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ADA/JDRF Type 1 Diabetes Sourcebook, Excerpt #1: Diagnosing Diabetes

Anne Peters, MD, and Lori Laffel, MD, MPH, editors
Jane Lee Chiang, MD, managing editor



Diagnosing Diabetes 

Michael J. Haller, MD

Standards of care endorsed by the American Diabetes Association (ADA) and the World Health Organization (WHO) provide a number of overlapping criteria for the diagnosis of diabetes. Based largely on data linked to risk of retinopathy in T2D patients, all subtypes of diabetes (with the exception of gestational diabetes) are currently diagnosed by any one of the following: 1) fasting plasma glucose ≥126 mg/dl (7.0mmol/L), 2) a 2-h plasma glucose ≥200 mg/dl during a formal oral glucose tolerance test (OGTT) as described by the WHO, 3) classic symptoms of hyperglycemia (polyuria, polydipsia, and weight loss) and a random plasma glucose ≥200mg/dl, or 4) hemoglobin A1c (A1C) ≥6.5% performed and confirmed in a National Glycohemoglobin Standardization Program (NGSP) – certified assay standardized to the Diabetes Control and Complications Trial (DCCT) (see Table 1.1).12 In the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing of the initially positive criteria as discordance between the different diagnostic criteria is not uncommon. Further, as the ADA/WHO diagnostic criteria are heavily influenced by the overwhelming burden of T2D worldwide (>90% of diabetes cases), clinicians must recall that these criteria are not T1D-specific and do not always provide optimal sensitivity for the diagnosis of T1D….

An NGSP method, standardized or traceable to the DCCT reference assay, for A1C should be used at diagnosis and for ongoing monitoring. The recent assimilation of A1C as a diagnostic standard for diabetes exemplifies the challenges of the diagnostic criteria when evaluating patients. Because A1C can be performed in the nonfasting state, has less day-to-day variability, and does not require stringent patient participation when measured for diagnostic purposes, A1C has several desirable qualities of a diagnostic tool. However, A1C may not provide optimal sensitivity when evaluating patients with diverse disease processes culminating in hyperglycemia. In patients who rapidly develop the disease, A1C may not rise above current diagnostic criteria despite marked hyperglycemia. Similarly, in patients known to be at increased risk for T1D, serial fasting and OGTT-stimulated glucose concentrations are likely a more sensitive diagnostic test than A1C when using a cutoff of 6.5%13. Given the need to prevent the serious morbidity and mortality of DKA at diagnosis, ongoing efforts to develop cost-effective screening or case-finding strategies in high-risk patients may eventually lead to diagnostic criteria more specific to T1D.13

Table 1.1 Diagnostic Criteria of Diabetes Fasting plasma glucose >126 mg/dl (7.0 mmol/L) or 2-h plasma glucose >200 mg/dl (11 mmol/L) during OGTT or Clinical symptoms Polyuria, polydipsia, weight loss, and random plasma glucose >200 mg/dl or Hemoglobin A1C >6.5%* *A1C should be performed using a method that is NGSP-certified and standardized to the DCCT assay.



ADA and WHO criteria are used to broadly diagnose diabetes, however, a combination of immunologic, genetic, and phenotypic features must be used to differentiate among the different forms of diabetes. A brief review of other forms of diabetes is necessary to frame our ongoing discussion of T1D. (See chapter 2 for further discussion of T1D diagnosis.)

T1D has at least two broad subcategories: type 1a diabetes and type 1b diabetes. Type 1a diabetes, the primary focus of the T1D Sourcebook, refers to diabetes that is autoimmune in its etiopathogenesis. Type 1b diabetes results from nonimmune-mediated β-cell loss (pancreatic agenesis, pancreatectomy, etc.). In addition to these broad subtypes, the inherent heterogeneity of T1D has necessitated additional monikers for patients within the broad framework of T1D. Some patients, classified as having fulminant T1D, experience rapid β-cell destruction; they present with DKA despite near normal A1C. Conversely, patients labeled as Latent Autoimmune Diabetes of Adulthood (LADA) develop T1D over many years, with gradual β-cell decline that may not be recognized as immune-mediated for years (and sometimes decades) after the development of hyperglycemia.

Given the growing epidemic of obesity, physicians must also remember that autoimmune diseases do not spare those who are overweight or obese. As such, when an obese patient presents with polyuria, polydipsia, and hyperglycemia, careful consideration should be given to making a diagnosis of T1D versus T2D. A missed or delayed diagnosis of T1D could result in rapid development of DKA. Moreover, because patients with T2D can develop glucose toxicity and a severe enough β-cell deficiency to cause DKA, clinicians must also be careful not to label all new-onset patients who present with DKA as having T1D. Ketonemia and ketonuria are not typically seen in T2D, but may be present. They more commonly occur in teens with new-onset T2D than in adults with T2D. Pancreatic islet autoantibodies are generally absent in T2D but have been reported in patients with a T2D phenotype. These cases emphasize the heterogeneity and crossover of these two distinct diseases. Some groups have used labels such as double diabetes or type 1.5 diabetes to describe children with characteristics of both diseases. Our preference is to not use such terms. Instead, we consider all patients with evidence of autoimmunity to have T1D, while acknowledging the presence of a T2D phenotype (also thought of as T1D plus the metabolic syndrome) and emphasizing the importance of monitoring for and treating associated comorbidities. In such cases, the presence of autoantibodies can be helpful. Definitive classification of diabetes as type 1 or type 2 can be delayed, but treatment with insulin should always be initiated.

