Differing clinical features in Aboriginal vs. non-aboriginal children presenting with type 2 diabetes

Transcription

1 Pediatric Diabetes 2012 doi: /j x All rights reserved 2012 John Wiley & Sons A/S Pediatric Diabetes Original Article Differing clinical features in Aboriginal vs. non-aboriginal children presenting with type 2 diabetes Amed S, Hamilton JK, Sellers EAC, Panagiotopoulos C, Hadjiyannakis S, Shah BR, Booth GL, Laubscher TA, Dannenbaum D, Dean H. Differing clinical features in Aboriginal vs. non-aboriginal children presenting with type 2 diabetes. Pediatric Diabetes Objectives: Childhood type 2 diabetes (T2D) is increasing and may present differently across various populations. This study compares clinical features of T2D at diagnosis in Aboriginal children with Caucasian children and children from other high-risk ethnic groups. Patients and methods: This retrospective observational study used data from a Canadian surveillance study where newly diagnosed cases of childhood T2D were reported (n = 227). Using descriptive statistics, clinical features at diagnosis of T2D were compared across different ethnic groups including Aboriginal (n = 100), Caucasian (n = 57), and other high-risk ethnic groups (n = 64). Comparisons were made between Aboriginal children living in central Canada (Manitoba/northwestern Ontario) (n = 74) and Aboriginal children from other regions of Canada (n = 26). Results: Aboriginal children were younger, less obese, and less likely to have polycystic ovarian syndrome and dyslipidemia when compared to Caucasian children and children from other high-risk ethnic groups (p < 0.05). Aboriginal children from central Canada vs. those from other regions of Canada did not differ in age, body mass index z-score, family history of T2D, or presence of acanthosis nigricans. Those from central Canada had lower hemoglobin A1c levels (p < 0.05) and were less likely to have dyslipidemia than Aboriginal children from other regions (p < 0.05). Conclusions: Clinical features and rates of comorbidity in children with newly diagnosed T2D differ across various populations (Caucasian, Aboriginal, and children who belong to other high-risk ethnic groups) and across distinct Aboriginal populations (those living in central Canada vs. those living in other regions of Canada). Future research should determine specific genetic and environmental factors that contribute to these differences. Shazhan Amed a,b, Jill K. Hamilton c,d, Elizabeth A.C. Sellers e,f, Constadina Panagiotopoulos a,b, Stasia Hadjiyannakis g,h, Baiju R. Shah c.i, Gillian L. Booth c,i, Tessa A. Laubscher j, David Dannenbaum k and Heather Dean e,f a Department of Pediatrics, University of British Columbia, Vancouver, BC, V6H 3V4, Canada; b BC Children s Hospital, Vancouver, BC, V6H 3V4, Canada; c Department of Medicine, University of Toronto, Toronto, ON, M5G 1X8, Canada; d The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada; e Department of Pediatrics, University of Manitoba Winnipeg, MB, R3E 0Z2, Canada; f Winnipeg Children s Hospital, Winnipeg, MB, R3E 0Z2, Canada; g Department of Pediatrics, University of Ottawa, Ottawa, ON, K1H 8L1, Canada; h Children s Hospital of Eastern Ontario, Ottawa, ON, K1H 8L1, Canada; i La Ki Shing Knowledge Institute of St Michael s Hospital, Toronto, ON, M5B 1W8, Canada; j Department of Academic Family Medicine, University of Saskatchewan, Saskatoon, SK, S7M 3Y5, Canada; and k Department of Family Medicine, McGill University, Montreal, QC, H3C 2M2, Canada Key words: epidemiology pediatrics type 2 diabetes mellitus Corresponding author: Shazhan Amed, MD University of British Columbia, 4480 Oak Street, ACB K4-206, Vancouver, BC V6H 3V4, Canada. Tel: (604) ; fax: (604) ; samed@cw.bc.ca Submitted 14 December Accepted for publication 31 January 2012

2 Amed et al. Type 2 diabetes (T2D) in children is increasing and disproportionately affects certain ethnic groups. Globally, indigenous populations demonstrate higher rates of T2D in both children and adults compared with non-indigenous populations (1). The first pediatric case of T2D was identified in 1984 in a Canadian Aboriginal child and was soon followed by case series of Aboriginal children with T2D living in Central Canada (province of Manitoba and northwestern Ontario) (2, 3). A polymorphism of the hepatic nuclear factor (HNF) 1-α transcription factor (HNF 1-α G319S), associated with reduced insulin secretion, has been identified in the First Nation people with Oji-Cree heritage from Central Canada and is associated with early-onset diabetes with a gene-dose dependent effect (6, 7). Multiple genetic traits may directly or indirectly, under certain prenatal or postnatal environmental conditions, influence the risk of T2D. Therefore, the