How More Dietary Protein Causes Insulin Resistance

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Last month we discussed how attempts to find a causal mechanism by which changing the type of dietary fat or carbohydrate or altering the ratio of those two macronutrients promotes insulin resistance (IR) and type 2 diabetes mellitus (DM). A closer look at the best available evidence shows that varying the amount and type of dietary fat and carbohydrate independent of any change in body weight or adiposity has very little or no direct role in causing IR to develop. By contrast, there has been growing scientific evidence linking an increase in dietary protein at the expense of either carbohydrate and/or fat appearing to cause IR to develop. This causal relationship between higher protein intake at the expense of dietary carbohydrate and/or fat appears to be promoted by elevated levels of serum amino acids. So while both dietary fat and carbohydrate intake can promote IR and type 2 DM, this development of IR appears to be dependent on increased total calories and increased body adiposity. For example, Dr. Tremblay and colleagues at Laval University in Canada showed that increased amino acid levels in the blood somehow caused IR to develop by leading to the over activation of S6 Kinase 1, (and activation of the mTORC-1 pathway). In vitro studies have shown that increased mTOR activation by higher insulin levels and/or increased amino acid availability induces IR in muscle cells and adipocytes. The branched chain amino acid (BCAA) leucine is the most potent at stimulating insulin release and stimulating the mTOR pathway (1,2). A diet low in leucine has been shown to improve insulin signaling in the liver as measured by increased phosphorylation of the insulin receptor, and also whole-body insulin sensitivity as measured by an insulin tolerance test (3). Methionine is another amino acid that may impact biomarkers associated with increased cancer risk and accelerated aging such as increased insulin and IGF-1. In mice there are many overlapping phenotypes shared both by calorie restriction and isolated methionine restriction, including reduced adiposity, extended maximal longevity, increased resistance to acetaminophen toxicity in the liver, reduced insulin and IGF-1 (insulin growth factor 1) levels and reduced thyroid hormone (4). Both BCAA and methionine tend to occur in higher amounts in animal proteins compared with plant-derived proteins, which may help explain why animal protein intake often correlates more strongly with the development of IR and type 2 DM than intake of protein from plants. However, it is hard to avoid concluding that a diet lower in protein and especially animal protein (and so lower in both BCAA and methionine) may reduce both IGF-1 and mTORC-1. Lower levels of mTORC-1 and IGF-1 not only appear to improve insulin sensitivity but also may inhibit aging and the slow the promotion and/or growth of cancer cells.

The BCAA Valine Shown to Cause Insulin Resistance

More recently, Dr. Newgaard at Duke University has conducted several studies showing that it is likely a component of the BCAA which is most strongly associated with a reduction in insulin sensitivity rather than some lipid component of the diet. The three BCAA are leucine, isoleucine, and valine. Dr. Newgaard concluded that, " Taken together, these findings suggest that chronic elevations of BCAA and related metabolites may synergize with a similar slow rise in fatty acids to drive a state of chronic hyperinsulinemia" (5). Last year a team of researchers led by Dr. Cholsoon Jang was able to determine which of the BCAA metabolites was most directly responsible for causing IR to develop. Dr. Jang showed that it is 3-hydroxy-isobutyrate (3-HIB), which is a metabolite from the breakdown of valine that most impacts the uptake of FFAs into muscle cells. Interestingly, except for 3-HIB, all other metabolites of the BCAAs remain trapped within muscle cells. Furthermore, Dr. Jang showed that increasing dietary protein, and specifically dietary valine intake, leads to an increased production and release of 3-HIB. Unlike other metabolites of the BCAA, 3-HIB escapes the muscle cells. Once outside the cell, Dr. Jang showed that 3-HIB acts as a parcrine regulator that increases the trans-endothelial transport of FFAs, thus stimulating the uptake of fatty acids by the muscle cells (6). Increased fatty acid uptake by muscle cells is believed to drive the loss of insulin sensitivity in muscle cells. This may be why data from the long-running Framingham Heart Study showed that an increased level of BCAA in the blood of subjects predicted their subsequent development of type 2 DM years later (7). Higher levels of BCAA in the blood are largely the result of increased dietary intake.

Metformin, like rapamycin, works in part by inhibiting mTOR (TOR is Target Of Rapamycin) and IGF-1 activity. These effects parallel those of a diet lower in protein and especially animal proteins with their higher BCAA and methionine content. Metformin improves insulin sensitivity and lowers blood sugar levels while sometimes reducing appetite and also inhibiting the growth of some types of cancer (8). Of course, in the DPPT, metformin was only about half as effective as a healthier diet (lower in fat and higher in fiber) and exercise program (which lowered body weight by about 7% on average) when it comes to preventing IR subjects with pre-diabetes from progressing to type 2 DM.

Another study examined the effects of a higher and lower protein diet in overweight postmenopuasal women. This study compared the effects of losing 10% of body weight with a hypocaloric diet containing either 0.8 g protein/kg/day and with a hypocaloric diet containing 1.2 g protein/kg/day on muscle insulin action in postmenopausal women with obesity. The higher-protein weight loss diet did limit the loss of LBM (by about 45%) but the higher-protein diet also eliminated the improvement in insulin sensitivity one would have expected when losing 10% of excess body weight. Women on the lower-protein weight loss diet did experience significant improvement in muscle insulin sensitivity with a similar weight loss as expected (9). A habitual higher protein intake has been associated with more IR and, over the longer term, with a heightened risk of developing type 2 DM (10). It now seems likely the greater intake of BCAA and specifically valine and its metabolite 3-HIB are likely what is preventing the improvement in insulin sensitivity one would have expected to see during weight loss. Over the longer term, this 3-HIB may also be contributing to a heightened risk of developing type 2 DM in people consuming a higher-protein diet.