Beyond our focus on T1D we must acknowledge that T2D accounts for the overwhelming majority of the world’s diabetes. In the U.S. alone, over 25 million people have T2D and more than 7 million of them are unaware of their diagnosis. Characterized by obesity, insulin resistance, dyslipidemia, hypertension, microvascular and macrovascular complications, and a predisposition in African Americans, Hispanics, and Native Americans, T2D indirectly accounts for nearly 1 in every 10 health care dollars.14 Given the tremendous burden T2D places on the U.S. health care system, it is not surprising that patients, health care providers, and researchers often use the nonspecific term diabetes when referring to T2D. However, the practice of referring to T2D as simply diabetes cultivates numerous dangerous misconceptions regarding the etiology, pathophysiology, and treatment of other subtypes of diabetes.

In addition to T1D and T2D, a growing number of Americans are diagnosed with diabetes during pregnancy. Gestational diabetes mellitus (GDM) currently affects ~7% of pregnancies (200,000 cases annually) with 5–10% of affected women diagnosed with T2D after delivery (and some are diagnosed with auto-immune T1D, as well).15 (See chapter 17 for more details.) Even for those who return to normal postpartum glucose metabolism, the 20-year risk of developing T2D approaches 60% once GDM has been diagnosed. Notably, the screening and diagnostic criteria for GDM are unique from other forms of diabetes.

Cystic fibrosis–related diabetes (CFRD) is another subtype of diabetes requiring a unique therapeutic approach. Named for the characteristic cyst and fibrosis formation noted in the exocrine pancreas of affected patients, cystic fibrosis (CF) is an autosomal recessive disorder caused by a mutation in a chloride transporter known as the cystic fibrosis transmembrane conductance regulator. While the primary complication in CF is chronic pulmonary disease, up to 75% of adults with CF develop glucose intolerance and nearly 15% have CFRD. CFRD is unique in that it shares some pathophysiology with both T1D and T2D. Namely, patients with CFRD have a combination of 1) reduced β-cell mass (a feature typically associated with T1D) secondary to the chronic pancreatic inflammation and 2) severe insulin resistance (a feature associated with T2D) as a result of chronic and often subclinical pulmonary infections. Given the unique hypermetabolic state associated with CF, patients with CFRD require high-calorie diets and tight glycemic control to avoid a catabolic state. As such, current CFRD guidelines discourage the use of oral hypoglycemics or calorie restriction and focus instead on the use of insulin to manage glucose abnormalities.16

Finally, clinicians should be aware of the monogenic forms of diabetes. Accounting for only 1–5% of all diabetes cases, monogenic diabetes results from single gene mutations that are inherited in an autosomal dominant fashion. These mutations do not result in insulin resistance or autoimmunity but instead induce diabetes by blunting the capacity of otherwise normal β-cells to release insulin. The two main forms of monogenic diabetes are neonatal diabetes mellitus (NDM) and maturity-onset diabetes of the young (MODY). NDM is a rare condition and occurs in 1/100,000 to 1/500,000 newborns and is often mistaken for T1D due to its association with ketoacidosis and its requirement for insulin therapy. However, T1D is exceedingly rare before 6 months of age and any child diagnosed with T1D before 9 months of age should be screened for monogenic diabetes. There are two forms of NDM, transient NDM, which resolves within weeks to months, and permanent NDM, which is associated with a lifelong dependence on insulin. Testing for known diagnostic mutations allows accurate differentiation of the two subtypes of NDM and emphasizes the need for clinicians to be aware of rare forms of diabetes. In contrast to NDM, MODY is a mild form of diabetes that is commonly, but not always, diagnosed in adulthood. Patients initially diagnosed with T1D who fail to demonstrate autoantibody positivity or who persist with near normal glycemic control on minimal insulin should be screened for MODY. Diagnosis of MODY is especially important as some forms of MODY may be controlled with oral hypoglycemic agents. For a subset of patients, the appropriate diagnosis can mean the difference between a lifetime of insulin injections or effective glycemic control with a sulfonylurea.17

T1-diabetes-sourcebookIf you would like to purchase the full text of The Type 1 Diabetes Sourcebook, Anne Peters, MD, and Lori Laffel, MD, MPH, editors, and Jane Lee Chiang, MD, managing editor, just follow this link. 

12. American Diabetes Association. Standards of medical care in diabetes: 2012. Diabetes Care 35 (Suppl. 1):S11–S63, 2012

13. Vehik K, Cuthbertson D, Boulware D, Beam CA, Rodriguez H, Legault L, Hyytinen M, Rewers MJ, Schatz DA, Krischer JP: Performance of HbA1c as an early diagnostic indicator of type 1 diabetes in children and youth. TEDDY, TRIGR, Diabetes Prevention Trial–Type 1, and Type 1 Diabetes TrialNet Natural History Study Groups. Diabetes Care 35:1821–1825, 2012 14. Economic costs of diabetes in the U.S. in 2007. Diabetes Care 31:596–615, 2008

15. American Diabetes Association. Standards of medical care in diabetes: 2010. Diabetes Care 33 (Suppl. 1):S11–S61, 2010

16. Moran A, Brunzell C, Cohen RC, Katz M, Marshall BC, Onady G, Robinson KA, Sabadosa KA, Stecenko A, Slovis B: Clinical care guidelines for cystic fibrosis–related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society. Diabetes Care 33:2697–2708, 2010

17. Shields BM, McDonald TJ, Ellard S, Campbell MJ, Hyde C, Hattersley AT: The development and validation of a clinical prediction model to determine the probability of MODY in patients with young-onset diabetes. Diabetologia 55:1265–1272, 2012

Used with permission by the American Diabetes Association. (C) 2013 American Diabetes Association.

Please note: We are proud to have Dr. Anne Peters as a member of our Advisory Board member for Diabetes In Control, Inc.