Metabolic Outcomes in Bariatric Surgery: A Review

| April 6, 2009

by Deborah Abeles, MD; Sajani Shah, MD;
Scott A. Shikora, MD;
and Michael E. Tarnoff, MD

All are from the Center for Minimally Invasive Surgery, Tufts Medical Center, Boston, Massachusetts.

Obesity-related comorbidities have garnered much attention recently both in the surgical and medical literature. The constellation of elevated fasting glucose, blood pressure, triglycerides, waist circumference, and reduced high density lipoprotein coins the term metabolic syndrome. Individuals with these characteristics are at risk for cardiovascular disease as well as type 2 diabetes mellitus (T2DM).[1] Although each criterion of the metabolic syndrome can be treated individually with a variety of medications, the focus of treatment has been aimed toward its root causes: diet, sedentary lifestyle, and obesity.[1,2] Intensive lifestyle modifications, including self-monitored diets, exercise, and medications, produce modest weight loss that is hard to sustain. Moreover, adherence to these lifestyle changes may deteriorate soon after starting.[3]

Bariatric surgery, however, produces significant weight loss that is maintained, resulting in the improvement of many aspects of the metabolic syndrome. Here, we provide an evidenced-based review of the unique metabolic outcomes that have been achieved with bariatric surgery.

Hypertension
The mechanism of hypertension in the morbidly obese is not completely understood. Possible mechanisms include alteration in the renin-angiotensin-aldosterone system, increased sympathetic nervous system activity, development of insulin resistance, hyperleptinemia and leptin resistance, altered coagulation factors, inflammation, and endothelial dysfunction.[4] Weight loss achieved with lifestyle changes, such as increased physical activity, diet modification, and behavioral intervention groups, produces an improvement in hypertension. However, weight regain secondary to a decay in these behavioral modifications results in an increase in blood pressure to near baseline levels.[5]  In contrast to these modest and even short-lived results, numerous studies have reported 60- to 80-percent resolution or improvement of hypertension after bariatric surgery.[6,7] It has been hypothesized that the normalization of blood pressure is due to the amount of weight loss rather than the final postoperative weight.[8] Furthermore, the resolution of hypertension appears to be independent of the type of bariatric procedure performed (gastric banding, gastric bypass, gastroplasty, biliopancreatic diversion, or duodenal switch).[9] In addition, there seems to be a relationship between the length of pre-existing hypertension preoperatively and the likelihood for resolution after surgery. Patients with complete resolution of hypertension at one month and 12 months after gastric bypass had a shorter duration of disease as compared to those without resolution.[10] While lifestyle modifications may produce short-term improvement of hypertension, bariatric surgery can reliably improve and may even resolve hypertension.

Dyslipidemia
The dyslipidemia associated with obesity is characterized by increased fasting triglyceride and decreased high-density lipoprotein-cholesterol concentrations.[11] The insulin resistance associated with obesity also results in elevated free fatty acids secondary to hydrolysis of stored triglycerides in adipose tissues. Weight loss of approximately 0.5kg per week by diet alone can lead to a decrease in triglycerides, low-density lipoprotein, and total cholesterol— an overall improvement in the lipid panel. This is similar to results gleaned by the administration of fenofibrate.[12] It stands to reason that the decay in lifestyle modifications resulting in the elevation in blood pressure would also lead to a return of dyslipidemia. As weight loss associated with bariatric surgery is sustainable, the improvement in the lipid profile may be superior after surgery. Dixon et al has shown that the weight loss after gastric banding produces a decrease in fasting triglyceride levels, an elevation of high-density lipoprotein-cholesterol levels to normal, and an improved total cholesterol to high density lipoprotein-cholesterol ratio.[7] Although weight loss associated with bariatric surgery does improve dyslipidemia, the changes in the lipid panel appear to be procedure-dependent. Buchwald et al noted 90 percent improvement in cholesterol and triglyceride levels after gastric bypass or biliopancreatic diversion (or duodenal switch) as compared to 50-to 70-percent improvement with gastric banding and gastroplasty.[9] It appears that the malabsorptive aspect of these mixed procedures, in addition to the associated weight loss, plays an important role in improvement in the lipid profile of morbidly obese patients in contrast to weight loss secondary to restriction alone.

