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Linda Barbour, MD, wins Norbert Freinkel Award

Linda Barbour, MD, MSPH, professor of medicine, obstetrics and gynecology at the University of Colorado School of Medicine (SOM) will receive the 2018 Norbert Freinkel Award next month at the American Diabetes Association’s 78th Scientific Sessions in Orlando, Fla.

The award, given in memory of Norbert Freinkel, a dedicated investigator and thought leader, honors a researcher who has made outstanding contributions to the understanding and treatment of diabetes in pregnancy.

In June, Barbour will deliver the Norbert Freinkel Award Lecture entitled, “Metabolic Culprits in Obese Pregnancies and Gestational Diabetes:  Big Babies, Big Twists, Big Picture.”

Barbour is a tenured professor in Endocrinology, Metabolism and Diabetes and Maternal-Fetal Medicine in the SOM.  She is medical director of the OB Diabetes and High-Risk Clinics at University of Colorado Hospital and serves on the editorial board for “Diabetes Care.”  

Barbour is a clinician/translational scientist in the management of obesity in pregnancy and gestational diabetes. She has made seminal observations on the hormonal and signaling changes that increase insulin resistance in pregnancy and the intrauterine and dietary factors that contribute to nutrient excess and affect newborn body composition.  Her NIH and ADA-funded studies have prompted guideline changes to improve maternal/fetal health. And she has published more than 100 manuscripts, book chapters, and guidelines.

As previous CME Director, Barbour loves to teach medical and obstetrics students, residents, fellows, and faculty. She also supervises treatment for the majority of mothers with type 1 and type 2 diabetes.  She is a dedicated mentor for junior investigators across neonatology, maternal-fetal medicine, and endocrinology and helped to build a Colorado translational research program in Maternal and Child Metabolic Health. 

She was recently profiled in an article in CU Medicine Today magazine for her work with Teri Hernandez, PhD, RN, associate professor of medicine and nursing.

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Existing drug may be effective at preventing onset of type 1 diabetes

A drug commonly used to control high blood pressure may also help prevent the onset of Type 1 diabetes in up to 60 percent of those at risk for the disease, according to researchers at the University of Colorado Anschutz Medical Campus and the University of Florida (UF) in Gainesville.

The study was published online this week in the Journal of Clinical Investigation.

Dr. Aaron Michels of the Barbara Davis Center for Childhood Diabetes.
Dr. Aaron Michels of the Barbara Davis Center for Childhood Diabetes.

“This is the first personalized treatment for Type 1 diabetes prevention,” said Aaron Michels, MD, a researcher at the Barbara Davis Center for Childhood Diabetes and associate professor of medicine at CU Anschutz. “We made this discovery using a supercomputer, on the lab bench, in mice and in humans.”

The drug, methyldopa, has been used for over 50 years to treat high blood pressure in pregnant women and children. It is on the World Health Organization’s list of essential drugs.

But like many drugs used for one condition, Michels and his colleagues found it useful for something totally unrelated.

Molecule blocking

Some 60 percent of people at risk of getting Type 1 diabetes possess the DQ8 molecule which significantly increases the chance of getting the disease. The researchers believed that if they could block specifically the DQ8 molecule they could also block the onset of the disease.

“All drugs have off-target effects. If you take too much acetaminophen you can hurt your liver,” Michels said. “We took every FDA-approved small molecule drug and analyzed HLA-DQ8 binding through a supercomputer. We searched a thousand orientations for each drug to identify those that would fit within the DQ8 molecule binding groove.”

After running thousands of drugs through the supercomputer, they found that methyldopa not only blocked DQ8, but it didn’t harm the immune function of other cells like many immunosuppressant drugs do.

The research spanned 10 years and its efficacy was shown in mice and in 20 Type 1 diabetes patients who took part in a clinical trial at the Barbara Davis Center at the University of Colorado School of Medicine.

“We can now predict with almost 100 percent accuracy who is likely to get Type 1 diabetes,” Michels said. “The goal with this drug is to delay or prevent the onset of the disease among those at risk.”

The drug is taken orally, three times a day.

Implications for treatment

Michels and UF Health researcher David Ostrov, PhD, hope this same approach of blocking specific molecules can be used in other diseases.

“This study has significant implications for treatment of diabetes and also other autoimmune diseases,” said Ostrov, associate professor of pathology, immunology and laboratory medicine in the UF College of Medicine and a member of the UF Health Cancer Center, Genetics Institute and Center for NeuroGenetics. “This study suggests that the same approach may be adapted to prevent autoimmune diseases such as rheumatoid arthritis, coeliac disease, multiple sclerosis, systemic lupus erythematosus and others.”