While a higher percent of energy from protein during a calorie-restricted weight loss program may well spare some loss of lean tissue over the short term, there is no convincing evidence that a diet with more than 20% protein calories is health-promoting over the long term. Indeed, there is growing evidence that a higher-protein diet may be harmful in people younger than 65. One study found that higher protein intake was associated with higher levels of IGF-1 and an increased risk of developing type 2 DM, cancer, and an overall increase in total mortality. However, this association between higher protein intake and more disease risk appeared to reverse in people older than 65, although even in people older than 65 a higher-protein diet continued to be associated with much greater risk of type 2 DM mortality. The association between animal protein and increased diabetes mortality was stronger than for plant-based protein intake (11). Over a lifetime it appears likely that the optimal consumption of dietary protein as a percent of total energy intake for preventing the development of IR and type 2 DM (and perhaps also improving the prospects for a longer and healthier life) is no more than about 10 to 15% of total energy intake. A diet with a % protein greater than about 15% of energy may still be beneficial when calorie intake is low and weight is being lost because the higher levels of IGF-1 may help minimize the loss of muscle mass, at least in the short term. Also, in older people with cachexia the benefits of a higher protein intake can help limit further loss of muscle mass and strength. This benefit might still yield a net benefit for some individuals older than 65. However, more research is needed on the pros and cons of higher % protein diets in younger obese people and especially those who already have some IR and the metabolic syndrome. In very old type 2 DM who are cachexic, it seems more likely that the metabolic effects of higher protein intake might outweigh the metabolic dysfunctions that are now known to develop in response to a greater protein intake.

Bottom Line: To prevent and treat type 2 DM, a more plant-based diet with a lower calorie density and a higher fiber content coupled with regular exercise remains the top priority. Lowering calorie density, increasing dietary fiber, and reducing beverage calories all lead to a reduction in ad libitum calorie intake and a reduction in body fat stores. This was convincingly demonstrated in the Diabetes Primary Prevention Trial (DPPT), which clearly showed the reduction in body fat stores is the primary therapeutic path for both improving insulin sensitivity and over the longer term preventing the development of type 2 DM in people who are pre-diabetic (12). A diet composed largely of minimally-processed plant-based foods that is also low in salt, saturated fat, and cholesterol likely helps reduce the risk of some cancers, cardiovascular disease, and other degenerative diseases as well. So the growing enthusiasm among some healthcare professionals and fad diet book writers and bloggers for a lower-carbohydrate and higher-protein diet to prevent or treat type 2 DM appears unwarranted. Over the long term the known and suspected negative metabolic effects of a higher-protein diet with its higher levels of BCAA and methionine is likely to enhance IR independent of any change in body weight. Many sources of animal proteins that are also high in AGEs may also be playing a role in promoting IR and type 2 DM. Most animal protein foods will be high in saturated fat and/or cholesterol, making them a particularly poor choice for people with type 2 DM who have a two- to four-fold greater risk of heart disease and stroke compared with people of the same age but without diabetes.

By James J. Kenney, PhD, FACN


  1. Tremblay F, Marette A. Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway: a negative feedback mechanism leading to insulin resistance in skeletal muscle cells. J Biol Chem 2001;276:38052-60.
  2. Tremblay F, Krebs M, Dombrowski L, et. al. Overactivation of S6 Kinase 1 as a cause of human insulin resistance during increased amino acid availability. Diabetes 2005;54:2674-84.
  3. Xiao F, Huang Z, Li H, Yu J, Wang C, Chen S, Meng Q, Cheng Y, Gao X, Li J, et al. Leucine deprivation increases hepatic insulin sensitivity via GCN2/mTOR/S6K1 and AMPK pathways. Diabetes 2011;60:746–756.
  4. Miller RA, Buehner G, Chang Y, Harper JM, Sigler R, Smith-Wheelock M. Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-1 and insulin levels, and increases hepatocyte MIF levels and stress resistance. Aging Cell. 2005;4:119–125.
  5. Newgaard C. Interplay between lipids and BCAA in the development of insulin resistance. Cell Metabolism 2012;15:606-14.
  6. Jang C, Oh SF, Wada S, et. al. A branched chain amino acid metabolite drives vascular transport of fat and causes insulin resistance. Nat Med 2016;22:421-6.
  7. Wang TJ, Larson MG, Vasan RS, et. al. Metabolite profiles and the risk of developing diabetes. Nat Med 2011;17:448-53.
  8. Nadal, Angel, ed. "Metformin Downregulates the Insulin/IGF-I Signaling Pathway and Inhibits Different Uterine Serous Carcinoma (USC) Cells Proliferation and Migration in p53-Dependent or -Independent Manners"  PLOS 1 April 2013:
  9. Smith, Gordon I, et. al. High-Protein Intake during Weight Loss Therapy Eliminates the Weight-Loss-Induced Improvement in Insulin Action in Obese Postmenopausal Women. Cell Reports 17, 849–861 October 11, 2016.
  10. Tinker, L.F., Sarto, G.E., Howard, et. al. Biomarker-calibrated dietary energy and protein intake associations with diabetes risk among postmenopausal women from the Women’s Health Initiative. Am J Clin Nutr 2011;94:1600–06.
  11. Levine, Morgan E, et. al. Low Protein Intake Is Associated with a Major Reduction in IGF-1, Cancer, and Overall Mortality in the 65 and Younger but Not Older Population. Cell Metabolism 19, 407–417, March 4, 2014.
  12. Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin. N Engl J Med 2002; 346:393-403 February 7, 2002.
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