Carbohydrates, glycemic index and diabetes mellitus

Effects of different fractions of whey protein on postprandial lipid and hormone responses in type 2 diabetes



Exacerbated postprandial lipid responses are associated with an increased cardiovascular risk. Dietary proteins influence postprandial lipemia differently, and whey protein has a preferential lipid-lowering effect. We compared the effects of different whey protein fractions on postprandial lipid and hormone responses added to a high-fat meal in type 2 diabetic subjects.


A total of 12 type 2 diabetic subjects ingested four isocaloric test meals in randomized order. The test meals contained 100 g of butter and 45 g of carbohydrate in combination with 45 g of whey isolate (iso-meal), whey hydrolysate (hydro-meal), α-lactalbumin enhanced whey (lac-meal) or caseinoglycomacropeptide enhanced whey (CGMP-meal). Plasma concentrations of triglyceride, retinyl palmitate, free fatty acid, insulin, glucose, glucagon, glucagon-like peptide 1 and glucose-dependent insulinotropic peptide were measured before and at regular intervals until 8-h postprandially.


We found no statistical significant differences between meals on our primary variable triglyceride. The retinyl palmitate response was higher after the hydro-meal than after the iso- and lac-meal in the chylomicron-rich fraction (P=0.008) while no significant differences were found in the chylomicron-poor fraction. The hydro- and iso-meal produced a higher insulin response compared with the lac- and CGMP-meal (P<0.001). Otherwise no significant differences in the hormone responses were found in the incremental area under the curve over the 480-min period.


A supplement of four different whey protein fractions to a fat-rich meal had similar effects on postprandial triglyceride responses in type 2 diabetic subjects. Whey isolate and whey hydrolysate caused a higher insulin response.


Dyslipidaemia is a significant risk factor for cardiovascular disease (CVD) in type 2 diabetes (T2DM),1 and CVD is a major cause of morbidity and mortality in T2DM patients.2 Postprandial hypertriglyceridaemia is a distinct component of dyslipidaemia in T2DM3, 4 and is associated with CVD.5, 6 Two long-term prospective cohort studies recently showed that levels of non-fasting triglyceride independently and better predicts future cardiovascular events than levels of fasting triglyceride.7, 8

Meal composition is one of the major modifiable factors implicated in the postprandial lipaemia (PPL). Thus, it is well documented that both the amount and type of fat influence PPL.9, 10, 11 Most data indicate that addition of readily digestible carbohydrates to a fatty meal augments PPL.12 Recently, there is a growing interest in dietary protein and PPL.

Epidemiological studies indicate that the consumption of protein containing milk and dairy products is inversely associated with a lower risk of metabolic disorders and CVD.13 Dairy proteins in bovine milk are comprised of 80% casein and 20% whey protein.

Two studies have shown that the unfavourable effect of carbohydrate on PPL, seen in T2DM, can be reduced by adding the milk protein casein to a meal.14, 15 Although, the milk protein casein per se did not modulate the postprandial triglyceride response in T2DM.14 However, when whey protein, another milk protein, was added to a fat-rich meal it acutely reduces the postprandial triglyceride response in T2DM subjects compared with casein, cod and gluten.16 Pal et al.17 has confirmed the improvement in PPL after ingestion of whey protein in overweight postmenopausal women.

Interestingly, whey protein is particularly insulinotropic compared with other dietary proteins18 and it has been shown that the hydrolysed whey protein induces a greater insulin response than the intact protein.19 Insulin, in turn, is known to potently modify postprandial triglyceride responses.20 Also, a single injection of the glucagon-like peptide 1 (GLP-1) analogue exenatide before a fat-rich meal has been shown to reduce PPL in T2DM subjects.21

It has been shown that whey proteins are more effective on physiological systems than casein, most likely because of the faster digestion and absorption kinetics.13 Whey protein also includes bioactive components and is an important source of branch chained amino acids, which could have a further role in its physiological effects. Consequently, it is of interest to study the impact on PPL of commercially available whey fractions such as α-lactalbumin and caseinoglycomacropeptide (CGMP)22 to develop functional foods with an optimal cardiovascular profile.

We have previously shown promising effects of whey protein on CVD risk markers in T2DM.16 The aim of this study was to compare in T2DM subjects the acute effect on PPL and hormone responses of four commercially available whey fractions applied to a fat-rich meal. We have used two subfractions of whole whey; α-lactalbumin enhanced whey and CGMP enhanced whey and a structurally modified derivate; whey hydrolysate, which is hydrolysed whey isolate consisting of di-and tripeptides. As comparator we have used whey isolate to investigate if other whey fractions induced additional improvement in PPL.

