Therapy for Diabetes Mellitus and Related Disorders

Chapter 1

Diagnosis

Silvio E. Inzucchi, MD

DOI: 10.2337/9781580405096.01

Introduction

Diabetes is a chronic multisystem disease of complex and variable pathogenesis, associated with multiple long-term complications, predominately involving the vasculature. Its diagnosis is based on the documentation of hyperglycemia, either through the direct measurement of plasma glucose concentrations or elevations in glycated hemoglobin, a stable measure of long-term systemic glucose concentrations. In some circumstances, symptoms of hyperglycemia also may be used for diagnostic purposes, in conjunction with direct measurement of plasma glucose.

Type 1 diabetes (T1D) occurs from autoimmune destruction of pancreatic β-cells, which are responsible for the secretion of insulin. This typically is encountered in children, teens, and young adults, but the diagnosis of T1D may be made at any age. Because circulating glucose concentrations usually are elevated markedly in this condition, the diagnosis is straightforward. Indeed, the presentation may be fulminant, accompanied by metabolic decompensation (i.e., diabetic ketoacidosis.) In contradistinction, type 2 diabetes (T2D) evolves over many years and has a lengthy asymptomatic period. Its identification therefore is more challenging and relies predominately on the clinical laboratory. This condition is preceded by years of mildly elevated glucose levels that are above the normal range but not high enough to indicate diabetes. This period often is referred to as prediabetes, encompassing stages referred to as impaired fasting glucose or impaired glucose tolerance, each having specific diagnostic criteria. Admittedly, glycemia in the development of T2D is a continuum and the cut points used for its diagnosis remain somewhat arbitrary. Gestational diabetes mellitus (GDM) is a distinct condition that is related to T2D and presents during pregnancy; its identification is discussed in chapter 13.

Diagnosis and Screening for Diabetes

The American Diabetes Association (ADA) recommends the periodic screening of individuals at risk for T2D. Criteria for whom to screen and when are listed in Table 1.1.¹ Before 1997, the diagnosis of diabetes had been defined by the ADA as a fasting plasma glucose (FPG) ≥140 mg/dl (7.8 mmol/l) or a 2-hour PG during a 75-gram oral glucose tolerance test (OGTT) of ≥200 mg/dl (11.1 mmol/l). These criteria were based on recommendations of a widely cited consensus document from the National Diabetes Data Group.² The cut points were selected because they identified a group of individuals who were subsequently at risk for developing symptoms of uncontrolled hyperglycemia. Two decades later, the Expert Committee on the Diagnosis and Classification of Diabetes³ recommended that the criteria be changed to better reflect the impact of hyperglycemia on complication risk. They advised that the diagnostic threshold for FPG be lowered to 126 mg/dl (7.0 mmol/l), since this was the range at which the risk of diabetic retinopathy appeared to initiate. The ADA endorsed this recommendation and has used this arguably more biologically relevant diagnostic criterion ever since. (The OGTT threshold remained unchanged [≥200 mg/dl (11.1 mmol/l) at 2 hours].) Although the OGTT is known to be a more sensitive test, its reproducibility is lower than that of FPG. It is also more inconvenient, cumbersome, and expensive; outside of the research setting, and screening for GDM, it is not widely used in the United States. As a result, the FPG has remained the favored test in the U.S., although the OGTT still is considered the gold standard in many parts of the world.⁴

Table 1.1 Recommendations of the ADA for Screening Asymptomatic Individuals for Diabetes

1. Screen beginning at age 45 years at least every 3 years.

2. Screen at any age and more frequently if overweight (BMI ≥25 kg/m²) and at least one additional risk factor:

• Family history of diabetes (first-degree relative)

• High-risk race or ethnicity (African Americans, Hispanic Americans, Native Americans, Asian Americans, Pacific Islanders)

• A1C ≥5.7%, IFG, or IGT on prior testing

• History of gestational diabetes or delivery of a baby weighing >9 pounds

• Women with polycystic ovary syndrome

• Hypertension (≥140/90 mmHg or therapy for hypertension)

• HDL cholesterol <35 mg/dl (0.90 mmol/l) or a triglyceride level >250 mg/dl (2.82 mmol/l)

• History of cardiovascular disease

• Physical inactivity

• Other clinical conditions associated with insulin resistance (severe obesity, acanthosis nigricans)

Note: ADA = American Diabetes Association; BMI = body mass index; A1C = hemoglobin A1C; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; HDL = high-density lipoprotein.

Source: Adapted from American Diabetes Association. Standards of medical care in diabetes-2014. Diabetes Care 2014;37(Suppl1):S14.

Glycated hemoglobin (or hemoglobin A1C) is used in clinical diabetes care and research studies as a simple method to evaluate the quality of blood glucose control over the previous 2–3 months. The test measures the result of nonenzymatic glycation of the most prevalent protein in blood, namely hemoglobin. Lack of global standardization prevented its use for diagnostic purposes for many years. However, the International Federation of Clinical Chemistry in conjunction with the National Glycohemoglobin Standardization Program established an international reference method and A1C reference standard, the latter based on the assay used in two large clinical trials (Diabetes Control and Complications Trial and U.K. Prospective Diabetes Study) that validated its relationship to clinical outcomes in both T1D and T2D, respectively.⁵ In response to these improvements, the International Expert Committee, in 2009, recommended that the A1C be used for screening and diagnosis purposes, with a cut point of ≥6.5%. The committee actually felt that A1C should become the preferred test for the diagnosis of diabetes. This recommendation was based on the clear demonstration from several large observational studies that the threshold of 6.5% correlated as well with retinopathy risk as did the glucose-based measures (FPG, OGTT). In addition, there were several recognized advantages to A1C versus fasting glucose, including global standardization, the lack of requirement for fasting by the patient, its reflection of long-term glycemia without any perturbations from acute illness, and physical sample stability (see Table 1.2).⁶ While endorsing the committee’s recommendation for use of A1C for diagnosis, the ADA did not adopt its status as the preferred test, acknowledging ongoing uncertainties about A1C testing (see Table 1.3) and the lack of availability in certain parts of the world. Accordingly, as of 2010, the ADA recommends that either FPG, OGTT, or A1C can be used for screening and diagnostic purposes (see Table 1.3), with the choice left to the clinician, depending on patient and visit circumstances.⁷ Per these guidelines, the diagnosis of diabetes is confirmed when two abnormal results of the same test on separate days (e.g., A1C 6.7 and 6.8% or FPG 128 and 131 mg/dl [7.1 and 7.3 mmol/l]) or an abnormal result of two separate tests on the same (or a different) day (e.g., A1C 6.7% and FPG 128 mg/dl [7.1 mmol/l]).¹,⁷

Table 1.2 Advantages and Disadvantages of Three Screening Tests for Diabetes

Note: FPG = fasting plasma glucose; OGTT = oral glucose tolerance test; A1C = hemoglobin A1C; RBC = red blood cell.

