Diabetes Resolution
Diabetes Resolution
Abstract & Commentary
By Peter Crookes, MD, FACS, Associate Professor of Surgery, Department of Surgery, USC. Dr. Crookes reports no financial relationship relevant to this field of study.
This article was peer reviewed by Helen Sohn, MD
Synopsis: This study shows that bypassing a short segment of proximal intestine directly ameliorates type 2 diabetes, independently of effects on food intake, body weight, malabsorption, or nutrient delivery to the hindgut.
Source: Rubino F, et al. The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes. Ann Surg. 2006;244:741-749.
Diabetic rats were subjected to 3 differing operative procedures in an attempt to isolate the gastrointestinal construction which is responsible for the resolution of diabetes. Rubino and colleagues reported that bypassing the duodenum and proximal jejunum is key in improving glucose tolerance in this species of diabetic rats. In order to reduce serum cholesterol, it was necessary to bypass the terminal ileum. Rubino et al discuss the relevance of these results to the current management of Type 2 diabetes mellitus.
Commentary
The discovery of insulin in 1921 by Banting and Best represents one of the great landmark medical advances in the 20th century, and the hope it offered to patients and their families was so far in advance of what was then available that the discoverers were awarded the Nobel Prize in 1923. In the past 80 years, diabetes mellitus has become many times more common, now affecting over 20 million persons in the USA,1 though it commonly presents in a less acute form in middle aged and older adults. However, the cumulative morbidity and mortality from the condition is enormous, such that it is estimated that 10 cents out of every dollar spent on health care in the United States is spent on diabetes and its sequelae.2
In the past decade, a new treatment has emerged which has equally profound repercussions for the treatment of diabetes, though no one has yet been awarded a Nobel Prize for discovering it: one of the serendipitous benefits of bariatric surgery, and specifically Gastric Bypass, is the capacity to cure diabetes mellitus.3 And by cure, I mean normalization of blood sugars and glycated hemoglobin (HbA1c) while being able to discontinue hypoglycemic medications and insulin. In the bariatric population, it is fairly clear that type 2 Diabetes Mellitus can be cured in about 70-80% of cases, and the care substantially simplified in the remainder: it has emerged that the longer the disease is present preoperatively, the lower the chances of success are, and that purely restrictive operations are less efficacious than bypass operations such as gastric bypass and biliopancreatic diversion.4-8
Many, perhaps the majority, of type 2 diabetic patients are obese.9 A smaller fraction is morbidly obese, and typically about 20-25% of patients presenting for bariatric surgery are diabetic. The ability to cure the majority of these patients is a very dramatic finding and one whose implications have yet to be realized by the endocrinological community. The most striking element of this phenomenon is that glucose tolerance after gastric bypass is frequently normalized long before any significant weight loss has occurred.
It is characteristic of many medical advances that there is pressure to put them into practice before they are understood. The introduction of anesthesia, antisepsis, blood transfusion, and the laparoscopic revolution in surgery, all demonstrate this pattern. Bariatric surgery is no exception. It is only recently that workers have begun to dissect out the elements of the common clinically available operations and attempt to discover what does what.
This paper by Rubino et al from Strasbourg, and collaborators from Rome and Seattle, marks a major step in understanding. They begin by reviewing the 2 major theories which explain the mode of action of gastric bypass: in the hindgut theory, it is postulated that the arrival of undigested food stimulates the release of one or more hormones from the ileum, the most promising of which are GLP-1 and Peptide YY, which have the capacity to improve glucose tolerance. GLP-1 is known to reduce appetite, to delay gastric emptying, and to reduce apoptosis in beta cells of the pancreatic islets. In contrast, a foregut theory hypothesizes that glucose tolerance is improved by diverting ingested nutrients away from the duodenum and proximal jejunum through the action of a hormonal mediator as yet uncharacterized.