The next step will be a larger clinical trial sponsored by the National Institutes of Health in spring.

“With this drug, we can potentially prevent up to 60 percent of Type 1 diabetes in those at risk for the disease,” Michels said. “This is very significant development.”

The other authors include: Aimon Alkanani of the Barbara Davis Center at CU Anschutz; Kristen McDaniel of the Barbara Davis Center; David Ostrov of the University of Florida in Gainesville; Stephanie Case of the Barbara Davis Center; Erin Baschal of the Barbara Davis Center; Laura Pyle of the Barbara Davis Center and Colorado School of Public Health; Sam Ellis of the Barbara Davis Center and Dept. of Clinical Pharmacy at CU Anschutz; Bernadette Pollinger at the Novartis Institutes for Biomedical Research in Basel, Switzerland; Katherine Seidl at Novartis; Viral Shah at the Barbara Davis Center; Satish Garg at the Barbara Davis Center; Mark Atkinson at the University of Florida and Peter Gottlieb at the Barbara Davis Center.

 

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Curiosity: It’s what makes new interim vice chancellor tick

Robert Eckel at desk
Dr. Robert “Bob” Eckel is serving as interim vice chancellor for research while a search for a permanent replacement is underway. Eckel has served as program director of the Clinical Translational Research Center Network of the Colorado Clinical Translational Sciences Institute (CCTSI) and the CU Adult General Clinical Research Center. He was only the second endocrinologist ever to serve as president of the American Heart Association.

It might have been what killed the cat, but to Dr. Robert “Bob” Eckel, the University of Colorado’s new interim vice chancellor for research, curiosity reigns in propelling a successful career and research program.

“It’s what drives the bus here,” said Eckel, MD, recently tapped for the job left vacant by Dr. Richard “Dick” Traystman’s death this fall, as CU administrators launch a search for a permanent vice chancellor.

Although “filling Dick’s shoes is impossible,” Eckel, an international expert in his field of lipid and lipoprotein metabolism and a recognized face on the CU Anschutz Medical Campus after nearly 40 years, said he hopes his ingrained curiosity can serve as a catalyst for furthering the research enterprise at an institution that has been good to him and his profession.

“There are many components to a successful career in science and medicine,” Eckel said. “But curiosity, in my opinion, is one of the most important factors. If curiosity is driving you, then grants, papers and quality research will follow.”

Fanning the curiosity flame

The curiosity flame was lit early in Eckel’s career. After conceding that he was no Vivaldi and ditching the thought of a profession in music (a passion that led him to his first wife, a talented violinist), Eckel decided his idea of medical school was more on track. “And I knew it would make my mother happier.”

But his vision of being solely a clinically-focused doctor soon vanished. “I found out during my residency in internal medicine that I was starting to get increasingly curious about what made people sick and why they weren’t responding to therapy,” said Eckel, an endocrinologist in both the School of Medicine’s Division of Endocrinology, Metabolism and Diabetes and Division of Cardiology. He also has an appointment in the Department of Physiology and Biophysics.

“I thought if I wanted to pursue that drive, that ultimately I needed to be trained in research,” said Eckel, crediting his subsequent research-fellowship experience at the University of Washington for fanning the flames. “I came out on fire for research.”

‘There are many components to a successful career in science and medicine. But curiosity, in my opinion, is one of the most important factors. If curiosity is driving you, then grants, papers and quality research will follow.’ – Robert Eckel, MD

Bringing a dual perspective

Eckel, who often calls himself a “cross-dresser” as a preventive cardiologist and endocrinologist, said he loves all components of his job. “As a clinician, I’m more of a preventive cardiologist, but as a scientist, I’m a metabolically-driven guy,” he said, adding that his physician-scientist perspective brings a different “twist” to the vice chancellor position.

As an investigator, Eckel thrives on being tucked in his lab, where he and Assistant Research Professor Kimberley Bruce, PhD, have expanded their longtime focus on how lipids (such as cholesterol and triglycerides) and lipoproteins (which carry lipids) relate to obesity, metabolic syndrome, diabetes and cardiovascular disease.

The two have joined forces with Wendy Macklin, PhD, a leading expert on glial biology in the Department of Cell and Developmental Biology, in investigating how lipids and lipoproteins play a role in neurological disorders, such as Multiple Sclerosis and Alzheimer’s disease, with a renewed funding award on Feb. 1.