Source: Adapted from Sacks DB. A1C versus glucose testing: a comparison. Diabetes Care 2011;34:518.

Table 1.3 Major Diagnostic Criteria for Diabetes and Prediabetes/At-Risk States from ADA and WHO

Note: ADA = American Diabetes Association; WHO = World Health Organization; IFG = impaired fasting glucose; OGTT = oral glucose tolerance test; IGT = impaired glucose tolerance; PG = plasma glucose.

*All plasma glucoses denoted on this table are from venous sampling.

†All tests (except for casual PG in a symptomatic patient) should be repeated and confirmed on a separate day. (ADA allows for A1C to be paired with FPG on same day—if both are in the diabetic range, the diagnosis is confirmed.)

Source: Adapted from American Diabetes Association. Standards of medical care in diabetes-2013. Diabetes Care 2013;36(Suppl.1):S13.

In spite of its advantages, A1C testing has several drawbacks,⁸ including falsely high or falsely low values in some assays in certain hemoglobinopathies (e.g., thalassemia) and in any hematological condition characterized by increased red blood cell turnover (e.g., hemolytic anemias; see Table 1.2). Lower values than would be anticipated by ambient glucose levels also are seen in patients with chronic kidney disease (CKD), especially those on erythropoietin analog therapy for CKD-associated anemia. In contrast, iron deficiency and other states characterized by decreased red cell turnover may result in falsely elevated A1C levels. Moreover, inconsistencies in measured A1C levels between various ethnic and racial groups suggest some influence of genetic factors on intracellular glycation.⁹ A glycation gap has been described by several groups as the phenomenon of significantly different A1C levels in patients with similar ambient glycemia.¹⁰,¹¹ Because the glycation reaction is nonenzymatic and should be relatively consistent from individual to individual exposed to similar glucose concentrations, the gap may stem from differential access of glucose to the intracellular compartment or from variations in red cell life span. These caveats must be considered when interpreting A1C levels for diagnosing (and also for managing) diabetes.

On the basis of these disadvantages, since the International Expert Committee and ADA recommendations were released, several investigative groups have called into question the appropriateness of A1C testing for diagnosis.¹²–¹⁷ Several studies have compared the diagnostic accuracy of A1C to traditional glucose-based criteria. Most have demonstrated that A1C testing identifies fewer patients with diabetes than either FPG or OGTT. In addition, most studies have revealed significant discrepancies among these various measures with regard to which individuals are identified with diabetes. As in prior comparison between FPG and OGTT, when both FPG and A1C are tested, three separate patient groups are identified:

• Those who are diagnosed with diabetes using either measure (i.e., have both FPG ≥126 mg/dl and A1C ≥6.5%)

• Those with an abnormal FPG only (i.e., FPG ≥126 mg/dl but with A1C <6.5%)

• Those with abnormal A1C only (i.e., with A1C ≥6.5% but with FPG <126 mg/dl)

The lack of overlap in individuals identified by these now commonly used measures is somewhat disconcerting and the implications of being diagnosed by one but not the other are not entirely clear. It is interesting to note that such discordance between FPG and OGTT has not been a well-recognized clinical problem in the U.S. because of the uncommon use of the latter for diagnosis. Given the ease with which FPG and A1C are measured, however, and the fact that both tests frequently are encountered in clinical practice, practitioners now confront discordant data sets. Lack of agreement between tests may stem from inherent measurement variability, from change in glycemic status over time, or from the fact that FPG and A1C (as well as post-OGTT challenge glucose) actually assess different physiological processes. Admittedly, in most circumstances when the tests are discordant, the values are near the margins of the abnormal thresholds, and these differences therefore are less relevant clinically.

Several investigators have reported that a greater proportion of African Americans make up the A1C-only group, and others have found an A1C level in African Americans 0.2–0.4% higher than in other racial groups.⁹,¹⁵,¹⁶ It is not known whether this pattern results from higher postprandial glucose levels in this group or fundamental (i.e., genetically determined) differences in glycation rates or red cell turnover. With increasing use of A1C testing for diagnosis, these differences between groups are important to recognize. Some have proposed race-based A1C cut points for this purpose, although this may be difficult to implement.¹⁸

The main concern with each of these studies is their definition of the glucose-based tests as gold standards. Because FPG, 2-hour PG, and A1C each correlate equally well with the risk of retinal microvascular complications, it remains arguable which measure is truly best. To determine this would require a large, long-term, prospective study, which currently is not available. A1C actually may yield a closer relationship to complications because one theory as to the development of microvascular disease is the glycation of cellular proteins. It may be proposed logically that A1C is the optimal diagnostic test because it may directly reflect an individual’s susceptibility to the pernicious effects of hyperglycemia. Preliminary data would suggest that those identified as having diabetes by A1C (which represents and integrates both fasting and postprandial glucose over many weeks), might be better predictor of cardiovascular complications, but these data require confirmation.¹⁹ Clearly, more research is needed to better characterize those individuals whose glycemic status is categorized differently by the available tests (i.e., FPG, OGTT, and A1C).

The ADA currently recommends that when two tests are available (e.g., FPG and A1C) and their results are discordant (e.g., FPG 130 mg/dl but A1C 6.3% or FPG 124 mg/dl but A1C 6.7%), clinicians should default to the most abnormal test (if it is repeated and confirmed). Repeat testing should be performed as soon as is feasible.⁷

Identifying At-Risk States

As β-cell function begins to decline and is no longer able to maintain normal glucose concentrations in the face of insulin resistance, T2D is preceded by an asymptomatic state of mild but usually progressive hyperglycemia. The only recognized at-risk category for T2D before 1997 was referred to as impaired glucose tolerance (or IGT). It was identified during a 75-gram OGTT when the 2-hour PG fell between 140 and 199 mg/dl (7.8 and 11.1 mmol/l). When the diabetes diagnostic criteria were revised in 1997, there was a need to develop an analogous criterion for an equally impaired and at-risk level based on FPG. Thus, the category of impaired fasting glucose (or IFG) emerged, defined by a fasting glucose substantially above (>110 mg/dl [6.1 mmol/l]) the normal range of 70–99 mg/dl (3.9–5.5 mmol/l) but lower than the diagnostic threshold for diabetes itself (126 mg/dl [7.0 mmol/l]). In 2003, with the intent to approximate the proportion of the population who might be identified at risk by either OGTT or FPG, the Expert Committee recommended reducing the lower bounds of this diagnostic category to 100 mg/dl (5.6 mmol/l).²⁰ This recommendation was incorporated by the ADA, although the World Health Organization, which had agreed with the revised criteria of 1997, continues to use the 110 mg/dl (6.1 mmol/l) threshold to define IFG (see Table 1.3).

