Clinical Update on Genetic and Autoimmune Biomarkers in Pediatric Diabetes

Abstract

Purpose:

The purpose of this clinical update is to review the etiology of diabetes types affecting youth under 20 and describe diabetes-related genetic and autoimmune biomarkers based on the most recent literature. This information will support diabetes care providers’ efforts to better explain the complex topic to patients and families.

Method:

A PubMed search identified 396 reviews published from 2008 to 2011 that included the topics of etiology, epidemiology, genetics/epigenetics, pathogenesis, or immunology related to diabetes in youth. The current clinical update includes 19 of these.

Results:

The majority of youth under 20 years with diabetes have Type 1 diabetes. Other forms of the disease affecting this population include Type 2, monogenic, and secondary diabetes. Genetic and autoimmune biomarkers can help determine the risk and diagnosis of both Type 1 and monogenic diabetes. An accurate diagnosis of diabetes type allows for determination of optimal treatment options.

Conclusion:

The complexity of determining etiology, risk, diagnosis, and treatment for diabetes in youth is increasing with the rate of related genetic and immunologic advances. Diabetes care providers must be able to explain the complex genetic and autoimmune biomarkers used in determining the risk of diabetes, diagnosis of the disease, and identification of treatment options to patients and families.

More than 150,000 youth in the United States below the age of 20 have been diagnosed with diabetes, a disease that may reduce their life expectancy by up to 27 years (Liese et al., 2006; Mayer-Davis et al., 2009). While the vast majority of these youth (85%) have Type 1 diabetes (T1D), several other forms of diabetes occur in this population, including Type 2 diabetes (T2D), monogenic, and secondary diabetes (Liese et al., 2006). Due to the variable etiology of secondary diabetes, which is specific to either the primary disease process (endocrinopathies involved in cystic fibrosis, Down’s syndrome, etc.) or the treatment (drug-induced glucose intolerance from glucocorticoids, certain chemotherapy agents, etc.), an in-depth discussion of these forms of diabetes is beyond the scope of this clinical update (Margulies, Ergun-Longmire, Ten, & Maclaren, 2010).

An accurate diagnosis of diabetes type in youth is critical to determine the best course of treatment; however, determining diagnosis (as well as establishing the risk of developing each type) can be complex. Clinicians use biomarkers to determine disease risk, diagnose diabetes type, and ultimately develop the appropriate treatment for youth with diabetes. For example, single gene mutations can identify monogenic diabetes or help determine the risk of developing T1D through identification of specific genetic alleles (or different versions of a single gene) that place individuals at risk of or protect them from T1D (Bonifacio & Ziegler, 2010; Owen, Skupien, & Malecki, 2009). Similarly, autoimmune biomarkers play a role in diagnosing and determining the risk of developing T1D. The presence of T1D-related autoantibodies (markers of autoimmune activity) in serum tests confirms a diagnosis of T1D (American Diabetes Association, 1997; Reasner, DeFronzo, & Cersosimo, 2011). In addition, the presence of these autoantibodies in the serum of individuals without the disease indicates an increased risk of developing T1D (Bingley, 2010).

As our knowledge of rarer forms of diabetes that affect children and adolescents grows, so does the complexity involved in determining the risk of, diagnosing, and treating the disease. In this clinical update, we review the etiology of diabetes types affecting youth under 20 years of age and describe diabetes-related genetic/genomic and autoimmune biomarkers based on the most recent literature. By synthesizing and summarizing the latest information, we seek to provide clear and concise knowledge of diabetes-related biomarkers and resources for finding additional information in order to support nurses, educators, and other diabetes care providers’ efforts to better explain the complex topic to patients and families.

Research Design/Methodology

We searched PubMed for reviews published from 2008 to 2011 that included the topics of etiology, epidemiology, genetics, epigenetics, pathogenesis, and/or immunology related to diabetes in youth. Our keywords included diabetes, Type 1 diabetes (T1D), youth, genetics, immunology, and biomarkers, and we limited our results to reviews, human studies, and English language and the search type to reviews in order to keep the number of articles manageable and because clinical studies often do not provide enough of the specific information we needed for this article. We excluded reviews if they did not have diabetes as a major focus, included case studies, or were not related to diabetes risk, diagnosis, treatment, or outcomes (e.g., discussion of specific single nucleotide polymorphisms). We initially identified a total of 396 reviews, 19 of which met inclusion criteria for discussion in this clinical update.

