by Edward E. Mason, MD, PhD, FACS
Regulation of the concentration of sugar and oxygen is necessary for life. In early dinosaur times, there was a lizard Heloderma suspectum(the Gila monster) that remains alive today. It has a tooth/gland/venom/hormone apparatus designed for regulating blood sugar. The hormone is now known as exendin-4. Serpents and man have inherited and moved various parts of the lizard’s glucose regulating apparatus. In man the cells producing this hormone are located in the distal ileum. In order to stimulate secretion of glucagon-like peptide-1 (GLP-1) early in ameal, it is necessary for glucose or fat to reach the human ileum. GLP-1 and exendin-4 are chemically closely related and they have the same effects in humans. They are both brake hormones and incretins.
The Gila monster kept the whole apparatus in the lower jaw. Vonk et al in the study of the evolution of snakes has shown how the back teeth moved around to form fangs in the front or back of the upper jaw in various snakes. Some of us have dealt with buried wisdom teeth in the lower jaw. They may be left over from the lizard’s glucose regulating apparatus. The Gila monster appeared 200 million years ago. Snakes appeared 120 million years ago. Mammals and humans, appearing much more recently, have continued use of the glucose-regulating hormone now known as GLP-1. In humans, the hormone-producing cells moved to the ileum, but exposure to glucose and lipids early in a meal remains necessary for stimulating secretion. Obesity interferes with this exposure and results in an increased insulin requirement.
Some of the evidence for all of this is as follows:
Shortly after a high-glucose meal, in lean, healthy people there is a flush of the intestine that may encourage a trip to the bathroom, a “gastrocolic reflex.” According to Brener et al, the volume of stomach contents governs initial emptying. If the initial gush is large enough to overflow the duodenum and if the stomach contents are highly concentrated, the small bowel flushes the overflow to the ileum. L-cells in the ileum are stimulated by glucose and fat to secrete GLP-1.3, This process in lean people fails with increasing obesity. No gush, no flush. Deficient GLP-1 stimulation of insulin receptors causes susceptible people to develop type-2 diabetes (T2D). Both intestinal bypass and gastric bypass prevent and cure T2D by exposing the ileum to glucose and fat, which stimulate secretion of GLP-1. GLP-1 stimulates insulin receptors. After the initial gush, the duodenum controls subsequent squirts. The words gush and squirt are Brener’s, and apropos to explaining the control of GLP-1 secretion. When further ingestion increases the volume of stomach contents, a new “initial gush” occurs and another sample of gastric contents reaches the ileum. GLP-1 was first known as a brake hormone, which stops gastric emptying. The duodenal calorie counting, glucose receptors, and osmoreceptors resume regulation of subsequent stomach squirts to maintain the optimum rate of entry of calories into the duodenum.
In 1945, I began surgical training at the University of Minnesota with a focus on stomach surgery. Clarence Dennis, vice chairman of surgery, explained that he and Leo Rigler, chief of radiology, had studied patients with Wangensteen’s modification of Billroth II gastrectomy.
They had observed fluoroscopically a portion of the standard meal appearing in the ileum within five minutes. Dennis recommended a small opening between the stomach pouch and jejunum so as to retard the rate of emptying of the pouch. The concern at the time was avoiding dumping syndrome. This is a marked reaction to hypertonic liquids and foods high in glucose. Patients complain of postprandial abdominal discomfort, weakness, sweating, diarrhea, and even a need to lie down. Dumping was considered an undesirable complication to be avoided.
It now appears that mild, usually asymptomatic dumping occurs in healthy, normal-weight people. Schirra et al studied normal, lean humans and demonstrated that there is a threshold for glucose infused into the duodenum, above which plasma GLP-1 rises. When a 400mL solution containing 50 grams of glucose was infused over three hours, the concentration of glucose required to stimulate GLP-1 secretion was twice as high as was required if the glucose was given by mouth in 400mL of fluid in five minutes. Schirra showed that the duodenum dilutes stomach contents so that when they reach the jejunum there is no flush, but if the threshold of glucose entering the duodenum is exceeded either by rate of stomach emptying or concentration of the glucose, a small bowel flush results.
Vilsboll et al showed that it is possible to modulate secretion of GLP-1 by meal size. Increasing meal size increases the number of “initial gushes.” The study compared the response of patients with T2D, T1D, normal weight, and obesity. Each patient was studied after a 260kcal meal and after a 520kcal meal. Intact GLP-1 and total GLP-1 were measured. The total GLP-1 included the inactivated portion. GLP-1 has a 90-second half-life. The highest levels for intact GLP-1 were observed in the lean, healthy group, with an early sharp peak. The larger meal caused the highest rise and sustained level. The GLP-1 rise was less for the healthy obese subjects and those with T1D and T2D. The least rise after both meals occurred in the patients with T2D. These observations are supportive of impairment in initial gush, which is the stomach volume-controlled emptying that overflows the duodenum. It is important to note that the healthy obese subjects had almost the same impairment of GLP-1 secretion as the subjects with T2D. It is known from other studies that serum insulin levels rise with increasing body weight. It is only when the pancreas cannot meet the demand for insulin that diabetes is diagnosed. The diagnosis of diabetes should not be a requirement for treatment. Failure to show an adequate rise in GLP-1 with consequent high serum insulin level needs to be treated. Surgeons know that all patients with severe obesity are candidates for treatment. This increases the number of candidates with T2D in the United States from 23 million to 100 million.
