have examined the effects of these putative mediators of whey's action on insulin secretion from isolated mouse Langerhans islets.

Methods: Mouse pancreatic islets were incubated with serum drawn from healthy individuals after ingestion of carbohydrate equivalent meals of whey protein (whey serum), or white wheat bread (control serum). In addition the effect of individual amino acid combinations on insulin secretion was also tested. Furthermore, the stimulatory effects of whey serum on insulin secretion was tested in vitro in the absence and presence of a GIP receptor antagonist ((Pro(3))GIP[mPEG]).

Results: Postprandial amino acids, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) responses were higher after whey compared to white wheat bread. A stimulatory effect on insulin release from isolated islets was observed with serum after whey obtained at 15 min (+87%, P < 0.05) and 30 min (+139%, P < 0.05) postprandially, compared with control serum. The combination of isoleucine, leucine, valine, lysine and threonine exerted strong stimulatory effect on insulin secretion (+270%, P < 0.05), which was further augmented by GIP (+558% compared to that produced by glucose, P < 0.05). The stimulatory action of whey on insulin secretion was reduced by the GIP-receptor antagonist (Pro(3))GIP[mPEG]) at both 15 and 30 min (-56% and -59%, P < 0.05).

Conclusions: Compared with white wheat bread meal, whey causes an increase of postprandial insulin, plasma amino acids, GIP and GLP-1 responses. The in vitro data suggest that whey protein exerts its insulinogenic effect by preferential elevation of the plasma concentrations of certain amino acids, GIP and GLP-1.

Figures

Figure 1

Amino acid responses in humans. Mean (± SEM) values of isoleucine, leucine, valine, lysine and threonine in plasma obtained at different time points in response to the whey (▴) and WWB (■) meal.

Figure 2

Incretin responses in humans. Mean (± SEM) values of GIP (A) and GLP-1 (B) in plasma obtained at different time points in response to the whey (▲) and WWB (■) meal.

Figure 3

Insulin secretion of Langerhans islets incubated with human serum. Insulin secretion of isolated pancreatic islets incubated with serum obtained from healthy subjects after ingestion of whey (grey bars) and WWB (control, white bars), and 8.3 mM glucose alone (reference, black bar). The islets were pooled from 8 different NMRI mice and values are means ± SEM for 10 observations in each group performed at three different occasions. Significant differences between whey and control serum for each time point are denoted by **P < 0.01, ***P < 0.001.

Figure 4

Insulin secretion of Langerhans islets incubated with amino acid. Insulin secretion from isolated pancreatic islets incubated at 8.3 mM glucose in the absence or presence of leucine, isoleucine, valine, lysine and threonine, a cocktail of the 5 amino acids or a cocktail + GIP. Values are means ± SEM for 8 observation in each group performed at three different occasions. The experiments were performed on the islets isolated and pooled from 6 different NMRI mice. Values with different letters are significantly different, P < 0.05.

Figure 5

Insulin secretion of Langerhans islet incubated with human serum in presence of a GIP-receptor antagonist. Insulin secretion from isolated mice pancreatic islets incubated at 8.3 mmol/l glucose + whey serum (obtained before intake time 0 as well as at 15 and 30 min after meal ingestion) in the absence (white bars) and presence (black bars) of GIP-receptor antagonist ((Pro(3))GIP[mPEG]) (100 nmol/l). Values are means ± SEM for 8 observations in each group performed at three different occasions on the isolated islets from 6 different NMRI mice. Significant differences between absence and presence of the antagonist are denoted by * P < 0.05; * * P < 0.005.