Results

Overview of Diabetes Typology Affecting Youth

The types of diabetes affecting youth can be divided into two broad etiological categories: (1) Polygenic disease that results in a T1D or T2D phenotype or (2) Monogenic disease that can result in either permanent or transient neonatal diabetes (PNDM/TNDM) or maturity-onset diabetes in the young (MODY), which includes six subtypes (see Table 1; Rubio-Cabezas & Argente, 2008). In the United States, T1D comprises 85% of diabetes cases in youth under 20 years of age, T2D accounts for approximately 12% of cases, and monogenic diabetes accounts for 1–3% of cases (Hattersley, Bruining, Shield, Njolstad, & Donaghue, 2009; Liese et al., 2006). Reviewing the etiology of each type with patients and families can help clarify differences in diabetes typology and various treatment options available for each type.

Table 1.

Overview of Diabetes in Youth.

Disease characteristic	T1D	T2D	Monogenic
Frequency of cases in children and adolescents (%)	85	12	1–3
Age of onset	6 months to early adulthood	Pubertal/postpubertal (age of onset is slowly decreasing)	PNDM: 0–6 months
			TNDM: 0–7 days
			MODY: 0 to postpubertal
Type of onset	Acute	Varies from insidious to acute	Varies from insidious to acute
Genetic etiology	Polygenic	Polygenic	Monogenic
Parent with diabetes (%)	2–4	80	90
Autoimmune mediated	Yes	No	No
Ketosis prone	Frequent	Rare	MODY: rare
			PNDM/TNDM: present
Obesity present	Varies	Yes	Varies
Acanthosis nigricans present	No	Yes	No
Treatment regimen	Insulin	ODM ± insulin	PNDM due to KCNJ11/ABCC8 mutation: ODM
			PNDM due to INS mutation: insulin
			TNDM: initially insulin, then no tx until relapse (ODM ± insulin)
			MODY1/3: ODM
			MODY2: no tx-ODM (± insulin during pregnancy)
			MODY 4/6: no tx-ODM
			MODY 5: usually insulin

Note. Adapted from Rubio-Cabezas and Argente, 2008, p. 944, © 2008 by Walter de Gruyter GmbH., with permission of Walter de Gruyter GmbH. MODY = maturity-onset diabetes in the young; ODM = other diabetes medications (all except insulin); PNDM permanent neonatal diabetes mellitus; T1D = type 1 diabetes; T2D = type 2 diabetes; TNDM = transient neonatal diabetes mellitus; tx = treatment.

Type 1 Diabetes Etiology.

The incidence of T1D in youth has been increasing consistently by nearly 3% per year globally over the last 20 years (Whittmore, Jaser, Guo, & Grey, 2010). Genomic factors involved in the development of T1D are well established, but this relatively rapid increase in disease incidence also points to environmental components of disease etiology. The etiology of T1D is complex, involving chronic, progressive T-cell-mediated autoimmune destruction of β cells in the pancreas over months or years prior to diagnosis (Bluestone, Herold, & Eisenbarth, 2010; Taplin & Barker, 2008). The disease model for T1D suggests that a susceptible individual has a genetic predisposition for developing the disease, which is compounded by an environmental trigger or modifier (Atkinson & Eisenbarth, 2001). This trigger then initiates an autoimmune response in the pancreas and ultimately leads to symptomatology and diagnosis of T1D. Autoimmune activity prior to the onset of T1D diagnosis begins with the infiltration of insulin-producing β cells in the pancreas by macrophages, dendritic cells, and T cells (CD4 and CD8; Taplin & Barker, 2008). Specific environmental triggers or modifiers remain elusive, but potential candidates include viral infections (e.g., coxsackie B4 or B5), vitamin D deficiency, a reduction of exposure to microbes in developed nations (the “hygiene hypothesis”), or early introduction of dietary components such as bovine milk protein (Bluestone et al., 2010; Eizirik, Collie, & Ortis, 2009; Maahs, West, Lawrence, & Mayer-Davis, 2010; Margulies et al., 2010). Exposure to such triggers is thought to speed the autoimmune activity and lead to complete and irreversible β-cell destruction over time (Atkinson & Eisenbarth, 2001). Symptoms of T1D emerge when more than 80% of the β-cell function is irreversibly lost (Margulies et al., 2010). As a result of this destruction, patients with T1D must rely on exogenous insulin for blood glucose management for the rest of their lives.

