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Polyagonists for the Treatment of Obesity and Diabetes

This morning, I spoke at the German Diabetes Congress in Berlin on the issue of whether or not metabolic surgery offers a cure (or just remission) in patients with type 2 diabetes.

I also had the pleasure of attending the Hans Langerhans Award Lecture, the highest distinction awarded by the German Diabetes Society, given by my colleague Matthias Tschöp, who is also the Director of the Helmholtz Centre for Diabetes Research in Munich.

Tschöp focussed his acceptance speech on his ground-breaking work on polyagonists, i.e. molecules that can co-stimulate two or more peptide receptors (e.g. for GLP-1, GIP, and glucagon).

Tschöp began his presentation by declaring that we could almost completely reverse the global epidemic of type 2 diabetes, if only we had more effective treatments for obesity.

As we now know, appetite and energy regulation is tightly controlled by a host of neuroendocrine signals, which act on the central nervous system as part of a complex homeostatic system that acts to sustain and defend body weight.

Based on these findings, Tschöp’s work has pursued the notion that effective obesity treatments require targeting of the homeostatic centres in the brain. As we have learnt from the extensive research on bariatric surgery, there are a number of signal molecules released by the gut (incretins) that directly affect central mechanism of appetite and satiety.

However, given the complexity and redundancy of the system, just targeting one of these molecules may not be effective enough to counteract the powerful mechanisms that defend against long-term weight loss. This insight, led Tschöp to pursue the idea that developing single synthetic molecules, that could simultaneously stimulate  several distinct but synergistic pathways, may prove to be more effective than targeting a single molecular target.

This idea, ultimately led to the development of molecules that simultaneously act as dual co-agonists (e.g. for GLP-1 and glucagon or for GLP-1 and GIP ) or even tri-co-agonists (e.g. for GLP-1, GIP, and glucagon). These co-agonists appear to have potent metabolic and anti-obesity effects both in animal models and in early human studies. Indeed, this approach is now being actively pursued by a number of pharmaceutical companies hoping for more effective anti-obesity medications.

While these studies are currently underway, they certainly hold great promise for the future of medical treatments for obesity and diabetes.

Congratulations to Matthias Tschöp and his team for this most well-deserved award.

@DrSharma
Berlin, Germany

p.s. As an aside, I will have the pleasure of playing guitar with the “Sugar Daddies”, featuring Matthias Tschöp on drums (along with other prominent German diabetes researchers) at the Diabetes Gala Evening this evening.

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Bariatric Surgery For Adolescents – 5 Year Outcomes

Given that our efforts to stop the childhood obesity have so far yet to show any signs of success and that treatment efforts of kids already struggling with excess weight have been sketchy at best, there is unfortunately a growing number of adolescents living with severe obesity, for who we have very little choice but to consider bariatric surgery.

As drastic as surgery may seem, it is important to recognise that for adolescents weighing in at 250 lbs or more, waiting and hoping for obesity to spontaneously resolve, while these kids miss out on opportunities ranging from education to social relationships (never mind the bullying and discrimination), is hardly an acceptable option.

Thus, a study by Thomas Inge and colleagues published in the New England Journal of Medicine, showing that 5-year outcomes of adolescents undergoing bariatric surgery are as positive as in (most) adults, is heartening.

The study looks at 5-year outcomes in 161 adolescent patients enrolled from 2006 through 2012) and a cohort of adults (396 patients enrolled from 2006 through 2009) undergoing Roux-en Y gastric bypass surgery.

Overall, the extent of weight loss 5 years after surgery in the adolescents (-26%) was similar to that in adults (-29%). Adolescents were significantly more likely than adults to have remission of type 2 diabetes (86% vs. 53%) and of hypertension (68% vs. 41%).

Three adolescents (1.9%) and seven adults (1.8%) died in the 5 years after surgery. In the adolescent cohort, one death was attributed to suspected sepsis in a patient with type 1 diabetes who had multiple complications after a hypoglycemic episode 3 years after surgery, and features of the other two deaths in adolescents, both of which occurred 4 years after surgery, were consistent with overdose (acute combined drug toxicity). Among the adults, three died of early complications of surgery, one died of colon cancer, one of suicide, and the cause of death in the two remaining cases was unclear.

Adolescents experienced a greater rate of abdominal reoperations than the adults (19 vs. 10 reoperations per 500 person-years). As a possible explanation for this, the authors offer: “…closer monitoring for complications in adolescent patients and the potential for a lower threshold to reoperate for suspected complications in younger patients, which would lead to the capture of more events.” Nutritional deficiencies were slightly more common in adolescents compared to adults, which the authors attribute to less compliance with recommended nutritional supplements.

While 5-years of follow up may not seem particularly long, it is important to note that this occurs at a critical stage of development for adolescents and can potentially change the life-trajectories of these kids. Nevertheless, decisions to proceed with bariatric surgery in adolescents should be made on a case-by-case basis, carefully weighing the pros and cons for each case.

