Insulin resistance (IR) and eventually type 2 diabetes mellitus (DM) are now believed to be largely caused by the consumption of excess calories and an increasing BMI. Excess calories when combined with an inactive lifestyle worsen IR. IR is generally associated with elevated levels of free fatty acids in the blood and with the increased accumulation of fat inside muscle cells, liver cells, and beta cells. Indeed, the Diabetes Prevention Program Trial (DPPT) demonstrated that when people who had become IR and pre-diabetic lost a modest amount of weight (about 7% of their initial body weight) and kept it off for nearly 3 years with a diet lower in saturated fat, salt, and cholesterol and higher in complex carbohydrates (compared with a typical American diet) and combined that healthier diet with regular aerobic exercise, then they cut their risk of progressing to type 2 DM by 58% compared to the control group that simply took a placebo pill. [http://www.nejm.org/doi/full/10.1056/NEJMoa012512#t=article]. So type 2 DM is believed to develop in large part from excessive calorie intake and inactivity, which lead to increased body fat stores.Do Dietary Fats or Carbohydrates Promote IR and Type 2 DM?The impact of the three major macronutrients (fat, protein, & carbohydrate) on insulin sensitivity and the development of type 2 DM has been debated for more than 100 years. There have been thousands of studies attempting to evaluate the impact of the type of dietary fat and carbohydrate on the development of IR and type 2 DM. Even so, the impact of the three major sources of calories (independent of total energy intake) remains controversial. It is well established that an extremely low carbohydrate (ketogenic) diet with its resultant high levels of circulating free fatty acids (FFA) promotes IR. Indeed, even a short-term fast of 67 hours which also elevates circulating FFA can cause transient IR in young, healthy, lean men. Dr. Johnson showed that both a ketogenic diet and a short-term fast lead to an increased circulating FFA and an increased amount of fat stored inside muscle cells. [Johnson NA, Stannard SR, Rowland DS, et. al. Effect of short-term starvation versus high-fat diet on intramyocellular triglyceride accumulation and insulin resistance in physically fit men Exp Physiol 2006 Jul;91(4):693-703]. So higher levels of FFA in the blood can lead to greater uptake of FFA by cells. Greater FFA uptake by cells has been shown to increase fat accumulation in muscle and other cells. Increased circulating FFA cause a dose-dependent inhibition of insulin-stimulated glucose uptake (by decreasing glycogen synthesis and carbohydrate oxidation) and these increased FFA levels increase insulin suppression of hepatic glucose output and thus caused IR in the liver as well as in muscle cells and adipocytes. [Boden G, Chen X, Ruiz J, et. al. Mechanisms of fatty acid-induced inhibition of glucose uptake. J Clin Invest 1994;93:2438-46]. It appears that anything that causes increased FFA uptake and fat accumulation in cells can lead to IR and, over the long term, a heightened risk of beta-cell failure and type 2 DM.However, aside from an extremely low carbohydrate diet, there is actually little evidence that the ratio of dietary fat to carbohydrate in the diet have much impact on insulin sensitivity, which is independent of a change in body weight. Despite years of research, there still remains no clear evidence of a strong causal association between the amount, type, and/or ratio of dietary fat and carbohydrate in the diet with the risk of developing IR and type 2 DM that is independent of total energy intake and body weight. [http://ajcn.nutrition.org/content/92/4/748.full]. This is not to say that the amount and type of dietary fat and carbohydrate play no role in the development of insulin resistance (IR) and type 2 DM, but rather that whatever effect they have appears to be mediated largely (if not entirely) by promoting a change in body weight. This is also not to say that people with the metabolic syndrome, pre-diabetes, or type 2 DM should not be concerned about the amount and type of dietary fat and carbohydrate they consume as there is no doubt that diets higher in saturated and trans fats (and cholesterol) and higher in refined carbohydrates (especially sugar-rich drinks) and low in fiber tend to promote weight gain and dyslipidemia. It is well established that an increase in adiposity promotes the development of IR and type 2 DM. Of course, some people become obese and do not develop much IR or type 2 DM and a small percent of people with a BMI under 25 develop IR and type 2 DM, so clearly there are genetic factors involved in the development of