Both these categories sometimes are referred to as prediabetes, denoting their underlying purpose, that is, to identify those at risk for future T2D. Longitudinal studies show that people with either IGT or IFG proceed, without intervention, to develop diabetes at a rate of ~5–10% per year, with those at the higher ends of the glycemic ranges at the greatest risk. Notably, as with the diagnosis of diabetes using different measures, some individuals are identified as having IFG but not IGT, and vice versa, and some individuals fall into both abnormal categories. The last group appears to include individuals who are at the highest risk for developing diabetes. The risk in those with isolated IFG (i.e., without IGT) and isolated IGT (i.e., without IFG) is similar in most analyses.²¹ Because the proportion of patients with IGT tends to be greater than IFG in most populations (particularly in women), the former category represents a proportionately greater number of people at risk. Although both prediabetic states carry with them an increased risk of mortality, particularly cardiovascular mortality, IGT has been demonstrated to be a more robust marker for this specific adverse outcome, perhaps because it is more tightly aligned to insulin resistance, which independently has been associated with incident cardiovascular disease.²¹

The 2009 International Expert Committee report on using A1C for diabetes diagnosis underscored the continuum of risk for diabetes with each glycemic measure.⁶ Accordingly, the committee elected to actually not identify an equivalent intermediate glycemic category for A1C as it already had been defined for both FPG and OGTT. It did note, however, that people with levels above the laboratory normal range but below the diagnostic cut point for diabetes (i.e., 6.0 to <6.5%) were at very high risk of developing diabetes—more than 10 times that of individuals with lower levels.

In considering these recommendations, the ADA observed that this high (but not quite diabetic) A1C range did not adequately identify a large enough number of individuals who would be categorized as having IFG or IGT by the prevailing conventional criteria. In fact, several prospective studies have demonstrated that the relative incidence of diabetes in those with A1C levels in the range of 5.5 to 6.0% is substantially increased as well, with relative risks three to eight times that of the general U.S. population—a risk not dissimilar to individuals with more mild degrees of IFG or IGT. Data from the National Health and Nutrition Examination Survey (NHANES) indicate that the A1C value that most accurately identifies people known to have IFG or IGT actually falls somewhere between 5.5 and 6.0%.²² In addition, in the Diabetes Prevention Program (DPP), the clinical trial that confirmed the value of identifying and treating patients with prediabetes, the mean baseline A1C was 5.9 ± 0.5%.²³ This finding indicates that preventive interventions are effective in those with A1C levels both <5.9 and >5.9%. When it revised its criteria to incorporate use of A1C in 2010, the ADA felt that any cut point for prediabetes needed to balance failing to identify those who are destined to develop diabetes with the costs of resource expenditures on falsely identifying individuals who will not. Receiver operating curve analyses of nationally representative U.S. data (NHANES 1999–2006) indicate that an A1C value of 5.7% has modest sensitivity (39–45%) but high specificity (81–91%) to identify cases of IFG (FPG >100 mg/dl [5.6 mmol/l]) or IGT (R.T. Ackerman, personal communication). Another study suggested than an A1C of 5.7% is associated with similar diabetes risk to the high-risk participants in the DPP.²⁴ After some deliberation, the ADA decided that a reasonable A1C range to identify individuals at risk for diabetes (i.e., prediabetes) would be 5.7 to 6.4%.⁷ As with other glycemic measures, however, those with the A1C levels closest to the diabetic threshold are at the highest risk. Accordingly, prevention interventions and follow-up should be most aggressive for those with A1C >6.0%. Other risk factors, including obesity and family history, should be incorporated into this risk assessment as well. Subsequent economic analysis involving nondiabetic patients in the NHANES has suggested that interventions prompted by the ADA’s A1C range for prediabetes would be cost-effective.²⁵

Discordant results also may be obtained in the evaluation of prediabetes when two different measures are available. In a recent NHANES analysis, the crude prevalence of prediabetes in U.S. adults >18 years of age was found to be 14.2% for A1C 5.7–6.4%, 26.2% for IFG (≥100 mg/dl [5.6 mmol/l]), and 13.7% for IGT. Not unexpectedly, there was considerable discordance between the various definitions of prediabetes. Among those with IGT, 58.2% had IFG and 32.3% had an A1C between 5.7 and 6.4%; 67.1% had the combination of either IFG or A1C 5.7–6.4%.²⁶ It remains unknown whether prediabetes by FPG but not by A1C (or vice versa) identifies a group at lower (or higher) risk for developing diabetes. Preliminary data suggest that using both tests (i.e., A1C and FPG) to reveal at-risk states may increase the diagnostic yield substantially versus one or the other test. Similar reports concerning the suboptimal performance of A1C to identify at-risk individuals (if compared with glucose-based testing as the gold standard) also have emerged.¹⁶,²⁷,²⁸ Here, the challenges versus FPG (and OGTT) are accentuated by the larger number of individuals who make up these mildly abnormal metabolic states and the inherent imprecision of distinguishing a normal from a mildly increased glycemia. The ADA does not prefer any single test in the evaluation of prediabetes and has no recommendations as to which test may be favored for patient categorization when the results are discordant. Because diabetes risk as determined by any measure is actually on a gradual continuum, any differences between testing results are likely to be less clinically relevant.

A proposed algorithm for diabetes screening is presented in Figure 1.1.

Figure 1.1—Suggested algorithm for diabetes screening.

From: Inzucchi SE. Clinical practice. Diagnosis of diabetes. N Engl J Med 2012;367(6):548. Reprinted with permission.