“Myelin is loaded with lipids,” Eckel said, referring to the myelin sheath that protects the body’s nervous system. With MS, a disabling degenerative disease that affects an estimated 400,000 Americans, myelin is slowly destroyed. “So we are involved in understanding how lipids and lipoproteins can be processed to re-myelinate nerves that have been demyelinated.”

Eckel and wife at Nuggets game
Dr. Robert Eckel poses with Rocky and wife, Margaret, at a Nuggets game. Eckel credits the women in his life for much of his success.

Encouraging research partnerships

Bruce and Eckel have also teamed up with another top CU Anschutz Medical Campus researcher, SOM’s Department of Neurology’s Huntington Potter, PhD, in their work on the role of lipids and lipoproteins and the brain-degenerating Alzheimer’s disease. Alzheimer’s affects at least 5.5 million Americans, a number expected to soar with an aging population.

During her years working beside him, Bruce said Eckel has served as a great mentor and role model. “I’ve learned a great deal from Bob, not just about lipid and lipoprotein biology, but also about how to strive for scientific excellence while still keeping your feet on the ground,” she said. “I honestly can’t think of anyone better for this vice chancellor role.”

No stranger to cross-disciplinary collaboration, Eckel said researcher success also depends on networking. “None of us is an island anymore in science and medicine. There are no single-authored papers anymore. Science is really teamwork, and that’s something I will consider as I look at the big network of research on both campuses.”

Recognizing research’s influence

Eckel, winner of the Endocrine Society’s 2016 Outstanding Clinical Investigator Award, understands the power of research on both a professional and a personal level.

Diagnosed at age 5 with Type 1 diabetes, a disease he shares with two sons and opted early on to separate from his lab work, Eckel said he’s grateful for his colleagues who have made huge research strides in the insulin-related disorder.

“There’s been so much improvement in therapeutics for Type 1 diabetes,” he said. “I have a pump and a sensor,” he said, patting his lower chest, where a pump automatically infuses the insulin his body cannot make. “I’ve had this disease for 65 years now, and I’ve never felt better in my life. I feel fortunate to be alive, and that’s research,” he said.

Finding collaboration on all fronts

Eckel with family
Dr. Robert Eckel balances career and family, which includes three grandchildren and five grown children. Eckel, who emphasizes the importance of music in a well-rounded lifestyle, taught each of his kids piano until they were in sixth grade.

Eckel doesn’t just stand out in his field. In 2016, he won Father of the Year from the American Diabetes Association, for which he serves on the board. A devoted but humble family man, he doesn’t take the credit for his well-rounded success.

“It’s the women I’ve done it all with,” he said, acknowledging his first wife, who worked as a teacher while he went through medical school and then raised their five children before she died of breast cancer at age 45. “She was a great mom.”

Eckel eventually married his current wife, Margaret. “She stepped up and became a stepmom who’s now loved by all of my kids, and I’ve been married to her almost as long as I was my first wife. So I had great companionship and love from two women, and I probably didn’t deserve either one of them.”

On the professional side, Eckel said Bruce “runs the bus” in his research lab. “She’s smarter than I am. I’m lucky to have her.” With a retirement date set for July 1, 2019, Eckel hopes to have his research program ready to hand over to Bruce and to have fulfilled his new interim post to the best of his ability.

“I work at a great institution that’s been incredibly supportive, and it’s a privilege to serve,” said Eckel, who will not vie for the permanent post. “But right now, I’m neither intellectually nor emotionally ready to retire. The science is just too much fun.”

 

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Enough vitamin D when young associated with lower risk of diabetes-related autoimmunity

Getting enough vitamin D during infancy and childhood is associated with a reduced risk of islet autoimmunity among children at increased genetic risk for type 1 diabetes, according to a study published this week in the journal Diabetes.

The study’s lead author, Jill Norris, MPH, PhD, of the Colorado School of Public Health, and her co-authors examined the association between vitamin D levels in the blood and islet autoimmunity. Islet autoimmunity, detected by antibodies that appear when the immune system attacks the islet cells in the pancreas that produce insulin, is a precursor to type 1 diabetes.

Professor Jill Norris, PhD, MPH, is lead author of the study.
Professor Jill Norris, PhD, MPH, is lead author of the study.

“For several years there has been controversy among scientists about whether vitamin D lowers the risk of developing of islet autoimmunity and type 1 diabetes,” said Dr. Norris.