Surgeons have been treating T2D by exposing the ileum to glucose. The operations bypass the antro-duodenal-ileal control of gastric emptying, or shorten the distance to the ileum, so that glucose is not absorbed before it reaches the ileum. However, surgical operations eliminate the possibility of normal feedback control of GLP-1 secretion. Näslund observed very high plasma levels of GLP-1, 20 years following intestinal bypass.5 Valverde demonstrated with biliopancreatic diversion in nondiabetic obese patients a marked increase in plasma GLP-1 at one month, with further increase at three and six months. The peak levels were reached earlier after the meal at three and six months. The total GLP-1 secretion was markedly above normal after these operations. Continual excessive stimulation of the beta cells by GLP-1 may result in excessive insulin secretion even when blood glucose levels are normal or low. Service et al reported six patients with hyperinsulinemic hypoglycemia, requiring partial pancreatectomy, following Roux-en-Y gastric bypass (RYGB). There followed other similar reports.[11,12] Bantle et al demonstrated successful treatment of three such patients with a low carbohydrate diet. This dietary management should be tried before resorting to pancreatectomy.
Treatment with Bypass Operation
Bypass operations (whether intestinal or gastric) cause ingested glucose to reach the ileum and GLP-1 secretion results. GLP-1 has numerous effects.[14,15] It is a brake hormone that causes contraction of the pyloric muscle to stop gastric emptying and slows intestinal peristalsis. It is also an incretin. It stimulates insulin secretion provided the concentration of blood glucose is above normal. GLP-1 also stimulates growth of beta cells. GLP-1 blocks glucagon stimulated production of glucose in the liver. It promotes glycogenesis in liver and muscle and lipogenesis in fat. GLP-1 causes satiety through the arcuate nucleus in the hypothalamus.
The cure of T2D after gastric bypass led some surgeons to postulate that there was a foregut hormone that was responsible.16 There has not been any hormone forthcoming to support this hypothesis. Nãslund’s paper provided evidence of failure of glucose to reach the hindgut and stimulate GLP-1 secretion in patients who were candidates for intestinal bypass.5 Nãslund’s paper led to my suggestion of moving a portion of ileum to a juxtaduodenal position to cure T2D without bypassing the upper digestive tract.17 This paper discouraged use of transposition of the ileum in humans without further animal study. Strader performed ileal transposition in rats and showed that it increased GLP-1 secretion, decreased food intake, and decreased body weight compared with the sham operation controls.18 Strader also showed greater reduction of plasma glucose concentration after the same dose of intraperitoneal insulin in ileal-transposed rats compared with sham animals. This indicated that ileal transposition increased GLP-1 secretion and improved insulin receptor function.
Duodenal-jejunal Bypass SLeeve
The duodenal-jejunal bypass sleeve has been shown to eliminate need for medications to treat T2D in four patients. This is a 60cm plastic liner that is anchored in the proximal duodenum. It causes stomach contents to bypass the glucose-regulating cells and osmoreceptors in the duodenum so that stomach contents enter the duodenum without dilution to isotonicity or an optimum glucose concentration. The stomach contents pass through the duodenum within the sleeve while bile and pancreatic juice pass through the duodenum between the sleeve and the duodenal wall. Weight loss in 10 patients over 12 weeks was 23.6 percent. The sleeve is a temporary duodenal bypass procedure. The rapidity of improvement in T2D in four patients unrelated to any change in weight was similar to that observed after RYGB. Measurements of plasma GLP-1 were not obtained but would provide additional evidence regarding the hindgut hypothesis: that any procedure that exposes ileum to glucose will stimulate GLP-1 secretion.
Gastric Contractility Modulation
If the defect causing T2D is a failure of sufficiently strong initial gushing to cause overflow of hypertonic gastric contents into the jejunum, then stimulation of the antrum to augment gastric emptying should be an effective way to treat T2D. The Tantalus Gastric Contractility Modulator (GCM) has been reported to provoke an early response of the gut typical of a full meal. It has also been reported to improve diabetes. Measurements of plasma GLP-1 levels are needed.
Roux-en-Y gastric bypass
RYGB is the standard of care today for the treatment of severe obesity. It cures T2D unless the beta cells have been exhausted, in which case type-1 diabetes also exists. Ideally, obesity should be eliminated before the beta cells are exhausted. Many patients with newly diagnosed T2D and with BMIs greater than 35 could probably be successfully treated with exendin-4, although this needs further documentation. There are other GLP-1 mimetics that might be substituted. If treatment with GLP-1 mimetics failed, a surgical operation might then be indicated. My preference beginning in 1971 was to use a restriction operation when possible because of the complications of bypass operations.
Even though T2D is usually cured by bypass operations, the normal control of GLP-1 secretion is lost. Medication can be stopped or given as needed. If hyperinsulinemic hypoglycemia should turn out to be a frequent complication of either bypass operations or medical treatment, it might be beneficial to provide GLP-1 mimetics in courses, with time between courses to maintain normal regulatory mechanisms. Determination of optimum schedules for treatment may require a considerable effort and lengthy studies. Metabolic obesity surgeons and endocrinologists could benefit their patients by increasing collaboration in such clinical research.
There is also an urgent need to reduce the overall cost of treatment of obesity and its complications, as the prevalence continues to rise. We need treatment for obesity now in 100 million people in the United States, and the number and severity continues to rise. I have suggested to pharmacists that they provide us with coated sugar that would be released in the ileum. This might take the place of bypass operations for many of the patients with BMI s greater than or equal to 30. Prevention of obesity remains the most important goal. Humans need to return to a more physical and less sugarcoated lifestyle.
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Category: Metabolic Perspective