Conclusion

Patients with risk factors for diabetes should be screened periodically for diabetes. Three screening tests are now endorsed by the ADA. Which test to use is dependent on several factors, including convenience, availability, cost, and specific patient characteristics that might invalidate a certain measure. Abnormal values generally should be repeated and confirmed on a different day, unless two abnormal tests (e.g., FPG and A1C) already are available from the same day. In certain high-risk individuals, combined A1C and FPG testing is an option. Patients identified as having diabetes should be treated following recent guidelines.²⁹ Patients with levels above the normal but still not in diagnostic range are at risk for developing progressive hyperglycemia. Recommendations for these individuals to prevent future diabetes mainly include lifestyle changes.³⁰

When testing results are discordant, diabetes diagnosis should default to the most abnormal test, if it is repeated and confirmed. In these circumstances, the nondiagnostic test usually hovers near the abnormal range, adding confidence in assigning the diagnosis of diabetes. When test results are widely disparate, however (e.g., FPG 128 mg/dl [7.1 mmmol/l] but A1C 5.3% or A1C 6.9% but FPG 83 mg/dl [4.6 mmol/l]), one of the measures may be misleading or unreliable. This may result from the effects of acute illness on glycemia or, potentially, an aberrant glycation pattern in a specific patient. In such a circumstance, repeat testing is mandatory before diagnostic assignment. Consideration should be given to conducting an OGTT to better clarify the patient’s actual status. Recommendations have not addressed the implications of discordant values for prediabetes, although it is reasonable to recommend simple, healthy lifestyle changes in any patient with any test in this range, unless it is clearly an outlier. Evaluation of patients at risk also should incorporate a global risk factor assessment for both diabetes and cardiovascular disease. Importantly, screening for and counseling about the risk of diabetes always should be in the realistic context of the patient’s comorbidities, life expectancy, personal capacity to engage in lifestyle change, and overall health goals.

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Chapter 2

Classification of Diabetes

M. Sue Kirkman, MD

Guillermo E. Umpierrez, MD, CDE

DOI: 10.2337/9781580405096.02

Diabetes mellitus includes a group of metabolic diseases leading to hyperglycemia, the sine qua non of the disorder. The name emphasizes the pathologic signs and symptoms of advanced hyperglycemia: diabetes, from the Ancient Greek word for a passer-through or siphon, eloquently describes polydipsia and polyuria; mellitus, Latin for honey-sweet, was added in the 1600s to connote that the urine from people with diabetes tasted sweet. The primary metabolic disorders of diabetes stem from deficient or abnormal secretion of insulin or impairment in the hormone’s action.

The majority of prevalent cases of diabetes fall into two major classes: type 1 diabetes (T1D) and type 2 diabetes (T2D), which have distinct pathophysiologies. Gestational diabetes, which might be considered a forme fruste of T2D, occurs during the insulin-resistant phase of later pregnancy in predisposed women. Myriad other types of diabetes have been identified, including monogenic forms, cystic-fibrosis–related diabetes (CFRD), diabetes due to pancreatic damage or resection, and drug-induced diabetes. Classifying an individual patient’s type of diabetes is not always straightforward, as will be discussed, and there is likely more overlap and ambiguity among the types than classically has been taught.

Type 1 Diabetes

T1D is characterized by progressive destruction of the insulin-producing β-cells of the pancreatic islets, leading to severe insulin deficiency or absence. In its classic form (type 1A diabetes), the β-cell destruction is autoimmune in nature. More rarely, patients may develop severe insulin deficiency without evidence of autoimmunity (type 1B diabetes). T1D accounts for ~5% of cases of diagnosed diabetes in the U.S. It is more common in Caucasians than in other ethnic groups and has equal incidence between sexes. Its onset occurs most often during childhood or adolescence, but the disease can occur at any age; incidence in adulthood accounts for a significant, but not precisely known, proportion of new cases of T1D. This fact plus the reality in most of the world that children with T1D grow into adulthood means that most people with T1D are adults.

The pathophysiology of type 1A diabetes involves a complex and as yet incompletely understood interplay between genetic risk and environmental triggers to autoimmunity. Although 90% of cases occur in the absence of family history, relatives of those with T1D are at substantially higher risk of developing the disease than those in the general population. The strongest genetic determinants are those in the human leukocyte antigen (HLA) complex on chromosome 6; specifically, two HLA class II haplotypes (DR3 and DR4, DQA0302/501 and DQB0301/0201). More than 90% of children with T1D carry one or both haplotypes. At least one of the high-risk DR haplotypes, however, is found in ~20% of the Caucasian population, and <5% of population with one or both haplotypes develops T1D. Protective haplotypes also have been discovered, particularly the DR haplotype DQB1*0602 gene, which is found in <1% of those with T1D but in 20% of the Caucasian population without diabetes. Weaker genetic associations include the protein tyrosine phosphatase gene PTPN22 on chromosome 1 and the insulin gene on chromosome 11. Genetic predisposition alone is clearly not sufficient to lead to T1D. The concordance rate in identical twins is only 50–65%, and the age of onset between twins can vary by decades, suggesting that one or more environmental factors must combine with genetic risk to trigger the disease.

Autoimmunity is a central feature of the pathogenesis of T1D. Antibodies to islet cells or specific islet antigens are found in most patients before and at the time of diagnosis, while in relatives of index cases, islet antibodies are strong predictors of future development of the disease. Validated antibodies include those to islet cells (ICA), glutamic acid decarboxylase (GAD), tyrosine phosphatase (IA-2), insulin (IAA), or the zinc transporter (ZnT8). It is clear, however, that the antibodies themselves are not pathologic and that cellular immunity is the cause of islet destruction. Histologic examination of pancreatic specimens from people with T1D demonstrates infiltration of lymphocytes (insulitis) with the absence of β-cells and distorted islet architecture. This seems to be the result of activation of CD8 T-cells with specificity for β-cell destruction. β-Cell death results in the release of intracellular antigens accessed by CD4 T-cells and mature B-lymphocytes, with the latter producing the islet-specific antibodies as a result of exposure to autoantigens.

Potential environmental triggers to islet autoimmunity in those with genetic risk have been studied widely, but as yet no clear candidate has been found. Proposed triggers include infections, early introduction of specific dietary components (cow’s milk, gluten), vitamin D deficiency, nitrosamine compounds, vaccines, and many others. Conflicting evidence has been found for most. The increased incidence of T1D along with that of asthma and allergies has led to the hygiene hypothesis, which suggests that reduced exposure to infectious agents early in life may shift immune pathways toward autoimmunity or allergy.

