Endocrine mechanisms mediating remission of diabetes after gastric bypass surgery

University of Washington School of Medicine, Seattle, WA 98195, USA.
International journal of obesity (2005) (Impact Factor: 5). 05/2009; 33 Suppl 1(supplement 1):S33-40. DOI: 10.1038/ijo.2009.15
Source: PubMed


Bariatric surgery is currently the most effective method to promote major, sustained weight loss. Roux-en-Y gastric bypass (RYGB), the most commonly performed bariatric operation, ameliorates virtually all obesity-related comorbid conditions, the most impressive being a dramatic resolution of type 2 diabetes mellitus (T2DM). After RYGB, 84% of patients with T2DM experience complete remission of this disease, and virtually all have improved glycemic control. Increasing evidence indicates that the impact of RYGB on T2DM cannot be explained by the effects of weight loss and reduced energy intake alone. Weight-independent antidiabetic actions of RYGB are apparent because of the very rapid resolution of T2DM (before weight loss occurs), the greater improvement of glucose homeostasis after RYGB than after an equivalent weight loss from other means, and the occasional development of very late-onset, pancreatic beta-cell hyperfunction. Several mechanisms probably mediate the direct antidiabetic impact of RYGB, including enhanced nutrient stimulation of L-cell peptides (for example, GLP-1) from the lower intestine, intriguing but still uncharacterized phenomena related to exclusion of the upper intestine from contact with ingested nutrients, compromised ghrelin secretion, and very probably other effects that have yet to be discovered. Research designed to prioritize these mechanisms and identify potential additional mechanisms promises to help optimize surgical design and might also reveal novel pharmaceutical targets for diabetes treatment.