pathophysiology of T2D in children may vary across ethnic groups and across distinct Aboriginal populations. In a recent population-based national surveillance study for newly diagnosed T2D in Canadian children <18 yr of age, 44% were Aboriginal, 25% were Caucasian, 11% were African/Caribbean, 10% were Asian, and the remaining were Hispanic, Middle Eastern or mixed ethnicity (8). The minimum incidence of T2D in Canadian Aboriginal children <18 yr of age was 23.2 cases/ /year; a value 40 times higher than that of their Caucasian counterparts (0.54 cases/ /year) (8). Understanding the different clinical presentations of childhood T2D across ethnic populations is critical in informing population specific screening, treatment, and prevention strategies. This information is important to health professionals and policy makers in primary health, public health, and Aboriginal health. The objectives of this study were to: (i) describe the clinical features of T2D at diagnosis in Canadian Aboriginal children; (ii) compare the clinical features of newly diagnosed T2D in Aboriginal children vs. Caucasian children and children from other highrisk ethnic groups (i.e., Asian, African/Caribbean, Hispanic, and Middle Eastern); and (iii) compare the clinical presentation of T2D in Aboriginal children living in Central Canada (province of Manitoba/northwestern Ontario) vs. Aboriginal children living in other regions of Canada. Methods Surveillance methodology and subjects Active surveillance methodology and physician recruitment has been described in a previous publication (8). Briefly, a national network of physicians was established in partnership with the Canadian Paediatric Surveillance Program and the College of Family Physicians of Canada, National Research System, both nationally recognized surveillance programs. Physicians who participated in surveillance included almost all Canadian pediatricians including pediatric endocrinologists (participating/total in Canada; 2567/2835) and a convenience sample of family physicians (98/31 127) and adult endocrinologists (49/368). Participating physicians were provided with a case definition of non-type 1 diabetes which included T2D, medication-induced diabetes, and monogenic diabetes. Physicians were requested to report new cases of nontype 1 diabetes in a child <18 yr of age, on a monthly basis from 1 April 2006 to 30 March If a new case was reported, a detailed questionnaire was completed by the reporting physician and included information on clinical presentation, self-declared ethnicity, family history, laboratory investigations, treatment, and coexisting comorbidities (i.e., obesity, hypertension, dyslipidemia, polycystic ovarian syndrome, non-alcoholic liver disease, and albuminuria). Detailed questionnaires were reviewed independently by three principal investigators, and a diagnosis of T2D, medication-induced diabetes, or monogenic diabetes was assigned. If consensus was not achieved, the questionnaire was forwarded to three pediatric endocrinology coinvestigators to independently assign a diagnosis. In the event of disagreement, the case was labeled as indeterminate. All cases met criteria for diabetes as defined by the Canadian Diabetes Association (9). The diagnosis of T2D was supported by clinical features including obesity, a positive family history of T2D, a history of exposure to diabetes in utero, evidence of insulin resistance (i.e., acanthosis nigricans and polycystic ovarian syndrome), and belonging to a high-risk ethnic group (i.e., Aboriginal, African, Hispanic, and South-Asian). When available, the absence of pancreatic autoantibodies was also used to support the diagnosis. Diabetic ketoacidosis was defined as a ph <7.35 in the presence of hyperglycemia and ketosis. Response rates among pediatricians/pediatric specialists (79%), family physicians (96%), and adult diabetes specialists (85%) remained consistent over the 24-month period. Ninety-two percent of cases of non-type 1 diabetes were reported by a pediatrician or pediatric endocrinologist, a finding consistent with Canada s health care model where most children with a chronic condition are cared for by a pediatrician or pediatric specialist. A total of 227 cases of T2D were reported over 2 yrs of surveillance, and of these, 100 (44%) occurred in Aboriginal children. Seventy-four of these 100 cases were reported by physicians in Manitoba from the Winnipeg Children s Hospital which provides pediatric services to central Canada (provinces of Manitoba and northwestern Ontario). The majority of Aboriginal 2 Pediatric Diabetes 2012