Subjects and methods


A total of 12 T2DM subjects (7 women and 5 men) were recruited from our outpatient clinic. All subjects were diagnosed with T2DM for1 year (3±2.5). The clinical characteristics of the subjects are given in Table 1. Three subjects were treated with diet alone, four with metformin, two with sulfonylurea and three with a combination of metformin and sulfonylurea. Insulin treatment was an exclusion criterion. In all, 10 of the subjects received lipid-lowering drugs (9 received simvastatin and 1 received a combination of simvastatin and gemfibrosil). All subjects continued taking their regular medication without any changes in dosage during the entire study period, except for the anti-diabetic medication, which was discontinued for 24 h before each study day. All subjects gave their written informed consent to participate in this study and the Central Denmark Region Committee on Biomedical Research Ethics approved the study according to the Helsinki Declaration. The study is registered on ID: NCT00819975.

Table 1 Clinical characteristics of the type 2 diabetic subjectsa


According to a single-blind crossover design, all subjects were studied on four separate occasions with a washout period 2 weeks between the four test meals. The subjects were randomly assigned to the sequence of the test meals by using a Latin-Square design. For 24 h preceding each study day, the subjects ingested a standard diet containing 56% of energy as carbohydrate, 24% of energy as fat and 20% of energy as protein, which was supplied by the study. Food amounts were adjusted for gender, that is, females received a diet of 7000 kJ and males a diet of 9000 kJ, respectively. The subjects were instructed not to drink alcohol or to perform strenuous exercise from the day before each test meal. After a 12-h fasting period the subjects arrived at the experimental settings at 07:30 h after a minimum of physical activity. On arrival, a catheter was inserted into an antecubital vein and after 15 min of rest a fasting blood sample was drawn. Immediately after this, the test meal was ingested within 20 min. The rest of the test day the subjects rested at the clinic and were only allowed to drink water. During the subsequent 8 h, blood samples were drawn regularly for the measurement of triglyceride, retinyl palmitate (RP), glucose, insulin, glucagon, free fatty acid (FFA), glucose-dependent insulinotrophic peptide (GIP) and GLP-1. Plasma was immediately separated by centrifugation at 2000 × g for 20 min at 4 °C and thereafter frozen and stored at −80 °C.

Test meals

Each test meals consisted of an energy-free soup with 100 g added butter (Lurpak; Arla Foods amba, Viby J, Denmark) corresponding to 80 g of fat (68% of energy as saturated fatty acids). About 45 g of carbohydrate was added as white wheat bread (Läntmann Schulstad A/S, Hvidovre, Denmark) and finally, 45 g of protein was dissolved in 200-ml cold water as a milkshake containing one of the four whey protein fractions: whey isolate (Lacprodan DI-9224; iso-meal) (Arla Foods Ingredients amba, Viby J, Denmark); whey hydrolysate (Lacprodan DI-3065; hydro-meal); α-lactalbumin enhanced whey (Lacprodan α-10; lac-meal); CGMP enhanced whey (Lacprodan CGMP-10; CGMP-meal). The different whey protein fractions used were spray-dried milk proteins kindly provided by (Arla Foods Ingredients amba, Viby J, Denmark). The different components of the spray dried whey proteins are shown in Table 2. Besides protein the fractions contain fat, ash, moisture and lactose. The main difference between the fractions was the content of lactose, which was adjusted by adding lactose powder kindly provided by (Variolac 950, Arla Foods Ingredients amba) to some of the protein drinks (iso-meal and CGMP-meal) to obtain a similar amount of lactose (2 g). The energy-free soup contained 25 g sliced raw leek to make it more palatable. For all meals, butter was added to the soup and heated in a microwave to 65° C. The test meals had the same macronutrient composition: 17% of energy from protein, 15% of energy from carbohydrate and 68% of energy from fat. The total amount of energy in the test meals was 4817 kJ. The subjects took a standard dose of vitamin A (30 mg) in tablet form with the first spoonful of soup. Ingestion of vitamin A with fat causes retinyl ester labelling of chylomicrons.23 Supplementation of the test meal with vitamin A is therefore used as a mean of quantifying lipoproteins of intestinal origin, that is, chylomicrons and chylomicron remnants in the postprandial state.

