TORONTO – When Brandy Wicklow, MD, began her pediatric endocrinology fellowship at McGill University in 2006, about 12 per 100,000 children in Manitoba, Canada, were diagnosed with type 2 diabetes mellitus each year. By 2016 that rate had more than doubled, to 26 per 100,000 children.
“If you look just at indigenous youth in our province, it’s probably one of the highest rates ever reported, with 95 per 100,000 Manitoba First Nation children diagnosed with type 2 diabetes,” said Dr. Wicklow, a pediatric endocrinologist at the University of Manitoba and the Children’s Hospital Research Institute of Manitoba.
Many indigenous populations also face an increased risk for primary renal disease. One study reviewed the charts 90 of Canadian First Nation children and adolescents with T2DM (Diabetes Care. 2009;32[5]:786-90). Of 10 who had renal biopsies performed, nine had immune complex disease/glomerulosclerosis, two had mild diabetes-related lesions, and seven had focal segmental glomerulosclerosis (FSGS); yet none had classic nephropathy. An analysis of Chinese youth that included 216 renal biopsies yielded similar findings (Intl Urol Nephrol. 2012;45[1]:173-9).
It’s also known that early-onset T2DM is associated with substantially increased incidence of end-stage renal disease (ESRD) and mortality in middle age. For example, one study of Pima Indians found that those who were diagnosed with T2DM earlier than 20 years of age had a one in five chance of developing ESRD, while those who were diagnosed at age 20 years or older had a one in two chance of ESRD (JAMA. 2006;296[4]:421-6). In a separate analysis, researchers estimated the remaining lifetime risks for ESRD among Aboriginal people in Australia with and without diabetes (Diabetes Res Clin Pract. 2014;103[3]:e24-6). The value for young adults with diabetes was high, about one in two at the age of 30 years, while it decreased with age to one in seven at 60 years.
“One of the first biomarkers we see in terms of renal disease in kids with T2DM is albuminuria,” Dr. Wicklow said at the Pediatric Academic Societies meeting. “The question is, why do kids with type 2 get more renal disease than kids with type 1 diabetes?” The SEARCH for Diabetes in Youth (SEARCH) study from 2006 found that hypertension, increased body mass index, increased weight circumference, and increased lipids were factors, while the SEARCH study from 2015 found that ethnicity, increased weight to height ratio, and mean arterial pressure were factors.
“Insulin resistance is significantly associated with albuminuria,” Dr. Wicklow continued. “It’s also been shown to be associated with hyperfiltration. Some of the markers of insulin resistance are important but they make up about 19% of the variance between type 1 and type 2, which means there are other variables that we’re not measuring.”
Enter ICARE (Improving Renal Complications in Adolescents with Type 2 Diabetes through Research), an ongoing prospective cohort study that Dr. Wicklow and her associates launched in 2014 at eight centers in Canada. It aims to examine the biopsychosocial risk factors for albuminuria in youth with T2DM and the mechanisms for renal injury. “Our theoretical framework was that biological exposures that we are aware of, such as glycemic control, hypertension, and lipids, would all be important in the development of albuminuria and renal disease in kids,” said Dr. Wicklow, who is the study’s coprimary investigator along with Allison Dart, MD. “But what we thought was novel was that psychological exposures either as socioeconomic status or as mental health factors would also directly impinge on renal health with respect to chronic inflammation in the body, inflammation in the kidneys, and long-term kidney damage.”
Courtesy Dr. Brandy Wicklow
During winter, Dr. Wicklow and her colleagues take a hovercraft to visit ICARE study participants in Garden Hill First Nation, in the northeast section of the Canadian Province of Manitoba on the shore of Lake Island.
The first phase of ICARE involved a detailed phenotypic assessment of youth, including anthropometrics, biochemistry, 24-hour ambulatory blood pressure monitoring, overnight urine collections for albumin excretion, renal ultrasound, and iohexol-derived glomerular filtration rate (GFR). Phase 2 included an evaluation of psychological factors, including hair-derived cortisol; validated questionnaires for perceived stress, distress, and resiliency; and a detailed evaluation of systemic and urine inflammatory biomarkers. Annual follow-up is carried out to assess temporal associations between clinical risk factors and renal outcomes, including progression of albuminuria.
At the meeting, Dr. Wicklow reported on 187 youth enrolled to date. Of these, 96% were of indigenous ethnicity, 57 had albuminuria and 130 did not, and the mean ages of the groups were 16 years and 15 years, respectively. At baseline, a higher proportion of those in the albuminuria group were female (74% vs. 64% of those in the no albuminuria group, respectively), had a higher mean hemoglobin A1c (11% vs. 9%), and had hypertension (94% vs. 72%). She noted that upon presentation to the clinic, only 23% of participants had HbA1c levels less than 7%, only 26% had ranges between 7% and 9%, and about 40% did not have any hypertension. Of those who did, 27% had nighttime-only hypertension, and only 2% had daytime-only hypertension.
