Dr. Sharma's Obesity Notes

The idea of using electrical stimulation to affect gastric motility and emptying as a means to increase satiety and reduce appetite has received a considerable amount of attention.

Regular Readers may recall that, although two gastric stimulators have now been approved for obesity treatment in Europe, US studies on gastric stimulators for the treatment of obesity, have unfortunately not lived up to expectations.

A study published in OBESITY suggests that perhaps rather than electrical stimulation of the stomach, stimulation of the large intestine (colon) may provide a more promising approach.

This idea is based on the finding that key hormones and neuronal signals that affect gastric motility and satiety (e.g. PYY-36) are in fact released by the colon.

In this pilot study, Hanaa Sallam and Jiande Chen from the University of Texas, Galveston, examined the effect of colonic electrical stimulation (CES) using implanted electrodes in dogs and found (compared to sham-stimulation) that CES delayed gastric emptying of solids by 77%, reduced intestinal contractility, and resulted in a 60% reduction in food intake.

The fact that this response was partially inhibited by guanethidine (an autonomic ganglion blocker) suggests a role for the autonomic nervous system in mediating this effect. In fact, CES decreased vagal activity in both fasting and fed states, increased the sympathovagal balance and marginally increased sympathetic activity in the fasting state.

While these findings do suggest that the colon may prove a novel target for efforts to use electrical stimulation to treat obesity (remember, electronic pacemakers are now routinely used on a number of other organs in medical practice), it will certainly take a lot more research before this may indeed be considered an actual treatment option for obesity.

In particular, one would like to certainly better understand exactly how colonic electrical stimulation produces this profound effect on appetite and food intake and that this acute effect continues to be active with prolonged stimulation.

Nevertheless, the results do point to the fact that the colon can potentially play an important role as a target organ in the treatment of obesity.

AMS
Edmonton, Alberta

Sallam HS, & Chen JD (2011). Colon Electrical Stimulation: Potential Use for Treatment of Obesity. Obesity (Silver Spring, Md.) PMID: 21660079

This morning at the EASD in Stockholm, I attended a session with the title, “Manipulating the Gut to Treat Metabolism”.

In the first presentation, Alberto Morabito (Italy) and colleagues discussed a meta-analysis showing the beneficial effect of bariatric surgery on cardiovascular mortality. However, as pointed out by many discussants, this data is confounded by lack of ransomised studies, poor controls, and other methodological shortcomings. Nevertheless, the impact of bariatric surgery on mortality is so obvious that it is difficult to doubt the positive effect.

Ji Yan and colleagues (Sweden) examined the effect of gastric bypass surgery on the methylation of various mediators of metabolic control measured in skeletal muscle biopsies. The researchers found changes in DNA methylation patterns of various genes, which can significantly alter their expression and function. Of course, as patients undergoing surgery also show profound changes in their dietary intake patterns, it is not clear from these studies whether or not the observed changes are indeed simply related to weight loss or other factors induced by surgery.

Sergio Vencio and colleagues (Brazil) examined the effect of ileal interposition on insulin secretion and insulin sensitivity in diabetic patients with a BMI less than 35. Improvements in glucose tolerance, insulin sensitivity, and both first and second-phase insulin secretion was markedly improved within the first few months after surgery (i.e. with minimal if any weight loss). The study shows that even diabetic patients below the current cut-offs for bariatric surgery (i.e. with a BMI less than 35) show marked improvements in metabolic control after gut surgery. Whether or not these improvements are related to changes in incretin secretion remains unclear but seems highly likely.

Claudia Ress and colleagues (Austria) examined the expression of Apo-lipoprotein 5 expression in liver biopsies before and after bariatric surgery. Despite an almost 6 pt drop in BMI units and a marked decrease in hepatic steatosis, there was no significant change in plasma lipids. However, Apo-5 expression in the liver was substantially decreased. Using in vitro knockdown of Apo-5, they also showed that reducing Apo-5 reduces intracellular triglyceride accumulation in liver cells - suggesting that this molecule may play a role in fatty liver disease.