Type 2 Diabetes Etiology.

The etiology of T2D also appears to be a combination of genomic and environmental factors that results in both insulin resistance and inadequate insulin secretion (Reasner et al., 2011). Over time, T2D may progress to complete β-cell dysfunction and ultimately insulin deficiency. Environmental factors contributing to the development of T2D include a high-calorie diet, lack of sufficient exercise, and obesity (Khardori, Bessen, Buehler, Schraga, & Torkamani, n.d.). There is also strong evidence to suggest genomic involvement in the development of T2D, as evidenced by a higher prevalence of T2D in certain minority groups (Hispanic, Native American, African American, Asian American, Hawaiian/Pacific Islander) and a correlation between development of T2D and a family history of the disease (Khardori et al., n.d.). However, the specific mechanisms involved in the genomic predisposition to the development of T2D remain unclear (Lyssenko & Groop, 2009). T2D may be treated with a combination of modifications to diet and exercise and medications such as insulin secretagogues, meglinitides, biguanides, PPAR-γ agonists, and α-glucosidase inhibitors. It may, however, ultimately require exogenous insulin therapy (Ergun-Longmire, Margulies, Ten, & Maclaren, 2010). While autoimmune and genomic biomarkers associated with T1D and monogenic diabetes are widely used in research and clinical care, biomarkers associated with T2D is an ongoing area of study. Due to the limited knowledge in this area, we will not consider T2D-related biomarkers further in this review.

Monogenic Diabetes Etiology.

Monogenic diabetes is a result of a single gene mutation at different allelic loci and does not involve an environmental component in disease formation as with polygenic forms. Monogenic subtypes are relatively rare and include neonatal diabetes that is either permanent or transient (PNDM/TNDM) and MODY (Rubio-Cabezas & Argente, 2008). It is crucial to correctly identify this type of diabetes because treatment regimens, along with age of onset and clinical characteristics, vary depending on the specific type of genetic mutation involved (Hattersley et al., 2009; Malecki & Mlynarski, 2008).

The above definitions of diabetes affecting youth are based on the unique etiologies of each type. Highlighting the distinction between each disease process sets the stage for clinicians to understand the role of biomarkers in determining the risk, diagnosis, and treatment of diabetes in youth.

Genetic/Genomic Biomarkers in Diabetes Affecting Youth

Biomarkers are naturally occurring molecules (e.g., blood glucose, genes) or other biological characteristics (e.g., blood pressure) that can be objectively measured and are associated with normal physiologic processes, pathological or disease processes, or responses to treatment interventions (Atkinson et al., 2001). T1D-associated biomarkers include both genomic and autoimmune markers, while known biomarkers associated with monogenic diabetes are solely genetic. The genomic biomarkers implicated in the development of T1D include multiple genes, with nearly 50% of disease risk linked to the human leukocyte antigen (HLA) genes (see Table 2; Morran, Omenn, & Pietropaolo, 2008). Of the patients diagnosed with T1D, a full 90% have high-risk alleles of the HLA-DR and HLA-DQ genes located in the major histocompatibility complex (MHC) on chromosome 6p21.3 (see Figure 1; Concannon, Rich, & Nepom, 2009).

Table 2.

Major Genes That Confer Risk for Diabetes in Youth.

