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Is Type 2 Diabetes an Operable Intestinal Disease?
The antidiabetic effect of GI bypass surgery is not unique to obese individuals, and weight loss/decreased caloric intake cannot entirely explain why surgery improves type 2 diabetes.
By Francesco Rubino, MD
The lifetime risk of developing type 2 diabetes by 2025 will be close to 20%.1 Clearly, the epidemic requires that new approaches to better understand and treat type 2 diabetes, be studied.
Conventional therapy cannot as of yet cure the progressive disease of type 2 diabetes. Today, however, a growing body of evidence points to remission of diabetes (long-term restoration of normal glycemia and A1C levels without medications) following bariatric surgery.2-5 Patients frequently return to euglycemia within days of surgery,5 a finding that suggests weight loss alone is not responsible for diabetes improvement. Experimental studies have revealed that a change to the gastrointestinal (GI) anatomy is the primary mediator of surgical control of diabetes.6 Although the exact molecular explanation is not yet clear, it may be that GI bypass operations can correct dysfunctional intestinal mechanisms responsible for glucose homeostasis abnormalities. It may be time to consider a new paradigm in which type 2 diabetes is characterized as an intestinal disease that is potentially amenable to surgical treatment. The author discussed this topic in a recent Diabetes Care article (2008;31[Suppl 2]:S290–S296); below is a summary.
TYPE 2 DIABETES AS AN INTESTINAL DISEASE
Diabetes rapidly resolves following Roux-en-Y gastric bypass (RYGB) and biliopancreatic diversion (BPD). Experimental rodent studies suggest diabetes control following GI bypass operations is a direct consequence of a change in the GI anatomy and not due to decreased caloric intake and resulting weight loss alone. The GI tract appears to play an important role in energy homeostasis, a finding consistent with evidence that many gut hormones are involved in glucose homeostasis.
It seems reasonable that anatomical rearrangements of the GI tract cause changes in energy and glucose homeostasis and that it in turn influences diabetes. It is important to understand whether this occurs as the effect of changes that improve glucose homeostasis per se or as the result of reversing abnormalities of glucose metabolism. The latter implies that the GI tract itself plays a role in diabetes pathophysiology.
The procedure ileal interposition (interposition of an isolated segment of ileum into the jejunum) increases glucagon-like peptide (GLP)-1 and peptide YY (PYY) levels in rodents.7 This may be due to early stimulation of the distal small bowel with relatively undigested nutrients.8 Increased GLP-1 and PYY levels may improve insulin secretion and action. De Paula and colleagues9 reported early outcomes of ileal interposition in humans that suggest the operation may improve diabetes. Long-term data are not yet available, however.
It has also been speculated that RYGB similarly controls diabetes, however, its more complex anatomy suggests different or additional mechanisms at work. Unlike RYGB, ileal interposition preserves gastroduodenal continuity enroute with the transit of food. In RYGB, nutrients empty into the mid- or distal jejunum, not in the ileum, as in ileal interposition.
DJB AS A MODEL OF RYGB
Our group investigated the mechanisms of action of the GI bypass procedures using duodeno-jejunal bypass (DJB) as a model of RYGB. There are two hypotheses regarding which part of the RYGB anatomical rearrangement plays a role in diabetes. According to the hypothesis of the distal bowel, diabetes control results from the expedited delivery of nutrient chyme to the distal intestine, enhancing a response that improves glucose metabolism.10,11 This effect may be mediated by GLP-1 and/or other distal gut peptides. The hypothesis of the proximal intestine says that exclusion of the duodenum and proximal jejunum from the transit of nutrients may prevent secretion of a putative signal that promotes insulin resistance and type 2 diabetes.12,13 This hypothesis implies that the proximal small intestine is directly involved in the etiology of insulin resistance.
We performed a study that supports the proximal hypothesis.14 DJB greatly improves diabetes in Goto-Kakizaki (GK) rats. Performing an equivalent shortcut for ingested nutrients to the hindgut, however, without excluding nutrient flow through the proximal intestine (via a simple gastrojejunostomy), does not improve diabetes in the same animal model. Diabetic abnormalities of glucose tolerance return in animals receiving DJB when nutrient flow through the proximal intestine is surgically reestablished via the normal route, even though the gastrojejunostomy is preserved. In animals that originally underwent a simple gastrojejunostomy without benefits, diabetes was improved by a reoperation that excluded the proximal intestine from nutrient flow but with the gastrojejunostomy left intact. We showed that isolating a segment of proximal intestine from nutrient flow is important in mediating the improvement of glucose tolerance after GI bypass procedures. These results support the hypothesis that a putative factor originating in the proximal small bowel may impair insulin sensitivity in individuals with diabetes.
