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 10–16 years old with insulin resistance, who received 2000 mg 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
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 MetAP2 inhibitor that showed remarkable weight loss efficacy both in patients with Prader-Willi Syndrome as well as hypothalamic 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 risk mitigation strategy. As announced by the company in a press release earlier 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. Like 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. ZGN-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 a 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.
POMC Mutation Obesity Responds To Melanocortin-4 Receptor Agonist
Melanocyte-stimulating hormone (a-MSH), which is produced from the hormone precursor proopiomelanocortin (POMC) and acts on the hypothalamic melanocortin-4 receptor, plays a key role in the regulation of satiety and energy expenditure. In very rare instances, mutations of the gene coding for POMC can cause severe early onset obesity characterised by increased appetite. Due to other effects of POMC deficiency, patients will present with pale skin, red hair and clinical signs of hypocortisolism. Now, a paper by Peter Kühnen and colleagues published in the New England Journal of Medicine, shows that treating patients with the melanocortin-4 receptor agonist, setmelanotide, can result in significant reduction in appetite and body weight. The open-label study was performed in two adult patients with POMC deficiency, in cooperation with Rhythm Pharmaceuticals, which provided the study medication and regulatory support. Both patients weighed around 150 Kg with marked hyperphagia and both responded to treatment with a substantial reduction in appetite and dramatic weight loss of over 20 Kg over 12-13 weeks. After a brief interruption, one patient was again treated for 42 weeks, ultimately losing 51 kg (32.9% of her initial body weight). As the authors note, “Setmelanotide appeared to completely reverse hyperphagia, leading to impressive weight loss and normalization of insulin resistance. More important, both patients reported a dramatic improvement in their quality of life after the initiation of setmelanotide therapy. Moreover, the substantial and ongoing reduction in body weight was similar to the changes observed after leptin administration in patients with leptin deficiency.” Over all the treatment was well tolerated with no major adverse effects. While these observations were made in very rare patients with documented POMC deficiency, these findings may have broader implications for individuals with more common “garden-variety” obesity. “Both patients described here had very high leptin levels before treatment, suggesting leptin resistance. In patients with proopiomelanocortin deficiency, the leptin signal is probably not properly transduced into anorexigenic responses, given the lack of melanocyte-stimulating hormone. Setmelanotide substitutes for melanocyte-stimulating hormone and binds at its receptor, thus overcoming leptin resistance. On the basis of the observation that obese patients without known genetic abnormalities have severe leptin resistance and regain weight owing to a post-dieting increase in appetite, we speculate that setmelanotide may also be effective in nongenetic forms of obesity.” Appropriate studies in patients with non-POMC deficient obesity are currently underway. @DrSharma Atlanta, GA
Bariatric Surgery Improves Mitochondrial Efficiency
One of the more frustrating aspects of weight loss, is that it is often associated with decreased metabolic rate and increased ‘fuel efficiency’. Thus, following weight loss, not only does the body need fewer calories, doing the same amount of physical work uses fewer calories than before (the joke is that, if you ran 5K a day to lose weight, you have to run 10K a day to keep it off). Now, a study by Maria Fernström and colleagues, published in Obesity Surgery, shows increased mitochondrial efficiency following bariatric surgery. The researchers performed skeletal muscle biopsies in 11 women before and at 6 months after gastric bypass surgery. Measurements in isolated mitochondria showed a marked increase in coupled respiration (state 3) and overall mitochondrial capacity (P/O ratio) with a non-significant increase in uncoupled (state 4) respiration. Thus, at 6 months following gastric bypass surgery, both the mitochondrial capacity for coupled, i.e., ATP-generating, respiration increased as well as the P/O ratio improved. As the authors note, not only would this increased “fuel efficiency” in part explain the decreased basal metabolism often associated with weight loss but also the propensity for weight regain that often follows weight-loss interventions. Obviously, due to lack of a control group, this study does not demonstrate that these changes are in any way specific to weight-loss following bariatric surgery. Also, given that the nadir of weight loss is generally not achieved until about 18 months following surgery, the changes observed in this study may not represent the maximum increase in mitochondrial efficiency to be achieved with further weight loss. @DrSharma Edmonton, AB
Fructose-Sweetened Beverages Do Not Promote Systemic Inflammation
There is little doubt that increased consumption of fructose-sweetened beverages can be a substantial source of extra calories, thereby potentially promoting weight gain. That said, fructose has also been implicated in non-caloric metabolic effects including promoting insulin resistance and systemic inflammation. Now a study by Jessica Kuzma and colleagues from the Fred Hutchinson Cancer Research Center, Seattle, WA, published in the American Journal of Clinical Nutrition, specifically addresses the hypothesis that fructose-sweetened beverages can promote systemic inflammation. For their study, they randomised 24 otherwise healthy participants to three 8 day periods during which participants consumed 4 daily servings of fructose-, glucose-, or HFCS-sweetened beverages accounting for 25% of estimated calorie requirements while consuming a standardized diet ad libitum. During the study subjects consumed 116% of their estimated calorie requirement while drinking the beverages with no difference in total energy intake or body weight. Neither fasting plasma concentrations of C-reactive protein or IL-6 changed during the study. Furthermore, there were no consistent changes in measures of adipose tissue inflammation or in intestinal permeability. Overall, the researchers conclude that consuming an excessive amount of fructose, HFCS, and glucose derived from SSBs consumed, at least in the short term (8 days), does not appear to promote systemic inflammation in otherwise healthy adults. Obviously, this study does not address the issue of wether or not overconsumption of sugar-sweetened beverages can promote obesity or whether cutting out such beverages has any other advantages short of lowering caloric consumption. @DrSharma Edmonton, AB
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