3 Type 2 diabetes in Aboriginal vs. non-aboriginal children children with a clinical diagnosis of T2D reported by physicians living in Manitoba were assumed to be of Oji-Cree heritage (n = 74). The remaining Aboriginal children with T2D resided in other geographic areas across Canada (n = 26). Fifty-seven children (25%) with newly diagnosed T2D were Caucasian and 64 (28%) belonged to other high-risk ethnic groups (i.e., Asian, African/Caribbean, Hispanic, and Middle Eastern). Six cases where the ethnicity was unknown or marked as other were excluded. Data analysis Descriptive statistics were used to illustrate the demographic and clinical features of T2D at presentation. Comparisons between the groups were performed using Fisher s exact test for categorical parameters and t-test for continuous variables. Ethical approval was obtained from University of Manitoba Health Research Ethics Board, Winnipeg, Manitoba and the Hospital for Sick Children, Toronto, Ontario. Results Table 1 compares the demographic and clinical features of children with newly diagnosed T2D who were Aboriginal, Caucasian, and from other high-risk ethnic groups. Table 2 compares the demographic and clinical features of Aboriginal children from central Canada (Manitoba/northwestern Ontario) to Aboriginal children from other regions of Canada with newly diagnosed T2D. Aboriginal children were significantly younger at diagnosis compared to children who were Caucasian or belonged to other highrisk ethnic groups (12.9 yr vs and 14.3 yr respectively; p < 0.05) (Table 1). Aboriginal children and those from other high-risk ethnic groups were more likely to have a family history of T2D when compared to Caucasian children (94.7% and 94.9% respectively vs. 78.3%; p < 0.05) (Table 1). Although no differences were seen in the proportion of obese children across groups, Aboriginal children had a significantly lower body mass index (BMI) z-score at presentation of T2D compared to children who were Caucasian or from other high-risk ethnic groups [1.96 (95% CI: ) vs (95% CI: ) and 2.21 (95% CI: ) respectively; p < 0.05, Table 1]. This difference persisted but was no longer statistically significant when Aboriginal children living in central Canada were compared with those from other regions of Canada (Table 2). Aboriginal children were less likely to have polycystic ovarian syndrome and dyslipidemia compared with Caucasian children and those from other high-risk ethnic groups (Table 1). This difference was accounted for by Aboriginal youth from central Canada, as Aboriginal children from other regions of Canada did not differ from Caucasian children for these comorbidities (Table 2). There was no significant difference in age, BMI z-score, family history of T2D, and presence of acanthosis nigricans between Aboriginal children from central Canada vs. those from other regions of Canada (Table 2). Aboriginal children from other regions of Canada had increased hyperglycemia at presentation of T2D compared with central Canadian Aboriginal children as evidenced by a higher A1c at diagnosis [11.3% ( %) vs. 9.7% ( %); p < 0.05, Table 1. Comparison of Caucasian children, Aboriginal children, and children from other high-risk ethnic groups with a new diagnosis of type 2 diabetes Caucasian (n = 57) Aboriginal (n = 100) Other ethnicity* (n = 64) Mean age (yr) (95% CI) 14.4 (13.8, 15.1) 12.9 (12.4, 13.4), 14.3 (13.7, 14.9) Female (%) Positive family history T2D (%) Obese (%) Acanthosis Nigricans (%) DKA at presentation (%) Comorbidity (%) Polycystic ovarian syndrome , 15.1 Dyslipidemia , 45.7 Hypertension ALT > Micro/macroalbuminuria Mean BMI z-score (95% CI) 2.16 (2.02, 2.30) 1.96 (1.81, 2.10), 2.21 (2.04, 2.36) Mean A1c at diagnosis (95% CI) 8.7 (7.8, 9.5) 10.1 (9.4, 10.7) 9.6 (8.8, 10.4) BMI, body mass index; CI, confidence interval; DKA, diabetic ketoacidosis. *African/Caribbean, Asian, Hispanic, Middle Eastern. Aboriginal vs. Caucasian p < Aboriginal vs. other high-risk ethnic group p < Caucasian vs. other high-risk ethnic group p < Pediatric Diabetes

4 Amed et al. Table 2. Comparison of Aboriginal children from Manitoba/northwestern Ontario to Aboriginal children from other regions of Canada Aboriginal central Canada (n = 74) Aboriginal other regions of Canada (n = 26) Caucasian (n = 57) Mean age (yr) (95% CI) 12.7 (12.2, 13.3) 13.3 (12.4, 14.3) 14.4 (13.8, 15.1) Female (%) Positive family history of T2D (%) Obese (%) Acanthosis nigricans (%) DKA at presentation (%) Comorbidity (%) Polycystic ovarian syndrome Dyslipidemia 18*, Hypertension ALT > Micro/macroalbuminuria Mean BMI z-score (95% CI) 1.98 (1.82, 2.13) 1.90 (1.64, 2.17) 2.16 (1.98, 2.34) Mean A1c at diagnosis (95% CI) 9.7 (9.0, 10.4)* 11.3 (10.0, 12.7) 8.7 (7.8, 9.5) CI, confidence interval; DKA, diabetic ketoacidosis; BMI, body mass index. *Central Canadian Aboriginal vs. Aboriginal from other regions of Canada p < Central Canadian Aboriginal vs. Caucasian