Gene	Full gene name	Gene location	Diabetes association	Proposed/known diabetes-related mechanism of action
ABCC8 (aka SUR1)	ATP-binding cassette, subfamily C (CFTR/MRP), member 8	11p15.1	PNDM, TNDM, T2D	Modulator of potassium channels and insulin release
FOXP3	Forkhead box P3	Xp11.23	PNDM	Regulator of transcription (forkhead/winged family)
GCK (aka MODY2)	Glucokinase	7p15.3–15.1	MODY2, PNDM	Produces glucose-6-phosphate (usually first step in glucose metabolism pathway)
GLIS3	GLIS family zinc finger 3	9p24.2	PNDM	Activator and repressor of transcription; involved in development of pancreatic β cells
HLA-DQB1 (aka HLA-DQ8)	Major histocompatibility complex, Class II, DQ β 1	6p21.3	T1D	Determines extracellular peptide-binding specificities on antigen-presenting cells
HLA-DRB3 (aka HLA-DR3)	Major histocompatibility complex, Class II, DR β 3	6p21.3	T1D	Determines extracellular peptide-binding specificities on antigen-presenting cells
HLA-DRB4	Major histocompatibility complex, Class II, DR β 4	6p21.3	T1D	Determines extracellular peptide-binding specificities on antigen-presenting cells
HNF1A (aka MODY3)	HNF1 homeobox A	12q24.2	MODY3	Transcription factor involved in liverspecific gene expression
HNF1B (aka MODY5)	HNF1 homeobox B	17cen-q21.3	MODY5	Regulates development of embryonic pancreas
HNF4A (aka MODY1)	Hepatocyte nuclear factor 4	20q13.12	MODY1	Controls gene expression in liver; may play a role in liver development
HYMAI	Hydatidiform mole associated and imprinted	6q24.3	TNDM	Nonprotein coding, causative of TNDM; expressed only from paternal allele
IL2RA	Interleukin 2 receptor, α	10p15-p14	T1D	Encodes IL2 membrane protein; expression essential in T-cell suppression
INS	Insulin	11p15.5	PNDM, T1D	Binds to insulin receptor to stimulate uptake of glucose
KCNJ11 (aka Kir6.2)	Potassium inwardly rectifying channel, subfamily J, member 11	11p15.1	PNDM, TNDM, T2D	Regulates potassium flow into cells; associated with the sulfonylurea receptor (SUR)
NEUROD1 (aka MODY6)	Neurogenic differentiation 1	2q32	MODY6, T2D	Regulates expression of INS gene
PDX1 (aka IPF1, MODY4)	Pancreatic and duodenal homeobox 1	13q12.1	MODY4, PNDM	Activates INS, GCK genes; involved in pancreatic development; involved in glucose-dependent regulation of INS gene
PLAGL1 (aka ZAC)	Pleiomorphic adenoma gene-like 1	6q24	TNDM	Encodes C2H2 zinc finger protein involved in transactivation and DNA binding; overexpression in fetal development leads to TNDM; preferential expression of paternal allele
PTPN22	Protein tyrosine phosphatase, nonreceptor type 22 (lymphoid)	1p13.2	T1D	May be involved in regulating protein function in T-cell receptor pathway
TCF7L2	Transcription factor 7-like 2	10q25.3	T2D	Involved in blood glucose homeostasis

Note. DNA = deoxyribonucleic acid; IL2 = interleukin 2; MODY maturity-onset diabetes in the young; PNDM = permanent neonatal diabetes mellitus; T1D = type 1 diabetes; T2D = type 2 diabetes; TNDM = transient neonatal Information, 2011; Ounissi-Benkalha & Polychronakos, 2008).

Figure 1.

Visual representation of diabetes-related gene locations (National Center for Biotechnology Information, 2011).

