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Do SGLT-2 Inhibitors Change Fat Metabolism?
Since the introduction of SGLT-2 inhibitors (“gliflozins” or “glucoretics), as an insulin-independent treatment for type 2 diabetes, that works by blocking glucose reabsorbtion in the kidney┬áresulting in loss of glucose (and calories) through the kidney, much has been written about the (albeit modest) weight loss associated with this treatment. Several studies have documented that the weight loss leads to a change in body composition with an often significant reduction in fat mass. Now, Giuseppe Daniele and colleagues, in a paper published in Diabetes Care, show that treatment with these compounds may enhance fat oxidation and increase ketone production in patients with type 2 diabetes. The researchers┬árandomized 18 individuals with type 2 diabetes┬áto dapagliflozin┬áor placebo for two weeks. As expected, dapagliflozin reduced fasting plasma glucose significantly (from 167 ┬áto 128 mg/dL). It also increased insulin-stimulated glucose disposal (measured by insulin clamp) by 36%, indicating a significant increase in insulin sensitivity. Compared to baseline, glucose oxidation decreased by about 20%,┬áwhereas nonoxidative glucose disposal (glycogen synthesis) increased┬áby almost 50%. Moreover, dapagliflozin increased lipid oxidation resulting in a four-fold increase in plasma ketone concentration and┬áand a 30% increase in fasting plasma glucagon. Thus, the authors note that treatment with dapagliflozine┬áimproved insulin sensitivity and caused a shift from glucose to lipid oxidation, which, together with an increase in glucagon-to-insulin ratio, provide the metabolic basis for increased ketone production. While this may explain the recent observation of a greater (albeit still rather rare) incidence of ketoacidosis with the use of these compounds, these findings may also explain part of the change in body composition previously noted with SGLT-2 treatment. While this still does not make SGLT-2 inhibitors “weight-loss drugs”, there appears to be more to the fat┬áloss seen with these compounds than just the urinary┬áexcretion of glucose. @DrSharma Edmonton, AB
Metformin Attenuates Long-Term Weight Gain in Insulin-Resistant Adolescents
The biguanide metformin is widely used for the treatment of type 2 diabetes. Metformin has also been shown to slow the progression from pre to full-blown type 2 diabetes. Moreover, metformin can reduce weight gain associated with psychotropic medications and polycystic ovary syndrome. Now, a randomised controlled trial by M P van der Aa and colleagues from the Netherlands, published in Nutrition & Diabetes suggests that long-term treatment with metformin may stabilize body weight and improve body composition in adolescents with obesity and insulin resistance. The randomised placebo-controlled double-blinded trial included 62 adolescents with obesity aged 10ÔÇô16 years old with insulin resistance, who received 2000ÔÇëmg of metformin or placebo daily and physical training twice weekly over 18 months. Of the 42 participants (mean age 13, mean BMI 30), BMI was stabilised in the metformin group (+0.2 BMI unit), whereas the control group continued to gain weight (+1.2 BMI units). While there was no significant difference in HOMA-IR, mean fat percentage reduced by 3% compared to no change in the control group. Thus, the researcher conclude that long-term treatment with metformin in adolescents with obesity and insulin resistance can result in stabilization of BMI and improved body composition compared with placebo. Given the rather limited effective options for addressing childhood obesity, this rather safe, simple, and inexpensive treatment may at least provide some relief for adolescents struggling with excess weight gain. @DrSharma Edmonton, AB
The Weight Of Living
In its approach to addressing weight bias and discrimination, the Canadian Obesity Network recently launched the “Weight of Living” (WoL) project on its facebook page. Modelled on “Humans of New York”, WoL presents images and stories of Canadians living with obesity in all their diversity and variation. After all, nothing is more effective in breaking down stereotypes and barriers than realizing that people living with obesity are no different from everyone else, in their hopes, their dreams, their challenges, their aspirations – doing their best to cope and overcome what life throws at them. Rather than promoting a culture of fat-shaming and blaming, the Canadian Obesity Network seeks to destigmatise those living with obesity by encouraging them to share their real stories in their own words. Thus, this project seeks to dismantle the stereotypes that surround the lives of people who live with obesity, including the notion that everyone who has overweight or obesity wants to lose weight because they are unhappy with themselves. Many of the stories you will see in the upcoming weeks do not reflect this. The Canadian Obesity Network┬áhopes that, by sharing these experiences, we┬áall will realize that people who have┬áoverweight or obese have goals, dreams, and aspirations just like everyone else, and that their weight is not necessarily a barrier to achieving these, nor is it something that needs to be a source of fear and shame. In contrast to many other “weight-loss” sites, the Canadian Obesity Network will not┬ápublish stories that glorify weight loss journeys, commercial programs or products, or extreme weight loss attempts. “While we respect the importance and validity of each story we receive, publishing stories like these only serve to reinforce the idea that people who are overweight or obese are living unhappy, unfulfilling lives – and we know you are worth so much more than that.” Check out the first WoL stories here, here,┬áhere, and here For more information on how to participate in this project click here or send an e-mail to┬á @DrSharma Edmonton, AB
Can Planned Cheating Help You Stick With Your Diet?
