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#Diabetes and Endocrinology
Apart from a case report of successful remission of diabetes through surgery, in this article, we explain the rationale for achieving remission of diabetes mellitus (DM) by surgical manipulation of the gut endocrine axis, and present the scientific evidence available thus far in support of the same. The evolution of ‘metabolic’ surgery is presented here. The reduction in mortality and comorbidity is presented. The two main theories of causation of euglycemia are discussed in detail. Most authors now believe in both the theories, and the gastric bypass and the biliary pancreatic diversion are the procedures with the highest rate of remission. Finally, in the context of reappearance of hyperglycemia, the beneficial effects of a prolonged period of normal blood sugar are discussed.
Keywords: Diabetes mellitus, remission, gastric bypass, biliary pancreatic diversion
A 62-year-old male, known diabetic for the past 10 years, came to us for permanent remission of diabetes. His fasting and stimulated C-peptide levels were 2.2 IU and 6.8 IU, respectively (high levels); hence, a fit candidate for metabolic surgery. The patient’s body mass index (BMI) was 25.3, so we opted for sleeve gastrectomy + ileal transposition (SGIT), which is one of the recommended procedures for diabetic patients with lower BMI. After obtaining fitness from Diabetologist, Physician, Cardiologist and Anesthetist, patient was taken up for the procedure.
A loose sleeve gastrectomy (since weight loss should be minimum) + transposition of a 270 cm ileal segment to the mid jejunum level (Fig. 1) was performed laparoscopically. Postoperatively, the patient recovery was uneventful. His diabetic control was achieved within the first month and complete remission of diabetes mellitus was seen in the third month after surgery. After follow-up, he remains euglycemic without any oral hypoglycemic agents.
Ever since the monumental article in 1955, outlining the normalization of sugar levels after gastrectomy, a causal link between gut surgery and correction of diabetes was suspected. However, it was also attributed to the weight loss suffered by gastric cancer patients or the liver metastases interfering with hepatic glycogenolysis. Subsequently, an epoch-making article appeared in the Annals of Surgery (1995), documenting long-term control for both obesity and diabetes with a gastric bypass. Authored by Walter Pories, this paper analyzed results based on 14 years of gastric bypass surgery and 608 patients. This was a serendipitous finding in a cohort group that had the bypass but essentially as a weight reduction (bariatric) procedure. This was the first time that a direct link between gastric bypass surgery and blood sugar normalization was established. It was then believed by most surgeons and other researchers that the loss of weight, the reduction of caloric intake and the diminished insulin resistance accounted for these effects. However, the last 20 years of research into gastrointestinal endocrine molecules has completely changed the direction of surgical logic.
Based on the varied metabolic effects of these procedures, the American Bariatric Surgery Society renamed itself as the American Society of Metabolic and Bariatric Surgeons (ASMBS).
Let us study the available procedures:
- Gastric banding: In this procedure, a silastic or polyvinyl chloride (PVC) band is inserted 2 to 3 cms below the esophagogastric junction, causing a functional obstruction of the upper gastric segment, and restriction of food intake. It is not a very effective form of bariatric surgery and seems to have very little metabolic component. Although mild reductions of plasma glucose have been documented, its effects are more due to weight loss and resetting insulin resistance than due to a hormonal effect. Therefore, there will be no more discussion about this procedure in this article.
- Sleeve gastrectomy: In this increasingly popular procedure, a sleeve is made of the stomach by resecting the greater curvature and three-fourths of the left part of the stomach. This results in a maximal reduction of the gastric size, and also effects some endocrine changes by reducing serum levels of ghrelin. Although this operation was initially thought to be merely restrictive, we now know that it has a prominent role in endocrine manipulation.
- Gastric bypass: In this operation, the stomach is divided into a tiny proximal pouch and a large segment distally, which is bypassed. The proximal jejunum is divided 50 cm from the duodenojejunal flexure and the distal limb is anastomosed to the stomach (Fig. 2). The proximal jejunum is now anastomosed to the distal jejunum 100-150 cm from the site of the GJ. This operation has been proved to be the most efficacious to restore euglycemia.
