Monday, December 15, 2014

Triple-Homone Breakthrough For Obesity?

The new peptide offers a triple hormone effect in a single-cell molecule. Credit: Indiana University

The new peptide offers a triple hormone effect in a single-cell molecule.
Credit: Indiana University

This week, a group of researchers working from Munich, Germany and Indiana, USA, report, what may be a major breakthrough in the treatment of obesity and type 2 diabetes.

In their paper, published in Nature Medicine, the researchers use a range of sophisticated experiments to demonstrate that a novel peptide, which combines agonistic actions of three hormones (GLP-1, GIP and glucagon) into a single molecule, can fully reverse diabetes and reduce body weight by over 30% in mice.

Despite this just being a mouse study, the triple combination findings are no accident. Rather, these researchers have rationally designed this molecule based on the known actions of these three hormones.

As the authors describe it, their finding

predominantly results from synergistic glucagon action to increase energy expenditure, GLP-1 action to reduce caloric intake and improve glucose control, and GIP action to potentiate the incretin effect and buffer against the diabetogenic effect of inherent glucagon activity.”

According to their report, this “designer” peptide,

“…demonstrates supraphysiological potency and equally aligned constituent activities at each receptor, all without cross-reactivity at other related receptors. Such balanced unimolecular triple agonism proved superior to any existing dual coagonists and best-in-class monoagonists to reduce body weight, enhance glycemic control and reverse hepatic steatosis in relevant rodent models.”

Similar activity in humans would indeed represent a breakthrough, potentially providing a medical treatment that may be as (if not more) potent than bariatric surgery.

While the path to human development is generally long and stony, there are at least some folks who are optimistic: the molecule has been licensed to  Marcadia Biotech Inc., now fully owned by the Swiss pharma giant Roche. 

Clearly, this will be an exciting space to watch.

@DrSharma
Edmonton, AB

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Thursday, December 11, 2014

How Effective Is Obesity Management In Primary Care?

sharma-obesity-doctor-kidLosing weight with behavioural interventions in the context of a clinical trial, where you are often dealing with volunteers who are generally provided interventions that are far better structured and standardised than we can ever hope to deliver in a primary care settings, tells us little about the effectiveness of such interventions in real life.

Now a paper by Tom Wadden and colleagues from the University of Pennsylvania, published in JAMA, presents a systematic review of the behavioral treatment of obesity in patients encountered in primary care settings as delivered by primary care practitioners working alone or with trained interventionists (eg, medical assistants, registered dietitians), or by trained interventionists working independently..

A search of the literature yielded 12 trials, involving 3893 participants, that met inclusion-exclusion criteria and prespecified quality ratings.

At 6-months weight changes in the intervention groups ranged from a loss of 0.3 kg to 6.6 kg compared to a gain of 0.9 kg to a loss of 2.0 kg in the control group.

As one may expect, interventions that prescribed both reduced energy intake (eg, ≥ 500 kcal/d) and increased physical activity (eg, ≥150 minutes a week of walking), with traditional behavioral therapy, generally produced larger weight loss than interventions without all three specific components.

Also, more treatment sessions (in person or by telephone) were associated with greater mean weight loss and likelihood of patients losing 5% or more of baseline weight.

Unfortunately, overtime, weight loss in both groups declined with longer follow-up (12-24 months).

Thus, the authors conclude that,

“Intensive behavioral counseling can induce clinically meaningful weight loss, but there is little research on primary care practitioners providing such care. The present findings suggest that a range of trained interventionists, who deliver counseling in person or by telephone, could be considered for treating overweight or obesity in patients encountered in primary care settings.”

Whether any of this is worth the cost and effort was not discussed. My guess is that to see greater success in primary care we need better treatments that move well beyond the rather simplistic ‘eat-less move-more’ paradigm.

@DrSharma
Edmonton, AB

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Monday, December 8, 2014

Effectiveness Of Obesity Management For Osteoarthritis

sharma-obesity-knee-osteoarthritis1Osteoarthritis is one of the most common and disabling complications of obesity. Irrespective of whether or not the osteoarthritis is directly caused by excess weight, there is little doubt that the sheer mechanical forces acting on the affected joints will significantly impact mobility and quality of life.

Now the Canadian Agency for Drugs and Technologies in Health (CADTH) has released a report on the Clinical Effectiveness of Obesity Management Interventions Delivered in Primary Care for Patients with Osteoarthritis.

This systematic review of the literature leads to the following findings:

1) Dietary weight loss interventions, either alone or in combination with exercise produce greater reductions in the peak knee compressive force and plasma levels of interleukin-6 (IL-6) in knee OA patients compared with exercise-induced weight loss.