@DrSharma
Berlin, Germany

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A Non-BMI-Centric Approach To Diagnosing And Managing Obesity

Regular readers will be well aware of the limitations of applying BMI to obesity diagnosis – after all, BMI is a measure of size, not health. If there is one thing we have learnt, it is that good health is possible over a wide range of shapes and sizes and that using a static measure like BMI, will mean overdiagnosing obesity in people who have no relevant impairment in health and underdiagnosing obesity in people who would in fact stand to gain from obesity treatments.

As I have noted before, in a medical context, obesity should be defined as, “the presence of excess or abnormal fat tissue that impairs health“. In clinical practice this would mean asking the question (irrespective of BMI), “does this patient have a health impairment that is likely to get better with obesity treatment?” If yes, the patient most likely has obesity and should be offered obesity treatment. If not, the patient does not have obesity and will be unlikely to benefit from obesity treatment.

This approach would identify both the “high-BMI” individuals with medical issues likely to get better with obesity treatment, as well as the “normal-BMI” individual, who may stand to benefit from obesity management.

Not only will this “common-sense” approach to diagnosing obesity identify individuals over the entire BMI range, who would potentially benefit from obesity treatments, but will also help set specific targets for assessing the success of treatment.

Thus, if the presenting problem is hypertension (say in a patient with a BMI of 24 with clear signs of increased belly fat – but skinny arms and legs), then the goal of obesity treatment would be to lower blood pressure, rather than to simply reduce body weight. Similarly, a patient with a BMI of 24 with type 2 diabetes would likely benefit from obesity management in terms of better diabetes control. If, in these patients, effective obesity treatment (as measured by weight loss) does not lead to better hypertension or diabetes control, then their health issues are probably not related to their body fat, meaning that they probably don’t have obesity.

Thus, the obesity diagnosis and management algorithm would look something as follows:

Does the patient have any impairments in health likely to improve with obesity treatment? (list impairment/s)

if no, patient does not have obesity and does not need any obesity intervention (irrespective of BMI).

If yes, offer obesity treatment to see if this improves the health issues.

If health condition improves, continue obesity management.

If health condition does not improve, reconsider the obesity diagnosis (problem may be entirely unrelated to body fat). discontinue obesity treatment.

Basically, BMI, or for that matter body weight, does not have to enter the equation. The only thing that matters, is whether or not the presenting health problem actually responds to obesity treatment or not.

Fortunately, we have a long list of health issues that we know will improve with obesity treatment (e.g. hypertension, type 2 diabetes, sleep apnea, psoriasis, musculoskeletal pain, knee osteoarthritis, PCOS, etc. etc.), thus making clinical assessment of whether or not someone may have obesity relatively straightforward. Considering obesity treatments to better manage these conditions makes a lot of sense. On the other hand, treating obesity simply to lower body weight (without any measurable health benefits) does not.

@DrSharma
Copenhagen, Denmark

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Appetite As A Vital Sign

As any clinician knows, changes in appetite are an important part of taking a good medical history. While loss of appetite is generally a warning sign that your patient may be seriously ill (sometimes, loss of appetite is the first sign of an illness – physical or mental), an increase in appetite may likewise indicate a serious problem.

In order to assess whether the reported change in appetite is clinically relevant, it is important to follow any appetite question with a “weight change” question. Thus, if a patient reports loss of appetite, an obvious follow-up question would be to ask whether the patient has lost weight. In contrast, if the patient reports an increase in appetite, it is only fair to ask if this has been associated with weight gain. In fact, even if the patient says that their appetite has not changed, it would be fair to ask if their weight has been stable.

While some patients (and clinicians) may be wary of bringing up the issue of weight, no patient in my experience has ever objected to being asked about their appetite. In addition, no patient has ever objected to being asked a weight question after first being asked about their appetite.

Thus, in my experience, the easiest way to start a conversation about body weight, is to begin by asking about appetite.

A typical conversation could run as follows:

Clinician, “So have you notice any change in appetite?

Patient, “Funny you should ask, yes, I seem to be particularly hungry after dinner, I often have to eat a sandwich before I go to bed

Clinician: “So have you noticed any change in your weight?

Patient: “Well, I think I may have gained a few pounds since I last saw you

Clinician: “Is that something that concerns you, something you’d like to talk about?

Obviously, the tone of this conversation needs to be completely non-judgemental and if the patient is not interested or willing to talk about this issue, we can always park this discussion for later.

In any case, if you’ve ever wondered how to start a discussion about body weight with a patient, try first talking about appetite. As a mnemonic, I call this the A&W (Appetite & Weight) approach to discussing body weight.

@DrSharma
Copenhagen, Denmark

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Can Exercise-Induced Modulation of the Tumor Physiologic Microenvironment Improve Antitumor Immunity?

Both obesity and sedentariness have been linked to increased risk for a wide range of cancers. While there is some evidence that weight loss (e.g. through bariatric surgery) can reduce the incidence of and deaths from malignancies, the role of exercise on cancer morbidity and mortality is less clear. Although a growing body of literature suggests that increased physical activity can reduce the mental and physical stress of living with cancer, its role in directly influencing the malignant process is less clear.

Now, a paper by Xiaojie Zhang and colleagues, published in Cancer Research, discusses the many ways in which exercise may potentially promote the body’s ability to fight cancer by modulating the tumor microenviroment.