The MHC is a highly variable, large genetic region that plays a major role in autoimmune processes, infections, inflammatory diseases, and response to transplantation (Fernando et al., 2008; Ounissi-Benkalha & Polychronakos, 2008). MHC has three subregions: HLA Class I (subtypes A, B, and C) genes encode for molecules located on the surface of all nucleated cells and their role is to present intracellular antigens to CD8T cells; HLA Class II (subtypes DP, DR, and DQ) genes encode for molecules found on the surface of all antigen-presenting cells (dendritic cells, macrophages, and T cells) and their role is to present extracellular antigens to CD4T cells; and the HLA Class III gene encodes for various immune-related molecules (cytochrome 450 enzymes CYP21P and CYP21, cytokines such as tumor necrosis factor [TNF]α and TNFβ, and complement factors C4A, C4B, factor B, and C2; Morran et al., 2008; Ounissi-Benkalha & Polychronakos, 2008). Within the MCH, the HLA Class II haplotypes DR3/4 and DQ8 carry the highest genetic risk associated with the development of T1D (with an odds ratio of up to 49.2; Ounissi-Benkalha & Polychronakos, 2008). Haplotype variants (closely related genetic alleles) on the same chromosome are generally inherited together; therefore, many individuals at risk of T1D inherit the mutations in both the HLA DR3/4 and the DQ8 alleles in the MCH region of chromosome 6 (King, Stansfield, & Mulligan, 2007, haplotype). In a recent meta-analysis of genome-wide association studies (GWAS), authors confirmed the strong association between the HLA region and T1D and identified non-HLA genes also thought to confer disease risk (Concannon et al., 2009).

Biomarkers currently associated with monogenic diabetes are the result of a variety of single gene mutations. PNDM is most often caused by a single gene mutation either in the potassium channel regulators of β cells that affects the release of insulin (KCNJ11or ABCC8 genes) or in the INS gene, itself, that creates ineffective insulin molecules. Rarely, PNDM may involve single mutations in other genes (GCK, PDX1, GLIS3, or FOXP3; see Table 2 for additional information; Greeley et al., 2010; National Center for Biotechnology Information [NCBI], 2011; Rubio-Cabezas & Argente, 2008). TNDM involves different single mutations of either the KCNJ11 or ABCC8 gene resulting in abnormalities in the potassium channels of β cells or imprinting errors in the PLAGL1 and HYMAI genes (Hattersley et al., 2009). Up to 70% of TNDM results from imprinted PLAGL1 and HYMAI genes in which only the paternal allele of the gene is expressed in offspring (Mitchell & Pollin, 2010). MODY subtypes are also caused by single gene mutations resulting in b-cell transcription factor errors and are classified according to the gene affected: MODY1 (HNF4A gene), MODY 2 (GCK gene), MODY 3 (HNF1A gene), MODY 4 (PDX1 gene), MODY 5 (HNF1B gene), and MODY 6 (NEUROD1 gene; Margulies et al., 2010; NCBI, 2011).

Many ethical issues arise when clinicians are providing genetic results to youth and their families. Familiarization with these ethical considerations is crucial for diabetes care providers. Ross and Moon (2000) provide a general discussion of ethical issues related to genetic testing in children, and Gustafsson Stolt, Ludvigsson, Liss, and Svensson (2003) address specific issues related to parents, children, and T1D genetic testing.

Autoimmune Biomarkers in Diabetes Affecting Youth

Autoimmune biomarkers associated with the development of T1D are referred to as diabetes autoantibodies (DAAs). DAAs are markers of autoimmune activity targeted against various parts of β cells or against the insulin molecule directly. Current research suggests that they are by-products of autoimmune processes in the pancreas rather than a causative factor (Taplin & Barker, 2008). The first DAA identified was the islet cell antibody (ICA) in 1974, and while its specific target still remains unclear, it appears to be a variety of cytoplasmic and/or surface cell antigen. Four other DAAs play a major role in T1D: glutamic acid decarboxylase 65 (GAD65), protein tyrosine phosphatase insulinoma antigen 2 antibody (IA-2, also called ICA512), insulin antibody (IAA), and zinc transporter 8 antibody (ZnT8; see Table 3; Bingley, 2010; Wenzlau et al., 2007). Levels of DAAs fluctuate, and a patient can be positive for DAA and later negative and vice versa (Bingley, 2010; Bonifacio & Ziegler, 2010). DAAs can be present by 12–24 months after birth, but progression to the diagnosis of T1D may take up to 25 years.

Table 3.

Diabetes Autoantibodies (DAAs) in Type 1 Diabetes.

