Paper of the Month: The glucose paradox in stroke, and the OHSU team way around it

This month's featured paper is from a team led by Nabil Alkayed, M.D., Ph.D. It is titled, "Role of soluble epoxide hydrolase in exacerbation of stroke by streptozotocin-induced type 1 diabetes mellitus."

paper92013-journalSeptember 20, 2013

Hyperglycemia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. Having hyperglycemia, a common condition in Diabetes, can make stroke more severe and worsen stroke outcome—including the extent of brain damage.

For years, scientists have been challenged to discover how to reduce bad outcomes in diabetic patients, in particular how to prevent or minimize brain damage caused by hyperglycemia.

A 2001 study by van den Berghe et al indicated that aggressive glycemic control with insulin in hyperglycemic critically ill surgical patients improved many clinical end points, including mortality. However, two recent clinical trials (ACCORD and NICE-SUGAR) have shown that controlling glucose levels do not improve mortality or neurologic disability after stroke. With conflicting results, some in the scientific community thought a new approach was needed.

In a recent collaborative study between the labs of Dr. Nabil Alkayed, Dr. Daniel Marks and Dr. Robert Shangraw, scientists did just that; they tested an alternative approach: inhibiting a downstream injury mechanism triggered by hyperglycemia, rather than hyperglycemia itself. Their findings titled, "Role of soluble epoxide hydrolase in exacerbation of stroke by streptozotocin-induced type 1 diabetes mellitus," were published in the July '13 edition of Journal of Cerebral Blood Flow & Metabolism.

"We found that hyperglycemia increases the level and activity of an enzyme called soluble epoxide hydrolase (sEH), which leads to the breakdown of protective lipid molecules called epoxyeicosatrienoic acids (EETs)," said NabilAlkayed, M.D., Ph.D., a professor of anesthesiology & perioperative medicine and the Knight Cardiovascular Institute. "We also showed that inhibition of sEH increases EETs and protects diabetic mouse brain from experimental stroke."

paper92013-mainApproximately 40% of patients with acute ischemic stroke are hyperglycemic at admission, a percentage that will likely continue to rise in parallel with the increasing prevalence of diabetes mellitus. Given the apparent lack of benefit from tight glycemic control in clinical trials, there is a pressing need to pursue alternative therapeutic strategies for the prevention and treatment of ischemic stroke in hyperglycemic patients.

"Our study provides evidence that hyperglycemia exacerbates brain injury after stroke by acting on a specific mechanism," said Dr. Alkayed. "And that inhibition of this mechanism protects the diabetic brain from stroke related injury without the need to normalize glucose levels."

The study was conducted in a mouse model of type 1 diabetes. However, since then, the team has replicated their findings in type 2 diabetes, the more prevalent and clinically relevant model of diabetes.

"What I liked about this investigation was that the researchers were thinking about co-morbidities in a collaborative way," said Mary Heinricher, Ph.D., the assistant dean for basic science in the School of Medicine and a professor of neurological surgery. "We had a stroke lab (Alkayed) and an endocrinology lab (Marks), and a clinician specializing in the perioperative management of hyperglycemia (Shangraw) get together to investigate a common problem. They found a potential mechanism linking these two very common clinical problems together. This collaborative effort speaks volumes to the mission of the School of Medicine's Research Roadmap."

Another collaborative aspect to the study is that the work in the paper was started by the first author Sari Jouihan, M.S., a graduate student, who graduated last year, but the work was completed by the second author Kristen Zuloaga, Ph.D., a current postdoctoral fellow in the department of anesthesiology & perioperative medicine, who also wrote the paper.

The team has plans for future investigations with hope for a clinical trial. "Scientifically, our team will follow up on these studies by exploring the molecular mechanisms underlying sEH upregualtion by hyperglycemia," said Dr. Alkayed. "Clinically, we would like to use the sEH inhibitors in clinical trials to determine if they are protective against stroke in diabetic patients."

Paper Authors

Sari A Jouihan (1), Kristen L Zuloaga (1), Wenri Zhang (1), Robert E Shangraw (1), Stephanie M Krasnow (2), Daniel L Marks (2) and Nabil J Alkayed (1)

1 Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University
2 Department of Pediatrics, Papé Family Pediatric Research Institute, Oregon Health & Science University


About the Paper of the Month

The School of Medicine newsletter spotlights a recently published faculty research paper in each issue. The goals are to highlight the great research happening at OHSU and to share this information across departments, institutes and disciplines. The monthly paper summary is selected by Associate Dean for Basic Science Mary Stenzel-Poore, Ph.D., and Associate Dean for Clinical Science Eric Orwoll, M.D.

More Published Papers

The entire list of OHSU papers published this month is here.