As the authors point out, “Preclinical and human studies suggest that exercise elicits mobilization of leukocytes into circulation (also known as “exercise-induced leukocytosis”), especially cytotoxic T cells and natural killer cells. However, the tumor physiologic microenvironment presents a significant barrier for these cells to enter the tumor and, once there, properly function.

Among the mechanisms by which exercise can alter immunological response to tumors, the authors include positive changes to the tumor microvasculature as well as the tumor microenviroment including decreased hypoxia, hypoglucosis, lactosis, and reduced pH. For each of these potential mechanisms (that are likely to work in concert), the authors discuss current evidence from animal models that would support these potentially beneficial effects of exercise.

While we have yet to see a definitive controlled study on the long-tem benefits of exercise treatments on cancer survival (and not just rehabilitation and well-being), the authors make a strong case that such studies are perhaps long overdue. In addition, “Rigorous studies that elucidate the link between exercise and immune cell function in the tumor microenvironment and in the periphery will also serve as a guide of how to implement exercise in the context of immunotherapies that harness the immune system against cancer.

@DrSharma
Copenhagen, Denmark

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Ultra-Processed Foods Cause Weight Gain

Every now and then, a landmark study comes along that definitively answers an important question, and, perhaps more importantly, lays to rest many of the theories that float around both in the scientific literature and the lay media.

It would perhaps not be superlative to note that just such a study by Kevin Hall and colleagues (presented just a few weeks ago at the 6th Biennial Canadian Obesity Summit) has now been published in Cell Metabolism.

The study examines what happens to calorie intake and body weight when people have free access to a diet largely composed of ultra-processed foods vs. a diet composed of unprocessed foods. Ultra-processed foods have been described as “formulations mostly of cheap industrial sources of dietary energy and nutrients plus additives, using a series of processes” and containing minimal whole foods.

Importantly, the two diets were carefully matched for presented calories, energy density, macronutrients, sugar, sodium, and fiber. Although protein, carbohydrate, and fat content were virtually identical, the ultra-processed foods differed substantially from the un-processed foods in the proportion of added to total sugar (∼54% versus 1%, respectively), insoluble to total fiber (∼77% versus 16%, respectively), saturated to total fat (∼34% versus 19%), and the ratio of omega-6 to omega-3 fatty acids (∼11:1 versus 5:1).

The 20 weight stable healthy participants, who spent over four weeks in an in-patient metabolic ward, were instructed to consume as much or as little of the foods offered with one diet over a two week period before switching to two weeks of the other diet (in a random cross-over fashion).

In short, during the 2nd week of eating the ultra-processed diet, subjects consumed about 500 kcal more per day than during the 2nd week of the unprocessed diet. This was accompanied by an almost 2 lb weight gain on the ultra-processed diet (whereas weight reduced by about the same measure on the unprocessed diet). This response was seen irrespective of which diet came first or of the baseline BMI of participants.

To set this study in perspective, there have long been theories about how the increased availability of ultra-processed foods may be playing a causal role in the obesity epidemic. Thus, as the authors point out, “Ultra-processed foods may facilitate overeating and the development of obesity because they are typically high in calories, salt, sugar, and fat and have been suggested to be engineered to have supernormal appetitive properties that may result in pathological eating behavior. Furthermore, ultra-processed foods are theorized to disrupt gut-brain signaling and may influence food reinforcement and overall intake via mechanisms distinct from the palatability or energy density of the food.” As plausible as these “theories” many seem, to date, this hypothesis has never been tested in a well-controlled randomised trial.

The increased caloric consumption on the ultra-processed diet was not explained by greater palatability or familiarity of the ultra-processed diet, or differences in reported hunger, fullness, satisfaction, and capacity to eat. However, the rate of eating (measured as calories or grams per minute) was higher on the ultra-processed diet (as I have noted previously, the problem with fast food is more the “fast” than the “food”).

As the authors note, “The perpetual diet wars between factions promoting low-carbohydrate, keto, paleo, high-protein, low-fat, plant-based, vegan, and a seemingly endless list of other diets have led to substantial public confusion and mistrust in nutrition science. While debate rages about the relative merits and demerits of various so-called healthy diets, less attention is paid to the fact that otherwise diverse diet recommendations often share a common piece of advice: avoid ultra-processed foods.” Clearly this study strongly supports the idea that cutting ultra-processed foods from your diet will likely help avoid excess caloric intake and subsequent weight gain.

There is however one caveat: based on the cost of ingredients obtained from a local supermarket, the weekly cost for ingredients to prepare 2,000 kcal/day of ultra-processed meals was estimated to be $106 versus $151 for the unprocessed meals. This would mean a food bill that is 50% higher for the average household. In addition, there is a time cost for meal preparation (and chewing) of the unprocessed food diet.

Be that as it may, any diet that reduces the amount of ultra-processed foods in your diet is likely to help you better manage your caloric intake and reduce inadvertent weight gain. Whether or not such a diet can be implemented at a population level remains to be seen but clearly the more dependent we remain on ultra-processed foods, the harder it will be to contain the obesity epidemic.

@DrSharma
Berlin, Germany

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