How bariatric and metabolic operations control metabolic syndrome

Metabolic syndrome is a term for several interrelated diseases, including obesity, type II diabetes, dyslipidaemia and hypertension, that result in coronary, peripheral and cerebral atherosclerosis and premature death. Medical therapies exist for each component, but they are often not durable, especially for obesity. At best they offer a lifetime of costly medications. Metabolic and bariatric operations provide single interventions with a high percentage of resolution of the clinical and biochemical manifestations of the metabolic syndrome. Understanding the mechanisms by which these procedures work could lead to new treatments. It is becoming increasingly appreciated that the effects of metabolic and bariatric surgery, in particular with regard to co-morbidities, are due not only to forced caloric restriction but also to more sophisticated neurohormonal mechanisms. In essence, bariatric surgery is metabolic surgery1. A meta-analysis in 2004 revealed a mean excess weight loss of 61·2 per cent, with a gradation from 47·5 per cent for gastric banding, to 61·6 per cent for gastric bypass and 70·1 per cent for biliopancreatic diversion (BPD)/duodenal switch (DS)2. Restrictive procedures limit caloric intake, but they may alter afferent vagal impulses to the hypothalamus3, change the foregut hormonal balance4, and remove or exclude the fundic gastric pacemaker5. Restrictive/malabsorptive procedures also invoke hindgut hormonal changes, including accelerated and possibly enhanced secretion of the hormones glucagon-like peptide (GLP) 1 and pancreatic polypeptide Y4. The impact of surgery on type II diabetes was noted by Scopinaro and colleagues6 as early as 1986 and detailed by Pories and co-workers7 in 1995. A recent meta-analysis showed that the percentage resolution of type II diabetes was proportional to the percentage of excess weight lost. This was least for gastric banding (56·7 per cent), rising to 80·3 per cent for gastric bypass and 95·1 per cent for BPD/DS8. These results were maintained after 2 years. Experimental metabolic procedures have demonstrated that type II diabetes, however, can be resolved by intestinal surgery with minimal or no weight loss, such as duodenojejunal exclusion9 or bypass10 and gastric electrode implantation11. Type II diabetes is a disease of disordered insulin secretion in a setting of peripheral insulin resistance. Patients with type II diabetes are known to have an impaired incretin response (the difference in secretion of insulin after orally ingested versus intravenously administered glucose). The reputed stimulatory hormone for this incretin effect is GLP-1, secreted by the L cells of the hindgut. GLP-1 stimulates insulin secretion by the islet cells of the pancreas. GLP-1 has other functions, including a decrease in hepatic gluconeogenesis, decreased hunger mediated by the ventromedial hypothalamus, and partial glucagon blockade12. When intestinal transit time is increased, subsequent to gastric bypass, BPD or DS, as well as experimental procedures such as duodenojejunal bypass, GLP-1 is released earlier with a significant increase in the incretin effect of nearly 40 per cent13. Bypass of the duodenum also diminishes circulating gastrointestinal inhibitory peptide, which has an incretin effect opposite to that of GLP-1. There was a 79·3 per cent overall improvement in dyslipidaemias in the 2004 meta-analysis, again parallel to the weight response and the type of surgery employed; it was least after gastric banding (58·9 per cent) and highest after BPD/DS (99·1 per cent)2. Levels of total plasma cholesterol, low-density lipoprotein-cholesterol and triglycerides all decreased markedly. The Swedish Obese Subjects (SOS) study, in a non-operative matched-pair analysis, demonstrated a tenfold decrease in the incidence of hyperlipidaemia at 2 years14. The partial ileal bypass is a non-bariatric, solely metabolic procedure, and the Program on the Surgical Control of the Hyperlipidemias (POSCH) trial clearly demonstrated its effects15 and mechanisms to explain these outcomes16. Excluding the terminal 200 cm of ileum breaks the cholesterol and bile acid enterohepatic cycles, decreases cholesterol and bile acid absorption and reabsorption, and increases faecal cholesterol and bile acid excretion, leading to a compensatory increase in cholesterol synthesis and cholesterol turnover. This decreases the freely miscible cholesterol pool in plasma and liver, and the less freely miscible pool that includes the arterial intima. A study of patients who had undergone BPD showed that the procedure depleted intramyocellular lipid stores and induced metabolic normalization while the patient remained obese17. Depletion of circulating free fatty acids decreases their transfer to hepatocytes, and lowers peripheral insulin resistance and glucose-induced insulin secretion18. The effects of surgery on hypertension are no less dramatic. The 2004 meta-analysis demonstrated a 61·4 per cent rate of resolution of hypertension, rising to 78·5 per cent if improvement in hypertension was considered2. Blood pressure changes were independent of the degree of weight loss and, thereby, the operations used. In the longer follow-up of the SOS study, a return to baseline blood pressure levels was observed over time14. A number of potential mechanisms for the metabolic or bariatric effects of surgery on hypertension have been proposed19. There is some degree of gradual rate of failure after metabolic and bariatric surgery with respect to obesity, type II diabetes, dyslipidaemia, hypertension and even the full-blown metabolic syndrome. Although disappointing, the initial success rate is extremely high and more than half of these patients maintain the benefits of surgery for longer than 5 years. Over 300 000 metabolic and bariatric procedures are performed annually worldwide. Each patient offers the opportunity for human research, at no or minimal risk, to increase our knowledge of the mechanisms responsible for the effects of bariatric and metabolic procedures. Perhaps a better understanding of how these operations work may lead to hybrid drug therapies whereby surgery and the drug effects are complementary, therapeutic and lasting. The authors are grateful to Dr Robert B. Dorman for his assistance, in particular with regard to data acquisition. The authors declare no conflict of interest.