Experimental bariatric surgery controls blood sugar in rodents with diabetes via novel sensing signals in gut

ScienceDaily (May 20, 2012) — For the first time, scientists at the Toronto General Hospital Research Institute have shown that an experimental bariatric surgery can lower blood sugar levels in rats with type 1 diabetes.

See Also:Health & MedicineDiabetesDiet and Weight LossWounds and HealingHypertensionObesityHormone DisordersReferenceBlood sugarHyperglycemiaGlycemic indexDiabetic diet

A team led by Dr. Tony Lam and Dr. Danna Breen, a post- doctoral fellow in the lab of Dr. Lam, used a rat model to study novel nutrient-sensing signals in the jejunum, located in the middle of the intestine. Dr. Lam and his team demonstrate that duodenal-jejunal bypass surgery activates novel nutrient-sensing signals in the jejunum and rapidly lowers blood sugar levels in non-obese rats with uncontrolled diabetes. DJB surgery is a type of bariatric surgery which excludes the duodenum and proximal jejunum, the first section of the small intestine, and instead redirects food into the distal jejunum, the middle to last section of the intestine. This latter section of the intestine, as demonstrated by Dr. Lam and his team, can sense glucose and signal to the brain to let the liver know that it must lower glucose production, leading to better control of blood sugar in the diabetic rats.

The study showed for the first time that a surgical intervention induces a rapid glucose-lowering effect in non-obese type 1 uncontrolled diabetic rats, independent of a reduction in food intake and body weight as well as changes in blood insulin levels.

The research was published in a paper entitled, "Jejunal nutrient sensing is required for duodenal-proximal jejunal bypass surgery to lower glucose levels in uncontrolled diabetes," in the May 20, 2012 on-line edition of the international journal Nature Medicine.

"We report that shortly after a meal, the influx of nutrients into the jejunum of DJB surgical diabetic rats activates novel sensing mechanisms to lower blood sugar levels. Importantly, this occurs in the presence of insulin-deficiency and is independent of weight loss," says Dr. Lam, who holds The John Kitson McIvor (1915 -- 1942) Endowed Chair in Diabetes Research and the Canada Research Chair in Obesity at the Toronto General Research Institute and the University of Toronto. He is also Associate Director of Research at the Banting and Best Diabetes Centre at the University of Toronto.

Currently, patients with Type 1 diabetes lower their glucose through insulin injections (usually several times a day) and must regularly monitor blood glucose levels. High or uncontrolled glucose levels can result in damage to eyes, nerves and kidneys and increase the risk of heart attack, stroke, blindness, erectile dysfunction, foot problems and amputations. Many laboratories around the world are in a race to find alternative and effective ways in which to lower and better control glucose levels because of the severe complications which can result from high sugar levels.

Dr. Lam's laboratory is a world pioneer in exploring the role of the gut in regulating blood sugar. "The gut is an easier and therefore more promising therapeutic target in regulating blood sugar than the brain or liver, due to their potential side effects, " says Dr. Danna Breen, who is the lead author in the study. Dr. Breen adds that this type of surgery may potentially have therapeutic value in lowering glucose (sugar) levels in non-obese individuals with type 2 or 1 diabetes, but that many more years of future studies are required to determine whether this approach is effective and safe in humans who have diabetes.

In healthy individuals, insulin is a hormone whose primary role is to regulate blood sugar. It is produced by cells located on the pancreas in response to sugar intake, and it acts to bring blood sugar to appropriate levels, allowing the body to have the energy it needs to function properly. In persons with type 1 diabetes, the pancreas does not produce insulin, resulting in elevated blood sugar levels due to lack of insulin which cannot signal to the liver to reduce sugar production. People with type 1 diabetes need to take daily insulin shots and carefully monitor their blood sugar levels.

"If new medicines or surgical interventions can be developed that stimulate this sensing mechanism in the gut, we may have an effective and alternative way of slowing down the body's production of sugar, thereby lowering blood sugar levels in diabetes," says Dr. Lam, who is also an Associate Professor of Medicine and Physiology at the University of Toronto. Other ongoing studies of Dr. Lam's lab reveal novel molecular targets in the gut that effectively lower blood sugar in obesity and type 2 diabetes.

Studies reported in the New England Journal of Medicine this year have challenged medical therapy as the prevailing method of treating patients with type 2 diabetes. Two studies reported that bariatric surgery induced remission in severely obese patients with type 2 diabetes, and was associated with significant improvement in metabolic control over and above medical therapy, both conventional and intensive. An accompanying April 26, 2012 editorial by Drs. Zimmet and Alberti, states that "surgeons may now be able to claim greater success in achieving metabolic control," in these patients, although long-term studies with greater numbers of patients still need to be completed. No studies have yet reported on surgical interventions as treatments for patients with type 1 diabetes.

