Science Spotlight

Two in one: bypassing fat and diabetes

Type 2 diabetes (T2D) results from a combination of increased insulin resistance and beta-cell failure to compensate for this insulin resistance. Insulin resistance itself is thought to be derived predominantly from inflammatory processes, particularly in adipose tissue, which expands with increasing adiposity.
Image provided by Drs. Mario Kratz and Derek Hagman

Insulin is one of the key hormones that keep blood sugar levels within a certain range. Insulin resistance is a condition in which the body produces insulin but does not use it effectively. Once the body becomes resistant to the actions of insulin, beta-cells in the pancreas have to produce more insulin to compensate. If the beta-cells are unable to do that, blood sugar levels are chronically elevated, and type 2 diabetes develops (T2D).

It is thought that low-grade, chronic inflammatory processes, particularly in the expanded adipose tissue found in obese individuals, are a major cause of insulin resistance and T2D. One proposed mechanism is that as adiposity increases, activated immune cells enter adipose tissue in greater numbers leading to a proinflammatory environment that disrupts insulin signaling in adipocytes.

Roux-en-Y gastric bypass (RYGB) surgery offers a unique opportunity to examine the interplay between obesity, insulin sensitivity, and inflammation in humans. In RYGB, the surgeon re-routes the gastrointestinal tract, such that food bypasses much of the stomach and the first part of the small intestines, the duodenum. After RYGB surgery in patients with T2D, normal glucose levels are restored and T2D is reversed in ~85% of all cases, all within a few days and before any major weight loss. The mechanism for this is not well understood.

To address this question, Drs. Mario Kratz, and Derek Hagman (Public Health Sciences Division), along with collaborators at the University of Washington and Group Health Research Institute, conducted an ancillary study to the Calorie Reduction Or Surgery: Seeking Remission for Obesity And Diabetes (CROSSROADS) randomized controlled trial. Here they examined adipose tissue and systemic inflammation in T2D patients at baseline and again at 7% weight loss from either RYGB or an intensive lifestyle intervention. This design allowed the researchers to address whether RYGB exerts anti-inflammatory effects beyond those that may result from similar weight loss following a nonsurgical intervention. The results from their study were recently published in Obesity.

The investigators randomized sixteen people with obesity and T2D to RYGB or a very intensive lifestyle intervention. Fasting blood and subcutaneous abdominal adipose tissue were obtained before and after the loss of 7% of baseline weight. The researchers assessed adipose tissue inflammation using whole-tissue gene expression and flow cytometry-based quantification of the leukocytes infiltrating the tissue.

At 7% weight loss, fasting plasma glucose and insulin concentrations were reduced in both intervention groups, as can be expected with weight loss. Consistent with previous findings that RYGB can reverse T2D, participants in the RYGB group achieved the reductions in fasting plasma glucose and insulin concentrations even though they dramatically reduced their use of insulin and anti-diabetic medications, such as metformin. Unexpectedly, adipose tissue inflammation increased modestly after RYGB and nonsurgical weight loss. In both groups, mRNA levels of the proinflammatory cytokine interleukin-1b increased (P value = 0.037), mRNA expression of the anti-inflammatory and insulin- sensitizing adipokine adiponectin decreased (P value = 0.010), and the number of neutrophils (white blood cells that form an essential part of the innate immune system) increased several fold (P value < 0.001).

According to Drs. Hagman and Kratz, "our work shows that T2D is largely reversed within ~14 days of gastric bypass surgery in spite of persistent inflammation in adipose tissue. Given the very strong association between adipose tissue inflammation, insulin resistance, and glucose intolerance in rodent models of obesity, this is a somewhat unexpected finding."

The investigators also note, "one major strength of this study, and an almost unique feature, was that individuals with T2D were randomized to gastric bypass surgery vs. an intensive lifestyle modification. To make this possible, we collaborated with investigators at Group Health Research Institute and the University of Washington to identify, out of ~1,800 patients with type 2 diabetes, those who were interested in surgery, but also willing to consider an intensive lifestyle intervention. Forty-two such individuals were identified, randomized, and followed-up for 1 year. The results of the screening and recruitment procedure, and the main study results on changes in glucose metabolism in the entire cohort were published separately (Arterburn et al. and Cummings et al.). Our study was an ancillary study in a subgroup of those individuals, and benefited greatly from the ability to compare weight loss following gastric bypass surgery to equivalent weight loss from an intensive lifestyle modification program."

Funding for this study was provided by the National Institute of Diabetes and Digestive and Kidney Disease and a Cancer Center Support Grant subsidizing the use of the Prevention Center and Flow facility at the Fred Hutch.

Kratz M,Hagman DK,Kuzma JN,Foster-Schubert KE,Chan CP,Stewart S,van Yserloo B,Westbrook EO,Arterburn DE,Flum DR,Cummings DE. 2016. Improvements in glycemic control after gastric bypass occur despite persistent adipose tissue inflammation. Obesity. 24(7):1438-45

Arterburn D, Flum DR, Westbrook EO, Fuller S, Shea M, Bock SN, Landers J, Kowalski K, Turnbull E, Cummings DE; CROSSROADS Study Team. A population-based, shared decision-making approach to recruit for a randomized trial of bariatric surgery versus lifestyle for type 2 diabetes. 2013. Surg Obes Relat Dis.Nov-Dec: 9(6):837-44.

Cummings DE, Arterburn DE, Westbrook EO, Kuzma JN, Stewart SD, Chan CP, Bock SN, Landers JT, Kratz M, Foster-Schubert KE, Flum DR. 2016. Gastric bypass surgery vs intensive lifestyle and medical intervention for type 2 diabetes: the CROSSROADS randomised controlled trial. Diabetologia.