type 2 DM as well. However, except for at very extreme levels, the ratio of fat to carbohydrate in the diet appears to have little to do with the development of IR that is independent of some increase in body fat stores. Of course, foods contain far more than carbohydrates, fats, and proteins and it is likely that some of these other food components can impact insulin sensitivity, inflammation, blood lipids, blood pressure, cancer, and perhaps even aging. For example, foods higher in protein and fat tend to have higher levels of advanced glycation end products (AGEs), particularly when cooked at high temperatures. These AGE-rich foods are more likely to promote IR and aging in ways that are independent of their fat, protein, and carbohydrate content. [https://www.ncbi.nlm.nih.gov/pubmed/18473850]. Further, added dietary salt leads to elevated blood pressure and increased dietary cholesterol elevates LDL-C and promotes atherosclerosis no matter what the macronutrient content of the foods with which salt and cholesterol are consumed. Additionally, heme iron, which is found in higher amounts in red meats, appears to promote IR, type 2 DM, and cancer. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3941820/ ; and http://www.todaysdietitian.com/newarchives/030413p46.shtml]. High-temperature cooking creates polycyclic aromatic hydrocarbons and heterocyclic aromatic amines, many of which are known or suspected carcinogens. [https://www.cancer.gov/about-cancer/causes-prevention/risk/diet/cooked-meats-fact-sheet]. Because of these and many other confounding variables that are difficult to control for, determining the independent impact of the amount and types of fats, proteins, and carbohydrates in the diet on disease risk is very difficult. No study that is attempting to examine the independent effects of the types of macronutrients and/or the ratio of these macronutrients on insulin sensitivity and the risk of developing type 2 DM is going to perfectly control all of these confounding variables. Most published studies do not even adequately control for changes in body weight and adiposity, even though changes in body weight are likely the single most important confounding variable impacting insulin sensitivity, and over the longer term, the risk of developing type 2 DM. This failure to control for even this most basic confounding variable has led to many questionable conclusions about the impact the three major macronutrients have on insulin sensitivity that is independent of any change in body weight. A closer look at some of the better-quality research suggests that dietary protein probably has a greater impact on insulin sensitivity than the fat or carbohydrate content of the diet.Might Dietary Protein Actually Promote Type 2 DM?The results of a prospective study that followed 38,094 Dutch adults (21-70y) for 10.1 years featured observations that subjects consuming a diet higher in protein and lower in either fat or carbohydrate were significantly more likely to develop type 2 DM. Dr. Sluijs concluded: "Our findings suggest a similar association for total protein itself instead of only animal sources. Consumption of energy from protein at the expense of energy from either carbohydrates or fat may similarly increase diabetes risk. The findings indicate that accounting for protein content in dietary recommendations for diabetes prevention may be useful." [Sluijs I, Spijkerman AWM, Beulens JWJ, et. al. Dietary intake of total, animal, and vegetable protein and the risk of type 2 diabetes in the EPIC-NL Study. Diabetes Care 2010;33:43-8]. The authors of this observational study noted that the people consuming a higher percent of energy from protein tended to be heavier on average than those consuming more fat and/or carbohydrate and less protein. Adjusting for the confounding effects increased BMI partially mitigated, but did not eliminate, the positive association between consuming a higher % protein diet with a greater risk of developing type 2 DM.Back in 2005, a team of researchers from Drexel University and Temple University studied the impact of a high-protein or a high-carbohydrate diet on 12 obese inner city subjects with type 2 DM. Both groups of subjects were closely matched for age, BMI, blood pressure, blood lipids, and blood sugar levels at baseline. All subjects were then evaluated at baseline for body weight, waist/hip and % body fat, insulin sensitivity (using the hyperinsulinemic-euglycemic clamp technique), glycosylated hemoglobin (HbA1c), other blood tests to evaluate renal and liver function, and blood lipids. Following the measurement of their baseline diets and the series of clinical measurements, all subjects were