"More than two million Canadians have diabetes. Diabetes is an epidemic in Canada and around the world that is growing at an alarming rate," says Dr. Philip M. Sherman, Scientific Director of the Institute of Nutrition, Metabolism and Diabetes at the Canadian Institutes of Health Research. "Since many people are undergoing bariatric surgery in an attempt to manage morbid obesity and the associated health problems, such as diabetes, it is critical that we understand how it works. The Canadian Institutes of Health Research is pleased to support Dr. Lam's work which increases our understanding and may offer a new approach to managing morbidity and premature mortality resulting from this illness."

Working with rats, Drs. Lam, Breen and colleagues designed and performed a series of elegant experiments on two different groups of rats: rats whose insulin-producing pancreatic islet cells were destroyed by toxins; and genetically-altered rats which experienced spontaneous autoimmune destruction of islet cells -- similar to what happens in humans with type 1 diabetes.

Non-obese rats induced with uncontrolled diabetes or autoimmune type 1 diabetes had an experimental DJB surgery, a variation of the Roux-en-Y gastric bypass, the most common surgical method currently used to treat obese patients. Two days after DJB surgery, blood sugars were normal in the insulin-deficient diabetic rats.

Dr. Breen emphasized that further studies need to be undertaken to determine the long-term effects of this intervention in rodents, as well as to ensure the safety and efficacy of this procedure in humans.

Other researchers involved in the study include Brittany A. Rasmussen, Andrea Kokorovic and Grace W.C. Cheung from the Toronto General Research Institute and the Department of Physiology, University of Toronto; and Dr. Rennian Wang, from the Departments of Physiology and Pharmacology, University of Western Ontario.

The work was funded by the Canadian Institutes of Health Research, as well as a fellowship from the University Health Network and the Banting and Best Diabetes Centre, University of Toronto.

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Scientists use public-database search to identify novel receptor with key role in type 2 diabetes

ScienceDaily (Apr. 9, 2012) — Using computational methods, Stanford University School of Medicine investigators have strongly implicated a novel gene in the triggering of type-2 diabetes. Their experiments in lab mice and in human blood and tissue samples further showed that this gene not only is associated with the disease, as predicted computationally, but is also likely to play a major causal role.

See Also:Health & MedicineDiabetesObesityHypertensionDiet and Weight LossPersonalized MedicineHormone DisordersReferenceBlood sugarDiabetes mellitus type 1Diabetes mellitus type 2Hyperglycemia

In a study published online April 9 in Proceedings of the National Academy of Sciences, the researchers combed through freely accessible public databases storing huge troves of results from thousands of earlier experiments. They identified a gene never before linked to type-2 diabetes, a life-shortening disease that affects 4 percent of the world's population. These findings have both diagnostic and therapeutic implications.

The study's senior author is Atul Butte, MD, PhD, associate professor and chief of systems medicine in pediatrics; its first author is Keiichi Kodama, MD, PhD, a staff research scientist in Butte's group.

Ordinarily, cells throughout the body, alerted to the presence of sugar in the blood by insulin, hungrily slurp it up for use as an energy source. But excessive blood-sugar levels -- diabetes' defining feature -- eventually damage blood vessels, nerves and other tissues.

There are two broad categories of diabetes. In type-1 diabetes, a relatively rare autoimmune condition that typically begins in childhood, insufficient insulin is secreted by the pancreas. Type-2 diabetes, on the other hand, results from a phenomenon called insulin resistance: the tendency of cells in tissues throughout the body -- but especially in fat, liver and muscle -- to lose sensitivity and ignore the insulin's "gravy train" signal.

Drugs now used to treat insulin resistance can't reverse the progression to full-blown type-2 diabetes. "We don't really have a good grasp of the molecular pathology that makes people get it in the first place," said Butte, who is also director of the Center for Pediatric Bioinformatics at Lucile Packard Children's Hospital.

In searching for risk-increasing genes over the past 10 years, scientists have used two approaches to hunt them down. One way is to look for variations in genes' composition -- deviations in their chemical sequences that correlate with a higher likelihood of contracting a particular condition.

