Yesterday, I co-chaired and spoke at a session on obesity management at the 25th Annual Scientific Meeting of the American Society of Hypertension in New York.

Later in the afternoon, Jeff Friedman, who played a prominent role in the discovery of leptin, thereby hearkening in the modern era of adipocyte and appetite physiology, presented an update on the potential role of this system in the therapeutic management of obesity and diabetes.

While leptin has therapeutic efficacy in rare cases of genetic leptin deficiency, its use in non-genetic “garden-variety” obesity has proven disappointing. Indeed, there appears to be more evidence that leptin plays an important role in defending against weight loss, than to support its roled in the prevention of weight gain.

Thus, the dramatic decline in sympathetic activity, fall in metabolic rate and increased hunger that follows weight loss is likely due to the decrease in the leptin signal that unleashes the biological drive to rapidly regain weight and defend against further weight loss.

Indeed in most obese individuals, leptin levels increase in proportion to weight gain, while at the same time these individuals display leptin resistance, rendering these increased levels of leptin as biologically ineffective (a notion akin to the hyperinsulinemia associated with insulin resistance in patients with type 2 diabetes mellitus).

This state of affairs limits the use of leptin for the treatment of obesity, as the high doses of leptin that would be required to overcome the leptin resistance are poorly tolerated.

But recent research points to another possible use of leptin (or leptin analogues) in weight management, namely as a way to prevent weight regain after weight loss.

The basic idea here is to substitute leptin after weight loss in an attempt to trick the body into thinking that it still has as much body fat as it had before. Studies that have combined the peptide pramlinitide (which induces weight loss) with metreleptin (a long-acting analogue of leptin) are showing promise in terms of long-term weight loss maintenance (albeit at the cost of injections).

Friedman also discussed new data showing that leptin may have potent antidiabetogenic effects independent of any effects on weight loss or food intake. Some of this action may be mediated by leptin’s ability to increase plasma levels of Insulin-like Growth Factor Binding Protein 2 (IGFBP2), which has profound inhibitory effects on hepatic glucose output.

Several studies to further exploring the interaction between leptin and IGFBP2 and the antidiabetic effect of this protein are currently underway in Freidman’s lab to better understand these novel findings.

AMS
New York, New York

p.s. Join my new Facebook page for more posts and links on obesity prevention and management

Hedbacker K, Birsoy K, Wysocki RW, Asilmaz E, Ahima RS, Farooqi IS, & Friedman JM (2010). Antidiabetic effects of IGFBP2, a leptin-regulated gene. Cell metabolism, 11 (1), 11-22 PMID: 20074524

Yesterday, I attended the annual Spring Meeting of CANNeCTIN (Canadian Network and Centre for Trials Internationally), a national network funded by the CIHR/CFI Clinical Research Initiative program to improve the prevention and treatment of cardiac and vascular diseases and diabetes.

CANNeCTIN is jointly led by Dr. Salim Yusuf, from Hamilton Health Sciences and McMaster University, and Dr. John Cairns, from the University of British Columbia. CANNeCTIN facilitates the development, conduct and leadership of large international clinical trials, registries and epidemiologic studies across Canada and the world.

As it so happens, yesterday, also saw the online publication in Diabetes Care of a paper I was involved in during my time in Hamilton on the ethnic variation of risk factors associated with obesity.

In this paper, we looked at the relationship between body weight (BMI), adipokines, and insulin resistance in 1,176 South Asian, Chinese, Aboriginal, and European Canadians in the SHARE study (Study of Health Assessment and Risk in Ethnic groups).

Adjusted mean adiponectin (a protein secreted by fat cells that improves insulin sensitivity) concentration was significantly higher in Europeans [12.9] and Aboriginals [11.8] compared to South Asians [8.8] and Chinese [8.5].

Serum leptin levels were also significantly higher in South Asians [11.8] and Aboriginals [11.1] compared to Europeans [9.2] and Chinese [8.3].

BMI and waist circumference were inversely associated with adiponectin in every group except the South Asians.

The increase in HOMA-IR (a measure of insulin resistance) for each given decrease in adiponectin was larger among South Asians and Aboriginals compared to Europeans.

Interestingly, a high glycemic index diet was associated with a larger decrease in adiponectin among South Asians and Aboriginals, and a larger increase in HOMA-IR among South Asians relative to other groups.

This study clearly shows that South Asians have the least favourable adipokine profile of the studied ethnic groups, and like the Aboriginal people, display a greater increase in insulin resistance with decreasing levels of adiponectin.

The reasons for these differences are not clear but we are studying possible mechanisms to explain these findings in South Asians in a “molecular” version of this study.

AMS
Hamilton, Ontario

p.s. For more news and views follow me on Facebook

Mente A, Razak F, Blankenberg S, Vuksan V, Davis AD, Miller R, Teo K, Gerstein H, Sharma AM, Yusuf S, Anand SS, & for the SHARE, SHARE-AP investigators (2010). Ethnic variation in adiponectin and leptin levels and their association with adiposity and insulin resistance. Diabetes care PMID: 20413520

Although, in the end I spent less than 24 hrs in the Emirates, one of the highlights of attending the 1st International Abu Dhabi Diabetes Conference, was the opportunity to once again hear David Cummings (Seattle) speak about how bariatric surgery can lead to the remission of type 2 diabetes. Cummings’ talk certainly provided plenty of food for thought on my long flight back to Canada.