Table 2 Distribution of proteins in the spray dried whey fractions powder used in the test meals


To isolate chylomicrons from lower density lipoproteins, that is, very low-density lipoprotein, intermediate density lipoprotein, low-density lipoprotein and chylomicron remnants, we performed a single step of ultracentrifugation on our plasma samples. Plasma samples were defrosted at 4 °C. Plasma (4 ml) was overlayered with 2 ml of a saline solution with a density of 1006 g/ml in a quick seal tube (number 344 619; Beckman Instruments, Palo Alto, CA, USA) and then centrifuged for 30 min at 26 000 × g at 25 °C as described previously.10 The chylomicron-rich fraction (Svedberg flotation >1000) was aspirated and brought to a final volume of 4 ml with saline. The chylomicron-poor fraction contained the more dense lipoproteins (Svedberg flotation<1000).

Blood analysis

Plasma glucose was measured by a glucose oxidase method using the Roche Diagnostics Gmbh GOD-PAP glucose kit (11491253 216, Mannheim, Germany, (coefficient of variation: 1.8%). Serum insulin concentrations were determined by enzyme-linked immunosorbent assay (coefficient of variation: 1.7%) using the DakoCytomation insulin kit (K6219, Cambridgeshire, UK).24 Triglyceride and FFA were determined with standard enzymatic colorimetric assays using commercial kits (Roche Diagnostics GmbH and Wako Chemicals GmbH, Neuss, Germany). GIP and GLP-1 in plasma were measured after extraction of plasma with 70% ethanol (by vol, final concentration). Total GIP was measured as described previously,25 using the C-terminally directed antiserum R65, which reacts fully with intact GIP and the N-terminally truncated metabolite. Human GIP and 125I human GIP (70 MBq/nmol) were used for standards and tracer. The plasma concentrations of total GLP-1 were measured against standards of synthetic GLP-1 7-6 amide using antiserum code no. 89390,25, 26 which is specific for the C-terminal of the GLP-1 molecule and reacts equally with the intact GLP-1 and the primary metabolite, GLP-1 9-36 amide. Thus, it mainly reacts with GLP-1 of intestinal origin. For both assays, sensitivity was <1 pmol/l and the inter-assay coefficient of variation <6% at 20 pmol/l. The glucagon was measured by a radioimmunoassay using antibody no. 4305 in ethanol-extracted plasma. The glucagon assay was directed against the C-terminal of the glucagon molecule and therefore measured glucagon of mainly pancreatic origin.27 RP was extracted and determined by isocratic adsorption high-performance liquid chromatography as described previously.28

Statistical analysis

The power calculation was based on our primary effect parameter triglyceride. The number of participants needed to obtain a statistical power of 80% was calculated to 10 participants. We wanted to detect a minimal relevant difference for the area of (mean±s.d.) 50±30 mM* 480 min, which gives us a estimated effect size of 1.67. Comparisons between the four test meals were made by repeated measurement one-way analysis of variance. Whenever data were not normally distributed, the Friedman analysis of variance on ranks was applied. In cases of statistical differences between test meals, Tukey’s multiple comparisons test was used (SigmaStat for Windows version 11; Systat software Inc., San Jose, CA, USA). A P-value <0.05 was considered significant. Except for FFA, the postprandial response data are given as incremental area under the curve (iAUC), that is, the area above baseline.29 The trapezoidal rule was used to calculate the iAUC.29, 30 The FFA response was calculated as total AUC (tAUC), that is, the total increase above zero. One of the subjects did not participate in one of four test meals because of illness. Therefore the analyses are based on 11 subjects.


All of the subjects ingested the test meals without any problems. We found no significant differences in fasting concentrations or body weight between test days (Table 3).

Table 3 Plasma and serum concentrations in the fasting state in the 11 (6 women and 5 men) type 2 diabetic subjects on the 4 test daysa

Lipid responses

The postprandial triglyceride and RP responses are shown in Figure 1. The iAUC of triglyceride in plasma, the chylomicron rich and the chylomicron-poor fraction did not differ significantly between the four test meals (Table 4).

Figure 1

Triglycerides (TGs) and RP responses in plasma. The chylomicron (CM)-rich fraction and the CM-poor fraction to a test meal in 11 subjects with type 2 diabetes. The test meal consisted of an energy-free soup plus 100 g butter and 45 g carbohydrate consumed with 45 g whey isolate (iso-meal), 45 g whey hydrolysate (hydro-meal), 45 g α-lactalbumin enhanced whey (lac-meal) or 45 g CGMP enhanced whey (CGMP-meal). Data are mean±s.e.m. Repeated measures analysis of variance (P<0.05 for all). aHydro-meal significantly greater than lac-meal; bHydro-meal significantly greater than iso-meal.

Table 4 Incremental areas under the curve after 480 min in 11 (6 women and 5 men) type 2 diabetic subjects in response to the four test mealsa

In the chylomicron-rich fraction, the RP response expressed as iAUC was significantly higher after the hydro-meal than after the iso- and lac-meals (P=0.008; Table 4). In the chylomicron-poor fraction no significant differences were found in the RP responses (iAUC).