Preventing duodenal passage of nutrients by GI bypass operations improves glucose tolerance only in patients with diabetes. It is detrimental for glucose homeostasis when performed in healthy individuals, however. These findings are consistent with the possibility that surgical bypass of the proximal small intestine reverses a putative intestinal mechanism characteristic of diabetes. Therefore, type 2 diabetes might be characterized by a component of duodenal-jejunal dysfunction.
"ANTI-INCRETIN" THEORY
The "anti-incretin" theory helps explain how duodenal exclusion improves diabetes and the possible contribution of the proximal small bowel to the pathophysiology of diabetes.5,13,14 The entero-insular axis viewpoint is based on the concept of incretins. Gastric inhibitory peptide (GIP) and GLP-1 are known incretins that have overlapping actions on beta-cells. These incretin actions include enhancement of glucose-stimulated insulin secretion, beta-cell growth, and improved insulin action.15-17 The incretin system promotes actions that can lead to hypoglycemia.
It is reasonable to consider a counterregulatory mechanism stimulated by the same passage of nutrients. An anti-incretin system would have opposite actions, such as decreased insulin secretion, reduced insulin action, and reduced beta-cell growth. These actions would prevent postprandial incretin-induced hypoglycemia.
Currently there are no candidates for the anti-incretin role. It should be noted, however, that GIP action and the expression of its receptor are defective in diabetic patients.17,18 Early-phase insulin secretion after glucose stimulation, which is regulated by GIP,19 is blunted in people with type 2 diabetes.20 These abnormalities are consistent with a potential proximal anti-incretin factor interfering with the GIP system. The reversal of the alteration of the early phase of insulin secretion after RYGB35 suggests a possible return to normal GIP functions. Further research in this direction is necessary.
IS TYPE 2 DIABETES AN OPERABLE DISEASE?
A meta-analysis that examined 136 studies of 22,094 patients showed that type 2 diabetes was completely resolved in 76.8% and resolved or improved in 86.0% of patients who had bariatric surgery.21 Complete remission of diabetes occurred in 48% of patients after laparoscopic gastric banding, 84% after RYGB, and >95% after BPD.21 The remission of diabetes after RYGB and BPD was durable, and recurrence was rare.22 Remission of diabetes after laparoscopic gastric banding typically occurred over several weeks to months,23 consistent with the consequences of weight loss, but RYGB and BPD can cause complete remission of diabetes within days to weeks after surgery, long before substantial weight loss.4,5
Why is bariatric surgery effective in controlling diabetes? A simple explanation would be that it works by inducing massive weight loss in patients who are morbidly obese, thereby eliminating the obesity that puts the patient at risk for diabetes. Therefore, diabetes should remit only when this type of surgery is performed on obese individuals and as a consequence of substantial weight loss.
To investigate this, we conducted an experimental study in GK rats.6 We found that a stomach-preserving DJB dramatically improved fasting glycemia and glucose tolerance, independent of weight loss and/or decreased caloric intake. This study was the first to show that the antidiabetic effect of GI bypass surgery is not unique to obese individuals and that weight loss/decreased caloric intake cannot entirely explain why surgery improves type 2 diabetes.
Preliminary studies appear to confirm these findings in humans. Cohen et al24 performed DJB to treat diabetes in two patients who were not morbidly obese. The operation did not cause significant changes in body mass index (BMI) and body weight, however, these patients had normal glucose and A1C levels. Remission of diabetes in patients who were not morbidly obese has also been reported after RYGB and BPD,25-27 as well as diabetes improvement and/or remission after gastrectomy and partial gastric resections.28
These data show that GI bypass operations (Figure 1) can achieve diabetes control by mechanisms that are independent of the treatment of obesity and surgically induced weight loss.
DIABETES SURGERY—NOT JUST BARIATRIC SURGERY
Using surgery explicitly to treat diabetes is a revolutionary concept and represents a major change in current therapeutic paradigms. Scientific data, however, suggest that a surgical approach offers much promise.