Using a species of diabetic (Goto-Kakizaki) rats, Rubino et al performed 2 different operative procedures, one of which resembles the diversion produced by a gastric bypass, though not restricting the size of the stomach (duodenal-jejunal bypass, or DJB), and the second being a simple gastrojejunostomy (GJ), with the stomach joined to a loop of jejunum in the same location as that of a typical gastric bypass. The essential difference between these procedures is that the former diverted food away from the foregut, but the latter did not. In both operative procedures, undigested food had the same capacity to reach the mid jejunum and ileum. A third procedure, ileal bypass, was also studied to observe the effect on lipid metabolism: the ileum was divided and the proximal portion anastomosed to the right colon to bypass the terminal ileum.
The initial end points were body weight and measures of glucose tolerance. All animals initially lost weight and had reduced oral intake. Weight loss was similar for DJB and GJ rats. However, glucose tolerance markedly improved, as measured by the Oral Glucose Tolerance Test (Area under the curve and 30 minute and 60 minute peak for the DJB rats, but not for the GJ group). To study the phenomenon further, the rats then underwent a form of reversal of their procedure after four weeks. In the GJ group, the duodenum was divided, preventing food from passing into the duodenum and proximal jejunum: in this group, the glucose tolerance improved similarly to the DJB group. Rubino et al attempted to perform a gastrojejunostomy to restore a duodenal passage in the DJB rats but operative difficulty caused most of the rats to succumb. However, in the 2 animals who survived, glucose tolerance tests were markedly worsened.
In the rats subjected to the gastric procedures (DJB and GJ), there was little alteration in lipid metabolism. Only the group with ileal bypass had significant reduction in serum cholesterol.
This paper, therefore, provides strong evidence that passage of food through the duodenum and/or proximal jejunum is associated with a factor which worsens glucose tolerance and that a surgical reconstruction which diverts food away from this portion of the GI tract improves glucose tolerance. This factor has yet to be identified. Nevertheless, bypass of the foregut appears to be of critical importance compared with other operations producing similar weight loss.
The implications of this study are far reaching. We have already seen how the identification of GLP-1 as a mediator of improved glucose control has led to the development of synthetic analogues such as exenatide (Byetta), which was recently approved by the FDA as adjunctive therapy in the treatment of Type 2 diabetes. Experiments such as these reported by Rubino et al have the potential to uncouple the individual elements of the combined package and to separate the effect of surgery on body weight, glucose tolerance, and lipid metabolism. Not only may this lead to the development of novel therapeutic agents, but may also enable the development of operations which can be tailored to diabetics who are not morbidly obese, or to patients with hyperlipidemia who are not diabetic.
References
1 http://www.cdc.gov/diabetes/pubs/factsheet05.htm
2 http://www.cdc.gov/diabetes/pubs/estimates05.htm#costs
3 Pories WJ, et al. Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg. 1995;222:339-352.
4 Schauer PR, et al. Effect of Laparoscopic Roux-En Y Gastric Bypass on Type 2 Diabetes Mellitus. Ann Surg. 2003;238:467-485
5 Marceau P, et al. Biliopancreatic diversion with duodenal switch. World J Surg. 1998;22:947-954.
6 Scopinaro N, et al. Biliopancreatic diversion for obesity at eighteen years. Surgery. 1996;119:261-268.
7 Dixon JB, O'Brien PE. Health outcomes of severely obese type 2 diabetic subjects 1 year after laparoscopic adjustable gastric banding. Diabetes Care. 2002;25:358-363
8 Sjostrom C, et al. Reduction in incidence of diabetes, hypertension and lipid disturbances after intentional weight loss induced by bariatric surgery: the SOS Intervention Study. Obes Res. 1999;7:477-484.
9 http://www.cdc.gov/diabetes/statistics/comp/Fig7.htm
This study shows that bypassing a short segment of proximal intestine directly ameliorates type 2 diabetes, independently of effects on food intake, body weight, malabsorption, or nutrient delivery to the hindgut.Subscribe Now for Access
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