Mechanisms of Diabetes Improvement Following Bariatric/Metabolic Surgery

Abstract

More than 20 years ago, Pories et al. published a seminal article, "Who Would Have Thought It? An Operation Proves to Be the Most Effective Therapy for Adult-Onset Diabetes Mellitus." This was based on their observation that bariatric surgery rapidly normalized blood glucose levels in obese people with type 2 diabetes mellitus (T2DM), and 10 years later, almost 90% remained diabetes free. Pories et al. suggested that caloric restriction played a key role and that the relative contributions of proximal intestinal nutrient exclusion, rapid distal gut nutrient delivery, and the role of gut hormones required further investigation. These findings of T2DM improvement/remission after bariatric surgery have been widely replicated, together with the observation that bariatric surgery prevents or delays incident T2DM. Over the ensuing two decades, important glucoregulatory roles of the gastrointestinal (GI) tract have been firmly established. However, the physiological and molecular mechanisms underlying the beneficial glycemic effects of bariatric surgery remain incompletely understood. In addition to the mechanisms proposed by Pories et al., changes in bile acid metabolism, GI tract nutrient sensing and glucose utilization, incretins, possible anti-incretin(s), and the intestinal microbiome are implicated. These changes, acting through peripheral and/or central pathways, lead to reduced hepatic glucose production, increased tissue glucose uptake, improved insulin sensitivity, and enhanced β-cell function. A constellation of factors, rather than a single overarching mechanism, likely mediate postoperative glycemic improvement, with the contributing factors varying according to the surgical procedure. Thus, different bariatric/metabolic procedures provide us with experimental tools to probe GI tract physiology. Embracing this approach through the application of detailed phenotyping, genomics, metabolomics, and gut microbiome studies will enhance our understanding of metabolic regulation and help identify novel therapeutic targets.

Figure 1

Bariatric/metabolic operations discussed in this article. A: RYGB. The stomach is divided into two compartments, leaving only the small upper chamber in digestive continuity. Food passes from there to the proximal jejunum, bypassing most of the stomach, the duodenum, and a small portion of jejunum. B: VSG. Most of the stomach (primarily the body and fundus) is excised, leaving a narrow sleeve along the lesser curvature. Nutrients follow the normal route through the GI tract. C: LAGB. An inflatable silicon ring encircling the upper stomach is serially adjusted to optimize the diameter of a tight aperture that hinders food flow. D: BPD. A large majority of the small intestine is bypassed, purposely causing malabsorption. E: DJB. A modest segment of proximal intestine is bypassed, as in RYGB, without compromising gastric capacity.

Figure 2

Diagram of some of the metabolic effects and cross talk among BAs, GLP-1, and FGF-19.

Figure 3

Schematic of potential mechanisms contributing to improved glycemia after RYGB and VSG. A: Immediate effects of RYGB and VSG due to anatomical changes. B: Potential mediators/mechanisms involved. Cross talk occurs among these factors. C: Effects on glucose homeostasis.