But the most novel and intriguing studies were the following:

Thomas Adrian and colleagues (United Arab Emirates) presented data on the concept that a “bile salt brake” on the enteroendocrine L-cells in the distal gut (rectum) may provide a novel target for improving diabetes. These L-cells secrete GLP-1, PYY and oxyntomodulin, three gut peptides that all increase satiety. Interestingly, the release of these enterohormones is stimulated by bile salts, mediated through the TGR5 receptor. In a study involving 10 obese individuals with type 2 diabetes, the researchers demonstrated that rectal infusion of taurocholate (a bile salt) results in a dose-related increase in plasma levels of PYY and GLP-1 as well as a significant reduction in subsequent food intake (75 min after the end of the infusion). These observations not only prove the existence of the “bile salt brake” but also so that this system could possibly be harnessed to affect food intake and glucose metabolism (e.g. rectal TGR5 agonist suppositories, inhibition of ileal bile salt reabsorption, etc.).

And finally, in this session, Anne Vrieze and colleagues (Netherlands, France, Finland) presented a fascinating study on the transplantation of gut microbes from lean donors to obese subjects with the metabolic syndrome. Fecal transplantation has been previously assessed as a way to treat patients with recurrent clostridium difficile infections. In the present study, faeces from lean subjects (first screened for parasites and other infections) was “transplanted” to obese volunteers after bowel lavage. Controls consisted of “autotransplantation” of stool samples. While stool “allotransplanation” did not change weight, energy expenditure or body weight, it had a marked effect on systemic and hepatic insulin sensitivity and a marked decrease in plasma triglyceride level (the latter effect only lasted 12 weeks). Both faecal allo- and auto-transplantation was associated with a transient inflammatory response as measured by CRP levels. Obviously, at this time it is not clear which bacteria may be responsible for these effects or how this observation can be used to develop novel therapies for improving metabolic control - but the possibilities are truly intriguing.

AMS
Stockholm, Sweden

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Yesterday, on my last day at the 2010 ESC meeting in Stockholm, I attended a session on incretins.

As regular readers of these pages will recall, the term incretins refers to a group of gut hormones that elicit a wide range of biological actions affecting ingestive behaviour, gut function and metabolic control.

Michaela Diamant from the University of Amsterdam, The Netherlands, talked about the importance of the incretin GLP-1 as a determinant of the attenuated insulin response to a meal seen in patients with type 2 diabetes.

There are currently two approaches to harnessing the effects of this system to better treat diabetes:

1) by blocking DPP-IV, the major degrading enzyme of GLP-1, with “gliptins”

2) the direct administration of long-acting GLP-1 analogues (e.g. exenatide, liraglutide).

While both approaches have been shown to significantly improve glycemic control, GLP-1 analogues are of particular interest, as they also promote clinically relevant weight loss, thereby further reducing HbA1c levels. Current GLP-1 analogues require daily injections, but longer-acting forms that can be injected at weekly intervals are under development.

Gliptins, which, although not associated with notable weight loss, are at least weight neutral, a clear advantage compared to other antidiabetic agents (with the exception of metformin).

Oliver Schnell, Munich, Germany, discussed the cardiovascular effects of GLP-1 analogues. He pointed out that fluctuations in glucose levels has been associated with increased CV mortality, something that GLP-1 analogues can perhaps help prevent.

Not only do GLP-! analogues not cause hypoglycemia, but, by virtue of their effects on delaying gastric emptying and improving insulin secretion, they may significantly blunt the glucose variability seen with conventional diabetes treatments. Thus, studies using continuous glucose monitoring show decreased fluctuations in glucose levels over the course of a 24 hour time period.

In addition, the weight loss seen with GLP-1 analogues is associated with improvements in other CV risk factors including lipids and blood pressure.

