An Interview with Dr. Ralph A. DeFronzo
Professor of Medicine and Chief of the Diabetes Division at the University of Texas Health Science Center, San Antonio, Texas.
Dr. DeFronzo also is Deputy Director of the Texas Diabetes Institute. He is a graduate of Harvard Medical School and served his Residency in Internal Medicine at Johns Hopkins Hospital. He has completed Fellowships in Endocrinology at the National Institutes of Health/Baltimore City Hospitals, and in Nephrology at the Hospital of the University of Pennsylvania.
In this interview, Dr. DeFronzo discusses integrating bariatric and metabolic surgery into the treatment of type 2 diabetes mellitus (T2DM), a topic which he presented at Ethicon’s 2013 Product Theatre, shown at the 2013 American Association of Clinical Endocrinologists (AACE) Annual Meeting. The theater featured presentations from Dr. DeFronzo and Dr. Philip Schauer, Chief of Minimally Invasive Surgery and Director of the Cleveland Clinic Bariatric and Metabolic Institute.
Funding: No funding was provided in the preparation of this manuscript.
Financial disclosures: Dr. DeFronzo is on the advisory board of the following companies: Bristol Myers-Squibb, Boehringer Ingelheim, Janssen, Takeda, Lexicon Pharmaceuticals, Inc., and Novo Nordisk. He is on the speakers bureau of BMS, Janssen, Takeda and Novo Nordisk, and received grants from Takeda.
BT: Please briefly explain the pathophysiology of T2DM? Why is obesity a risk factor for developing this disease?
Dr. DeFronzo: We know that people who are destined to develop diabetes inherit a set of genes that make their tissues resistant to insulin. Early in the natural history of the disease, when their beta cells are healthy, they can increase their secretion of insulin to overcome the insulin resistance. However, with time the beta cells begin to fail and the insulin resistance in liver becomes manifest by an overproduction of glucose throughout the sleeping hours, leading to fasting hyperglycemia. Following ingestion of a meal, the majority of ingested glucose is taken up by muscle. Insulin resistance in muscle, in the presence of a failing beta cell and insulin deficiency, leads to an excessive rise in blood glucose after each meal. Collectively, insulin resistance in muscle and liver and beta cell failure are referred to as the Triumvirate.
Obesity leads to the accumulation fat in liver, muscle, and beta cells, thereby exacerbating three core defects that are present in individual with T2DM:
1. Muscle insulin resistance
2. Liver insulin resistance
3. Impaired insulin secretion
The development of T2DM occurs over time and overt diabetes becomes manifest when, the pancreas no longer is able to secrete a sufficient amount of insulin to overcome the insulin resistance in liver and muscle. Initially, the hyperglycemia can be controlled with oral agents and glucagon-like peptide-1 (GLP-1) receptor agonist but with time the beta cell “burn out” and eventually insulin is required.
Weight loss, through dieting or through surgery, mobilizes fat out of muscle, liver, and beta cells leading to improved insulin sensitivity and enhanced insulin secretion. Further, following Roux-en Y gastric bypass surgery, nutrients are delivered directly to the L cells in the early colon, leading to increased GLP-1 secretion, which augments insulin secretion and inhibits glucagon secretion. These hormonal changes promote the suppression of hepatic glucose production and increase muscle glucose uptake.
BT: Were you surprised at the results of the two studies[1,2] published on this topic in the New England Journal of Medicine?
Dr. DeFronzo: I was not surprised by the results of the two studies published in the New England Journal of Medicine in 2012.[1,2] We already had evidence from less well controlled studies that bariatric surgery improved hyperglycemia in T2DM. For example, the Swedish Obese Subjects (SOS) study by Sjöström evaluated patients who underwent bariatric surgery. Fasting and postprandial hyperglycemia in these patients was, in a large part, resolved after surgery. The study also showed decreases in blood pressure, reduced cardiovascular morbidity and mortality and decrease in cancer risk. Further, the improvement in glycemic control was long lasting. However, the SOS study was not a randomized controlled trial (RCT). The studies by Schauer et al  and Mingrone et al, which were RCTs, conclusively demonstrated the effectiveness of bariatric surgery over medical management in normalizing blood glucose levels in morbidly obese patients with T2DM.