Blood glucose, insulin, glucagon and FFA responses

The glucose, insulin, glucagon and FFA responses are presented in Figure 2. The iAUC for the glucose response was significantly higher up to 120 min after the hydro-meal than after the CGMP-meal (177±109 vs 121±79, mean iAUC 120min±s.d., respectively; P=0.035).

Figure 2

Glucose, insulin, glucagon, FFA, glucose-dependent insulinotropic peptide (GIP) and GLP-1 responses to a test meal in 11 subjects with type 2 diabetes. The test meal consisted of an energy-free soup plus 100 g butter and 45 g carbohydrate consumed with 45 g whey isolate (iso-meal), 45 g whey hydrolysate (hydro-meal), 45 g α-lactalbumin enhanced whey (lac-meal) or 45 g CGMP enhanced whey (CGMP-meal). Data are mean±s.e.m. Repeated measures analysis of variance (P<0.05 for all). aHydro-meal significantly greater than lac-meal and CGMP-meal; bIso-meal significantly greater than CGMP-meal; cHydro-meal significantly greater than iso-meal; dLac-meal significantly greater than hydro-meal.

The first phase insulin response (iAUC up to 30 min) was significantly enhanced after the hydro-meal compared with the three other meals (iAUC 30min median; 4710 (hydro-meal), 3006 (iso-meal), 2063 (lac-meal) and 2693 (CGMP-meal); P=0.001). The iso- and hydro-meal induced a higher insulin response expressed as iAUC at 480 min compared with the lac- and CGMP-meal (P<0.001; Table 4).

During the initial 60 min the glucagon response (iAUC up to 60 min) was significantly increased after the hydro-meal than after the lac- and CGMP-meal (mean iAUC 60min±s.d.; 290±92 (hydro-meal), 235±110 (iso-meal), 188±94 (lac-meal) and 177±117 (CGMP-meal); P=0.004). Otherwise we found no significant differences in glucagon responses.

All four test meals suppressed FFA initially, reaching nadir after 120 min while after 360 min FFA concentrations exceeded baseline concentrations. The tAUC up to 120 min was significantly lower after the hydro-meal than after the lac-meal (34±14; 42±14, mean tAUC 120min±s.d., respectively; P=0.021).

Incretin responses

The incretin responses are shown in Figure 2. The iAUC of GIP responses was significantly lower for the hydro-meal than for the iso-meal up to both 60 min (1277±676; 1936±872, mean tAUC 60min±s.d., respectively; P=0.019) and 120 min (3593±1392; 5029±1923, mean tAUC 120min±s.d., respectively; P=0.009). No significant differences were observed for iAUC at 480 min (Table 4).

The GLP-1 response expressed as iAUC up to 30 min was significantly higher for the hydro-meal compared with the CGMP-meal (iAUC 30min median; 593 (hydro-meal), 270 (CGMP-meal); P=0·045). Otherwise we did not find any significant differences in the GLP-1 response.


This study is the first to evaluate the acute effects of a supplement of four commercially available whey protein fractions on PPL and hormone responses to a fat-rich test meal in T2DM subjects. The main finding was that the four whey protein fractions—whey isolate, whey hydrolysate, α-lactalbumin enhanced whey protein and CGMP enhanced whey protein—had similar effects on postprandial triglyceride responses.

Recently, we found that whey protein seems to outperform other proteins in terms of PPL improvement in T2DM.16 Thus, it was found that whey protein added to a fat-rich meal significantly reduced the postprandial triglyceride response and suppressed the FFA response compared with casein, cod and gluten.16 Interestingly, whey derived peptides have previously been found to exert beneficial effects on other cardiovascular risk markers, for example, suppressing blood pressure31 and improving endothelial function.32 The finding in this study that the four whey fractions caused similar effects on PPL indicates that they may all constitute useful protein sources for reducing PPL in persons with T2DM. However, the fact that their effects were not compared with other protein sources such as casein, cod and gluten makes this assumption uncertain.