- Ileal transposition: The newest of the procedures, interposing a considerable length of ileum within the proximal jejunum in an isoperistaltic manner, is a technique of incretin stimulation by the pathways described in greater detail later. The advantage of this operation is its use in lower BMI individuals, between 22 and 30 BMI. When used for higher BMI patients, a sleeve gastrectomy is added and the procedure is known as sleeve gastrectomy with ileal transposition (SGIT). However, compared to the sleeve and the bypass, this is still an experimental procedure.
Bariatric and Metabolic Surgery
Although the procedures described for bariatric and metabolic surgery are the same, the latter term is used specifically for lower BMI individuals undergoing surgery for control of diabetes, dyslipidemias, hypertension or any other component of the metabolic syndrome.
Weight loss per se leads to reduction in blood sugar, a common finding in obese or overweight patients with diabetes in the Indian subcontinent. Almost all diabetics undergoing metabolic surgery manifest normalization of sugars within 2-3 weeks of surgery, whereas weight loss takes several weeks or months to be achieved. There are two main pathophysiological theories put forth to explain the correction of diabetes in these patients. They are the foregut and the hindgut theories.
This theory was first propounded by Rubino et al. According to this group of workers, the mucosa of the duodenum, coming in contact with the food, releases glucagon, which accounts for immediate postprandial hyperglycemia, a consistent feature of the pre-diabetic and diabetic state. A number of studies have shown that excess glucagon, rather than insufficient insulin, is the major derangement in diabetes. Patients undergoing Roux-en-Y gastric bypass procedure (RGBP) exhibit minimal or no increase in serum level of glucagon in the postprandial phase. The ‘Rubino’ factor refers to the putative duodenal contact cell, which triggers off the glucagon release.
Recent advances: Based on the Rubino hypothesis, the newest noninvasive treatment for diabetes mellitus is a loose and floppy plastic sleeve that completely coats the duodenum up to the jejunum and is introduced endoscopically. This is known as the endo gastrointestinal barrier and is said to be the treatment of choice in the future for low BMI patients with diabetes mellitus.
Proponents of the hindgut theory of diabetes control after RGBP invoke a set of internal insulin like secretions known as incretins. These are released from specialized cells of the ileal mucosa (K and L cells), which release a peptide known as glucagon-like peptide-1 (GLP-1). The latter is one of the most powerful insulin agonists known to man. It increases the serum insulin by whipping the beta cells of the pancreas. It is also anti-apoptotic towards the beta cells, putatively prolonging their lifespan. Indeed, there have been a few cases reported of nesidioblastosis or idiopathic hypertrophy of the beta cells, which in post bypass cases is said to be mediated by GLP-1.
The other incretin that is released by the ileal cells as part of the “ileal brake mechanism” in response to early passage of semi-digested chyme into the distal reaches of the ileum, is the peptide called gastric inhibitory peptide (GIP).
Peptide YY (PYY) is another peptide that is released after gastric bypass. Both GIP and PYY have antiglucagon effects, effectively tipping the balance in favor of insulin and pro-insulin molecules. Incretins are especially involved in the immediate postprandial glucose-insulin synergy. It is notable that high incretin levels in the post bypass patients correlate positively with lower postprandial sugar levels. Most bariatric surgery protagonists subscribe to the combination of foregut and hindgut theories. What is beyond debate; however, is the rapid fall of blood sugars seen immediately after surgery. Figure 3 depicts the mechanism of correction of diabetes with surgery while Figure 4 shows the pathways of adiposity and satiety signals.
Time to Euglycemia
Significant weight loss occurs about 4 weeks after bariatric surgery, about 8-10 kg. The common statement of physicians that improved glycemic control is a direct result of weight loss, cannot hold water as normalization of sugars takes an average of about 2-3 weeks, when the weight loss is barely 4-6 kg. This minimal loss of weight cannot account for complete euglycemia. It is now said to be a combination of two factors:
- Incretin levels especially GLP-1.
