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Clinical Professor of Medicine
University of Washington
Rockwood Center for Diabetes and Endocrinology
Rockwood Clinic/MultiCare Health System
Carol Hatch Wysham, MD, has disclosed that she has received funds for research support from Abbott, Allergan, Lilly, and Novo Nordisk; consulting fees from Abbott, Janssen, Novo Nordisk, and Sanofi; and fees for non-CME/CE services from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Novo Nordisk, and Sanofi.
When managing patients with type 2 diabetes, it is important to understand the contribution of obesity. First, we must recognize that obesity is not a problem of willpower; it is a complex pathophysiology driven by a strong genetic component as well as strong socioeconomic influences and the fact that we are hard wired to listen to our bodies when we feel hungry. Because of its impact on multiple organs, obesity plays a large role in the pathophysiology of diabetes.
Obesity and Insulin Resistance
We know that patients who are overweight and obese have increased insulin resistance and that insulin‑mediated glucose disposal is affected primarily at the skeletal muscle. What may be less well understood is that insulin helps to store fat by taking free fatty acids and triglycerides out of the bloodstream and into the appropriate storage depots. If an individual is insulin resistant at the level of adipose tissue, that creates an increase in circulating triglycerides and free fatty acids. That, in turn, leads to fat buildup in the liver, and we know that approximately 70% of persons with type 2 diabetes have fatty liver. Moreover, fatty liver leads to increased insulin resistance in the liver, where insulin’s job is to suppress the production of glucose. But it also may be fundamentally leading to the actual causative problem of diabetes, a decrease in insulin secretion.
Ectopic Fat Storage
What happens when an individual cannot store more fat in the periphery, either because of resistance to insulin or lack of capacity? The overflow phenomenon occurs, where fat is stored in the liver, pancreas, omentum, and even the muscle. In that situation, the muscle will preferentially use fat as an energy source vs taking up glucose, and that leads to more insulin resistance in the muscle. In the case of the pancreas, excessive fat is likely playing a large role in the rapid loss of β-cell function. Hence, managing a person’s weight has important implications beyond the number on the scale; it contributes to eliminating excess fat from these ectopic sources.
Weight Loss as Treatment
Studies suggest that losing as little as 5% of body weight can lead to a measurable reduction in fat in the liver and muscle. We don’t have the ability to measure fat in the pancreas as well, but we would presume the same. Hence, our target for weight loss of 5% is aimed at eliminating this ectopic fat, improving insulin sensitivity in the liver and skeletal muscle, and hopefully decreasing the driving factors of further loss of β-cell function.
So, when thinking about the management of diabetes, of course we need to improve glucose control, but we also need to consider the impact of body weight on the underlying pathophysiology of diabetes and cardiovascular disease, the most common cause of mortality in persons with diabetes. We know that obesity is a major risk factor for cardiovascular disease. Again, it is related to excess ectopic central fat that is associated with abnormalities in lipid metabolism, higher blood pressure, and increased tendency for thrombosis and inflammation.
When we meet with a patient in the exam room who has type 2 diabetes and is overweight or obese, we need to address all of his or her cardiovascular risk factors, including the frequently untreated risk factor that may be underlying many medical issues: obesity. Let’s not forget that obesity is also associated with higher rates of certain nonmetabolic complications, including cognitive impairment, cancer, sleep apnea, arthritis, reflux, gout, infertility, and so forth. Rather than treating each individual complication of obesity, we should consider the primary treatment of obesity. Unfortunately, insurance coverage of obesity treatment has been very poor (which is obviously very shortsighted when it comes to public health).
Pharmacologic Treatments for Weight Loss and Glycemic Control
Fortunately, we have powerful medications capable of lowering A1C as well as body weight: sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. Despite these and other treatments, significant numbers of patients fail to reach A1C targets of <7%. In clinical trials of GLP-1 inhibitors, approximately 40% to 80% of patients achieved A1C <7%. In routine clinical practice, it’s likely much lower because the patients are starting at higher A1C levels and the persistence of therapy tends to be much less. In addition, most of our patients do not meet their weight goals. Hence, we have some unmet needs of glycemic control and overall management of patients with type 2 diabetes where we would love to see new medications with more potent reduction in A1C and greater reduction in weight.
Recent efforts to identify new classes of diabetes drugs have focused on the many gut hormones that play a role in glucose homeostasis, either via primary effects on the islets of Langerhans, liver, or adipose tissue or via activity in the brain. At the same time, studies of combination therapies were launched to target multiple pathways involved in glucose homeostasis in pursuit of additive benefit. Among the most promising of these are the dual glucose‑dependent insulinotropic polypeptide (GIP)/GLP-1 agonists. Early studies showed that adding a GIP to a GLP‑1 receptor agonist led to additive benefit in both A1C and body weight. In some cases, combining the two caused fewer gastrointestinal adverse events, although that’s not always the case. Moreover, there were some intriguing nonglycemic effects, including a GIP-mediated decrease in bone resorption.
Mechanistically, the combined benefit of these 2 agents in reducing glucose levels is likely related to their role in mediating postprandial insulin secretion. In nondiabetic individuals, GIP is responsible for approximately 45% of postmeal insulin secretion and GLP-1 is responsible for approximately 29%. Taken together, approximately 74% of postprandial insulin secretion is determined by these 2 hormones. We know that patients with diabetes are resistant to the activity of these hormones, and therefore, their postprandial insulin secretion is markedly blunted. This new class of agents, the GIP/GLP-1 agonists, has exciting implications for both diabetes and obesity treatment.
When treating patients with type 2 diabetes and overweight/obesity, how do you approach weight reduction? Answer the polling question and join the conversation by posting in the discussion section.