Diabetes Mellitus is a disease identified by the body’s impaired ability to produce (or respond to) the pancreatic hormone insulin, which results in abnormal carbohydrate metabolism elevating sugar levels in the blood and urine. Greater than 90% of all cases of diabetes is classified as Type II (T2D) which will be the primary focus of this white paper.
Currently, 9.4% of the U.S. population, or 30.3 million people have T2D1. Some characterizations of T2D patients and risk factors leading to the diagnosis include:
There are many pharmacotherapy treatments that help manage T2D including oral medications and insulin. However, the last 15 years of clinical research has also shown promising dietary strategies as adjunct therapies when managing diabetes, most notably therapies aiming to manage postprandial glycemia, or after meal blood sugar levels.
One particular nutrient, whey, once viewed as a waste product, has garnered particular interest as demonstrated by its ability to diminish postprandial glycemia through many interrelated pathways. For every nine pounds of cheese that is produced there is about 9 pounds of liquid whey. This liquid contains approximately 0.8% protein by weight, and it’s been rapidly gaining recognition as a critical functional food2-3. With respect to T2D, there is tremendous clinical evidence that demonstrates that:
Due to the current cost of T2D, whey protein can be used as an adjunct dietary therapy in the managements of type 2 diabetes.
AVAILABLE FORMS OF WHEY PROTIEN
There are currently three main forms of whey protein available: whey protein concentrate (WPC), whey protein isolate (WPI) and whey protein hydrolysate (WPH). WPC is defined as containing 35% - 89% protein with fat, lactose and minerals comprising the balance. WPI is defined as containing at least 90% protein with very low levels of both fat and lactose. WPH can be either a concentrate or isolate (depending on level of protein), but contain a percentage of the whole proteins that’s been hydrolyzed by proteolytic enzymes3-6. In the presented studies, WPC and WPI were the primary forms of whey unless mentioned otherwise.
WHEY PROTIEN AND POSTPRANDIAL GLYCEMIA
There is clear clinical evidence that whey has an insulinotropic effect, meaning that it stimulates the release of insulin following food intake. However, it is less clear as to whether this effect is meaningful when evaluating postprandial glycemia in patients with T2D, often whom are severely insulin resistant and present with hyperinsulinaemia7-10. Data presented by Frid et al looked at the effects of adding whey protein into both high glycemic meals (breakfast and lunch) in patients with T2D. Plasma insulin levels were higher after both meals, especially when compared to controls that included lean ham protein or lactose11. In other studies evaluating dietary interventions for T2D there have been reports of up to 4 fold increase in insulin response to meals that contain both protein and carbohydrates, when compared to carbohydrates alone12-13. Lastly, in a study of male subjects (Nuttall et al) with diet controlled T2D, demonstrated that when adding protein to a mixed meal that glucose response as measured by blood glucose response (AUC) was 1/3 lower than no protein14-16.
WHEY PROTEIN AND GASTRIC EMPTYING
The term “preload” refers to small doses of a given macronutrient at a specified time before a main meal. The concept here is that a “preload” would be administered at some specified time before the actual meal in an attempt to encourage the small intestine to release the hormones glucagon like peptide 1 (GLP-1), gastroinhibitory peptide (GIP), cholecystokinin (CCK) and peptide YY (PYY) – all of which play roles in delaying gastric emptying and stimulating the release of insulin. In general, whey protein has been given as preloads (in healthy non T2D subjects) and shown to delay gastric emptying. In one study by Akhavan et al, blood measurements of oral paracetamol absorption (a common analgesic) were delayed, along with elevated postprandial GLP-1 levels17. In another instance where whey protein was given just prior to a meal, blood glucose measurements via AUC was decreased by over one third with accompanying elevated insulin and GLP-1 levels18.
When looking at specifically those patients with T2D, it’s well established that whey protein stimulates incretin hormones. Researchers Ma et al reported that in patients with T2D a preload given 30 minutes before a meal slowed gastric emptying. In this particular study gastric emptying was quantified by the accepted gold standard method scintigraphy, where radioactive tracers are used to track internal movement. Whey protein significantly reduced what’s known as postprandial glucose excursion, as well as stimulated hormones insulin, CCK, GIP and GLP-1. These findings have been confirmed in other studies as well19-20.