Classifying a patient with newly diagnosed diabetes as having T1D is sometimes, but not always, straightforward. A classic presentation would be a lean child presenting with a few days or weeks of hyperglycemic symptoms that then progress to diabetic ketoacidosis (DKA). The disease can present at any age, however, and many adults have a more indolent presentation. Some adults have mild hyperglycemia that may respond to oral agents for months or even several years before progressing to absolute insulin deficiency requiring replacement, a condition referred to as latent autoimmune diabetes of adults (LADA). The epidemic of overweight and obesity in the industrial world has not spared those at risk for T1D, so new-onset T1D in an overweight child or adult can be confused with T2D. Finally, as will be discussed, ketoacidosis (even unprovoked) can occur in patients who otherwise phenotypically have T2D. Autoantibody testing may be helpful when the type of diabetes is unclear; patients with one or more islet-directed antibodies are likely to have T1D.

Type 2 Diabetes

T2D is the most prevalent form of diabetes, accounting for ~90–95% of all cases. It is a heterogeneous disease characterized by peripheral insulin resistance, impaired regulation of hepatic glucose production, and declining b-cell function, eventually leading to b-cell failure. Insulin resistance is present in people predisposed to T2D before the onset of hyperglycemia, which may suggest that insulin resistance is the primary abnormality that is responsible for the development of diabetes. Defective β-cell function is also present before the onset of T2D in subjects with prediabetes and impaired glucose tolerance (IGT), and in first-degree relatives of people with diabetes who have normal plasma glucose concentrations. Therefore, although there is still controversy on the primary defect in T2D, both defects are present in essentially all subjects with the disorder, often from an early preclinical stage.

T2D is caused by complex interactions between adverse environmental and genetic factors. Several risk factors include common, easily measurable phenotypic features such as overweight and obesity, hypertension, elevated triglyceride levels, and a sedentary lifestyle. The prevalence of T2D increases with age; however, the prevalence in children is rising. Between 8 and 45% of children with newly diagnosed diabetes have T2D, in particular in minority adolescent populations compared with non-Hispanic whites. Most patients with this form of diabetes are obese, and obesity itself causes some degree of insulin resistance. Patients who are not obese by traditional weight criteria may have an increased percentage of body fat distributed predominantly in the abdominal region; this phenomenon is common in many Asian populations. T2D prevalence is higher in non-Caucasian populations. It is estimated that African Americans and Hispanic Americans are 1.5–1.7 and 2 times more likely to have diabetes, respectively, compared with non-Hispanic whites.

Epidemiological, observational, and experimental evidence suggests the role of genes in development of T2D, including ethnic variation in prevalence, a concordance rate of 60–90% in identical twins, and strong familial aggregation. Multiple genes that are associated with the risk of developing diabetes or the risk of diabetes complications have been identified by candidate gene analysis and genome-wide scanning. With the exception of specific monogenic forms of the disease that might result from defects largely confined to the pathways that regulate insulin action in muscle, liver, and fat or defects in insulin secretory function in the pancreatic β-cell, there is an emerging consensus that the common forms of T2D are polygenic in nature and are caused by a combination of insulin resistance, abnormal insulin secretion, and other factors. Whole genome scans have identified numerous regions on many different chromosomes that are linked to diabetes. The contribution to disease risk by any one of these genetic factors is small (typically <1.5-fold increased risk) and is less strong than environmental factors.

The clinical presentation of T2D is heterogeneous, with a wide range in age at onset, severity of associated hyperglycemia, and degree of obesity. Frequently, this form of diabetes goes undiagnosed for many years because the hyperglycemia develops gradually and at earlier stages often is not severe enough for the patient to notice any of the classic symptoms of diabetes. On the other hand, some patients present with severe hyperglycemia, even with DKA. DKA is rare in patients with established T2D; when seen, it usually arises in association with the stress, trauma, or another illness such as infection. In recent years, however, it has been well described that some children and adult subjects with T2D can debut with DKA without precipitating cause.¹–³ At presentation, they have markedly impaired insulin secretion and insulin action.³,⁴ Intensified diabetes management results in significant improvement in β-cell function and insulin sensitivity sufficient to allow discontinuation of insulin therapy within a few months of follow-up.⁵,⁶ This clinical presentation has been reported primarily in Africans and African Americans, but also in other ethnic groups, and has been referred to in the literature as idiopathic T1D (type 1B), atypical diabetes mellitus, type 1.5 diabetes, and more recently as ketosis-prone T2D. Despite their presentation in DKA, the majority of these patients appear to have T2D, given the presence of obesity, a strong family history of diabetes, measurable insulin secretion, and a low prevalence of autoimmune markers of β-cell destruction.

Patients with T2D often can be managed effectively with lifestyle modifications or oral hypoglycemic agents. At least initially, and for many people throughout their lifetime, these individuals do not need insulin treatment to survive. The progressive nature of β-cell failure that characterizes the disease means that many patients eventually will require insulin replacement therapy to manage hyperglycemia.

Gestational Diabetes

For many years, gestational diabetes mellitus (GDM) was defined as any degree of glucose intolerance with onset or first recognition during pregnancy.¹ Although most cases resolved with delivery, the definition applied whether or not the condition persisted after pregnancy and did not exclude the possibility that unrecognized T2D or other forms of diabetes may have antedated or begun concomitantly with the pregnancy. This definition facilitated a uniform strategy for detection and classification of GDM, but its limitations were recognized for many years. As the ongoing epidemic of obesity and diabetes has led to more T2D in women of childbearing age, the number of pregnant women with previously undiagnosed T2D has increased.

After deliberations in 2008–2009, the International Association of Diabetes and Pregnancy Study Groups (IADPSG) recommended that high-risk women found to have diabetes at their initial prenatal visit, using standard criteria, receive a diagnosis of overt, not gestational, diabetes, and that GDM be used to describe hyperglycemia that develops during midpregnancy. The American Diabetes Association (ADA) subsequently promulgated this same recommendation. Approximately 7% of all pregnancies (ranging from 1 to 14%, depending on the population studied and the diagnostic tests employed) are complicated by GDM, resulting in >200,000 cases annually in the U.S.