p < Aboriginal from other regions of Canada vs. Caucasian p < Table 2]. Central Canadian Aboriginal children were less likely to have dyslipidemia than Aboriginal children from other regions of Canada (18% vs. 53.9%; p < 0.05, Table 2). Although not statistically significant, twice as many Aboriginal children from central Canada had diabetic ketoacidosis at diagnosis of T2D when compared with Aboriginal children from other regions of Canada and Caucasian children (Table 2). Discussion Using data from a population-based national surveillance study for T2D in Canadian children, we compared the clinical presentation of new-onset T2D in children who were self-declared Aboriginal, Caucasian, or from other ethnic groups. Aboriginal children were younger, less obese, and less likely to have polycystic ovarian syndrome and dyslipidemia at diagnosis of T2D when compared to Caucasian children and children from other high-risk ethnic groups. Aboriginal children living in central Canada (Manitoba/northwestern Ontario) had less severe hyperglycemia and were less likely to have dyslipidemia at diagnosis of T2D than Aboriginal children from other regions of Canada. Aboriginal children with T2D lived in all regions of Canada but were concentrated (74%) in central Canada, a region where a polymorphism of the HNF 1-α gene has been described in Oji-Cree people. This polymorphism has been associated with earlier onset of T2D (6, 10). In this study, when the two populations of Aboriginal children (those living in central Canada and those from other regions of Canada) were compared to Caucasian children, they were younger at diagnosis of their T2D. In our previously published report from the Canadian surveillance study, 11% of Aboriginal children presented at <10 yr of age (8). This is not consistent with the experience in the United States where T2D in Navajo Indian children <10 yr of age is rare (11). The younger age of onset of T2D in Canadian Aboriginal children may be due to unique gene-environmental conditions. Aboriginal children had lower BMI z-scores at presentation when compared to Caucasian children and children from other high-risk ethnic groups. Sellers et al. reported a lower BMI and less acanthosis nigricans in their sub-population of Oji-Cree children with T2D from central Canada with the HNF 1-α G319S polymorphism suggesting less severe insulin resistance was required for T2D given the presence of lower insulin secretory capacity associated with this polymorphism (6). It is thus not surprising that shortterm insulin therapy has been shown to be effective in improving metabolic control in this population (12). Although acanthosis nigricans was reported more commonly in Aboriginal children from central Canada when compared to Caucasian children, this was not true for Aboriginal children living in other regions of Canada. Aboriginal children were less likely to have dyslipidemia reported than Caucasian children or children from other high-risk ethnic groups. Aboriginal children from central Canada were less likely to have dyslipidemia than Aboriginal children from other parts of Canada. Dyslipidemia has been previously 4 Pediatric Diabetes 2012

5 described in First Nation children and youth from central Canada where it was found that conventional measurement of low density lipoprotein-c and triglyceride levels without measurement of apolipoprotein B would have underestimated dyslipidemia in this population (13). It is possible that dyslipidemia was underestimated in Aboriginal children in our study because apolipoprotein B was not measured routinely by reporting physicians. Our study has its limitations. First, we could not confirm how many Aboriginal children with T2D from central Canada had one or two copies of the HNF 1-α G319S polymorphism. Based on previous data from this region (6), we can assume that roughly 40% of the 74 children in our study living in central Canada had at least one copy of the polymorphism. Second, dyslipidemia, hypertension, and polycystic ovarian syndrome were not formally defined and laboratory investigations confirming the presence of comorbidity (i.e., dyslipidemia) were not requested but rather, were considered to be present if the reporting physician indicated as such on the detailed case report form. Therefore, it is possible that comorbidity was over or underestimated in children with newly diagnosed T2D. The report forms requested information on the presence or absence of acanthosis nigricans. There is of course, the possibility of subjective interpretation by the reporting physician. We acknowledge that the availability of clinical data in this study is limited compared to expensive, more labour-intensive, multisite comprehensive clinical disease registries