Do High Protein Diets Promote Diabetes?

Over the last several decades we have seen a marked increase in BMI and type 2 DM throughout much of Asia as traditionally minimally processed high carbohydrate (CHO) diets low in animal products have been displaced by increasing amounts of refined sugars, animal protein, and fat. By contrast, in the USA and other developed countries, BMI and type 2 DM are also increasing markedly over the past several decades as the amount and % of dietary CHO has increased, while dietary fat intake has actually declined modestly as a % of total calories, although not in absolute terms. Much of this increase in dietary CHO in the US has come from increasing consumption of sugar-rich drinks. It seems likely that the increasing intake of sugar, especially in drinks, is a major factor promoting excessive calorie intake, increasing BMIs, and more insulin resistance (IR) and type 2 DM in both Asian countries and the West. There is reason to believe that calorie dense foods high in fat and/or refined CHO will cause many people to consume excess calories, accumulate body fat, and develop IR and type 2 DM. This has led to speculation that consuming more animal protein and less CHO will aid weight loss and reverse IR and perhaps even type 2 DM. Over the past two decades nearly all the best-selling diet books have promoted low-CHO diets higher in animal protein foods. The US Dietary Guidelines have long discouraged the intake of animal products and particularly those high in saturated fat and cholesterol. This dietary advice has led most Americans to consume fewer eggs, full fat dairy products, and fatty meats and so has helped reduce the average intake of saturated fat and cholesterol in the US and helped lower average serum cholesterol levels and no doubt contributed to the marked decline in deaths from heart attacks seen in the USA over the past 50 years. However, this advice has certainly not helped stem the expanding waistlines of most Americans over the past five decades. Today 75% of men and 68% of women age 25 or older are overweight or obese and the number of Americans with type 2 DM has increased dramatically. There seems to be no debate among nutrition experts about the need to limit refined CHOs and perhaps especially sugar-rich drinks. However, Paleo-diet advocates suggest more lean animal protein and fewer whole grains would be best for improving the health of most people and stemming the growing prevalence of type 2 DM.Does More Lean Animal Protein and Less CHO Reduce Diabetes?Not according to data from the very large European Prospective Investigation into Cancer and Nutrition (EPIC) study. After an average follow up period of 12 y who found a significantly increased risk of developing type 2 DM in those eating more protein and especially animal protein. This trend was strongest for obese women who were 19% more likely to develop type 2 DM for each 10g daily intake in animal protein. The authors concluded that, given the rapid rise in type 2 DM in Europe, "… limiting iso-energetic diets high in dietary proteins, particularly from animal sources, should be considered” (1). But how could consuming more animal protein and less dietary CHO be promoting IR and type 2 DM even after correcting for BMI? Past research had suggested that it is largely factors associated with red meat intake such as heme iron, advanced glycation end products (AGEs), and/or nitrites in processed meats that may account for this increased risk. However, data from the EPIC study showed protein from red and processed meats was not primarily responsible for promoting type 2 DM in muscle cells, as the results showed increasing protein from eggs, dairy, poultry, and fish were also associated with more type 2 DM. Indeed, while protein from vegetable sources did not appear nearly as bad as animal proteins for promoting type 2 DM, they certainly were not protective either. One plausible factor might be the relatively higher intake of branched chain amino acids (BCAA) found in animal proteins than in vegetable proteins. Data from the Framingham Heart Study show an elevation of BCAA levels in the blood precedes the development of type 2 DM by many years (2). However, the mechanism by which BCAA or some metabolite of these BCAA might be promoting the development of IR and type 2 DM has been a mystery. That is no longer the case as Dr. Zoltan Arany and his research team at the Perlman School of Medicine  at UPenn and colleagues at Harvard, Princeton, the University of Pittsburg, and the University of Alabama have determined that a metabolite of valine (one of the three BCAA) called 3-hydroxyisobutyrate (3-HIB) is largely responsible for promoting IR. In a series of elaborate studies on cultured mouse and human skeletal muscle cells Dr. Arany’s team were able to show how the increased breakdown of BCAA leads to increased 3-HIB release from muscle cells that triggers the increased uptake of free fatty acids  (FFA) into the muscle cells. This 4-5 fold increased influx of FFA into the muscle cells results in the accumulation of incompletely esterified intermediates such as diglycerides (or DAG). Increased DAG results in lipotoxicity and accumulation of fat inside muscle cells. We have long known muscle cells accumulating more fat generally show impaired insulin signaling leading to increased IR. People who develop type 2 DM generally develop IR long before their blood glucose levels reach the diabetes range. People with type 2 DM are known to accumulate fat in not only their muscle cells but also the liver and pancreatic cells that impairs their function and may eventually inflame and destroy cells. Weight gain and fatty meals lead to higher levels of FFA in the blood. The valine metabolite 3-HIB dramatically increases the uptake of FFA without increasing the levels of FFA in the blood. Couple these higher FFA levels from excessive fat intake and weight gain and we have a viable mechanism for why the typical Western-style diet high in animal proteins (which have more BCAA than plant proteins), refined sugars, and fat (especially saturated fatty acids) promotes increased FFA uptake and lipotoxicity in muscle, liver, pancreas, and other cells throughout the body, leading to IR. And over time the accumulation of excess fat and DAGs will lead many people to type 2 DM (3).Bottom Line: This recent study by Dr. Zoltan’s group shows how increased animal protein may increase FFA uptake into cells which they showed promotes lipotoxicity and likely leads to IR and eventually type 2 DM. Clearly advice to replace whole grains with lean animal protein may not be optimal for preventing and treating IR and type 2 DM, except perhaps in individuals who lose and keep off significantly more weight on the higher protein diet. Weight loss and regular exercise we know can reverse IR and improve blood sugar control in type 2 DM patients. So if more protein leads to more weight loss, then this will reduce FFA levels in the blood and mitigate the impact of higher 3-HIB levels. However, the long term impact of higher protein intake on promoting long term weight control needs to be validated by studies that control for all known and suspected confounding variables. In studies that have controlled for such confounders, the long term impact of more protein and more animal protein have shown very little or no sustained weight loss on such diets compared to diets higher in CHO, especially if those higher CHO foods like whole grains, fruit, or beans bring with them more fiber.By James J. Kenney, PhD, FACNReferences:

1. van Nielen M, et. al. Dietary protein intake and incidence of type 2 diabetes in Europe: The EPIC-InterAct Case-Cohort Study. Diabetes Care 2014;37:1854-62.
2. Wang TJ, et. al. Metabolite profiles and the risk of developing diabetes. Nat Med 2011;17:448-53.
3. Jang C. et. al. A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. Nature Medicine 2016;22:421-6 or doi:10.1038/nm.40570.