Many diet plans praise the importance of strict adherence to whatever the storyline of the diet happens to be. This includes tips on what foods to avoid or to never eat. Indulging in these “forbidden” foods, is considered cheating and failure. Now, research by┬áRita Coelho do Vale and colleagues, published in the Journal of Consumer Psychology, explores the notion that planned “cheats” can substantially improve adherence with restrictive diets. Using a set of controlled dietary experiments (both simulated and real dieting), the researchers tested the notion that┬ágoal deviations (a more scientific term for “cheats”) in the plan helps consumers to regain or even improve self-regulatory resources along the goal-pursuit process and can thus enhance the likelihood that the final goal is attained. That, is exactly what they found: Compared to individuals who followed a straight and rigid goal, individuals with planned deviations helped subjects┬áregain self-regulatory resources, helped┬ámaintain subjects’ motivation to pursue with regulatory tasks, and (3) has a positive impact on affect experienced, which are all likely to facilitate long-term goal-adherence. Thus, the authors conclude that, “…it may be beneficial for long-term goal-success to occasionally be bad, as long it is planned.” This is not really that new to those of us, who recommend or use planned “treats” as a way to make otherwise restrictive diets bearable. Good to see that there is now some research to support this notion. @DrSharma Edmonton, AB
How Do People With Obesity Spend Their Time?
We live in a time where most of us┬ácomplain about the lack of it. Thus, I often remind myself that our ÔÇ£fast-food cultureÔÇØ is more a time than a food problem. Now a study by Viral Patel and colleagues, published in OBESITY, takes a detailed look at how US Americans spend their time according to different BMI categories. The researchers analyse data from over 28,503 observations of individuals aged 22 to 70 from the American Time Use Survey, a continuous cross-sectional survey on time use in the USA. In a statistical model that adjusted for various sociodemographic, geographic, and temporal characteristics, younger age; female sex; Asian race; higher levels of education; family income >$75 k; self-employment; and residence in the West or Northeast census regions were all associated with a lower BMI relative to reference categories whereas age 50 to 59 years; Black, Hispanic, or ÔÇ£otherÔÇØ race; and not being in the labor force were associated with a higher BMI. That said, here are the differences in time use associated with higher BMI: Although there were no substantial differences among BMI categories in time spent sleeping, overweight individuals experienced almost 20 fewer minutes of sleeplessness on weekends/holidays than individuals with normal weight. Furthermore, there was a U-shaped relationship between BMI and sleep duration such that BMI was lowest when sleep duration was approximately 8 h per day and increased as sleep duration became both shorter and longer. Less sleep on weekends and holidays (5 to 7 h) was also associated with higher BMI than 8 to 9 h or sleep. There were also no major differences between BMI categories and the odds of participating in work or in the amount of time working. However, working 3-4 h on weekends/holidays was associated with the lowest BMI. Individuals with obesity were more likely to be working between 3:30 a.m. and 7:00 a.m. on weekdays than normal-BMI individuals, again perhaps cutting into restful sleep. Individuals with obesity were less likely to participate in food and drink preparation than individuals with normal weight on weekdays but spent about the same amount of time eating or drinking as the reference category. Interestingly, individuals with obesity were more likely than individuals with normal weight to participate in health-related self-care, and overweight individuals spent over 1 h more on weekdays than individuals with normal weight on health-related self-care and also spent an additional 15 min (almost double… Read More »
Effectiveness of Exercise Interventions After Bariatric Surgery
There is no doubt that exercise is good for you and that individuals with obesity, both before and after bariatric surgery (like everyone else), would stand to benefit from increasing their levels of physical activity. Following bariatric surgery, exercise may be particularly important not just to increase physical fitness, but also to limit the obligatory loss in muscle mass that generally accompanies weight loss. Now, a study by David Creel and colleagues, published in OBESITY, compares three┬álevels of exercise intervention in patients following bariatric surgery in terms of effectiveness and adherence. A total of 150 patients undergoing bariatric surgery were randomised to either┬ástandard care (SC), pedometer use (P), or exercise counseling group (C). The standard care group (SC)┬áreceived no exercise support by the bariatric center beyond a simple┬áeducational pamphlet. Participants in the pedometer group (P)┬áwere given a pedometer and a one-page information sheet on using the device to increase physical activity. This handout promoted the progressive attainment of 10,000 steps/day. Individuals were asked to wear their device daily and record date, steps achieved, and whether they wore the device the entire day, part of the day, or not at all. Journals were collected, but no feedback was provided. Participants in the exercise counselling group (C) were regularly seen at the bariatric centre and counselled by a certified exercise professional using motivational intervention techniques with individual goal setting. Based on physical activity measurements using an accelerometer over two weeks before and┬á2, 4, and 6 months postoperatively, there was no difference between the SC and P groups, with a statistically significant but modest increase in daily steps in the C group that emerged at 4 months and was maintained at 6 months (about 1,000 extra steps per day compared to SC). There was no notable difference in exercise tolerance, which increased in all three groups post surgery. No group┬áreached the 10,000 steps/day or 150 bout-minutes/week recommended for general health As may be expected from these rather modest results, no┬ásignificant differences in weight or weight change were found between groups at any time point. Thus, these findings suggest that handing out a pedometer and asking patients to journal their activity is no more effective┬áin promoting physical activity, than simply handing out a pamphlet; moreover, even adding in counselling by an exercise professional adds little (if anything) to the outcome. Although the researchers discuss the possibility that an even more intense intervention may provide… Read More »
What Behaviours Are Important For Optimal Outcomes With Bariatric Surgery?
