Milk consumption does not prevent but induces type 2 diabetes

Hidayat et al recently proposed in this journal that milk consumption may prevent type 2 diabetes mellitus (T2DM) especially by enhancement of incretin and insulin responses, consequently leading to lower postprandial glucose levels. Milk's insulinotropic index is three times higher compared with milk's glycemic index. The insulinotropic protein fraction of milk are the whey proteins (20% of cow milk protein), whereas caseins (80%) enhance serum levels of insulin‐like growth factor‐1 (IGF‐1). In fact, whey ingestion increases the secretion of glucose‐dependent insulinotropic polypeptide (GIP) and enhances insulin responses lowering postprandial glucose levels in healthy individuals and patients with T2DM. The branched‐chain amino acids (BCAAs) leucine, isoleucine, and valine are the major insulinotropic amino acid constituents of whey proteins. BCAAs activate mTORC1 of β‐cells and promote β‐cell proliferation, insulin synthesis, and insulin secretion. Physiologically, the BCAA‐mTORC1 signalling of milk is restricted to the postnatal breastfeeding period. Adult mammals are naturally protected from milk intake after the weaning period by physiological lactose intolerance except humanswho acquired LCTmutation‐induced lactase persistence allowing persistent milk consumption. A Mendelian randomization study in 97 811 Danish individuals demonstrated that milk intake is not associated with a lower risk of T2DM or overweight‐obesity, but in contrast identified an increased risk of T2DM. Of all animal‐derived proteins, milk proteins contain the highest amount of BCAAs with leucine levels in the range of 10% to 11%. Enhanced serum levels of BCAAs are metabolomic hallmarks of obesity, insulin resistance, and T2DM. Decreasing dietary BCAA levels improved obesity, insulin sensitivity, appetite control, and lifespan in mice. High concentrations of leucine repressed β‐cell differentiation in pancreatic bud cultures through the activation of the mTORC1 signalling pathway. Hyperstimulation of mTORC1 by high concentrations of leucine inhibits β‐cell proliferation by alterations of hypoxia‐inducible factor 1α and via S6 kinase 1 (S6K1)‐mediated Diabetes Metab Res Rev. 2019;35:e3200. https://doi.org/10.1002/dmrr.3200 wileyonlinelibrary.com/ inhibitory phosphorylation of insulin receptor substrate‐1 (IRS1) inducing insulin resistance (Figure 1). The combination of persistent glucose‐mediated and leucine‐mediated overstimulation of mTORC1‐ driven insulin synthesis enhances endoplasmic reticulum (ER) stress of β‐cells resulting in early β‐cell apoptosis, the key pathogenic mechanism of T2DM. Furthermore, it is noteworthy to mention that pasteurized milk provides bioavailable exosomal microRNAs including the diabetogenic microRNA‐29b. MicroRNA‐29b serum levels significantly increase after consumption of commercial pasteurized milk. MicroRNA‐29b targets and suppresses the expression of dihydrolipoamide branched‐ chain transacylase (DBT), the functionally important core protein of branched‐chain α‐ketoacid dehydrogenase (BCKD), and the key enzyme of BCAA catabolism. Thus, consumption of pasteurized milk not only provides abundant BCAAs but simultaneously impairs BCAA catabolism promoting the metabolomic BCAA signature of obesity, insulin resistance, and T2DM. There is at present no epidemiological milk‐T2DM study that clearly differentiates between heat treatment procedures especially pasteurization (78°C) and ultraheat treatment (UHT, 130°C) as well as fermentation. This is of critical concern because bioactive exosomal microRNAs survive pasteurization but are degraded by UHT and fermentation. A nested case‐cohort within eight European countries of the European Prospective Investigation into Cancer and Nutrition (EPIC) Study (n = 340 234) investigated the amount and type of dairy product intake and incident T2DM. This study demonstrated an increased risk for T2DM by milk consumption in five of eight countries. The Dutch Lifeline Cohort Study with 112 086 participants investigated the association of nonfermented milk products, milk, and fermented milk products on participants with prediabetes (defined as fasting plasma glucose between 5.6 and 6.9 mmol/L or HbA1c of 5.7%‐6.4%) and newly diagnosed T2DM (defined as fasting plasma glucose ≥7.0 mmol/l or HbA1c ≥ 6.5%). A positive association between full‐fat milk consumption (150 g/day)