Ed Mason at Large

This ongoing column is dedicated to sharing with readers the life and  experiences of Dr. Edward Mason.

Column Editor: Tracy Martinez, RN, BSN, CBN
Ms. Martinez is the Program Director for Wittgrove Bariatric Center in La Jolla, California.

Two recent studies[1,2] showed that bariatric surgery is superior to intensive medical therapy for the treatment of type 2 diabetes. How do you explain this? What are your reactions?

Dr. Mason: These two studies[1,2] should greatly improve the treatment of type 2 diabetes mellitus (T2DM). The authors used only operations that were known to be immediately effective unrelated to weight loss. Therefore, the operations stimulated secretion of the missing hormone, which is not insulin but glucagon-like peptide-1 (GLP-1). The operations exposed the distal bowel to glucose, bile acid, and other stimulants of secretion by L-cells which are high in number in the ileum and rectum. A large number of studies of GLP-1 made these comparisons possible and timely.

GLP-1 was initially called the brake hormone because it could stop gastric emptying and intestinal transit. We now know that GLP-1 is the hormone required for decreasing insulin resistance. Normal dumping prevents T2DM in healthy people by stimulating secretion of GLP-1. The first emptying of a meal is a gush governed by the volume of stomach contents.[3] It is normal for the initial emptying of the stomach to overflow the duodenum where dilution with bile and other digestive juices occurs. Undiluted contents from the stomach reach the jejunum and stimulate flushing to the lower bowel. Schirra et al[4] demonstrated that a threshold concentration of glucose is required to stimulate small bowel catharsis. Cells in the duodenum measure the concentration of glucose and osmolality. Signals from these cells regulate subsequent stomach squirts so that there is proper dilution before the digesting food stream enters the upper small bowel. This helps to maintain a normal blood glucose level in healthy people. This is an important part of nature’s intensive management of cellular glucose concentration. This evolved over a few million years.[5]

Intensive medical therapy in these studies was based upon whatever treatment each patient came with. This was often treatment with insulin but with an increased effort to maintain normal plasma glucose. GLP-1-based medical therapy has only recently been included and was added according to indications in the current standard of care. In summary, only the surgically treated patients were assured treatment with the required hormone, GLP-1.
The empiric reaction to these papers is to recommend that more patients have access to surgery sooner. I might have agreed 50 years ago when we knew that intestinal and gastric bypass prevented and cured T2DM, but we did not know the mechanism. Also at that time, neither obesity nor diabetes had become an epidemic. Bariatric surgery is now available for only one percent of those who could benefit, with or without diabetes.

Scientific study by Miholic et al[6] has shown that GLP-1 provides all of the effects required for the treatment of T2DM. GLP-1 mimetics are available in increasing number. Bariatric surgery revealed a nonsurgical approach that could be made available to millions of people who either have T2DM or are at high risk of the disease. All that is required is stimulation of secretion by the L-cells, which are in highest concentration in the ileum and rectum. This could be accomplished with glucose mimetics once approved, or by exposing L-cells to other stimulants of GLP-1 secretion.

Intestinal and then gastric bypass resolved non-insulin dependent diabetes almost immediately during the last 50 years, but those who were performing the operations could not explain the mechanism. Total gastrectomy stimulated GLP-1 secretion by dumping, but no one suggested that this should be used to treat diabetes.[6] Billroth provided a subtotal gastrectomy that bypassed the duodenum in 1885. In retrospect, Billroth II gastrectomy prevented and resolved T2DM even though it was never specifically used for treatment of the disease.[7]

Insulin has saved many lives from type 1 diabetes in the last century. It has been effective in reducing plasma glucose to normal even in patients with T2DM. But the insulin concentration remained high as shown in these studies.

Many physicians have treated all diabetes with insulin throughout their practice of medicine. Insulin for diabetes became a mantra, which resulted in the most intensive management of plasma glucose with insulin for T2DM.
Näslund et al[8] published a study in 1998 showing the postprandial rise in plasma GLP-1 following intestinal bypass. This suggested that the common denominator between intestinal and gastric bypass in resolving T2DM was exposure of the distal ileum to dextrose and other stimulants of GLP-1 secretion. An old laboratory model was suggested to test this “aha.”[9] Strader et al[10] performed ileal transposition in rats. It was effective; however, moving the ileum closer to the stomach is not necessary. In fact, the triumph of surgery may be the revelation that surgery is not required to stimulate the secretion of GLP-1—the missing hormone of T2DM.