- The sudden near total caloric restriction that occurs postoperatively washes out the fat from the cytoplasm of the beta cells, in which fat accumulation prevents adequate and appropriate release of insulin. This is known as lipotoxicity, and lipid washout is putatively a cause for early normalization of blood sugar.
How Effective are Metabolic Surgeries?
Looking at the data of Buchwald, Schauer, Gagner and Scopinaro, several hundred thousand patients have been followed up in careful detail, and the average figures of diabetes remission (no drugs, no insulin) are 83% for gastric bypass, 67% for sleeve, and 48% for the band, in the Caucasian population. This figure approaches 95% for the biliopancreatic diversion of Scopinaro. Our own experience over the last 11 years and that of several other Indian workers indicate a much higher percentage of remission in the Indian patient. Perhaps insulin resistance, which comes down sharply after bariatric surgery is an important factor, as is the viability of beta cells in our population.
In diabetics who are on insulin injections, the serum C-peptide represents their indigenous insulin output, as all injected insulins have only the A and B peptides. Finding a serum C-peptide of >3 ng/mL is a sign of a fairly well-functioning pancreas with sufficient reserve to be stimulated by the incretins.
Diabetes is often one of a host of diseases like hypertension, dyslipidemia, gout and hypertension. Several studies have shown significant resolution of these other ailments, to the tune of 80-90%. Also, like with diabetes, these parameters normalize very rapidly usually within a few weeks of the bariatric surgery.
Impact on Lifespan
The World Health Organization (WHO) figures and the Framingham study figures indicate that an obese smoker loses about 13 years of his life, and an obese nonsmoker about 10. Definite evidence has accumulated that these operations significantly increase the lifespan of the patient. Death due to vasculopathy of the coronary and cerebral vessels is especially prevented by this surgery. Also, the fluctuating insulin levels seen in poorly controlled diabetes trigger instability of the DNA, and trigger off the neoplastic process. Reversal of the diabetic state decreases the risk of cancer occurrence in this group of patients.
Small Vessel Disease
Diabetic retinopathy and nephropathy occur in up to 38% of patients who have well-controlled sugars. The disease process seems more related to the duration of the diabetes. Effecting a reversal of diabetes in these patients will move them to a 0% risk group as in the nondiabetics. This is a very powerful reason for attempting reversal of diabetes through surgical procedures.
How Long Do They Last?
A recent slew of articles has indicated that 5-10% of patients who undergo metabolic surgery return to the diabetic stage when followed up for 10-15 years. The medical community was quick to denounce these operations as merely temporary successes. However, careful follow-up data now indicates that even in this small percentage of patients who relapse into the hyperglycemic state, the arteriolar disease when followed up longitudinally, is much less than their nonoperated counterparts. Thus, the current understanding is that a period of euglycemia of 10-15 years is remembered by the cells with a much better vascular prognosis in this group of patients. This phenomenon is called “metabolic memory” of the cell, and is evoked to explain the overall better prognosis.
The last word about metabolic surgery has not been spoken, and will not be spoken for a long time. What emerges from a vast amount of data is that there definitely seems to be a role for attempting to reverse the diabetic process, and that doing so positively impacts upon the health and longevity of the individual. Until futuristic magic pills arrive upon the scene, the most efficacious treatment available right now is metabolic surgery.
For the higher BMI individual (32 and above), the RGBP remains the best option. In lower BMI individuals, the ileal transposition is an attractive alternative. Definite slowing down or reversal of microangiopathy has been documented in patients undergoing these operations. Incretin release either through the foregut or hindgut theory seems to explain return to euglycemia, which occurs within a few weeks of the procedure. Metabolic memory of the cell gives a survival and morbidity advantage, even in the small percentage of metabolic surgery patients who return to a hyperglycemic state, thus vindicating this procedure.
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- Available at: https://www.framinghamheartstudy.org/