Bariatric surgery is by far the most effective treatment for severe obesity but outcomes vary from one patient to the next. Now a paper by James Mitchell and colleagues, published in JAMA Surgery, reports on the postoperative eating behaviors and weight control strategies that are associated with differences in body weight seen at 3 years after bariatric surgery. The study looks at self-reported data from over 2000 participants in the The Longitudinal Assessment of Bariatric Surgery-2 (LABS-2) study, a multicenter observational cohort study at 10 US hospitals in 6 geographically diverse clinical centers in the USA. Participants completed detailed surveys regarding eating and weight control behaviors prior to surgery and then annually after surgery for 3 years. The researchers assessed 25 postoperative behaviors related to eating, weight control practices, and the use of alcohol, smoking, and illegal drugs. The three key behaviours associated with poor outcomes were lack of weekly self-weighing, continuing to eat when feeling full more than once a week, and eating continuously during the day. Thus, a participant who postoperatively started to self-weigh regularly, stopped eating when feeling full, and stopped eating continuously during the day after surgery would be predicted to lose almost 40% of their baseline weight compared to only 24% weight loss in participants who did not adopt these behaviours. Other behaviours that had negative influences on outcomes included problematic use of alcohol, smoking and illegal drugs. Thus, as one may have suspected all along, helping patients adopt and adhere to behavioural changes that include self-montioring and mindful eating behaviours can be expected to substantially affect the success of bariatric surgery. @DrSharmma Seoul, South Korea
Zafgen Abandons Belanorib Program But Continues Exploring MetAP2 Inhibitor For Obesity
Regular readers may recall previous posts on the novel anti-obesity compound belanorib, a┬áMetAP2 inhibitor that showed remarkable┬áweight loss efficacy both in patients with Prader-Willi Syndrome┬áas well as┬áhypothalamic obesity. Unfortunately, as noted before, several cases of venous thromoboembolisms led to a halt of ongoing trials during which the company (Zafgen) sought to better understand the possible mechanism for this serious adverse effect and explore the possibility of implementing a┬árisk mitigation strategy. As announced by the company in a press release┬áearlier this week, “Following its discussions with the FDA and review of other considerations, Zafgen has determined that the obstacles, costs and development timelines to obtain marketing approval for beloranib are too great to justify additional investment in the program, particularly given the promising emerging profile of ZGN-1061. The Company is therefore suspending further development of beloranib in order to focus its resources on ZGN-1061.” The press release also describes the new compound ZGN-1061 as a, “…fumagillin-class, injectable small molecule second generation MetAP2 inhibitor that was discovered by Zafgen’s researchers and has been shown to have an improved profile relative to previous inhibitors in the class.┬áLike other MetAP2 inhibitors that have shown promise in the treatment of metabolic diseases including severe and complicated obesity, ZGN-1061 modulates the activity of key cellular processes that control the body’s ability to make and store fat, and utilize fat and glucose as an energy source.┬áZGN-1061 is also anticipated to help reduce hunger and restore balance to fat metabolism, enabling calories to once again be used as a productive energy source, leading to weight loss and improved metabolic control. ZGN-1061 has an emerging safety profile and dosage form that are believed to be appropriate for the treatment of prevalent forms of severe and complicated obesity, and is currently in Phase 1 clinical development. Zafgen holds exclusive worldwide rights for the development and commercialization of ZGN-1061.” According to the press release, “The compound has similar efficacy, potency, and range of activity in animal models of obesity as beloranib, but displays highly differentiated properties and a reduced potential to impact thrombosis, supporting the value of the compound as a more highly optimized MetAP2 inhibitor.” Screening of patients for┬áa Phase 1 clinical trial evaluating ZGN-1061 for safety, tolerability, and weight loss efficacy over four weeks of treatment is currently underway. @DrSharma Edmonton, AB Disclaimer: I have served as a consultant to Zafgen.