It should be underlined, however, that we did find differences in the PPL responses in this investigation. Thus, the hydro-meal induced a higher RP response in the chylomicron-rich fraction than the iso- and lac-meals. This may indicate a larger production of chylomicrons after the hydro-meal than after the iso- and lac-meals. On the other hand, the difference may be ascribed to the formation of larger chylomicron particles containing more triglyceride after the hydro-meal. This is consistent with the trend towards a higher triglyceride response in the chylomicron-rich fraction after the hydro-meal (P=0.079). The use of RP responses as markers of chylomicrons and chylomicron remnants has some shortcomings. Thus, it does not provide uniform labelling of the chylomicrons, because the larger particles probably carry more RP than the smaller ones.33

Insulin enhances the activity of the enzyme lipoprotein lipase,34 which is the key enzyme in the hydrolysis of triglyceride in chylomicrons and very low-density lipoprotein.35 Thus, increased insulin response may lead to a reduced triglyceride response. It should be noted that we found a higher insulin response to the hydro-meal after 30 min and to the hydro- and the iso-meal after 480 min, however, the increased insulin levels were not followed by any significant improvement in the triglyceride responses. The insulinotropic effect of whey hydrolysate and whey isolate may have nutraceutical benefits in treatment of T2DM, especially in long-term diabetes where the glucose-sensing capacity of the pancreatic β cell is reduced. Thus, Manders et al.36 showed that in long-term T2DM patients the capacity to secrete insulin in response to amino acids remains intact, despite reduced carbohydrate sensitivity, and the increased insulin response after ingestion of protein hydrolysate with carbohydrate reduces postprandial glucose concentrations. As there are small differences in the composition of the products studied in addition to the whey component, we cannot entirely exclude that this may have influenced our results.

It is well known that insulin inhibits hormone-sensitive lipase and thereby suppresses the release of FFAs from adipose tissue. We found that the hydro-meal decreased FFA more than the lac-meal, which is in line with the observed increase in insulin response to the hydro-meal.

As previously mentioned the hydro-meal caused a higher initial 30-min insulin response compared with the other test meals. In the same period the GLP-1 response was also higher after the hydro-meal than after the CGMP-meal. It should be noted that the whey protein in the hydro-meal is hydrolysed and consists of short-chain peptides with a high content of di- and tripeptides. One might speculate whether whey hydrolysate is digested and absorbed more rapidly and consequently induces a higher initial GLP-1 response, which is known to stimulate insulin production.37 Also the initial glucagon response was higher after the hydro-meal compared with the CGMP- and lac-meal, possibly because of similar mechanisms. The higher glucagon level may at least in part explain the higher initial glucose response to the hydro-meal compared with the CGMP-meal.

We cannot exclude that differences in gastric emptying to the various meals may have influenced the results obtained. However, Calbet and Holst38 found that complete and hydrolysed whey protein elicit similar gastric emptying. This finding was confirmed by Power et al.,19 showing that hydrolysed whey protein augments insulin secretion by a mechanism that is unrelated to gastric emptying.

We found that the iAUC for the GIP response after the initial 120 min was significantly lower, when whey was hydrolysed compared with the complete protein whey isolate. In contrast, Calbet and Holst38 found that peptide hydrolysate elicited a higher GIP response than the complete proteins. The reason for this controversy is not known, but may be due to disparities in the study design; thus, the study of Calbet and Holst38 was carried out in healthy subjects and did not include a mixed meal.

In conclusion, we found that a supplement of four different whey protein fractions added to a fat-rich meal exerted similar effects on postprandial triglyceride responses in T2DM subjects. Whether these PPL responses differ from PPL responses to other proteins is unknown. In addition, whey isolate and whey hydrolysate induced higher insulin levels, and they may be used as potential nutritional protein sources to improve glucose homoeostasis in T2DM. Many different whey protein fractions are used for food ingredients and supplemental protein drinks. Further attempts to compare potential benefits of whey protein fractions with other proteins are needed, for example, in obese and T2DM subjects with increased cardiovascular risk.


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We thank Tove Skrumsager and Lene Trudsø for excellent technical assistance. This work was carried out as a part of the research programme of the Danish Obesity Research Centre (DanORC, and was supported by Nordic Centre of Excellence (NCoE) programme (Systems biology in controlled dietary interventions and cohort studies—SYSDIET, P no. 070014) and supported by a grant from Arla Foods Ingredients amba.

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Correspondence to L S Mortensen.

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Competing interests

Arne Astrup is a scientific member of Global Dairy Platform (Chicago) and receives speaker’s honoraria and research funding from the Danish Dairy Foundation, Arla and Danish Meat Association. Vivian K Jensen is employed by Arla Foods Ingredients amba. The rest of the authors declare no conflict of interest.

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Mortensen, L., Holmer-Jensen, J., Hartvigsen, M. et al. Effects of different fractions of whey protein on postprandial lipid and hormone responses in type 2 diabetes. Eur J Clin Nutr 66, 799–805 (2012).

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  • postprandial lipids
  • dietary protein
  • type 2 diabetes
  • atherosclerosis
  • triglycerides
  • whey protein

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