WHEY PROTEIN AND APPETITE REGULATION
It’s well studied that manipulating dietary macronutrient composition plays a significant role in energy expenditure and appetite reduction21. Also, it’s been demonstrated that protein has a more satiating effect than either dietary carbohydrates or fat22-26. Looking at the effects of whey protein specifically it has been shown to not only enhance satiety, but also reduce caloric intakes at subsequent meals. This effect is attributed to whey’s effect on appetite and regulatory hormones. More specifically, it’s purported that whey stimulates the secretion of PPY, GLP-1 and CCK by suppressing a different appetite hormone, ghrelin, one of our body’s orexigenic hormones. In one particular study by Bowen et al the intake of whey protein had actually suppressed ghrelin and elevation of both GLP-1 and CCK. This effect was associated with a reduction in energy intake for ad libitum meals. In one last study where an indexed hunger score was evaluated looking at the effects of whey versus casein, both GLP-1 and CCK levels were significantly higher following whey, contributing to a greater satiating effect. There is also other evidence that reports higher PPY after whey protein intake (compared to other proteins), that demonstrate comparable ghrelin and CCK responses27-31.
LONG TERM WHEY CONSUMPTION
A main outcome in the successful management of T2D is the measurement of glycated hemoglobin, or HbA1c; this is the body’s long-term response to carbohydrate metabolism. While it’s well known that higher protein diets positively affect weight loss (i.e. lose weight) and preserve lean body mass, there is still question as to long term HbA1c outcomes in patients with T2D. In a five week study conducted by Gannon et al, men with T2D were given diets with either 15% or 30% energy from protein. The group at 30% protein had a more significant reduction in HbA1c. Another area of concern in the long-term use of whey protein for the adjunct management of T2D are effects on both bone and renal health. One recent two year-long study of postmenopausal women found no difference in bone densities for those in the high protein diet; in a separate study that evaluated patients with T2D and microalbuminuria, there was no negative effects on renal function in the one-year weight loss trial32-35.
There’s a massive body of peer-reviewed evidence that’s accumulated over the years that shows the promising effect of whey protein to be used as an adjunct therapy in the management of TD2. Patients that add whey protein to their dietary intake (and subsequently reduce other nutrients like carbs) experience benefits in three main ways: 1) reduced postprandial glycemia, 2) delayed gastric emptying and 3) appetite regulation via increntin hormone stimulation. When it comes to supporting patients with T2D the clinical evidence is clear that including whey protein in meals and supplements that:
3. Smithers GW. Whey and whey proteins - from ‘gutter to gold’. Int Dairy J 2008; 18: 695-704 [DOI: 10.1016/j.idairyj.2008.03.008]
4. Marshall K. Therapeutic applications of whey protein. Altern Med Rev 2004; 9: 136-156 [PMID: 15253675]
5. Walzem RL, Dillard CJ, German JB. Whey components: millennia of evolution create functionalities for mammalian nutrition: what we know and what we may be overlooking. Crit Rev Food Sci Nutr 2002; 42: 353-375 [PMID: 12180777 DOI: 10.1080/104086902908 25574]
6. Krissansen GW. Emerging health properties of whey proteins and their clinical implications. J Am Coll Nutr 2007; 26: 713S-723S [PMID: 18187438 DOI: 10.1080/07315724.2007.10719652]
