Dietary proteins and aspects of the metabolic syndrome : evidence from observational studies and short-term interventions

<strong>Background </strong>Type 2 diabetes (T2D) and cardiovascular diseases (CVD) are important causes of morbidity and mortality worldwide. The metabolic syndrome (MetS) identifies people at elevated risk of T2D and CVD by its mutual risk factors, such as abdominal obesity, atherogenic dyslipidemia, raised blood pressure and impaired glucose tolerance. Improvements in individual aspects of MetS could be risk-reducing for T2D and CVD and could thus be clinically relevant. Besides by using drug therapy, this can be achieved by lifestyle changes, such as weight loss, increasing physical activity and changes in dietary composition. In addition to general dietary recommendations, such as diets rich in fiber, fruits and vegetables and low in refined grains and saturated fatty acids, increasing dietary protein and soy intake seem promising approaches to prevent MetS. Short-term trials report positive effects of dietary protein intake on weight loss and weight maintenance after weight loss. The postprandial and short-term effect of protein and soy consumption on insulin resistance, glucose homeostasis, and other aspects of MetS are not frequently studied in humans in energy balance. Also, the long-term association between dietary protein intake and T2D incidence is uncertain, it even seemed risk-increasing in prior research. <strong>Objectives </strong>We evaluated the impact of dietary protein intake on T2D incidence, aspects of MetS and other cardio-metabolic risk factors, by observational studies (long-term) and interventions (short-term). We studied not only total protein intake, but also specific protein types, more specifically soy protein and arginine-rich protein. We explored the long-term association between total, animal, and plant protein intake and the incidence of T2D. We further investigated the effects of a 4-week strictly controlled weight-maintaining moderate-high-protein diet rich in soy on insulin sensitivity and other cardio-metabolic risk factors. Next, we investigated if inflammatory markers were also changed as a possible pathway through which dietary protein affects cardio-metabolic risk factors. Lastly, we examined whether protein, and more specific arginine-rich protein, added to a high fat meal improved postprandial metabolism and cardiovascular risk factors. <strong>Methods </strong>The association between dietary protein intake and T2D incidence was studied in the EPIC-InterAct case-cohort study (nincident cases= 12,403; nsubcohort=16,154). In a randomized crossover trial of 2 4-week periods diets with a moderate-high-protein content, i.e. 22 energy percent (En%) protein, 27En% fat, and 50En% carbohydrate, were studied (n=15). In a diet with protein from mixed sources (HPmix) we partly replaced meat products with soy products (HPsoy) to investigate the effect of soy protein intake on insulin resistance, glucose homeostasis, and other aspects of MetS. A high-fat challenge test was used to study postprandial metabolic markers, inflammatory markers and arterial stiffness (n=18). We compared the postprandial response after a high-fat liquid control meal (95g fat) without protein with meals with 30g added protein. <strong>Results </strong>Intake of total protein (per 10 g: HR 1.06 [95% CI 1.02–1.09], Ptrend < 0.001) and animal protein (per 10 g: HR 1.05 [95% CI 1.02–1.08], Ptrend < 0.001) was associated with higher incidence of T2D, after adjustment for main confounders including other dietary factors. Partly replacing meat with soy in a moderate-high-protein diet resulted in greater insulin sensitivity (FSIGT: SI:34 ± 29 vs. 22 ± 17 (mU/L)-1min-1, P=0.048; disposition index:4974 ± 2543 vs. 2899 ± 1878, P=0.038). After HPsoy total cholesterol was 4% lower than after HPmix (4.9 ± 0.7 vs. 5.1 ± 0.6 mmol/L, P=0.001) and LDL cholesterol was 9% lower (2.9 ± 0.7 vs. 3.2 ± 0.6 mmol/L, P=0.004). The summary score for inflammation was lower after HPsoy compared with HPmix (ɀ-score: -0.2 ± 0.3 vs. -0.1 ± 0.2, P=0.04), after excluding participants with CRP>6mg/L and extreme outliers. Individual inflammatory markers were not significantly different. Adding protein to a high-fat meal increased the postprandial insulin response. No differences between arginine-rich and protein low in arginine on postprandial responses were seen. Intact proteins and hydrolysates resulted in similar responses. <strong>Conclusion </strong>High total and animal protein intake was associated with modestly elevated T2D incidence in a large cohort of European adults. In contrast, a moderate-high-protein diet for 4 weeks improved many cardio-metabolic risk factors. Partly replacing meat with soy in this moderate-high-protein diet had clear advantages regarding insulin sensitivity and total and LDL cholesterol, and it improved the overall inflammatory state, although not showing clear benefits at individual inflammation markers. We hypothesized to see an origin of these short-term health effects in postprandial properties of arginine-rich protein. However, arginine-rich protein was not superior to a protein low in arginine added to a high-fat meal, regarding postprandial excursions in glucose, insulin, lipids and inflammatory markers. In view of the rapidly increasing prevalence of MetS and T2D, limiting iso-energetic diets high in dietary proteins, particularly from animal sources, should be considered as on the long-term protein intake seems to increase T2D and CVD risk. However, at the short-term partly replacing meat with soy in a moderate high-protein diet could be preventive for several aspects of MetS, such as improvements in insulin sensitivity, total and LDL cholesterol and possibly a reduced inflammatory state.