Pregnancy normally is marked by progressive, significant insulin resistance that begins after ~20 weeks of gestation. The insulin resistance is primarily thought to be due to anti-insulin hormones secreted by the placenta, as it resolves rapidly after delivery. In normal women, pancreatic β-cells increase secretion of insulin to compensate for this insulin resistance, preserving normoglycemia. Elegant studies of women who develop GDM have shown that most have chronic insulin resistance that predates (and continues after) pregnancy. These women are able to increase insulin secretion in response to the additional acquired insulin resistance of pregnancy, but along an insulin sensitivity–secretion curve that is ~50% lower than in pregnant women without GDM.

A history of GDM is a strong risk factor for later development of T2D, with roughly a 50% risk by 10 years after the index pregnancy and long-term risk as high as 70%. Risk factors for GDM overlap with those for T2D (obesity, older age, non-Caucasian ethnicity), and progressive β-cell function has been found in Hispanic women who develop hyperglycemia after a GDM pregnancy. Taken together, these data suggest that GDM could be considered incipient T2D that temporarily was unmasked during the metabolic stress of pregnancy.

How to diagnose GDM (and therefore classify a woman as having this form of diabetes) is controversial. Five decades ago, the first diagnostic criteria were developed to identify women at high risk of later development of T2D. With the recognition that GDM was associated with adverse maternal, fetal, and neonatal outcomes, screening and diagnosis evolved to identify high-risk pregnancies. There was no worldwide consensus on the means of testing or glycemic cut points. The multinational Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study demonstrated a linear relationship between multiple pregnancy outcomes and the fasting, 1-hour, and 2-hour glucose values during a 75-gram oral glucose tolerance test (OGTT) performed at 24–28 weeks of gestation. The lack of any clear cut points above which rates of adverse outcomes accelerated markedly meant that a dichotomous GDM diagnosis was somewhat arbitrary.

A working group assembled by the IADPSG looked closely at the HAPO data and proposed that GDM be diagnosed when any one of the three OGTT values was above the point at which rates of adverse perinatal outcomes (particularly macrosomia and neonatal adiposity) were 1.75 times higher than adverse outcome rates at the mean glucose values for women in the HAPO study. Use of the IADPSG criteria subsequently was adopted by a number of countries. The IADPSG criteria, however, would identify significantly more pregnancies as being affected by GDM, and there is ongoing controversy as to whether treatment of mild hyperglycemia in pregnancy significantly reduces major adverse outcomes. Many countries have not changed from prior criteria, and in the U.S. both the American College of Obstetrics and Gynecology and a National Institutes of Health consensus panel recommended continuing with older diagnostic criteria. The ADA, citing the uncertainty in the field, currently recommends that either the IADPSG or prior methods and criteria be used for GDM screening and diagnosis.

Other Types of Diabetes

The other category includes many disorders associated with hyperglycemia, although most are rare. A summary of several broad classes follows.

Monogenic Diabetes

Genetic Defects of the β-Cell

Several forms of diabetes are associated with monogenetic defects in β-cell function. These forms of diabetes are inherited in an autosomal dominant fashion, usually are characterized by onset of hyperglycemia at an early age (generally <25 years old), and therefore are referred to as maturity-onset diabetes of the young (MODY). Abnormalities at six genetic loci on different chromosomes have been identified to date. The most common form is associated with mutations on chromosome 12 in a hepatic transcription factor referred to as hepatocyte nuclear factor (HNF)-1α. A second form is associated with mutations in the glucokinase gene on chromosome 7p and results in a defective glucokinase molecule, the glucose sensor for the β-cell. Less common forms result from mutations in other transcription factors, including HNF-4α, HNF-1β, insulin promoter factor (IPF)-1, and NeuroD1.

Most children with diabetes diagnosed in the first 6 months of life have monogenic diabetes and do not have autoimmune T1D. This so-called neonatal diabetes can be either transient or permanent. The most common genetic defect causing transient disease is a defect on ZAC/HYAMI imprinting, whereas permanent neonatal diabetes is most commonly a defect in the gene encoding the Kir6.2 subunit of the β-cell KATP channel. Diagnosing the latter has implications, as such children can be well managed with sulfonylureas.

Genetic Defects in Insulin Action

Uncommonly, diabetes results from genetically determined abnormalities of insulin action. The metabolic abnormalities associated with mutations of the insulin receptor may range from hyperinsulinemia and modest hyperglycemia to severe diabetes. Some individuals with these mutations have acanthosis nigricans, and women may have virilization and cystic ovaries. Leprechaunism and the Rabson-Mendenhall syndrome are two pediatric syndromes with mutations in the insulin receptor gene that cause extreme insulin resistance. The former has characteristic facial features and is usually fatal in infancy, while the latter is associated with abnormalities of teeth and nails and pineal gland hyperplasia. Alterations in the structure and function of the insulin receptor cannot be demonstrated in patients with insulin-resistant lipoatrophic diabetes, implying that defects must reside in postreceptor signal transduction pathways.

Diseases of the Exocrine Pancreas

Any process that diffusely injures the pancreas can cause diabetes. Acquired processes include pancreatitis, trauma, infection, pancreatectomy, and pancreatic carcinoma. With the exception of the last example, common wisdom is that damage to the pancreas must be extensive for diabetes to occur. Adenocarcinomas involving only a small portion of the pancreas have been associated with diabetes, implying mechanisms beyond just reduction in β-cell mass. Genetic defects such as cystic fibrosis and hemochromatosis also can damage β-cells and impair insulin secretion. CFRD is common in teens and adults with cystic fibrosis. It shares phenotypic features with both T1D and T2D, with both β-cell dysfunction or loss and insulin resistance, perhaps related to chronic inflammation.

Endocrinopathies

Excess amounts of these insulin-antagonizing hormones (e.g., acromegaly, Cushing’s syndrome, glucagonoma, pheochromocytoma) can cause diabetes. This generally occurs in individuals with preexisting defects in insulin secretion, and hyperglycemia typically resolves when the hormone excess is resolved. Somatostatinomas and aldosteronoma-induced hypokalemia can cause diabetes, at least in part, by inhibiting insulin secretion. Hyperglycemia generally resolves after successful removal of the tumor.

Drug- or Chemical-Induced Diabetes

Rarely encountered toxins such as the rat poison Vacor and administration of intravenous pentamidine can permanently destroy β-cells. High-dose thiazide diuretics are associated with the development of T2D, perhaps due to hypokalemia, but lower doses used in current practice generally do not. In clinical practice, common causes of drug-induced hyperglycemia include glucocorticoids, nicotinic acid, and atypical antipsychotics. Patients who develop hyperglycemia on these drugs often have risk factors for T2D. Like GDM, this may represent unmasking of latent T2D. Patients receiving α-interferon can develop autoimmune diseases of the thyroid and other organs, including severely insulin-deficient diabetes associated with islet cell antibodies. The use of statins has been associated with development of T2D, especially in those with underlying prediabetes, through unknown mechanisms.