7. Nilsson M, Stenberg M, Frid AH, Holst JJ, Björck IM. Glycemia and insulinemia in healthy subjects after lactose-equivalent meals of milk and other food proteins: the role of plasma amino acids and incretins. Am J Clin Nutr 2004; 80: 1246-1253 [PMID: 15531672]
8. Wildová E, Dlouhý P, Kraml P, Rambousková J, Smejkalová V, Potočková J, Anděl M. Orally administered whey proteins have comparable effect on C-peptide secretion in healthy subjects as standard C-peptide stimulation tests. Physiol Res 2013; 62: 179-186 [PMID: 23234418]
9. Gunnerud U, Holst JJ, Östman E, Björck I. The glycemic, insulinemic and plasma amino acid responses to equi-carbohydrate milk meals, a pilot- study of bovine and human milk. Nutr J 2012; 11: 83 [PMID: 23057765 DOI: 10.1186/1475-2891-11-83]
10. Gunnerud UJ, Ostman EM, Björck IM. Effects of whey proteins on glycaemia and insulinaemia to an oral glucose load in healthy adults; a dose-response study. Eur J Clin Nutr 2013; 67: 749-753 [PMID: 23632747 DOI: 10.1038/ejcn.2013.88]
11. Frid AH, Nilsson M, Holst JJ, Björck IM. Effect of whey on blood glucose and insulin responses to composite breakfast and lunch meals in type 2 diabetic subjects. Am J Clin Nutr 2005; 82: 69-75 [PMID: 16002802]
12. Manders RJ, Wagenmakers AJ, Koopman R, Zorenc AH, Menheere PP, Schaper NC, Saris WH, van Loon LJ. Co-ingestion of a protein hydrolysate and amino acid mixture with carbohydrate improves plasma glucose disposal in patients with type 2 diabetes. Am J Clin Nutr 2005; 82: 76-83 [PMID: 16002803]
13. Manders RJ, Koopman R, Sluijsmans WE, van den Berg R, Verbeek K, Saris WH, Wagenmakers AJ, van Loon LJ. Coingestion of a protein hydrolysate with or without additional leucine effectively reduces postprandial blood glucose excursions in Type 2 diabetic men. J Nutr 2006; 136: 1294-1299 [PMID: 16614419]
14. Nuttall FQ, Mooradian AD, Gannon MC, Billington C, Krezowski P. Effect of protein ingestion on the glucose and insulin response to a standardized oral glucose load. Diabetes Care 1984; 7: 465-470 [PMID: 6389060]
15. Ma J, Stevens JE, Cukier K, Maddox AF, Wishart JM, Jones KL, Clifton PM, Horowitz M, Rayner CK. Effects of a protein preload on gastric emptying, glycemia, and gut hormones after a carbohydrate meal in diet-controlled type 2 diabetes. Diabetes Care 2009; 32: 1600-1602 [PMID: 19542012 DOI: 10.2337/dc09-0723]
16. Mortensen LS, Hartvigsen ML, Brader LJ, Astrup A, Schrezenmeir J, Holst JJ, Thomsen C, Hermansen K. Differential effects of protein quality on postprandial lipemia in response to a fat-rich meal in type 2 diabetes: comparison of whey, casein, gluten, and cod protein. Am J Clin Nutr 2009; 90: 41-48 [PMID: 19458012 DOI: 10.3945/ ajcn.2008.27281]
17. Akhavan T, Luhovyy BL, Panahi S, Kubant R, Brown PH, Anderson GH. Mechanism of action of pre-meal consumption of whey protein on glycemic control in young adults. J Nutr Biochem 2014; 25: 36-43 [PMID: 24314863 DOI: 10.1016/j.jnutbio.2013.08.012]
18. Gunnerud UJ, Heinzle C, Holst JJ, Östman EM, Björck IM. Effects of pre-meal drinks with protein and amino acids on glycemic and metabolic responses at a subsequent composite meal. PLoS One 2012; 7: e44731 [PMID: 23028596 DOI: 10.1371/journal. pone.0044731]
19. Ma J, Stevens JE, Cukier K, Maddox AF, Wishart JM, Jones KL, Clifton PM, Horowitz M, Rayner CK. Effects of a protein preload on gastric emptying, glycemia, and gut hormones after a carbohydrate meal in diet-controlled type 2 diabetes. Diabetes Care 2009; 32: 1600-1602 [PMID: 19542012 DOI: 10.2337/dc09-0723]