Diabetes autoantibody	Sensitivity (%)	Comments
Insulin autoantibody (IAA)	Up to 92	Levels decrease with age
Glutamic acid decarboxylase (GAD)	84	Higher sensitivity in adult-onset T1D
Insulinoma antigen 2 (IA-2; aka ICA 512)	79	Rare in children <3 years of age, then levels increase
Zinc transporter 8 (ZnT8)	63	Positive in >25% of patients negative for IAA, GAD, IA-2; rare in children <3 years of age, peak in adolescence

Note. Adapted from Taplin and Barker (2008), © 2008, Informa Healthcare, with permission of Informa Healthcare.

Biomarkers and the Diagnosis of Diabetes in Youth

Clinicians and researchers use genetic biomarkers in the diagnosis of monogenic diabetes and autoimmune biomarkers in the diagnosis of T1D (see Figure 2). Health care providers may suspect a patient has a monogenic form of diabetes if one or more of the following are true:

Figure 2.

Diagnosis flow chart documenting steps to be taken to identify diabetes type and treatment in youth. DAA = diabetes autoantibodies; DM = diabetes mellitus; hx = history; ODM = other diabetes medications (all except insulin); s/sx = signs/symptoms; T1D = Type 1 diabetes; T2D = Type 2 diabetes; T1b = Type 1 b diabetes (idiopathic); tx = treat.

1. The patient is diagnosed before 6 months of age.

2. A parent has monogenic diabetes.

3. Endogenous insulin and c-peptide levels are normal.

4. The patient is not positive for DAAs (see discussion below).

5. The patient does not have a high-risk HLA haplotype.

6. The patient is not obese and has no evidence of insulin resistance (i.e., acanthosis nigricans). (Rubio-Cabezas & Argente, 2008).

Genetic testing for monogenic diabetes has recently become widely available for clinical use in the United States, and the National Center for Biotechnology Information has compiled a current listing of laboratories that provide monogenic testing (see section on Additional Resources, below). For example, Seattle Children’s Hospital provides MODY and neonatal diabetes sequencing panels for patients. The current costs are $2,034 for the MODY panel and $3,293 for the neonatal diabetes panel and are covered by Medicaid and most private insurance companies with prior authorization. It is important to reiterate that an accurate diagnosis of monogenic diabetes is critical for selecting an appropriate treatment regimen. Patients with PNDM due to KCNJ11 or ABCC8 mutations may be effectively treated with oral sulfonylureas; however, mutations in the INS gene result in the destruction of β cells and will require lifelong insulin treatment. Patients with TNDM may require insulin treatment upon initial diagnosis, but often their treatment can transition to lifestyle modifications and/or oral sulfonylureas (Rubio-Cabezas & Argente, 2008).

Autoimmune biomarkers are widely used at the time of diagnosis to confirm the typology of T1D. When four DAAs are measured, 96–98% of T1D patients are positive for at least one DAA at diagnosis (Bingley, 2010; Taplin & Barker, 2008). T1D is by definition an autoimmune disease, so the presence of DAAs confirms the diagnosis and excludes the diagnosis of monogenic diabetes or T2D (Atkinson & Eisenbarth, 2001). However, the absence of DAAs at diagnosis, alone, is not sufficient to rule out a diagnosis of T1D. Type 1b diabetes (idiopathic autoimmune diabetes) is a subtype of T1D in which patients have all the characteristics of T1D but test negative for all currently known DAAs (Maahs et al., 2010). The symptoms and treatment for T1D (technically considered Type 1a) and Type 1b are identical.

Biomarkers and Determining the Risk of Developing Diabetes in Youth

Genetic biomarkers can be used to determine an individual’s risk for developing either T1D or monogenic diabetes, and autoimmune biomarkers can aid in determining the risk of developing T1D in relatives of individuals with T1D. The HLA Class II haplotype DR3/4-DQ8 is associated with the highest genetic risk of developing T1D, while other HLA Class II haplotypes (DR15-DQ6, DQB1) are protective against the disease (Hewagama & Richardson, 2009; Morran et al., 2008). Based on studies in the United States and Europe, children and adolescents have an approximate risk of 6% of developing T1D by age 20 years if a high-risk HLA haplotype is present compared to a 0.39% risk for the general population and a 0.03% risk for those with a protective HLA haplotype (Bonifacio & Ziegler, 2010). However, clinicians do not currently use genetic testing to assess T1D risk in individuals.

