Type 2 Diabetes Mellitus: An Operable Disease?

by Ricardo Cohen, MD

Introduction
Type 2 diabetes mellitus (T2DM) is a major cause of death in the world given its relation to kidney failure, blindness, amputations, heart attack, and other conditions such as erectile dysfunction, diarrhea, and gastroparesis.1 Medical therapy for this disease has advanced considerably but still leaves a majority of patients susceptible to its severe effects. While new drug therapies continue to improve medical therapy for this disease, a majority never reach the defined targets for success.

RATIONALE FOR THE SURGICAL TREATMENT OF T2DM
Results following bariatric surgery. Clinical resolution of T2DM, usually defined as independence from all antidiabetic medications, was reported to occur in 48 percent of patients after adjustable gastric banding (AGB), 84 percent after Roux-en-Y gastric bypass (RYGB), and 98 percent after biliopancreatic diversion (BPD). T2DM resolution in AGB is proportional to weight loss. The remarkable resolution of diabetes after RYGB and BPD typically occurs too fast to be accounted for by weight loss alone, suggesting that there may be a direct and more profound impact on glucose homeostasis. The antidiabetic effect of bariatric surgery is long-lasting. Long-term control of glycemia and normal levels of glycosylated hemoglobin after RYGB have been documented in large series with up to 14 years of follow-up.2-4

While T2DM is often associated with obesity, this relationship is highly dependent on geographic location. The average body mass index (BMI) of a T2DM patient in the United States is 30, while in India the average is 27. Despite its efficacy with respect to weight loss and resolution of comorbid health conditions, bariatric surgery is, in theory, less desirable for normal or overweight patients. Bariatric operations have occasionally been performed in non-morbidly obese individuals. Cohen et al5 recently published the surgical treatment of 37 patients outside the standard 1991 NIH surgical indications, with BMIs varying from 32 to 35, all with T2DM among other comorbidities. These patients underwent laparoscopic RYGB and all had remission of their diabetes.

The final common pathway of current and past surgical experience with regard to diabetes resolution seems to be duodenal bypass, although there is some degree of swifter food delivery to the distal intestine in both RYGB and BPD. Eventually, amelioration of T2DM can be accounted for by the well-known effect of weight loss to increase insulin sensitivity, thereby decreasing glucotoxicity and lipotoxicity and improving b-cell function; but, again, T2DM remission usually occurs days or weeks after RYGB or BPD.

So, if T2DM resolution occurs long before considerable weight loss, it is long-lasting. So why not offer it to lower BMI patients?

Potential mechanisms for glycemic control. Regardless of the molecular explanation, which still remains to be elucidated, it is very important to understand which part of the typical anatomical rearrangement of RYGB/BPD is essential for the resolution effect on diabetes. Two mechanisms have been proposed, based on some elegant animal studies. The foregut or upper intestinal mechanism6-7 holds that the exclusion of the duodenum and proximal jejunum from the transit of nutrients may prevent the secretion of a putative signal that promotes insulin resistance and leads to T2DM control. An alternative proposal, the hindgut or distal intestinal mechanism,8 justifies T2DM remission that results from the expedited delivery of nutrient chyme to the distal intestine, enhancing a physiologic signal that improves glucose metabolism. A potential candidate mediator of this effect is GLP-1 and/or other distal gut peptides. Although no obvious candidate molecules can be identified with current knowledge, if proven true, those theories might open new avenues in the search for the cause and cure of diabetes.

Recently, a French group conducted an animal study9 that compared the effects of two types of surgery, a purely restrictive procedure (gastric banding) and duodenal exclusion, on T2DM control. The duodenal exclusion group specifically reduced food intake and increased insulin sensitivity as measured by endogenous glucose production. Intestinal gluconeogenesis increased after the duodenal exclusion procedure, but not after gastric banding. This provides mechanistic evidence that rearranging the upper gut anatomy produces a beneficial effect on food intake and glucose homeostasis involving intestinal gluconeogenesis independent of GLP1 levels or weight change. The study considered an important hepatoportal sensoring pathway.

Cure, Control, or Remission?
T2DM has a very complex pathophysiology. It includes inadequate hepatic glucose production, genetics, pancreatic amyloid deposition, insulin resistance, and lack of incretin effect through several mechanisms. It is very difficult to fully understand all mechanisms related to how surgery may contribute to improve T2DM. The term cure should never be used when describing the postoperative outcomes. Control or remission are more appropriate. Surgery, as all in other forms of treatment, should be interpreted as complementary and not exclusive therapies. It should never be forgotten that some drugs and even insulin may be very helpful in achieving T2DM control, mainly in the early postoperative period. Among them, metformin, pioglitazone, and sulphonylureas may be necessary to help mantain good blood glucose levels.