As outlined in a newly released Diabetes Surgery Position Statement published in the latest issue of the Annals of Surgery, surgical approaches may well prove to be the treatment of choice in carefully selected patients with poorly controlled type 2 diabetes and a BMI greater than 30.

While the authors of the Statement emphasize the need for more clinical trials to investigate the future role of surgery in diabetes treatment, they also call for further investigations on the mechanisms of surgical control of diabetes (which are far from being fully understood).

Although weight loss itself clearly plays a significant role in the reversal of diabetes generally seen with bariatric surgery, with gastric bypass surgery, this reversal of diabetes often precedes the weight loss and there are likely neuroendocrine consequences to allowing food to bypass the duodenum that may substantially affect glucose metabolism (including regeneration of pancreatic beta-cells).

Thus, a better understanding of exactly how gastrointestinal surgery “cures” diabetes, will hopefully also open new avenues for pharmacological treatments that can mimic the effects of surgery in these patients.

Indeed, certain gut-hormones, which are known to be dramatically affected by gastric bypass surgery (e.g. GLP-1), have already been shown to have a beneficial effect both on diabetes and weight management (e.g. liraglutide).

Health professionals who want to learn more about this topic should consider attending the upcoming First Canadian Summit Metabolic Surgery for Type 2 Diabetes to be held in partnership with the Canadian Obesity Network and the Canadian Diabetes Association at the Hôtel Le Centre Sheraton, Montréal, May 6-7, 2010.

To watch a recent episode of 60 Minutes on CBS, which features interviews with Cummings and others discussing the surgical approach to type 2 diabetes, click here.

Very much appreciate hearing from my readers on their thoughts regarding whether or not diabetes surgery (vs. lifelong medications or injections) will significantly change how we treat diabetes in the future.

AMS
Edmonton, Alberta

Arab Food Pyramid

When we think of the global obesity epidemic, we tend to conjour up images of of US-Americans, literally hefting along excess pounds as they go about their lives across America. We may also recall that Canada and most other Western countries have a problem.

But, interestingly, nowhere is the obesity problem as big as in the countries of the Gulf Region and the Middle East (exceeded perhaps only by populations on remote Oceanic islands).

According to the United Arab Emirates global school-based student health survey (GSHS) 2005 fact sheet, over 30% of 13-15 year olds exceed the 85th percentile for body weights. The adult population (though it is hard to find accurate statistics) apparently does not fare much better.

Why, you may wonder, am I interested in this?

Because tonight I am heading out from Munich to speak on Saturday at the 1st International Abu Dhabi Diabetes Conference, in the United Arab Emirates.

Although the conference focusses on diabetes, it is obvious that the prime driver of the diabetes epidemic in that region of the world (as elsewhere) is the obesity crisis.

It is therefore not surprising that the organisers have opted to include sessions on obesity assessment and management (although most of the conference of course focusses on diabetes management, which I have often described as “palliative care”).

As should be obvious to anyone who has recently visited the UAE, population-based prevention measures in a society that spends most of its time indoors (I would too when it’s 40-50 degrees C outside) and enjoys food as one of the only officially endorsed “vices” (there are tough restrictions on alcohol, gambling and other worldly “pleasures”), is lilkely to be challenging if not simply impossible.

Given that the Arab susceptibility to obesity appears similar to other Asians in that they appear more prone to abdominal obesity with all its dire metabolic consequences, diabetes may in fact be the least of their worries.

I look forward to attending the meeting and learning more about the Arab “diabesity” epidemic from my friends and colleagues in the Emirates.

AMS
Munich, Germany

Of course, obesity is associated with a wide range of health problems like high blood pressure, diabetes, arthritis, or reflux disease, all of which may all require pharmacological treatment. But this is not what this post is about.

Rather, this post is actually about the question whether or not larger patients need higher doses of medications to have an optimal treatment effect.

This topic was recently discussed by Matthew Falagas and Drosos Karageorgopoulos in a Lancet article that specifically addresses the issue of dose adjustments for antimicrobial agents in larger patients.

As the authors point out, body size is routinely considered in the optimization of drug therapy in oncology, anaesthetics and pediatrics. However, there remains a paucity of data on the optimal dosing of pharmacological agents for most of the drugs we use in clinical practice.

Thus, although regulatory agencies regularly demand special pharmacokinetic studies in children, elderly prople and patients with renal or hepatic impairment, no such studies are demanded for obese or even severely obese patients.

Requiring such studies would at least make theoretical sense as, conceivably, obesity can affect drug absorption, distribution, metabolism and clearance. Furthermore, it is obvious that body composition can particularly affect the disposition of lipophilic compounds. Obese patients are also likely to have comorbiditiesthat can affect these parameters (e.g. fatty liver disease) and are much more likely to be on multiple medications that can make drug-drug interactions problematic.

In short, as pointed out by Falgas and Karageorgopoulos the one-size-fits-all strategy for antimicrobial agents (and other drugs?) may well be outdated and require much more consideration than has been given to this issue in the past.

AMS
Winnipeg, Manitoba