2) There is a significantly greater reduction in pain and improvements in functions in patients who received diet plus exercise interventions compared with either diet–only or exercise–only interventions.

3) Regardless of the type of weight-loss interventions, participants who lost 10% or more of baseline body weight had greater reductions in knee compressive force, systemic IL-6 concentrations, and pain, as well as gained greater improvement in function than those who lost less of their baseline weight.

4) Participants who lost the most weight also experienced greater loss of bone mass density at the femoral neck and hip, but not the spine, without a significant change of their baseline clinical classification with regards to osteoporosis or osteopenia.

Thus, in summary, weight loss, particularly when achieved through a combination of both diet and exercise can result in significant improvement in physical function, mobility, and pain scores in individuals with osteoarthritis.

Unfortunately, this is by no means easy to achieve and even harder to sustain.

Although I may sound like a broken record – we desperately need better treatments for obesity.

@DrSharma
Edmonton, AB

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Wednesday, December 3, 2014

Does Your Liver Control Your Appetite?

Fatty Liver

Fatty Liver

The answer may well be “yes”, at least if you happen to be a mouse.

In a rather exciting study by Iliana López-Soldado and colleagues from the Institute for Research in Biomedicine, Barcelona, published in DIABETES, the researchers show that increased liver glycogen content may affect appetite (measured as food intake) and otherwise have beneficial effects on metabolism.

In their experiments, the researchers used genetically modified mice, which overexpress an enzyme (PTG) resulting in increased liver glycogen.

Not only did these animals reduce their food intake when fed a high fat diet, they also did not develop the typical glucose intolerance, elevated insulin levels and fatty liver seen in normal mice on this diet.

Apart from losing weight (associated with lower leptin levels), these animals also had lower expression of neuropeptide Y (NPY) and higher expression of propiomelanocortin (POMC) in the hypothalamus.

Thus, the authors summarize their findings as follows:

:…liver glycogen accumulation caused a reduced food intake, protected against the deleterious effects of a HFD and diminished the metabolic impact of fasting. Therefore, we propose that hepatic glycogen content be considered a potential target for the pharmacological manipulation of diabetes and obesity.”

As a number of compounds exist that may do exactly that, these studies may point to a novel pathway for the pharmacological treatment of obesity – but let’s keep in mind that the road from finding in mice to effective treatments in humans is a long and thorny road.

@DrSharma
Edmonton, AB

ResearchBlogging.orgLópez-Soldado I, Zafra D, Duran J, Adrover A, Calbó J, & Guinovart JJ (2014). Liver glycogen reduces food intake and attenuates obesity in a high-fat diet-fed mouse model. Diabetes PMID: 25277398

 

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Tuesday, November 25, 2014

Obesity Myth: Success Is Measured In Pounds Lost

sharma-obesity-5as-booklet-coverFinally, in this series of common misconceptions about obesity management, discussed in our article in Canadian Family Physician, we address the notion that success in obesity management is best measured in the amount of weight loss:

“Given the importance of obesity as a public health problem, there is widespread effort to encourage people with excess weight to attempt weight loss.

However, a growing body of evidence suggests that a focus on weight loss as an indicator of success is not only ineffective at producing thinner, healthier bodies, but could also be damaging, contributing to food and body preoccupation, repeated cycles of weight loss and regain, reduced self-esteem, eating disorders, and social weight stigmatization and discrimination. 

There is also concern that “anti-fat” talk in public health campaigns might further promote weight bias and discrimination. 

Therefore, it might be time to shift the focus away from body weight to health and wellness in public health interventions.

Recently, the Canadian Obesity Network launched a tool called the 5As of Obesity Management (www.obesitynetwork.ca/5As) to guide primary care practitioners in obesity counseling and management. 

Minimal intervention strategies such as the 5 As (ask, assess, advise, agree, and assist) can guide the process of counseling a patient about behaviour change and can be implemented in busy practice settings.

Obesity management should focus on promoting healthier behaviour rather than simply reducing numbers on the scale. The 5As of Obesity Management is a practical tool to improve the success of weight management within primary care.”

@DrSharma
Edmonton, AB

 

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In The News

Diabetics in most need of bariatric surgery, university study finds

Oct. 18, 2013 – Ottawa Citizen: "Encouraging more men to consider bariatric surgery is also important, since it's the best treatment and can stop diabetic patients from needing insulin, said Dr. Arya Sharma, chair in obesity research and management at the University of Alberta." Read article

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