Obstructive Sleep Apnea
Approximately 60 to 70 percent of morbidly obese patients have sleep apnea, characterized by the partial or complete collapse of the upper airways during sleep leading to excessive daytime somnolence.[13,14] A modest weight loss of even 10 percent has been shown to improve sleep apnea, while weight gain can result in an elevation of the apnea-hypopnea index and worsening of sleep-disordered breathing.[15] Surgical weight loss, independent of the procedure performed, also leads to the resolution of sleep apnea.[9] Significant improvement in the mean oxygen saturation during the night, reduction in the apnea-hypopnea index, and improvement in daytime somnolence 24 months after gastric bypass have been reported in patients who lost a mean excess weight of 70 percent.[16] The causal relationship between weight gain and worsening sleep apnea directs treatment not only to nasal continuous positive airway pressure (CPAPs), but also to weight loss whether by medical or surgical means.

Type 2 Diabetes
The resolution of diabetes is defined as the ability to maintain a normal fasting blood glucose level and normal HbA1c without hypoglycemic medication. The rapid improvement of glucose tolerance as evidenced by normalization of serum glucose levels and an immediate drop in insulin levels can be seen following gastric bypass before any weight loss is achieved.[17] The resolution of type 2 diabetes is more prevalent after mixed malabsorptive/restrictive procedures, such as biliopancreatic diversion, duodenal switch, or gastric bypass, as compared to purely restrictive procedures, such as gastroplasty or gastric banding.[9] In the Swedish Obese Subjects study, weight loss after bariatric surgery was accompanied by a concomitant decrease in the incidence of type 2 diabetes at two years and 10 years after surgery.[18] Further, the reduction in mortality in the surgical arm versus the control was largely attributed to the decrease in cardiovascular death, which was likely due to weight loss and an improvement in comorbidities including type 2 diabetes.[19] Similar to the resolution of hypertension, the resolution of type 2 diabetes appears to be influenced by the duration and the severity of the disease prior to surgery. Patients who had a remission of their diabetes and a reduction in HbA1c after gastric bypass had a shorter mean preoperative duration of disease as compared with patients who did not have remission.[20] In severe and long lasting cases, it is likely that the number of surviving beta cells is low at the time of bariatric surgery and cannot compensate even after the restoration of normal insulin activity.[21] Although predicting remission is difficult, possible factors include short duration of disease and the presence of type 2 rather than type 1 diabetes.[20]

Hormonal changes have also been implicated in diabetes resolution after gastric bypass. The exact mechanism by which this occurs has not been completely elucidated. One such hormone is glucagon-like peptide 1 (GLP-1), which is secreted from enteroendocrine cells of the distal ileum. GLP-1 has multiple functions, including induction of insulin secretion, promotion of glucose uptake, suppression of endogenous glucose production, reduction of glucagon secretion, and inhibitor of beta cell apoptosis, thereby increasing beta cell mass.[22,23] It has also been shown to induce satiety by slowing gastric emptying and reducing appetite.[24] The literature on the changes in GLP-1 after bariatric surgery has revealed conflicting reports. Korner et al reported similar fasting levels of GLP-1 between gastric band patients and gastric bypass patients. However, postprandial peak levels were three times higher in gastric bypass patients as compared to band patients. In addition, the lower homeostasis model assessment of insulin resistance (HOMA-IR) in bypass patients is suggestive of greater insulin sensitivity.[25] Le Roux also reported a significant increase in postprandial GLP-1 and insulin levels after gastric bypass with a minimal increase in levels after gastric banding.[26] Others have also confirmed an increase in GLP-1 postprandial after gastric bypass despite no change in fasting levels.[27–29] This is in contrast to Reinehr, who reported a significant decrease in fasting GLP-1 levels after gastric bypass, as compared to band patients, concomitant with lower fasting insulin and glucose levels.[30] It is likely that the mechanism that controls fasting GLP-1 levels after bariatric surgery is different from those controlling postprandial levels. The changes in GLP-1 levels after bariatric surgery appear not to be related to weight loss alone, as evidenced by the different results reported after similar weight loss after gastric banding as compared to gastric bypass, but may be multifactorial.