“The other risk factor these kids have for developing ESRD is that the majority were exposed to diabetes in pregnancy,” Dr. Wicklow said. “Murine models of maternal diabetes exposure have demonstrated that offspring have small kidneys, less ureteric bud branching, and a lower number of nephrons. Most of the human clinical cohort studies look at associations between development of diabetes and parental hypertension, maternal smoking, and maternal education. There is likely an impact at birth that sets these kids up for development of type 2 diabetes.”
In addition, results from clinical cohort studies have found that depression, mental stress, and distress are high in youth with T2DM. “Preliminary data suggest that if you have positive mental health, or coping strategies, or someone has worked through this with you and you are resilient, you might benefit in terms of overall glycemic control,” she said. For example, ICARE investigators have found that the higher the score on the Kessler Psychological Distress Scale (K6), the greater the risk of renal inflammation as measured by monocyte chemotactic protein-1 (MCP-1; P = .02). “Mental health seems to be something that can directly impact your health from a biological standpoint, and we might be able to find biomarkers of that risk,” Dr. Wicklow said. “Where does the stress come from? Most of my patients are indigenous, so it’s not surprising that the history in Canada of colonization of residential schools has left a lasting impression on these families and communities in terms of loss of language, loss of culture, and loss of land. There’s a community-based stress and a family-based stress that these children feel.”
Social factors also play a big role. She presented baseline findings from 196 youth with T2DM and 456 with T1DM, including measures such as the Socioeconomic Factor Index-Version 2 (SEFI-2), a way to assess socioeconomic characteristics based on Canadian Census data that reflects nonmedical social determinants of health. “It looks at factors like number of rooms in the house, single-parent households, maternal education attainment, and family income,” Dr. Wicklow explained. “The higher the SEFI-2 score, the lower your socioeconomic status is for the area you live in. Kids with T2DM generally live in areas of lower SES and lower socioeconomic index. They often live far away from health care providers. Many do not attend school and many are not with their biologic families, so we’ve had a lot of issues addressing child and family services, in particular in the phase of a chronic illness where our expectation is one thing and the family’s and community’s expectations of what’s realistic in terms of treatment and goals is another. We also have a lot of adolescent pregnancies.”
Courtesy Dr. Brandy Wicklow
An aerial view of Garden Hill First Nation in winter.
To date, about 80% of youth with T1D have seen a health care provider within the first year after transition from the pediatric diabetes clinic, compared with just over 50% of kids with T2D. “We transition youth with T1DM to internists, while our youth with T2DM go to itinerant physicians often back in their communities and/or rural family physicians,” she said. Between baseline and year 2, the rate of hospital admissions remained similar among T1DM at 11.6 and 11.8 admissions per 100 patient-years, respectively, but the number of hospital admissions for T2DM patients jumped from 20.1 to 25.5 admissions per 100 patient-years. “Kids with type 2 are showing up in the hospital a lot more than those with type 1 diabetes, but not for diabetes-related diagnoses,” Dr. Wicklow said. “We’re starting to look through the data now, and most of our kids are showing up with mental health complaints and issues. That’s why they’re getting hospitalized.”
Among ICARE study participants who have completed 3 years of follow-up, about 52% had albuminuria at their baseline visit and 48% sustained albuminuria throughout the study. About 26% progressed from normal levels of albuminuria to microalbuminuria, from microalbuminuria to macroalbuminuria, or from normal levels of albuminuria to macroalbuminuria. In addition, 16% persisted in the category that they were in, and 10% regressed. “The good news is, some of our kids get better over time,” Dr. Wicklow said. “The bad news is that the majority do not.”
Courtesy Dr. Brandy Wicklow
During summer, Dr. Wicklow reaches ICARE study participants in Garden Hill First Nation via helicopter.
Going forward, Dr. Wicklow and her associates work with an ICARE advisory group composed of children and families “who sit with us and talk about what mental health needs might be important, and how we should organize our study in a follow-up of the kids, to try and answer some of the questions that are important,” she said. “Working with the concept of the study’s theoretical framework, they acknowledged that the biological exposures are important, but they were also concerned about food security, finding strength/resilience within the community, and finding coping factors in terms of keeping themselves healthy with their diabetes. For some communities, they are concerned with basic needs. We’re working with them to help them progress, and to figure out how to best study children with type 2 diabetes.”
ICARE has received support from Diabetes Canada, Research Manitoba, the Canadian Institutes of Health Research, the Children’s Hospital Research Institute of Manitoba (specifically the Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) theme), and the University of Manitoba. Dr. Wicklow reported having no financial disclosures.