Treatment of the T2DM epidemic with glucose-mimetics should be our next goal. D-tagatose, a proposed artificial sweetener, needs sufficient study to obtain approval, or to demonstrate why it should not be approved.[11] There is an urgency in avoiding irreversible complications even before diabetes is diagnosed. Individuals with central obesity, who are at higher risk of complications of diabetes, might be provided prophylactic treatment. Resolution of the epidemic could eliminate the need for diabetic surgery except for those who remain severely obese. This could greatly reduce the cost of medical care. Resolution of T2DM will continue to be an added benefit for those severely obese who are able to obtain bariatric surgery. We must not over treat. Protein malnutrition and osteopenia after bariatric surgery are risks that increase with more extensive bowel bypass. Such complications were the reason that gastric bypass replaced intestinal bypass after 1967.[12] Well-designed studies of glucose mimetics could be a way of providing treatment for patients while we are waiting for approval for such treatment. This could provide experience in optimum dosing, possible combinations of surgery and medical therapy, safety, and efficacy in relation to initial body weight and other variables.

These two studies should be a great help in the paradigm shift from insulin to GLP-1-related medication for treatment of T2DM. I have age-related T2DM and prefer dipeptidyl peptidase-4 (DPP-4) blocking, diet, and swimming to gastric bypass, but I would like to stimulate my L-cells occasionally. They may die from lack of stimulation. My mentor, Owen H. Wangensteen wrote a history of surgery, with subtitle words Empiric and Scientific, which I included in my answer.[13] My final word concerning those of us with high glucose and insulin who are at risk of losing kidney function, sight, limbs, and life is compassion.

References
1.    Schauer PR, Kahyap SR, Wolske K, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Eng J Med. 2012;366:1567–1576.
2.    Mingrone G, Panunzi S, Gaetano A, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med. 2012;366:1567–1576.
3.    Brener W, Hendrix TR, McHugh PR. Regulation of the gastric emptying of glucose. Gastroenterology. 1983; 85:76–82.
4.    Schirra J, Katschinski M, Weidmann C, et al. Gastric emptying and release of incretin hormones after glucose ingestion in humans. J Clin Invest. 1996;97:92–103.
5.    Mason EE. Gila Monster’s Guide to Surgery for Obesity and Diabetes. J Am Coll Surg. 2008;206:357–360.
6.    Miholic J, Orskov C, Holst JJ, et al. Emptying of the gastric substitute, glucagon-like peptide-1, and reactive hypoglycemia after total gastrectomy. Digestive Diseases and Science. 1991; 36:1361–1370.
7.    Friedman NM, Sancetta AJ, Magovern GJ. The amelioration of diabetes mellitus following subtotal gastrectomy. Surg Gynecol Obstet. 1955;100:201–204.
8.    Näslund E, Backman L, Holst JJ, et al. Importance of small bowel peptides for the improved glucose metabolism 20 years after jejunoileal bypass for obesity. Obes Surg. 1998;8:253–260.
9.    Mason EE. Ileal transposition and enteroglucagon/GLP-1 in obesity (and diabetic?) surgery. Obes Surg. 1999;9:223–228.
10.    Strader A D, Torsten P V, Ronald JJ, 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.
11.    Lu Y, Levin GV, Donner TW Tagatose, a new antidiabetic and obesity control drug. Diabetes Obes Metab. 2008;10:109–134.
12.    Mason EE, Ito C. Gastric bypass in obesity. Surg Clin N Am. 1967; 47:1345–1351.
13.    Wangensteen OH, Wangensteen Sarah D. The Rise of Surgery: From Empiric Craft to Scientific Discipline. University of Minnesota Press, Minneapolis Minn. 1978.

Category: Ed Mason at Large, Past Articles