Peptide YY is another gut hormone that is secreted from enteroendocrine cells in the distal ileum, similar to GLP-1. It is hypothesized that its main function is to increase satiety by suppressing intestinal motility and gastric emptying leading to reduced food intake.[31] Although changes in both fasting and postprandial levels have been seen after bariatric surgery, they appear to be inconsistent. Some authors have noted no change in fasting levels in patients exhibiting significant weight loss after gastric banding and gastric bypass.[27,32] Meanwhile, others have noted an increase in peptide YY levels after gastric banding, gastric bypass, and biliopancreatic diversion.[30,33] In contrast to inconsistent changes in fasting levels of peptide YY, postprandial levels appear to consistently increase after bariatric surgery. Numerous reports have noticed a significant increase in peptide YY levels in response to a meal after gastric bypass.[26,34] While a blunted postprandial response in patients who had received the gastric band has been reported, others have shown an increase in both fasting and postprandial levels after sleeve gastrectomy.[26,35] Although the reason for the differential peptide YY response among different bariatric procedures remains elusive, it appears that perhaps the type of surgery, and perhaps even some aspect of intestinal bypass, is more important than weight loss alone. Together, the theoretical increase in GLP-1 and peptide YY may explain the reduced caloric intake and improved glucose homeostasis after surgery.

Additional hormonal changes have been noted after gastric bypass that seem to correlate to the improvement in insulin sensitivity and the resolution of diabetes. These include a reduction in ghrelin levels, glucagon, adipocyte hormones, leptin, visfatin, fasting PP, acylation stimulating protein, and retinol binding protein 4.[36,37] Adiponectin, an adipocyte hormone, increases tissue sensitivity to insulin by promoting lipid uptake and oxidation in muscle and the inhibition of triglyceride synthesis in hepatocytes.[38,39] Increased levels have been reported after gastric bypass.[40,41] The exact mechanism by which these hormones improve insulin sensitivity is unclear. In addition, it is unknown whether their changes are dependent on the type of surgical procedure performed. Nevertheless, these hormones may serve as an additional potential neurohormonal mechanism for the resolution of diabetes after bariatric surgery.

Obese individuals have also been noted to have elevated c-reactive protein (CRP) and other cytokines reflective of a proinflammatory state that may contribute to insulin resistance.[42–45] Reduced levels of CRP have been reported after both gastric bypass and gastric banding.[37,43] In addition, a reduction in IL 6 has been noted after gastric bypass.[37] How these cytokines interact to potentially induce diabetes remains to be seen. In addition, it is unknown whether the cytokine changes are dependent on the type of surgical procedure performed.
Resolution of Metabolic Syndrome
As the obesity-related comorbidities improve or resolve after bariatric surgery, one would expect a concordant improvement in the metabolic syndrome. Nugent et al noted 39 percent of patients met the criteria for metabolic syndrome prior to surgery, whereas 10 percent met the same criteria at a mean followup of 10 months.[46] Others have also reported resolution of metabolic syndrome after bariatric surgery.[47–49] Arterburn et al reported an average 10-year cardiovascular risk (based on age, sex, blood pressure, smoking status, presence of diabetes, total cholesterol, and HDL) of 5.4 percent one year after gastric bypass as compared to a baseline of 6.7 percent, representing an absolute relative risk reduction of 1.3 percent.[50,51] However, the metabolic syndrome by itself does carry a significant cardiovascular morbidity and mortality. Varela et al reported a significantly higher overall morbidity after bariatric surgery in patients with metabolic syndrome as compared to those who did not meet the criteria.[52]

Conclusion
Bariatric surgery leads to the resolution of obesity-related comorbidities. The resolution of hypertension and obstructive sleep apnea appears to be procedure-independent and likely due to weight loss, while the resolution of diabetes and dyslipidiemia seems to be procedure-dependent and likely independent of weight loss alone in the case of gastric bypass and biliopancreatic diversion. Gastrointestinal, pancreatic, and adipocyte hormones have all been reported to change in response to bariatric surgery. However, the exact mechanisms by which these changes exert their effects still need to be
elucidated.

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Category: Past Articles, Surgical Perspective

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