Uncommon Forms of Immune-Mediated Diabetes

The stiff-man syndrome is an autoimmune disorder of the central nervous system characterized by stiffness of the axial muscles with painful spasms. Patients usually have high titers of the glutamic acid decarboxylase (GAD) autoantibodies, and approximately one-third will develop diabetes. Anti-insulin receptor antibodies, occasionally found in patients with lupus or other autoimmune diseases, can cause diabetes by binding to the insulin receptor, blocking the binding of insulin to its receptor in target tissues. In some cases, however, these antibodies can act as an insulin agonist and cause hypoglycemia.

Other Genetic Syndromes Sometimes Associated with Diabetes

Genetic syndromes that are accompanied by an increased incidence of diabetes include the chromosomal abnormalities Down syndrome, Klinefelter syndrome, and Turner syndrome. Wolfram syndrome is an autosomal recessive disorder characterized by insulin-deficient diabetes, absence of β-cells at autopsy, diabetes insipidus, hypogonadism, optic atrophy, and neural deafness.

Conclusion

Although there are numerous causes of diabetes, the majority of cases are either T1D or T2D. Nevertheless, the varying clinical onset of even the common types of diabetes means that classification is not always straightforward. Features that might prompt consideration of alternative classification of a patient include atypical features in the age of onset, family history, body weight, or response to conventional therapies for the presumed type of diabetes.

References

1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2014;37(Suppl 1):S81–S90.

2. Centers for Disease Control and Prevention. National Diabetes Fact Sheet: National Estimates and General Information on Diabetes and Prediabetes in the United States, 2011. Atlanta, GA, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2011.

3. Haller MJ. Type 1 diabetes in the 21st century: a review of the landscape. In Type 1 Diabetes Sourcebook. Peters A, Laffel L., Eds. Alexandria, VA, American Diabetes Association, 2013.

4. Umpierrez GE, Smiley D, Kitabchi AE. Narrative review: ketosis-prone type 2 diabetes mellitus. Ann Intern Med 2006;144(5):350–357.

5. Buchanan TA, Xiang AH. Gestational diabetes mellitus. J Clin Invest 2005;115:485–491.

6. American College of Obstetrics and Gynecology, Committee on Obstetric Practice. ACOG Committee Opinion No. 435: postpartum screening for abnormal glucose tolerance in women who had gestational diabetes mellitus. Obstet Gynecol 2009;113:1419–1421.

Chapter 3

Role of Diabetes Education in Patient Management

Martha M. Funnell, MS, RN, CDE

Gretchen A. Piatt, MPH, PhD

Robert M. Anderson, EdD

DOI: 10.2337/9781580405096.03

Recent advances in knowledge, therapies, and technology have greatly enhanced our ability to effectively care for patients with diabetes. In spite of these advances, people with diabetes still experience less-than-optimal blood glucose, blood pressure, and cholesterol levels as well as acute and long-term complications. Health care professionals often are frustrated by their patients’ inability to make changes in their behavior, and people with diabetes sometimes feel that they are just a blood sugar number to their providers. Clearly, there is a gap between the promise and the reality of diabetes care. One of the keys to closing the gap is effective self-management.

Diabetes Self-Management

Diabetes self-management refers to all of the activities in which patients engage to care for their illness; promote health; augment physical, social, and emotional resources; and prevent long- and short-term effects from diabetes. Patient education is the essential first step in becoming an effective self-manager. Traditional views of diabetes self-management education (DSME) were based on information transfer with the goal of compliance or adherence. On the basis of the current evidence, DSME has evolved to recognize the right and responsibility of patients to make decisions and set self-selected goals that make sense within the context of their lives. There is also increasing recognition of the need to address psychosocial issues, such as diabetes-related distress and depression, as a component of DSME because of their prevalence, impact on glycemic outcomes, and self-management behaviors. Therefore, the current goals of DSME are to help patients make informed decisions and then to evaluate the costs and benefits of those choices in order to cope with the self-management demands of a complex chronic illness such as diabetes.

Although patients need a comprehensive understanding of diabetes, its effect on their lives, and how to change behavior, it is unreasonable to think that a one-time educational intervention is adequate to manage diabetes for a lifetime. Diabetes self-management support (DSMS) is the ongoing assistance that patients need from health care professionals, the community, family and friends, and other relevant organizations to make and sustain behavioral changes and cope with diabetes. DSMS incorporates the provision of the needed emotional, behavioral, clinical, psychosocial, and tangible resources to enable patients to manage their illness effectively. Strategies for providing ongoing self-management support include the following:

• Assess patient self-management knowledge, behaviors, confidence, coping skills, and barriers.

• Incorporate effective interventions and ongoing support from family, peers, and professionals.

• Incorporate strategies including effective communication to help patients cope with the distress that often results from the many physical, self-management, and emotional demands of living with diabetes.

• Ensure collaborative care planning and problem solving with a team of health care professionals.

• Redesign practice patterns and health care systems to be better able to provide continuing education and support for patients over a lifetime of a chronic illness.

Diabetes Self-Management Education and Support

Because of the growing body of evidence about the importance of ongoing self-management support following DSME, the title of the national standards was changed in the most recent revision to the National Standards for Diabetes Self-Management Education and Support (DSME/S). These standards were developed by key diabetes organizations based on a review of the evidence.

Recent reviews and meta-analysis indicate that DSME/S is effective for improving metabolic outcomes, enhancing quality of life and healthy coping, increasing use of primary and preventive services, and reducing diabetes-related costs, at least in the short term. More time spent with the educator increases the effect. In addition, DSME/S interventions that integrate the physiological, behavioral, and psychosocial aspects of diabetes are more effective than programs that focus strictly on knowledge.

DSME is primarily available through outpatient group programs often offered by hospitals or community-based organizations. Programs that achieve American Diabetes Association (ADA) Recognition or American Association of Diabetes Educators Accreditation by meeting standards for process, structure, and outcomes are eligible to bill for education services and receive reimbursement from the Centers for Medicare and Medicaid Services and other payers. Both ADA Recognition and AADE Accreditation certify that the program both meets quality standards and can be reimbursed for services.