Autoimmune biomarkers can also play a role in determining risk of T1D. In individuals without diabetes, total number of DAAs in serum blood tests is currently the most predictive measure of T1D risk, with higher numbers of DAAs present correlating with greater risk (Bingley, 2010). First-degree relatives of individuals with T1D who are positive for three or more DAAs have ≥50% risk of developing the disease over 5 years (Bingley, 2010; Mahon et al., 2009; Taplin & Barker, 2008). However, serum blood tests for DAAs are currently available to nondiabetic family members of individuals with T1D only through ongoing research studies (see Diabetes TrialNet information in the section on additional resources, below).

Risk of monogenic diabetes is largely determined by Mendelian inheritance patterns. The monogenic subtypes PNDM and TNDM may be caused by spontaneous mutations or by either autosomal recessive inheritance (25% chance offspring will be affected) or autosomal dominant inheritance (50% chance the offspring will be affected; Rubio-Cabezas & Argente, 2008). The monogenic forms of MODY are autosomal dominant disorders and are passed on to offspring 50% of the time.

Implications for Nurses and Other Diabetes Providers

The rapid increases in knowledge in the fields of genetics/genomics and immunology related to diabetes presents challenges to health care providers, who must integrate this knowledge into their daily practices (Jenkins, Bednash, & Malone, 2011). Since completion of the Human Genome Project in 2003, substantial developments in genetics/genomics such as the International HapMap Project (www.hapmap.org) and high throughput technologies that have enabled rapid growth of GWAS have underscored these challenges (Lea, Skirton, Read, & Williams, 2011). The American Nurses Association published Essentials in Genetic and Genomic Nursing: Competencies, Curricula Guidelines, and Outcome Indicators in 2008, highlighting the importance of increasing genetic and genomic knowledge among nurses and other care providers so that they are better equipped to inform and support patients and families on the topic (American Nurses Association, 2008; Lea et al., 2011).

An understanding of the genetic and autoimmune biomarkers related to diabetes types affecting youth will enable nurses and other diabetes care providers to educate and support patients and families by (1) explaining diabetes etiology using results from genetic and autoimmune biomarker tests to determine diabetes type; (2) discussing treatment implications of the diabetes etiology; (3) explaining an individual’s likelihood of developing T1D (and/or monogenic diabetes) using genetic and autoimmune biomarkers as indicators, keeping in mind that the assessment of risk is not static (i.e., if a child is DAA positive or a sibling is diagnosed with T1D, the calculated risk of developing the disease increases significantly); (4) providing options for genetic and/or autoimmune testing if requested by patients or families or indicated by clinical presentation; and (5) providing additional resources for patients and families to get further information.

Additional Resources for Health Care Providers, Patients, and Families

Many laboratories now offer MODY and neonatal diabetes testing, including Seattle Children’s Hospital (www.seattlechildrens.org). The National Center for Biotechnology Information (NCBI) publishes a directory of additional laboratories providing genetic testing at www.genetests.org. DAA testing for patients diagnosed with diabetes is widely available, for example, from the Mayo Clinic (www.mayomedicallaboratories.com), the Barbara Davis Center (www.uch.edu/for-healthcare-professional/Clinical-Laboratory/), and Quest Diagnostics (www.questdiagnostics.com). The Type I Diabetes TrialNet provides additional information on DAA screening of first- and second-degree family members of T1D patients at www.diabetestrialnet.org

Additional educational resources on genetics/genomics generally and on diabetes include

• Free online genetics course from Duke’s Center for Human Genetics (www.chg.duke.edu/education/online.htm), which covers basic areas of genetics;

• The special series on genetics and genomics in the Journal of Nursing Scholarship (starting March 2011, 43[1]), and a special issue on genetics and genomics that includes an article on the genomics of diabetes (March 2013, 45[1]);

• Articles and competencies related to genetics/genomics and nursing on the International Society of Nurses in Genetics website (www.ISONG.org);

• In-depth diabetes etiology and pathogenesis information at www.endotext.org;

• Information and guidelines regarding monogenic diabetes at www.diabetesgenes.org;

• Specific information on T1D-related genes at www.t1dbase.org.