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Surgery and diabetes remission

Insights into surgery and diabetes remission

The study reveals that bariatric surgeries increase bile acid concentrations, and in concert with a bile acid receptor called TGR5, play critical roles in balancing glucose levels in the body

Although many patients often experience remission of type 2 diabetes following bariatric surgery, the exact mechanism behind these effects are unknown. A recently published Cornell-led study, ‘{{TGR5 contributes to glucoregulatory improvements after vertical sleeve gastrectomy in mice]]’, featured in the journal Gut provides clues to the mystery. The findings open doors for novel drug treatments to treat type 2 diabetes.

The study, which was done with mice, reveals that bariatric surgeries increase bile acid concentrations, and in concert with a bile acid receptor called TGR5, play critical roles in balancing glucose levels in the body, which help treat diabetes. Signalling from TGR5 was found to regulate several metabolic outcomes, including: glucose homeostasis, inflammation and liver insulin signalling. However, the researchers caution that bariatric surgery may not be the answer for all patients suffering from type 2 diabetes.

"In the US, bariatric surgeries are primarily allowed for obesity treatment, generally requiring a BMI>40 or a BMI>35 with significant obesity-related co-morbidities," though some clinicians argue for expanding the use of these surgeries for treatment of diabetes, said Dr Bethany Cummings, assistant professor of biomedical sciences in Cornell's College of Veterinary Medicine and the paper's senior author. "Our goal is to study these surgeries in order to identify novel therapeutic targets, because surgery is not without risks and a drug is much easier to widely distribute amongst patients.”

Dr Bethany Cummings

This study points to TGR5 as a possible target for diabetes treatment, and more research on this bile acid receptor may also lead to treatments that exploit TGR5 and bile acid links.

In the study, the researchers conducted a sham surgery or vertical sleeve gastrectomy (VSG) in high-fat-fed normal lab mice, and in specially engineered mice without TGR5 receptors.

In a VSG, surgeons cut along the curve of the stomach and remove roughly 70 percent, leaving a tubular organ. The sham surgery created sutures in the stomach but didn't remove any stomach tissue, to test if surgery itself contributed to effects. A third group of normal mice were given a sham surgery but were also placed on a restricted diet to control for weight loss.

Cummings and colleagues found that after the VSG, circulating concentrations of bile acids in the normal mice greatly increased – for reasons not yet understood. Furthermore, VSG in the normal mice favoured beneficial bile acids.

Bile acids come in different forms, a less beneficial hydrophobic (water repelling) form and a healthier hydrophilic (water attracting) form. The experiments revealed that signalling from TGR5 specifically contributed to the increase in hydrophilic bile acids, which in turn helped balance and regulate glucose in these mice after VSG surgery.

Overall, they found that VSG decreased food intake and body weight, increased energy expenditure and circulating bile acid concentrations, improved fasting glycaemia, glucose tolerance and glucose-stimulated insulin secretion, enhanced nutrient-stimulated glucagon-like peptide 1 secretion and produced favourable shifts in gut microbial populations in both genotypes.

However, the body weight-independent improvements in fasting glycaemia, glucose tolerance, hepatic insulin signalling, hepatic inflammation and islet morphology after VSG were attenuated in Tgr5−/− relative to Tgr5+/+ mice. Furthermore, VSG produced metabolically favourable alterations in circulating bile acid profiles that were blunted in Tgr5−/− relative to Tgr5+/+ mice. TGR5-dependent regulation of hepatic Cyp8b1 expression may have contributed to TGR5-mediated shifts in the circulating bile acid pool after VSG.

While weight loss does contribute to type 2 diabetes remission, "the thing we are excited about is it's not just the weight loss," said Cummings. "Coming up with methodologies other than weight loss to treat diabetes is critical."

Future work will further explore TGR5 function, as there appears to be a lot that we still don't know about the function of this receptor, Cummings sai

"Doing these surgeries in tiny mice is no small feat, but it helps move our understanding of how bariatric surgery causes type 2 diabetes remission forward," she added.

Dr Anne McGavigan, a postdoctoral researcher in Cummings' laboratory, is the paper's first author.

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