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Available from: David E Cummings, May 06, 2014
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    • "Numerous studies have confirmed this assertion [10] [11] [12] [13] [14] [15] [16] [17], and other studies [16] [18] have suggested that bariatric surgery should be considered as a treatment modality for the resolution of T2 DM regardless of body mass index (BMI). Among various forms of bariatric procedures, Roux-en-Y gastric bypass (RYGB) has been the most common surgery in morbidly obese patients [19] [20]. Yet, despite the increased recognition of the routine resolution of diabetes in most T2 DM patients after RYGB, it is unclear what mechanism(s) are responsible for the remission. "
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    ABSTRACT: Background: Bariatric surgery is the most effective treatment for the reduction of weight and resolution of type 2 diabetes mellitus (T2 DM). The objective of this study was to longitudinally assess hormonal and tissue responses after RYGB. Methods: Eight patients (5 with T2 DM) were studied before and after RYGB. A standardized test meal (STM) was administered before and at 1, 3, 6, 9, 12, and 15 months. Separately, a 2-hour hyperinsulinemic-euglycemic clamp (E-clamp) and a 2-hour hyperglycemic clamp (H-clamp) were performed before and at 1, 3, 6, and 12 months. Glucagon-like peptide-1 (GLP-1) was infused during the last hour of the H-clamp. Body composition was assessed with DXA methodology. Results: Enrollment body mass index was 49±3 kg/m(2) (X±SE). STM glucose and insulin responses were normalized by 3 and 6 months. GLP-1 level increased dramatically at 1, 3, and 6 months, normalizing by 12 and 15 months. Insulin sensitivity (M of E-clamp) increased progressively at 3-12 months as fat mass decreased. The insulin response to glucose alone fell progressively over 12 months but the glucose clearance/metabolism (M of H-clamp) did not change significantly until 12 months. In response to GLP-1 infusion, insulin levels fell progressively throughout the 12 months. Conclusion: The early hypersecretion of GLP-1 leads to hyperinsulinemia and early normalization of glucose levels. The GLP-1 response normalizes within 1 year after surgery. Enhanced peripheral tissue sensitivity to insulin starts at 3 months and is associated with fat mass loss. β-cell sensitivity improves at 12 months and after the loss of ≈33% of excess weight. There is a tightly controlled feedback loop between peripheral tissue sensitivity and β-cell and L-cell (GLP-1) responses.
    Surgery for Obesity and Related Diseases 08/2014; 10(6). DOI:10.1016/j.soard.2014.07.011 · 4.07 Impact Factor
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    • "Some studies also report reduced food reward post-surgery (Shin and Berthoud, 2011; Miras et al., 2012) but this reduction is not detected by others (Mathes et al., 2012). The effect of bariatric surgery on the GLP-1 system is also well-established (Cummings, 2009). The peripheral GLP-1 system is more responsive to both meals and alcohol after bariatric surgery (Davis et al., 2012b). "
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    ABSTRACT: Glucagon-like-peptide-1 (GLP-1) and its long acting analogs comprise a novel class of type 2 diabetes (T2D) treatment. What makes them unique among other T2D drugs is their concurrent ability to reduce food intake, a great benefit considering the frequent comorbidity of T2D and obesity. The precise neural site of action underlying this beneficial effect is vigorously researched. In accordance with the classical model of food intake control GLP-1 action on feeding has been primarily ascribed to receptor populations in the hypothalamus and the hindbrain. In contrast to this common view, relevant GLP-1 receptor populations are distributed more widely, with a prominent mesolimbic complement emerging. The physiological relevance of the mesolimbic GLP-1 is suggested by the demonstration that similar anorexic effects can be obtained by independent stimulation of the mesolimbic and hypothalamic GLP-1 receptors (GLP-1R). Results reviewed here support the idea that mesolimbic GLP-1R are sufficient to reduce hunger-driven feeding, the hedonic value of food and food-motivation. In parallel, emerging evidence suggests that the range of action of GLP-1 on reward behavior is not limited to food-derived reward but extends to cocaine, amphetamine, and alcohol reward. The new discoveries concerning GLP-1 action on the mesolimbic reward system significantly extend the potential therapeutic range of this drug target.
    Frontiers in Neuroscience 10/2013; 7(7):181. DOI:10.3389/fnins.2013.00181 · 3.66 Impact Factor
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    • "Bariatric surgery includes a number of surgical procedures that alter the gastrointestinal tract primarily for the purpose of producing weight loss that in turn, may also induce T2DM remission. Weight loss is believed to be the primary mechanism by which restrictive bariatric procedures improve T2DM; however, it is increasingly clear that the gut plays a role in glucose homeostasis, by influencing insulin secretion and possibly sensitivity; and procedures that include an intestinal bypass probably improve glucose control by influencing multiple gastrointestinal pathways in complementary ways [6]. A recent meta-analysis of 621 randomized trials and observational studies published by Buchwald et al. indicates that bariatric surgery has profound and potentially long-lasting effects on T2DM [7]. "
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    ABSTRACT: Although all weight-loss approaches may improve insulin sensitivity in type 2 diabetes, bariatric surgery is believed to be the only reliable means of achieving diabetes remission. We conducted a retrospective cohort study to compare rates of diabetes remission, relapse and all-cause mortality among severely obese individuals with diabetes who underwent bariatric surgery vs. nonsurgically treated individuals. Severely obese adults with uncontrolled or medication-controlled diabetes who underwent bariatric surgery or received usual medical care from 2005 to 2008 in three health care delivery systems in the United States were eligible. Diabetes status was identified using pharmacy, laboratory, and diagnosis information from electronic medical records. A propensity approach and exclusion criteria identified 1395 adults with diabetes who had bariatric surgery and 62,322 who did not. Most procedures were Roux-en-Y gastric bypass (72.0% laparoscopic; 8.2% open); 4.4% were gastric banding, 2.4% sleeve gastrectomy, and 13.2% were other procedures. At two years, bariatric subjects experienced significantly higher diabetes remission rates [73.7% (95% CI: 70.6, 76.5)] compared to nonsurgical subjects [6.9% (95%CI: 6.9, 7.1)]. Age, site, duration of diabetes, hemoglobin A1c level, and intensity of diabetes medication treatment were significantly associated with remission. Bariatric subjects also experienced lower relapse rates than nonsurgical subjects (adjusted HR: 0.19; 95% CI: 0.15–0.23) with no higher risk of death (adjusted HR: 0.54; 95% CI: 0.22–1.30). We conclude that bariatric surgery can effectively induce remission of diabetes among most severely obese adults, and this treatment approach appears to be superior to nonsurgical treatment in inducing diabetes remission.:
    Obesity Research & Clinical Practice 07/2013; 7(4):e235-320. DOI:10.1016/j.orcp.2012.08.196 · 1.18 Impact Factor
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