20. Jakubowicz D, Froy O, Ahrén B, Boaz M, Landau Z, Bar-Dayan Y, Ganz T, Barnea M, Wainstein J. Incretin, insulinotropic and glucoselowering effects of whey protein pre-load in type 2 diabetes: a randomised clinical trial. Diabetologia 2014; 57: 1807-1811 [PMID: 25005331 DOI: 10.1007/s00125-014-3305-x]
21. Bowen J, Noakes M, Clifton PM. Appetite regulatory hormone responses to various dietary proteins differ by body mass index status despite similar reductions in ad libitum energy intake. J Clin Endocrinol Metab 2006; 91: 2913-2919 [PMID: 16735482 DOI: 10.1210/jc.2006-0609]
22. Bendtsen LQ, Lorenzen JK, Bendsen NT, Rasmussen C, Astrup A. Effect of dairy proteins on appetite, energy expenditure, body weight, and composition: a review of the evidence from controlled clinical trials. Adv Nutr 2013; 4: 418-438 [PMID: 23858091 DOI: 10.3945/an.113.003723]
23. Clifton PM, Keogh J. Metabolic effects of high-protein diets. Curr Atheroscler Rep 2007; 9: 472-478 [PMID: 18377787 DOI: 10.1007/ s11883-007-0063-y]
24. Porrini M, Crovetti R, Testolin G, Silva S. Evaluation of satiety sensations and food intake after different preloads. Appetite 1995; 25: 17-30 [PMID: 7495324 DOI: 10.1006/appe.1995.0038]
25. Poppitt SD, McCormack D, Buffenstein R. Short-term effects of macronutrient preloads on appetite and energy intake in lean women. Physiol Behav 1998; 64: 279-285 [PMID: 9748094 DOI: 10.1016/S0031-9384(98)00061-4]
26. Latner JD, Schwartz M. The effects of a high-carbohydrate, highprotein or balanced lunch upon later food intake and hunger ratings. Appetite 1999; 33: 119-128 [PMID: 10447984 DOI: 10.1006/ appe.1999.0237]
27. Akhavan T, Luhovyy BL, Brown PH, Cho CE, Anderson GH. Effect of premeal consumption of whey protein and its hydrolysate on food intake and postmeal glycemia and insulin responses in young adults. Am J Clin Nutr 2010; 91: 966-975 [PMID: 20164320 DOI: 10.3945/ajcn.2009.28406]
28. Zafar TA, Waslien C, AlRaefaei A, Alrashidi N, AlMahmoud E. Whey protein sweetened beverages reduce glycemic and appetite responses and food intake in young females. Nutr Res 2013; 33: 303-310 [PMID: 23602248 DOI: 10.1016/j.nutres.2013.01.008]
29. Luhovyy BL, Akhavan T, Anderson GH. Whey proteins in the regulation of food intake and satiety. J Am Coll Nutr 2007; 26: 704S-712S [PMID: 18187437 DOI: 10.1080/07315724.2007.10719 651]
30. Hall WL, Millward DJ, Long SJ, Morgan LM. Casein and whey exert different effects on plasma amino acid profiles, gastrointestinal hormone secretion and appetite. Br J Nutr 2003; 89: 239-248 [PMID: 12575908 DOI: 10.1079/BJN2002760]
31. Bendtsen LQ, Lorenzen JK, Bendsen NT, Rasmussen C, Astrup A. Effect of dairy proteins on appetite, energy expenditure, body weight, and composition: a review of the evidence from controlled clinical trials. Adv Nutr 2013; 4: 418-438 [PMID: 23858091 DOI: 10.3945/an.113.003723]
32. Clifton P. Effects of a high protein diet on body weight and comorbidities associated with obesity. Br J Nutr 2012; 108 Suppl 2: S122-S129 [PMID: 23107523 DOI: 10.1017/S0007114512002322]
33. Gannon MC, Nuttall FQ, Saeed A, Jordan K, Hoover H. An increase in dietary protein improves the blood glucose response in persons with type 2 diabetes. Am J Clin Nutr 2003; 78: 734-741 [PMID: 14522731]
34. Clifton P. Effects of a high protein diet on body weight and comorbidities associated with obesity. Br J Nutr 2012; 108 Suppl 2: S122-S129 [PMID: 23107523 DOI: 10.1017/S0007114512002322]
35. Jesudason DR, Pedersen E, Clifton PM. Weight-loss diets in people with type 2 diabetes and renal disease: a randomized controlled trial of the effect of different dietary protein amounts. Am J Clin Nutr 2013; 98: 494-501 [PMID: 23719550 DOI: 10.3945/ ajcn.113.060889]