Recent Human Reports (Duodenal jejunal bypass (DJB)). A case report by Cohen et al10 published in early 2007—a step toward extending animal studies’ findings into the clinical arena—reported two cases of patients with diabetes who underwent DJB. The patients were overweight or mildly obese, with BMIs of 29 and 30.3kg/m2. Their diabetes was not particularly longstanding (2 and 7 years, respectively), and was treated before surgery with insulin plus metformin in one case and with rosiglitazone in the other. Although no preoperative laboratory data were shown, evaluations at one week, one month, and thereafter at monthly intervals for nine months demonstrated rapid and unequivocal improvements in several simple measures of glucose control. Fasting blood sugars were initially in the diabetic range (148 and 178mg/dL), but they decreased steadily after surgery, reaching nondiabetic values by one month and remaining at 100mg/dL throughout postoperative Months 3 through 9. Similarly, fasting insulin levels started high (27 and 29mmol/L) but declined quickly and progressively after surgery, remaining at levels typical of persons without diabetes (approximately 5mmol/L) throughout postoperative Months 3 through 9. Reflecting the improvement in glycemia, hemoglobin A1c values fell from diabetic (8%–9%) to normal (5%–6%) values by three months, and they remained equally low thereafter during the remaining six months of observation.

One patient was discharged a few days after surgery without any diabetes medications and the other had discontinued diabetes medications by five weeks after surgery. In short, both patients converted from having poorly controlled diabetes, despite being on medications, to having normoglycemia and being off of all such medications. A key finding was that this salutary transformation occurred with no weight loss in either patient. At our facility, we continue to enroll patients in our investigational study. So far, nearly 90 patients have submitted to DJB, with BMI ranging from 22 to 34. Those who have had a longer follow-up, from 9 to 12 months, have shown 78-percent full remission or improvement of T2DM, regardless of weight loss or gain. There is no doubt that these findings are a strong paradigm shift in the treatment of patients with diabetes.

In this series, there have been strong responders—patients without either insulin or medications who actually regained weight after surgery but are still diabetes-free, with no significant increase of GLP-1 levels. There are several unanswered questions in the mechanism of action of diabetes control after rearranging the upper gastrointestinal anatomy.

Recently, we performed a “sleeved duodenal exclusion” in 17 patients, by adding a sleeve gastrectomy with a 40G bougie. This step turned the 20-percent nausea and vomiting incidence rate to virtually zero in the early postoperative period. Interestingly, it was found that, with a follow-up raging from 3 to 8 months, adding the sleeve gastrectomy does not add any weight loss to this leaner group, and carries thus far around 81 percent of T2DM remission. We believe that resecting the stomach longitudinally and removing one of the major ghrelin production sites—the gastric fundus—may lead to a swifter gastric emptying. Preserving the pylorus is likely to be very important in decreasing the glycemic peaks after food ingestion, leading to a better first phase insulin response and better glycemic outcomes.

Is BMI as Important as Thought?
There is no doubt that the findings described here are a strong paradigm shift in the treatment of patients with diabetes. In our series, there have been strong responders—as mentioned, these are patients without either insulin or medications who actually regained weight after surgery, but are still diabetes-free. In fact, BMI alone is not an ideal tool to accurately evaluate the risk–benefit ratio in patients with diabetes. Presently, there is no scientific evidence that a clear BMI threshold can distinguish between patients for whom surgery can resolve diabetes and patients in whom surgery would be ineffective.

Conclusions
Conventional gastrointestinal operations for morbid obesity have been shown to dramatically improve T2DM, resulting in normal blood glucose and HbA1c levels with discontinuation of all diabetes-related medications or insulin. Often, the return to fasting euglycemia and normal levels of postprandial and regular insulin levels are observed within days or weeks after surgery, suggesting that weight loss alone cannot entirely explain why surgery improves diabetes. Although there is clear and rapid amelioration of diabetes symptoms, the withdrawal of medication and insulin has to be balanced and slow.

Recent experimental studies illustrate that the rearrangement of the gastrointestinal anatomy is a primary mediator in the surgical control of diabetes. The same outcomes have been reported in humans in investigational trials. These findings raise the possibility that putative mechanisms from the proximal small bowel may be implicated in the pathophysiology of T2DM. Together, these data suggest a novel revolutionary concept about an old disease: T2DM may be an operable intestinal illness.

References
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8. Strader AD, Vahl TP, Jandacek RJ, et al. Weight loss through ileal transposition is accompanied by increased ileal hormone secretion and synthesis in rats. Am J Physiol Endocrinol Metab. 2005;288:E447–E453.
9. Troy S, Soty M, Ribeiro L, et al. Intestinal gluconeogenesis is a key factor for early metabolic changes after gastric bypass but not after gastric Lap-Band in mice. Cell Metabolism. 2008;8:201–211.
10. Cohen R, Schiavon CA, Pinheiro JC, et al. Duodenal-jejunal bypass for the treatment of type 2 diabetes in patients with body mass index of 22–34 kg/m2: a report of two cases. Surg Obes Relat Dis. 2007;3:195–197.

Category: Commentary, Past Articles