Type 1 diabetes is a chronic autoimmune disease that is increasing by 3-5 percent annually worldwide. The disease is now the most common metabolic disorder in children under age 10. In younger children, the number of new cases is particularly high. And the risks seem to be greater at higher latitudes, further north from the equator.

Vitamin D represents a candidate protective factor for type 1 diabetes as it regulates the immune system and autoimmunity. Moreover, vitamin D status varies by latitude. But associations between vitamin D levels and islet autoimmunity have been inconsistent. This may be due to different study designs, population variation in vitamin D levels, or a failure to account for the combined effect of exposure and underlying genetic variation in the vitamin D pathway.

The findings are part of The Environmental Determinants of Diabetes in the Young (TEDDY) study, a large, multi-national study funded by the National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases.

TEDDY’s effort began in 2004 with children from six clinical centers: three in the U.S. (Barbara Davis Center for Childhood Diabetes at CU Anschutz, the Pacific Northwest Research Institute in Seattle, and Augusta University in Georgia) and three in Europe (Universities of Turku, Oulu, and Tampere in Finland, Helmholtz Zentrum München in Germany, and Lund University in Sweden). The aim of the study is to search for triggers and protective factors for type 1 diabetes in 8,676 children with elevated type 1 diabetes risk.

The TEDDY children were followed with blood samples drawn every three to six months from infancy, to determine the presence of islet autoimmunity, as well as levels of vitamin D.

The authors compared 376 children who developed islet autoimmunity with 1,041 children who did not.  The authors found that in children with a genetic variant in the vitamin D receptor gene, vitamin D levels in infancy and childhood were lower in those that went on to develop islet autoimmunity compared with those that did not develop autoimmunity.

This study is the first to show that higher childhood vitamin D levels are significantly associated with a decreased risk of IA.

“Since this association does not prove cause-and-effect, we look to future prospective studies to confirm whether a vitamin D intervention can help prevent type 1 diabetes,” Dr. Norris said.

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New oral diabetes drug shows promise

A University of Colorado Anschutz Medical Campus study finds sotagliflozin helps control glucose and reduces the need for insulin in patients with type 1 diabetes.

Principal results were published today in the New England Journal of Medicine of a global Phase 3 clinical trial in patients with type 1 diabetes treated with sotagliflozin. Sotagliflozin is an investigational new oral drug for patients with type 1 diabetes that has shown promise in improving glucose control without any increase in severe hypoglycemia or diabetic ketoacidosis compared to insulin alone.

Garg
Dr. Satish Garg

Among 1,402 trial participants given the drug, sotagliflozin showed clinically meaningful and statistically significant effects on glucose control. Concentrations of hemoglobin A1C, a measure of plasma glucose, were improved. Patients experienced a lower rate of confirmed severe hypoglycemia than observed in patients on placebo and also had weight loss.

According to lead investigator Satish Garg, MD, professor of medicine and pediatrics at the Barbara Davis Center for Diabetes at the University of Colorado Anschutz Medical Campus, no oral medication has ever been approved for the treatment of type 1 diabetes and sotagliflozin has the potential to become the first new treatment innovation in nearly a century since insulin.

Most patients do not achieve optimal glycemic control with insulin alone. A1C concentrations, hypertension and reduction in body weight are critical issues which significantly impact people living with type 1 diabetes.

“If approved by the FDA, sotagliflozin may be the first oral drug that helps patients with type 1 diabetes in improving their glucose control without any weight gain or increase and severe hypoglycemia,” Garg said. “If long-term use continues to show similar metabolic improvements in patients with type 1 diabetes, it is likely that the long-term complications of diabetes would be significantly reduced.”

Sotagliflozin would be used in conjunction with insulin. Trial participants taking the drug as an oral pill alongside traditional insulin treatments experienced significant improvements in glucose control, a drop in systolic and diastolic blood pressure and weight loss.

Sotagliflozin is a unique dual inhibitor that works by inhibiting two sodium-glucose transporters: SGLT1 and SGLT2. Each modulates glucose levels. SGLT1 regulates the uptake of glucose in the gut while SGLT2 regulates the re-uptake of glucose in the kidney, according to the authors.

“Sotagliflozin added to insulin therapy can potentially help patients with type 1 diabetes improve their glucose control and hopefully manage the disease with fewer complications,” Garg said. “This would not be a replacement for insulin; it is an adjunctive therapy. However, because it works in the gut and the kidneys, it doesn’t require insulin to have an effect.”