But genes don't change from one tissue to the next, and -- with the exception of mutations that accrue gradually over a lifetime in particular cells and can lead to cancer and other conditions -- they remain largely unaltered by disease and the aging process. What does change dynamically, from one tissue or state to another, is what all those genes are doing: how actively each of them is involved in cranking out the starting materials for the many thousands of proteins critical to each cell's or tissue's identity and to every organism's survival. In any given cell in a person's body, at any given time, some genes are switched off, others somewhat on and still others working overtime.

And so a second approach to understanding our genes has been devised. This latter method flags differences in genes' activity levels, for example in diseased vs. normal tissues, for each of the 20,000 genes in the entire genome.

Both types of approaches have generated staggering amounts of data -- far more than can fit onto the pages of standard, peer-reviewed journals, whose editors routinely demand (as do federal-government funding agencies) that researchers park their experiments' results in online, public repositories accessible to others. Now, investigators such as Butte are starting to reach in, drill down and pull out a treasure-trove of potentially valuable information.

In this study, the Stanford scientists wanted to know which genes showed especially marked changes in activity, as indicated in earlier comparisons of diabetic vs. healthy tissue samples (notably fat, muscle, liver and beta cells, the only cells in the body that release insulin). Mining public databases, they located 130 independent gene-activity-level experiments -- in rats, mice and humans -- comprising 1,175 separate individual samples in all. Then, integrating that data, they searched for those genes that showed activity-level differences in the most experiments.

They zeroed in on a single gene, called CD44, whose activity changed substantially in diabetic tissues compared with healthy tissues in 78 of the 130 experiments. The chance of this occurring "just due to dumb luck," Butte said, was vanishingly small: less than one in 10 million-trillion. The uptick in CD44's activity was especially pronounced in the fat tissue of people with diabetes, he said -- intriguing, because obesity is known to be a strong risk factor for type-2 diabetes.

The gene was interesting in itself. CD44 codes for a cell-surface receptor not found on fat cells, although those cells do have surface molecules that bind to it. Rather, this receptor sits on the surface of scavenger cells called macrophages (from the Greek words for "big eater") that can cause inflammation. In obese individuals, macrophages migrate to and take up positions in fat tissue. (Indeed, as many as half the cells in a big potbelly can be macrophages.) Recent medical research has strongly implicated inflammation in initiating type-2 diabetes.

CD44 was first identified more than a decade ago by immunologists looking for a possible connection to autoimmune disease. To test that connection, those immunologists created a strain of laboratory mouse lacking the gene. By chance, these "CD44 knockout" mice were derived from a lab-mouse strain that, if fed a high-fat diet, has a propensity for becoming obese, insulin-resistant and diabetic. With the exception of that missing gene, these two strains are identical.

Butte and his colleagues obtained these two strains of mice (one carrying the gene, the other lacking it) and divided them into two subgroups, which they fed either a normal or a high-fat diet, representative of today's increasingly common human diet. The team studied these mice using tests commonly applied to humans, for example measuring fasting blood sugar and measuring blood sugar after administering sugar or insulin. As anticipated, the mice on normal diets stayed slim and retained good insulin sensitivity. CD44-containing mice on high-fat diets, also as expected, got tubby and developed insulin resistance. But mice lacking the suspect gene never lost their sensitivity to insulin and didn't become diabetic on high-fat diets, although they became as plump as their CD44-carrying peers.

This suggested that knocking out CD44's function could improve insulin sensitivity, and that blocking CD44 with a drug might turn out to be an interesting new way to treat type-2 diabetes. So the team tested a prototype drug: antibodies that shut down the receptor's action in CD44-carrying mice fed a high-fat diet. Though these overfed mice didn't get any thinner, the prototype drug did reduce their blood-sugar levels within a week. Moreover, the number of macrophages in these mice's fat tissue plummeted.

Turning to human blood samples, Butte and his associates found that insulin-resistant people (those prone to developing type-2 diabetes) have higher levels of free-roving CD44-receptor molecules circulating in their blood than do people with normal insulin-processing capability. This suggests a potential early diagnostic test, or biomarker, that could help detect or predict insulin resistance. Plus, the antibody results suggest, a small molecule that blocked this receptor could have profound therapeutic potential for type-2 diabetes.

Funding for the study was provided by the Lucile Packard Foundation for Children's Health and the National Library of Medicine. Other Stanford co-authors of the study, done in collaboration with investigators at the University of Tokyo, Kitasato University, Keio University and RIKEN, all in Japan, were former graduate students Marina Sirota, PhD, and Alexander Morgan, PhD; and former staff bioinformatics programmer Rong Chen, PhD, all then in Butte's lab.

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