A meta-analysis by Buchwald and colleagues21 showed that RYGB results in an average of 50% to 60% long-term excess weight loss. This shows that after bariatric operations, patients rarely return to an entirely normal condition. Many patients remain overweight or frankly obese and fail to achieve complete remission of their obesity. This is in contrast with the evidence that >80% of RYGB patients and >90% of BPD patients have a complete sustained remission of type 2 diabetes. Considered in terms of its ability to induce disease remission, RYGB (and BPD) appear more effective in treating diabetes than obesity. Therefore the definition of bariatric operations might be inadequate to define surgical procedures that result in more than just weight loss. Perhaps the definition of diabetes surgery should be considered for operations performed on type 2 diabetes patients, regardless of their degree of obesity.
CLINICAL TRIALS OF DIABETES SURGERY
Choosing surgery to treat type 2 diabetes must be based on a careful evaluation of the risk-to-benefit ratio, as there are risks associated with the procedures. Micronutrient deficiency and potential long-term complications of GI bypass procedures29 must be considered. Much data are available regarding the long-term efficacy and morbidity of surgery in morbidly obese patients, however, the experience in patients with less severe obesity is modest. Clinical trials are needed to evaluate whether or not surgery may be preferable to other treatment options. We should not, however, ignore the opportunity offered by surgery, at a time when a medical cure is not available and diabetes grows at epidemic rates.
It has been proposed that the standard BMI cutoff of 35 kg/m² for bariatric surgery30,31 should be lowered to 30 kg/m² in patients with diabetes. This strategy reflects the misleading and inaccurate idea that surgical treatment of type 2 diabetes is an extension of bariatric surgery. It will be necessary to use limited BMI ranges when including patients in future clinical trials of diabetes surgery, however, the aim of such studies should be to find better criteria for patient selection and for changing the focus from BMI to diabetes-specific parameters.
THINGS TO CONSIDER
BMI alone is not ideal to accurately evaluate the risk-to-benefit ratio of surgery in patients with diabetes. At this time, there is no scientific evidence that any clear BMI cutoff can distinguish between patients in whom surgery can resolve diabetes and patients in whom surgery would be ineffective for this purpose. Other parameters may better define both the risk from diabetes and the diabetes-related outcomes of surgery.
Large clinical series have revealed that the relatively few patients whose diabetes does not completely resolve after RYGB have had the disease for >8 to 10 years and required more insulin to maintain glycemic control before surgery.4,5 These findings suggest that end-stage beta-cell failure, characteristic of longstanding type 2 diabetes, may render these patients' condition irreversible. A surgical approach should be offered early in the natural course of the disease.
There is evidence from both animal studies and clinical series that GI bypass procedures do not cause significant body weight loss when performed in individuals with normal body weight and BMI.6,32 DJB can achieve adequate diabetes control in overweight patients (BMI, 29–30 kg/m²) without causing significant weight loss,24 and BPD also has been reported to resolve type 2 diabetes in lean individuals without any weight loss.27
Another question for clinical trials is which bariatric operation is best suited to treat diabetes. Randomized clinical studies are needed to properly answer this question; however, it is clear that some procedures have greater potential efficacy (RYGB, BPD) than others. Future research may also help devise new surgical operations that could retain the benefit on diabetes without the potential drawbacks of current bariatric procedures. New approaches and devices may have potential for diabetes treatment and could further minimize the invasiveness of interventional diabetes therapy.
CONCLUSIONS
Type 2 diabetes is a medically incurable disease. Even though there have been tremendous advancements in the pharmacological treatment of the condition, overall, it remains a poorly controlled disease. A growing body of evidence, however, appears to indicate that type 2 diabetes can be treated surgically. This not only provides a new opportunity to develop new and more effective therapies, but it may also facilitate research that can better clarify our understanding of the etiology of the disease itself. It is time to consider a novel concept about an old disease.
Francesco Rubino, MD, is Chief of the Section of Gastrointestinal Metabolic Surgery, Department of Surgery, Weill Medical College of Cornell University-New York Presbyterian Hospital, and the Department of Surgery, Catholic University of Rome, Italy. He may be reached at frr2007@med.cornell.edu.
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