The inTandem3 study was a double-blind, placebo controlled and randomized Phase 3 trial including adults with type 1 diabetes at 133 sites worldwide. In conjunction with this publication, the data were announced today at the 53rd Annual Meeting of the European Association Study for Diabetes in Lisbon, Portugal.

The 24-week trial evaluated the safety and efficacy of sotagliflozin at 400mg per day in randomized patients treated with any insulin regimen – pumps or injections. Eligible patients included men and nonpregnant women aged 18 and older, and they were required to self-monitor blood glucose.

The study met its primary endpoint with statistical significance, demonstrating the superiority of sotagliflozin 400 mg compared to placebo in the proportion of patients with A1C less than seven percent at week 24, no episode of severe hypoglycemia and no episode of diabetic ketoacidosis after randomization.

The outcome on every secondary endpoint favored sotagliflozin over placebo, achieving statistical significance for all four secondary endpoints, including change from baseline in A1C, body weight, systolic blood pressure in patients with baseline SBP less than or equal to 130 mm Hg and bolus insulin dose. Sotagliflozin significantly reduced A1C compared to placebo after 24 weeks of treatment.

“As is known with sodium glucose cotransporter 2 (SGLT2) inhibitors, patients experienced more episodes of diabetic ketoacidosis in the trial,” Garg said.

Diarrhea and genital mycotic infection also affected participants more than placebo, but less than one percent discontinued the study due to these effects.

“Sotagliflozin may reduce the bad effects of insulin and the dose patients need,” Garg said. “Patients in our study had lower weights, no severe hypoglycemia and better blood pressure.”

Garg is a faculty member at the University of Colorado School of Medicine at the Anschutz Medical Campus and is editor in-chief of Diabetes Technology and Therapeutics Journal.

Garg and his colleagues are working to publish more results on other inTendem1 and 2 phase 3 clinical trials in type 1 diabetes, including data on continuous glucose monitoring in future publications.

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Type 2 diabetes diagnosis in youth leads to increased health complications

A new report published this month in the Journal of the American Medical Association points to a significantly higher burden of diabetes-related complications in adolescents and young adults with type 2 diabetes compared to type 1 diabetes, with greater health complications in minority youth.

The study, from researchers involved with the nationwide SEARCH for Diabetes in Youth Study, looked at five health complications and co-morbidities of diabetes, including: retinopathy (eye disease), diabetic kidney disease, peripheral neuropathy (altered sensation in the feet), arterial stiffness and high blood pressure.

The researchers studied 1,746 adolescents and young adults with type 1 diabetes and 272 with type 2 diabetes. Their findings showed that, after less than eight years following a diagnosis, approximately one-third of teenagers and young adults with type 1 diabetes and almost 75 percent of those with type 2 diabetes had at least one health complication or comorbidity. Additionally, any adjustment for differences in age, sex, race/ethnicity, and levels of glucose control over time, did not remove the excess prevalence among those with type 2 diabetes.

“The high burden of early complications in youth with diabetes requires additional research to clarify the underlying causes and to identify effective intervention strategies,” said Dr. Dana Dabelea, lead author and co-chair of the national SEARCH Study and professor of epidemiology at the Colorado School of Public Health at the University of Colorado Anschutz Medical Campus. “It is extremely useful to have these estimates of the presence of complications in adolescents and young adults who are being treated with current therapies, especially because the complications are frequent. We need to make sure each risk factor is under the best control possible to reduce future problems.”

The SEARCH for Diabetes in Youth Study has been monitoring the burden of diabetes in youth with onset less than 20 years of age since 2000. Five U.S. clinical centers and principal investigators participated, including: Seattle Children’s Hospital, (Dr. Catherine Pihoker); Kaiser Permanente Southern California, (Dr. Jean Lawrence); Colorado School of Public Health (Dr. Dana Dabelea); Cincinnati Children’s Hospital, (Dr. Larry Dolan); and the Universities of North and South Carolina Schools of Public Health, (Dr. Elizabeth Mayer-Davis, SEARCH co-chair). The central laboratory is at the Northwest Lipid Research Laboratory, (Dr. Santica Marcovina) and the Coordinating Center is at the Wake Forest School of Medicine (Dr. Ralph D’Agostino and Dr. Lynne Wagenknecht, co-directors).

SEARCH is funded by the National Institutes of Health and the Centers for Disease Control and Prevention.

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