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The global prevalence of type 2 diabetes mellitus (T2DM) is increasing at an alarming rate. Previous studies have shown that diet and lifestyle modifications may play an important role in preventing T2DM. Furthermore, improvement of insulin resistance, which is pathologic basis in T2DM, is the key factor for T2DM prevention. In recent years, the role of dairy products, milk-derived whey protein and whey protein containing leucine has created considerable attention in the etiology of T2DM.Objective:To elucidate the association of dairy products consumption with T2DM and to further investigate the underlying mechanism by which whey protein and leucine improving insulin resistance.Methods:1. Meta-analysis: English databases from January 1990 to December 2010 were searched for the cohort studies reporting the relationship between dairy product consumption and T2DM.2. Effect of whey protein on insulin resistance in model rats: (1) Inducement of insulin resistance model rats: Male Wistar rats were randomly divided into two groups. Control group was fed with routine diet. High-fat group was fed a high-fat diet (38.5% of calories-fat) for 12 weeks, and then switched to a diet containing 51.3% of calories-fat for 4 weeks. After 16 weeks, body weight, fasting blood glucose (FBG) and fasting insulin (FINS) were measured. According to FBG and FINS, insulin sensitivity index (ISI) and homeostasis model assessment of insulin resistance (HOMA-IR) were calculated. On the other hand, oral glucose tolerance test (OGTT) was performed for valuing AUC of plasma glucose. (2) The effect of whey protein on insulin resistance: Model rats were then randomly divided into 3 groups of 10 animals each and fed on 0% whey protein (WP), 5% WP and 15% WP. Another group was set with non-model rats feeding routine diet. After 8 weeks, FBG, FINS, ISI, HOMA-IR and OGTT were determined or calculated. Liver was removed to measure liver glycogen and gastrocnemius muscle was removed to measure the expression of glucose transporter type 4 (Glut4). Also, plasma lipids and plasma index for anti-oxidation were determined.3. Effect of leucine on insulin secretion and insulin resistance: (1) Effect of leucine on normal rats: Twenty male Wistar rats were randomly divided into 4 groups and gave water, glucose, leucine and glucose + leucine, respectively. FBG, FINS and AUC of plasma glucose and insulin were measured.(2) Effect of leucine on insulin secretion in vitro: Rat’s pancreases were digested with collagenase and islet cells were harvested. Leucine in different levels (0 mmol/L, 10 mmol/L and 20 mmol/L) was added in rat islet cells which were incubated in DMEM containing 5.6mmol/L glucose and 25mmol/L glucose. After further 120 min incubation, insulin level in supernatant was measured.(3) Effect of leucine on model rats: Model rats were randomly divided into 2 groups of 10 animals each and fed on 0% leucine (0%Leu) and 2.16% leucine (2.16%Leu) for 8 weeks. Determined parameters are the same as above.Results:1. Seven related cohort studies were identified for this meta-analysis. A combined RR of 0.86 (95%CI, 0.79?0.92) was revealed on T2DM risk associated to dairy intake, with little evidence of heterogeneity. For subgroup analysis, a combined RR was 0.82 (95%CI, 0.74?0.90), 1.00 (95%CI, 0.89?1.10), 0.95 (95% CI, 0.86?1.05) and 0.83 (95%CI, 0.74?0.93) for the intake of low-fat dairy, high-fat dairy, whole milk and yogurt, respectively. Dose-response analysis showed that T2DM risk could be reduced 5% for total dairy products and 10% for low-fat dairy products.2. After 16 weeks, high-fat diet significantly decreased ISI; while, increased HOMA-IR. Furthermore, the AUC of plasma glucose was significantly higher in high-fat group than in control group, suggesting the establishment of insulin resistance model rats. Whey protein intake for 8 weeks did not affect FBG and glucose AUC in the model rats. However, FINS and HOMA-IR were significantly lower in 15% WP group than in 0% WP group. The level of liver glycogen was significantly higher in 15% WP group than in 0% WP group. The plasma levels of HDL-C, T-AOC, SOD and GSH were significantly higher in 15% WP group than in 0% WP group. On the other hand, the expression of Glut4 in gastrocnemius muscle deceresed in the IR rats and increased after the intake of whey protein (5%WP, 15%WP).3. Leucine administration alone did not affect plasma glucose level and insulin secretion. Comparing with glucose administration, leucine combined with glucose significantly decreased plasma glucose at 60 min and 120 min after administration and increased insulin secretion; In the DMEM medium with 25mmol/L glucose, 20mmol/L leucine significantly decreased insulin secretion in islet cells; After 8 weeks intervention in model rats, FINS and HOMA-IR were significantly lower and ISI significantly higher in 2.16% Leu group than in 0%Leu group. Liver glycogen and Glut4 expression in gastrocnemius muscle were significantly higher in 2.16% Leu group than in 0%Leu group. On the other hand, plasma level of HDL-C, T-AOC and SOD were significantly higher, while MDA significantly lower, in 2.16% Leu group than in 0% Leu group.Conclusions:1. Inverse association of daily intake of dairy products with T2DM was revealed, indicating a beneficial effect of dairy consumption in the prevention of T2DM.2. Whey protein was likely to improve insulin resistance. After 8 weeks of intervention in insulin resistance model rats, whey protein increased insulin sensitivity, liver glycogen synthesis, Glut4 expression and antioxidant capacity.3. Leucine, which is rich in whey protein, has been proved an insulinotropic effect in both vivo and vitro experiments. Leucine also improved hyperinsulinaemia and insulin sensitivity and increase Glut4 expression and antioxidant capacity in model rats.4. Thus, one of factors for dairy protecting T2DM is the improvement of insulin resistance by whey protein. The possible mechanism is the leucine, which is rich in whey protein, improved hyperinsulinaemia, insulin sensitivity, glucose transport and antioxidant capacity.
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