however, our methodology provides more robust data than population-based disease surveillance conducted using inexpensive health insurance administrative data. This is the first study to compare the clinical features and comorbidity of new-onset T2D in Aboriginal children vs. Caucasian children and children from other high-risk ethnic groups. Our results indicate that Aboriginal children, in general, present with different clinical features (i.e., younger age and lower BMI z-score) and rates of comorbidity (i.e., less dyslipidemia) when compared with non-aboriginal children. Also, Aboriginal children from central Canada have different clinical features than Aboriginal children from other regions of Canada. These findings suggest differences in the pathogenesis of T2D across ethnic and tribal groups. Further studies are required to better understand these differences to inform targeted prevention and management strategies for childhood T2D. Careful ethnographic and genetic studies in Aboriginal children are warranted to enhance our understanding of the gene-environmental contribution to the development of childhood T2D in Aboriginal people living in Canada. National and international clinical practice guidelines, national, regional, and public health policies, and private practice patterns Type 2 diabetes in Aboriginal vs. non-aboriginal children must incorporate and reflect this important regional variation. Acknowledgements We would like to thank the CPSP and CFPC-NaReS for their role in the coordination of surveillance. We also thank physicians who participated in this study as well as the Canadian Pediatric Endocrine Group (CPEG) members who coordinated reporting of cases within their individual centers. We are grateful to the Canadian Diabetes Association, Manitoba Institute for Child Health and SickKids Hospital for funding this study. Funding agencies did not play a role in the collection, analysis, and interpretation of the data, writing of the report and decision to submit the article for publication. S. A. s research fellowship was provided by the CPEG fellowship award. Conflict of interest The authors have no conflict of interest to disclose. Author contributions All authors contributed to the conception and design of the study and the interpretation of data. SA, JH, ES, SH, CP; and HD contributed to the acquisition and analysis of the data. SA, JH, ES and HD drafted the manuscript, and all authors participated in the critical revision of the article. All authors approved the final version to be published. References 1. Yu CH, Zinman B. Type 2 diabetes and impaired glucose tolerance in aboriginal populations: a global perspective. Diabetes Res Clin Pract 2007: 78: Dean HJ, Mundy RL, Moffatt M. Non-insulindependent diabetes mellitus in Indian children in Manitoba. CMAJ 1992: 147: Harris SB, Perkins BA, Whalen-Brough E. Noninsulin-dependent diabetes mellitus among First Nations children. New entity among First Nations people of north western Ontario. Can Fam Physician 1996: 42: Dean HJ, Young TK, Flett B, Wood-Steiman P. Screening for type-2 diabetes in aboriginal children in northern Canada. Lancet 1998: 352: Dannenbaum D, Kuzmina E, Lejeune P, Torrie J, Gangbe M. Prevalence of diabetes and diabetesrelated complications in First Nations Communities in Northern Quebec (Eeyou Istchee), Canada. Can J Diabetes 2008: 32: Sellers EA, Triggs-Raine B, Rockman-Greenberg C, Dean HJ. The prevalence of the HNF-1alpha G319S mutation in Canadian aboriginal youth with type 2 diabetes. Diabetes Care 2002: 25: Hegele RA, Cao H, Harris SB, Hanley AJ, Zinman B. Hepatocyte nuclear factor-1 alpha G319S. A private mutation in Oji-Cree associated with type 2 diabetes. Diabetes Care 1999: 22: 524. Pediatric Diabetes

6 Amed et al. 8. Amed S, Dean HJ, Panagiotopoulos C et al. Type 2 diabetes, medication-induced diabetes, and monogenic diabetes in Canadian children: A prospective national surveillance study. Diabetes Care 2010: 33: Canadian Diabetes Association. Clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes 2008: Hegele RA, Hanley AJ, Zinman B, Harris SB, Anderson CM. Youth-onset type 2 diabetes (Y2DM) associated with HNF1A S319 in aboriginal Canadians. Diabetes Care 1999: 22: Dabelea D, DeGroat J, Sorrelman C et al. Diabetes in Navajo youth: prevalence, incidence, and clinical characteristics: the SEARCH for diabetes in youth study. Diabetes Care 2009: 32(Suppl. 2): S141 S Sellers EAC, Dean HJ. Short-term insulin therapy in adolescents with type 2 diabetes mellitus. J Pediatr Endocrinol Metab 2004: 17: Sellers EA,Yung G,Dean HJ. Dyslipidemia and other cardiovascular risk factors in a Canadian First Nation pediatric population with type 2 diabetes mellitus. Pediatr Diabetes 2007: 8: Pediatric Diabetes 2012