Diet and Metabolic Inflammation (AIM Study)

One proposed mechanism linking obesity with an increased risk of breast, colon, liver and pancreatic cancer is the low-grade chronic inflammation found in adipose tissue. This inflammation is also a concern for other chronic diseases, most importantly type 2 diabetes, given that the low-grade chronic inflammatory processes in expanded adipose tissue are thought to be a major factor in the development of insulin resistance.

Macrophages are a major effector cell type in adipose tissue inflammation. The prevailing paradigm is that adipose tissue macrophages undergo a phenotypic switch towards a more pro-inflammatory phenotype when adipose tissue expands, though the pro-inflammatory phenotype differs from classically activated macrophages. Currently the cause of this phenotypic switch is unknown. Preliminary evidence suggests that exposure of macrophages to high physiological doses of glucose, insulin, and free fatty acids triggers inflammatory pathways within the cells, which may contribute to the phenotypic switch in adipose tissue macrophages. This model, which we call ‘metabolic activation’ of macrophages, is based on a recent translational research project conducted in collaboration with Dr. Lev Becker, University of Chicago, published in Cell Metabolism. The AIM Study investigates whether changes in diet composition to minimize the exposure of adipose tissue macrophages to hypothesized pro-inflammatory factors can reverse the metabolic activation of adipose tissue macrophages. Reduced metabolic activation would in turn be expected to be associated with reduced expression of pro-inflammatory mediators in adipose tissue (i.e., reduced ‘inflammation’) and possibly improved insulin sensitivity.

This parallel design, randomized controlled pilot trial compares the impact of the newly designed Anti-Inflammatory Milieu (AIM)-diet with that of a healthy control diet consistent with the 2010 “Dietary Guidelines for Americans”. Study procedures, conducted at baseline and again after the 12-week dietary intervention, include assessment of body weight and composition (by DEXA-scan), a fasting blood draw, a frequently sampled oral glucose tolerance test to assess glucose tolerance and insulin sensitivity, a stool collection, and an adipose tissue biopsy to assess measures of metabolic activation in adipose tissue macrophages.

Status: In progress (as of April 2016), completion expected by fall of 2016
Clinicaltrials.gov: NCT02539355
Publications: None

The Impact of Low-fat and Full-fat Dairy Consumption on Glucose Homeostasis (DAIRY Study)

Several large observational studies suggest that the amount of dairy products consumed is inversely related to the risk of type 2 diabetes. However, the data are largely inconsistent on whether the reduction in type 2 diabetes risk is greater with the consumption of low-fat or full-fat dairy products, and whether there may be specific benefits associated with the consumption of fermented dairy products (i.e. yogurt or cheese). Importantly, because observational studies can establish only associations, such studies have not been able to provide any insight into whether dairy product consumption actually cause a reduction in type 2 diabetes risk. Even if the effect was causal, the mechanisms through which dairy foods may act to improve glucose tolerance have yet to be elucidated.

The DAIRY Study is a randomized controlled trial aimed at addressing whether the consumption of dairy foods generally improves glucose homeostasis compared to a largely dairy-free diet, and whether low-fat dairy products differ in this regard from full-fat dairy products. Additionally, this study begins to investigate the mechanisms by which dairy-rich diets may affect glucose tolerance and its determinants. We aim to enroll 72 insulin resistant men and women with the metabolic syndrome who consume diets differing in their type and content of dairy foods, in a parallel-design randomized controlled trial. In a 16-week dietary intervention, we will compare the effects of consuming a diet largely free of dairy foods (limited dairy diet) vs. a diet rich in nonfat milk and yogurt and low fat cheese (low-fat dairy diet) vs. a diet rich in full-fat milk, yogurt and cheese (full fat dairy diet) on glucose tolerance and major determinants of oral glucose tolerance. We will also assess the impact of the intervention diets on energy balance and a wide range of risk factors for cardiometabolic disease.

Status: In progress (as of April 2016), completion expected by 2018
Clinicaltrials.gov: NCT02663544
Publications: None

Diet and Systemic Inflammation (DASI)

Low-grade chronic systemic inflammation is a risk factor for type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), and several types of cancer. While it is known that obesity is associated with inflammation, the cause of low-grade inflammation in humans is not well understood. Data from a previous pilot study by our group as well as several experiments in rodent models indicated that the consumption of large amounts of fructose- but not glucose-sweetened beverages induces low-grade systemic inflammation in a manner largely independent of increased adiposity. The DASI study was designed to test whether fructose-sweetened beverages trigger low-grade systemic inflammation in healthy men and women who are normal weight to obese. Twenty-five participants were enrolled into this double-blind randomized cross-over design trial where every subject completed three 8-day standardized dietary periods that differed only in the type of sweetened beverage administered. Specifically, we compared how consumption of four servings daily of a beverage sweetened with glucose, fructose, or high fructose corn syrup impacted markers of systemic low-grade inflammation (C-reactive protein, interleukin-6, and adiponectin), intestinal permeability, adipose tissue inflammation, and ad libitum energy intake from a standardized diet.

Status: completed, additional statistical analyses in progress (as of April 2016)
Clinicaltrials.gov: NCT01424306
Publications:

Kuzma JN, Cromer G, Hagman DK, Breymeyer K, Bates P, Roth CL, Foster-Schubert KE, Holte S, Callahan HS, Weigle DS, Kratz M. No difference in ad libitum energy intake in healthy men and women consuming beverages sweetened with fructose, glucose, or high-fructose corn syrup: a randomized trial. American Journal of Clinical Nutrition 2015; 102: 1373-80. (with link to PubMed site)