GLP-1 receptors have also been identified on vascular endothelial cells and GLP-1 infusions appear to improve endothelial function in patients with type 2 diabetes. There is also some preliminary data from animal studies to suggest that GLP-1 may improve post-ischemic ventricular function and a reduction in infarct size. A small study in patients with heart failure, GLP-1 infusion were observed to promote cardiac ejection fraction and improve physical function.

It appears that there are both GLP-1 receptor dependent and receptor independent effects of GLP 1.

Despite these putative positive effect, whether or not GLP-1 based therapies will provide cardiovascular benefits that go beyond glucose control remains to be seen.

AMS
Stockholm, Sweden

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Regular readers will recall previous posts on the VBLOC device, which uses intermittent electrical signals to block the vagal nerve thereby leading to weight loss. The previous post followed Enteromedic’s announcement that the early results from the EMPOWER study failed to quite meet its primary and secondary efficacy endpoints (resulting in a 70% fall in share price).

Yesterday, however, the share price of Enteromedics more than doubled after the company announced the follow-up results of two studies, to be presented in the coming days at the American Society for Metabolic and Bariatric Surgery Meeting in Las Vegas.

After soldiering on in the randomized, double-blind, controlled pivotal EMPOWER Study, participants now at 20 months experienced an almost 20% excess weight loss, while averaging 9 hours of device use per day.

Perhaps more interestingly, in another ongoing study (VBLOC-DM2 ENABLE), obese patients with Type-2 diabetes mellitus showed an improvement in HbA1c levels of 0.8% as well as a 25% excess weight loss over 12 months while averaging about 14 hours per day of therapy with the implantable Maestro RC System.

The novelty of this second generation Maestro device lies in the rechargeability of the implanted batteries via an external mobile charger and transmitter coil that can be worn for a few hours each week, thereby allowing delivery of a far more extensive treatment that with the previous version of the device.

Although this treatment required laparoscopic implantation of electrodes and the battery pack, with the usual risks entailed in such surgery, the treatment appears to be well tolerated with few side effects.

As outlined in yesterday’s press release, the company certainly appears optimistic about the future of this treatment for obesity and diabetes - the investors clearly appear to share this enthusiasm.

AMS
Edmonton, Alberta

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Last week I visited the University of Toronto to present city-wide rounds to the division of Gastroenterology. I also happened to meet with Tony Lam, a bright young basic researcher, who studies how intestinal nutrient-sensing mechanisms can potentially regulate glucose control.

I was most intrigued by his findings, published last year in NATURE, in which he provided substantial evidence in support of the hypothesis that exposure of the upper intestine to dietary lipids activates an intestine-brain-liver neural axis to regulate glucose homeostasis.

Thus, in rodents, direct administration of lipids into the upper intestine suppressed hepatic glucose production, an effect that could be abolished by co-infusion of tetracaine (an anesthetic) or with subdiaphragmatic vagotomy or gut vagal deafferentation as well as hepatic vagotomy, thereby suggesting that the neural connection between the gut-brain-liver is essential for this response.

These findings indicate that upper intestinal lipids activate an intestine-brain-liver neural axis to inhibit glucose production, thereby revealing a previously unappreciated pathway that regulates glucose homeostasis.

In subsequent studies, Lam has demonstrated that gut cholecystokinin (CCK) may be in part responsible for this inhibition of hepatic glucose production through a neuronal network and provides data to suggest that intestinal CCK resistance (as found in obese rodents) may contribute to hyperglycemia in response to high-fat feeding.

These findings are most intriguing for at least three reasons:

1) They point to a new pathway through which the gut via the brain controls glucose homeostasis.

2) Lipid ingestion (as in a high-fat diet) could play a key role in signaling to the brain that it is time to tell the liver to shut down glucose production - a mechanism that may be less effective in obesity.

3) These findings also relevant to the issue of how different types of bariatric surgery (e.g. bypassing the proximal small bowel as occurs in Roux-en-Y gastric bypass) could have different effects on glucose metabolism.

AMS
Edmonton, Alberta