BT: Have these findings changed your perspective of bariatric surgery? If so, how?
Dr. DeFronzo: These findings have not changed my perspective, since I already was convinced about the benefits of bariatric surgery, but they will change the perspective of others who may have been less enthusiastic about the role of bariatric surgery.
BT: Do you think these findings have or will change the field of endocrinology, specifically patient care/treatment options?
Dr. DeFronzo: Endocrinologists need to become familiar with these results, which clearly demonstrate the efficacy of bariatric surgery in the treatment of the morbidly obese T2DM patient. I think they will have a big impact on the healthcare community.
These types of RCTs studies help to demystify the surgery. Patients and their physicians have a myriad of choices for treating T2DM. Surgical intervention adds one more option and it has been shown to be safe and effective in randomized controlled trials. Doctors and patients now have another choice—one that is shown to be much more effective than the current modalities in the morbidly obese diabetic patient. As both physicians and patients become familiar with the outcomes of these studies, I think we will see a greater use of surgery in the properly selected patient.
BT: Has this research caused you to make changes in patient care in your practice? Are you now more inclined to educate patients on bariatric surgery as a treatment for T2DM and refer appropriately?
Dr. DeFronzo: I have worked with bariatric surgeons and have been referring patients for bariatric surgery for some time. I believe that medical and surgical treatment need to be complimentary to each other.
BT: Do you think it is important to share this research and educate other doctors seeing patients with T2DM on the benefits of bariatric surgery for this patient population? If so, how will you, and how should we as a medical community already educated in bariatrics, spread this information to other disciplines (e.g., endocrinologists, primary care physicians).
Dr. DeFronzo: Of course, it is important information to share the results with physicians in other disciplines. Only a small percentage of patients with morbid obesity respond favorably to medical intervention alone. Those patients who respond poorly to medical management should be considered for bariatric surgery. Endocrinologists are familiar with bariatric surgery as a treatment option and the Schauer and Mingrone studies[1,2] make the efficacy of surgery even clearer.
What is important is to educate primary care physicians. Education can be a slow process, but it will happen gradually in the coming years.
Educating the patients is critical too. We need to help them understand that the choice is safe, effective, and durable.
BT: What can these two fields—bariatric surgery and endocrinology—learn from each other? Is such collaboration necessary and important to treating patients with obesity and T2DM?
Dr. DeFronzo: The two fields can collaborate in elucidating the mechanisms via which bariatric surgery improves/normalizes glucose tolerance in obese T2DM patients. As we continue to learn how the improvement in hyperglycemia occurs, we will arrive at better outcomes. As mentioned earlier, we know that increased GP-1 secretion plays a pivotal role in the improvement in glucose homeostasis. The beta cells in patients with T2DM do not respond normally to GLP-1 and this defect is responsible, in large part, for the defect in insulin secretion. Bariatric surgery leads to a marked increase in GLP-1, resulting in increased insulin and decreased glucagon secretion. These hormonal changes lead to a reduction in the excessive production of glucose by the liver.
The majority of patients in the Schauer et al1 and Mingrone et al2 studies were able to come off of their diabetic medications and still maintain normal glucose tolerance. However, bariatric surgery cannot correct the inherited genetic abnormalities responsible for the insulin resistance and beta cell failure in T2DM. Therefore, it is important for patients whose diabetes has “resolved” by bariatric surgery to continue to be followed by the combined surgical/endocrine team.
Endocrinologists demand data. Surgeons require patients to develop that data. Papers like those from Schauer et al and Mingrone et al will help to develop the trust needed by physicians and surgeons to work in concert for the benefit of the patient. A collaborative, team approach to treating patients and following them throughout the treatment process is critical.
1. Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med. 2012;366(17):1567–1576. Epub 2012 Mar 26.
2. Mingrone G, Panunzi S, De GA, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med. 2012;366(17):1577–1585. Epub 2012 Mar 26.
3. Sjöström CD, Lissner L, Wedel H, Sjöström L. Reduction in incidence of diabetes, hypertension and lipid disturbances after intentional weight loss induced by bariatric surgery: the SOS Intervention Study. Obes Res. 1999;7(5):477–484.