PracticeUpdate: Diabetes

ADA 2018 23

YouthWith Type 1 Diabetes Can Have Insulin Resistance Researchers want to intervene before damage to cardiovascular system is irreversible By the PracticeUpdate Editorial Team B oth lean and obese youth with type 1 diabetes (T1D) can expe- rience insulin resistance and signs of vascular dysfunction resulting from this resistance, but treatment with metformin was able to mitigate both, according to a presentation given at ADA 2018.

techniques] is that they’re not invasive, so they are tolerated well by kids, but they also give us a lot more information than we used to be able to get. We can attain more information at a younger age, but in a safer way.” At baseline, T1D youth had significantly elevated aortic pulse wave velocity and wall shear stress compared to non-diabetic controls. The T1D youth were then randomized 1:1 to 2 g of metformin or placebo daily. The T1D youth had ultrasounds of the carotid artery, called carotid intima-media thickness (cIMT), which is used to measure athero- sclerosis. To measure insulin resistance, a gold standard method was used. According to Dr. Nadeau, adolescents were admitted into hospital and an overnight intravenous glycemic control was used. The next day a hyperinsulinemic-euglycemic clamp admin- istering intravenous insulin along with intravenous glucose was used to assess insulin action in the tissues. Instead of an estimate of insulin sensitivity, the method provided a direct measurement. “We found improvement in insulin sensitivity and improvement in markers of cardiovascular health, implying that the metformin is doing something that may help improve long-term cardiovascular health,” said Dr. Nadeau. She pointed out that a major limitation of the study is its short- term nature. “You would need to follow people for longer to see what actually happens and to see if it translates into fewer cardi- ovascular events.” The mechanism of insulin resistance in T1D remains unknown. A better understanding of the mechanism will help researchers find the best treatment for insulin resistance in patients with T1D. The aspiration is to one day be able to prevent future morbidities and mortalities related to cardiovascular events for these patients. “We are focusing on the adolescent population because we are try- ing to prevent changes at a stage when [those changes] may be reversible,” said Dr. Nadeau. Reference 1. ClinicalTrials.gov Identifier: NCT01808690. Available from https://clinicaltrials. gov/ct2/show/NCT01808690 www.practiceupdate.com/c/70045

“In type 1 diabetes, cardiovascular disease is the leading cause of death, and it has not been well addressed, even though we’ve had a lot of emphasis on blood sugar control,” said Kris- ten Nadeau, MD, MS, with the University of Colorado and the Children’s Hospital Colorado, in an interview with Elsevier’s PracticeUpdate . “Also, it has more recently been recognized that [both] adolescents and adults with type 1 diabetes can have insulin resistance, whereas,

Dr. Kristen Nadeau

traditionally, type 1 diabetes was thought of more as a disease that is just insulin deficiency and you treat it by replacing insulin.” In other populations, she noted, insulin resistance correlates with cardiovascular disease, and there is now more evidence from our data in adolescents that insulin resistance correlates with markers of cardiovascular disease risk, and in adults, with actual cardiovascular outcomes. “Because of that connection, we felt that an important step would be to address insulin resistance to see if we could improve insulin sensitivity in type 1 diabetes and see if that would help to improve cardiovascular disease risk.” Beyond T1D, there are additional factors that can decrease sensi- tivity to insulin. Puberty is a particularly vulnerable time for patients with T1D because it decreases insulin sensitivity, so patients can experience insulin resistance from both puberty and from their disease at the same time. Obesity is also a problem. According to Dr. Nadeau, “Obesity is also increasing in type 1 diabetes and that’s making insulin resistance worse.” It is also driving the urgency for additional adjunctive therapies in type 1 diabetes, she noted. In the United States, metformin is indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes mellitus. “Insulin and metformin are the only medications approved for children with type 2 diabetes. The rea- son we started with metformin in the adolescent type 1 diabetes population is because it is known to be safe and approved for use. It’s not [indicated] in type 1 diabetes, but we knew it is a safe med- ication that had pediatric approval,” said Dr. Nadeau. Prior to this study, little was known about vascular health in T1D youth or about the effect of metformin on directly measured insu- lin resistance. The Effects of MEtformin on cardiovasculaR function in AdoLescents with type 1 Diabetes (EMERALD) study first deter- mined whether T1D youth have vascular dysfunction. 1 Due to the age of the participants, study investigators could not assess actual cardiovascular events, so they used two markers for vascular health that could be measured by magnetic resonance imaging (MRI): vascular stiffness and compliance, and blood flow. In all, 49 T1D youth aged 12–21 years (40% with body mass index ≥ 90%ile) and 24 controls of similar age, body mass index and sex under- went phase contrast MRI of the ascending and descending aorta to determine aortic pulse wave velocity and wall shear stress. Dr. Nadeau said that this was the first study that used these MRI techniques in adolescents. “The neat thing about [the MRI

© ADA/Rodney White 2018

VOL. 2 • NO. 3 • 2018