divided into two groups and both received intensive dietary counseling (written and oral). One group was instructed to follow a low-calorie diet that was higher in protein and lower in carbohydrate, while the second group was instructed to follow a higher-carbohydrate and lower-protein diet. Measurement of dietary compliance was assessed by three 24-hour diet recalls during the first week and then another three during the 8th and final week of the study. Dietary assessment found that protein intake averaged 27% of calorie intake on the high-protein diet and 19% on the high-carbohydrate diet or 87g vs 68g of protein/day, respectively. Carbohydrate intake averaged 51% vs. 43% of calories on the higher-carbohydrate diet compared to the higher-protein diet. Dietary fat intake averaged 30% of energy on both diets with the amount of saturated, polyunsaturated, and monounsaturated fatty acids and cholesterol consumed daily on both diets not significantly different. However, the higher-protein diet was significantly lower in sodium (1691 vs 2484mg/day) and significantly higher in fiber content (18 vs 15g/day) than the higher-carbohydrate diet. Weight loss on the two diets was not significantly different after 8 weeks. Those on the higher-protein diet lost an average of 2.5kg, while those on the higher-carbohydrate diet lost 2.2kg. Perhaps not surprisingly (given the significantly lower sodium intake on the higher-protein vs higher-carbohydrate diet), blood pressure did fall significantly more on the higher-protein diet. However, HbA1c improved significantly from 8.2 to 6.9% on the higher-carbohydrate diet after 8 weeks. This drop in HbA1c was accompanied by a significant drop in fasting blood glucose (from 8.8 to 7.2mmol/L) and also a significant improvement in insulin sensitivity on the higher-carbohydrate diet. By contrast, blood sugar regulation and insulin sensitivity did not improve significantly on the higher-protein diet despite a similar loss of body weight. [Sargrad KR, Homko C, Mozzoli M, Boden G. Effect of high protein vs. high carbohydrate intake on insulin sensitivity, body weight, hemoglobin A1c, and blood pressure in patient with type 2 diabetes mellitus. J Am Diet Assoc 2005;105:573-80]. The results of this 8-week clinical trial demonstrated that a diet lower in protein and higher in carbohydrate was significantly better for improving insulin sensitivity and lower fasting blood glucose and dropping HbA1c than one higher in protein.Another study led by Dr. Weickert in Germany was a randomized clinical trial over 18 weeks. An initial group of 111 overweight subjects were placed on four different weight maintenance diets that varied mainly in protein and cereal fiber content for 18 weeks. Data was analyzed on the 84 subjects who successfully completed the study protocol. Insulin sensitivity was 25% greater after the first 6 weeks (when dietary adherence was greatest) in the group assigned to the lower protein (17% en.) and higher cereal fiber (43g/day) diet (HCF) than for the group assigned to the higher protein (28% en.) and lower fiber (13g/day) diet (HP). This improved insulin sensitivity on the HCF diet relative to the HP diet occurred despite no significant difference in the amount of visceral or subcutaneous or liver fat content and no significant difference in lean body mass. They also observed no significant differences in the amount of inflammatory cytokines or adiponectin in the blood between the groups that are associated with insulin sensitivity. However, they did note a tendency for increased dietary protein to stimulate increased S6 Kinase 1 activity in subcutaneous fat cells. This suggests the decreased insulin sensitivity observed on the HP diet compared with the HCF diet might be due to the elevated amino acid levels in the blood, which have been shown to increase IR by increasing S6 Kinase 1 activity. [Weickert, MO, Roden M, Isken F, et. al. Effects of supplemented isoenergetic diets differing in cereal fiber and protein content on insulin sensitivity in overweight humans. Am J Clin Nutr 2011;94:459-71].Bottom Line: While it appears that the amount and type of dietary carbohydrate and fat have little impact on insulin sensitivity that is independent of a change in body fat stores, this does not appear to be the case for dietary protein. Without a change in total calorie intake, replacing dietary fat or carbohydrate with protein appears to promote IR in a way that is independent of any change in body weight. The mechanism by which the isocaloric replacement of carbohydrate calories with protein causes IR to develop will be discussed in next month's Communicating Food For Health issue.By James J. Kenney, PhD, FACN