Provision of Diabetes Self-Management Education and Support

Essential content areas have been defined in the National Standards for DSME/S (Table 3.1). These content areas were written in behavioral terms to maximize creativity on the part of the educator and to allow programs to match instruction and methodology to the culture, literacy, and other needs of their target populations. The particular content areas provided to an individual patient are based on an assessment of needs, personal priorities, learning style, cultural influences, health literacy, and coping style. Evaluation of the effectiveness of DSME/S is based on patient achievement of self-selected behavior change goals, metabolic measures, and psychosocial and other outcomes.

Table 3.1 Recommended DSME/S Content Areas

• Describing the diabetes disease process and treatment options

• Incorporating nutritional management into lifestyle

• Incorporating physical activity into lifestyle

• Using medications safely and for maximum therapeutic effectiveness

• Monitoring blood glucose and other parameters and interpreting and using the results for self-management decision making

• Preventing, detecting, and treating acute complications

• Preventing, detecting, and treating chronic complications

• Developing personal strategies to address psychosocial issues and concerns

Any health care professional who provides diabetes education is a diabetes educator. A certified diabetes educator is a health care professional who has specialized knowledge and practical experience in diabetes education and who has passed an examination developed by the National Certification Board for Diabetes Education. Board-Certified–Advanced Diabetes Managers are advanced practice nurses, dietitians, or pharmacists who have passed an examination administered jointly by the American Nurses Credentialing Center and the American Association of Diabetes Educators.

Role of the Provider in Diabetes Self-Management Education and Support

Models of chronic illness care, including the chronic care model, were designed to address the epidemic of chronic diseases and aid in their management. The chronic care model includes six elements (health systems, community resources and policies, self-management support, delivery system design, decision support, and clinical information systems) that when implemented successfully result in more actively involved patients working in partnership with a proactive practice team. Thus, effective diabetes management occurs at the individual, practice, and system levels. Although it is unrealistic to expect providers to provide comprehensive DSME in the context of a busy practice, they do have an essential role to play in providing DSME and DSMS.

Starting at the time of diagnosis, providers need to provide key messages about diabetes, its treatment and the value of DSME and DSMS. Key messages for patients and their family members include the following:

• All types of diabetes need to be taken seriously.

• Diabetes is a self-managed disease, which means that your day-to-day care is in your hands. DSME/S can help you make informed and wise decisions as you go through each day, teach you how to cope with diabetes, and make changes in your health behaviors.

• The decisions you make each day will have a major impact on your future health and quality of life. It is a big responsibility and a lot of work, but it is worth the effort. The long-term complications of diabetes are not inevitable.

• It is common to have a strong feelings about having and living with diabetes. A collaborative partnership between you, your family, and your health care team is essential to provide you with the ongoing support and strategies you need to live a long and healthy life.

Because of the increasing emphasis on shared decision making and patient engagement, it is also useful to discuss the roles of the patient and the provider in diabetes care. Because chronic illness care differs from acute care, many patients will not have experienced working in a collaborative partnership with their health care team. It is important to stress that the person with diabetes is the primary decision maker and is responsible for the daily care of diabetes. It takes the provider’s knowledge about diabetes combined with the expertise of the patients about their own goals and priorities to create a truly workable care plan. A plan that is not working is not a negative reflection on either the patient or the provider but simply needs to be revised using what was learned from that experience.

Providers also need to stress the importance of DSME/S for successful self-management and shared decision making and actively offer referral to approved DSME/S programs and registered dietitians. Patients value physician opinions and recommendations. Providers need to let patients know that DSME/S is a wise investment in their future health and will provide the knowledge they need to make informed decisions as they care for themselves each day.

Providers can acknowledge how difficult it is to live with diabetes and provide reinforcement for the education that has been provided based on feedback from the patient and the DSME/S program. Although most practices cannot offer comprehensive DSME/S, practitioners can take advantage of teachable moments that present during any patient encounter. For example, pointing out at-risk areas during a foot examination or making the link between heart disease and diabetes when reviewing lab results are powerful education moments. Specific strategies that can be used with individual patients are listed in Table 3.2.

Physicians can not only ensure that individual patients receive DSME but also can design their practices to facilitate ongoing self-management support. Including a diabetes educator into the practice or models, such as patient-centered medical homes that incorporate team members designated and trained to provide ongoing care management, are consistent with recent recommendations for both DSME/S and for improving chronic care delivery.

Table 3.2 Effective Provider-Based Strategies for Self-Management Support

• Stress the importance of taking diabetes seriously.

• Stress the importance of both DSME and ongoing DSMS.

• Stress the importance of the patient’s role in self-management

• Reinforce education provided in the DSME program.

• Begin each visit by asking the patient to identify their concerns, questions, and progress toward metabolic and self-determined behavioral goals.

• Assess and address patient-identified fears and concerns.

• Ask for the patient’s opinions about home blood glucose monitoring results and other laboratory and outcome measures.

• Review and revise the diabetes care plan as needed based on both the patient and provider assessment of its effectiveness.

• Provide ongoing information about the costs and benefits of therapeutic and behavioral options to promote shared decision making.

• Take advantage of teachable moments that occur during each visit.

• Ask patients to teach back what you have discussed at the end of each visit.

• Ask patients to identify one thing they will do differently to manage their diabetes before the next visit.

• Establish a partnership with patients and their families to develop collaborative goals.

• Provide information about behavior change and problem-solving strategies to assist patients to overcome barriers to self-management.

• Support and facilitate patients’ efforts in their role as the primary decision maker in their self-management.

• Encourage the use of self-management experiments, such as monitoring blood glucose before and after exercise or before and 2 hours after a meal to help patients understand the metabolic consequences of their choices.

• Abandon traditional dysfunctional models of care (e.g., adherence and compliance; provider-centered care).

Source: Adapted from Funnell MM, Anderson RM: Patient empowerment. In: Psychology in Diabetes Care, 2nd edition. FJ Snoek and TC Skinner, eds. West Sussex, U.K., John Wiley & Sons, 95–108, 2005.

Although DSME and DSMS work best when provided by a team of health care professionals, the team does not need to work in the same setting or in traditional roles. Better use of technology allows virtual teams to work and communicate effectively with each other and with patients. Table 3.3 lists strategies shown to be effective in facilitating self-management education and ongoing support in a variety of practice settings.

Table 3.3 Effective Practice-Based Strategies for Self-Management Support

• Use continuous quality improvement to develop, implement, maintain,