Classification

Introduction

Diabetes mellitus and other categories of glucose intolerance can be divided into three main clinical categories:

• Diabetes mellitus (with four clinical subclasses)
• Gestational diabetes mellitus (GDM)
• Impaired glucose tolerance (IGT)/impaired fasting glucose (IFG).

The group of metabolic disorders that constitute diabetes result from impaired insulin action, production, or both. Features shared by these disorders are elevated plasma glucose and/or glycated hemoglobin (A1C) levels above the limits established by the American Diabetes Association (ADA) Clinical Practice Recommendations. The four clinical classes of diabetes mellitus are:

• Type 1 diabetes mellitus (insulin-dependent)
• Type 2 diabetes mellitus (non–insulin-dependent)
• GDM
• Other specific types of diabetes associated with certain conditions.

Each of these subclasses has distinctive characteristics (Table 3-1).

Enlarge 

Type 1 Diabetes Mellitus and Latent Autoimmune Diabetes of Adults (LADA)

Type 1 diabetes (T1D) is defined by the presence of one or more autoantibodies that mediate the destruction of pancreatic β-cells, leading to the eventual loss of insulin production. Autoimmune markers include circulating antibodies to islet cells, endogenous insulin, glutamic acid decarboxylase (GAD), tyrosine phosphatases IA-2 and IA-2β, or to zinc transporter 8 (ZnT8). In patients with classic acute symptoms (eg, hyperglycemia), a random plasma glucose measurement of ≥200 mg/dL is part of diagnosis, since it confirms the patient’s symptoms are due to diabetes and will help direct management decisions. Patients commonly are lean at presentation and may have experienced considerable weight loss prior to diagnosis. Approximately 5% to 10% of all individuals who have been diagnosed with diabetes in the United States have type 1 diabetes (T1D). Therapy with exogenous insulin is required throughout the patient’s life to prevent metabolic decompensation, ketoacidosis and death. Most patients are diagnosed with T1D before age 20, although it can develop at any age.

Latent autoimmune diabetes in adults (LADA) is roughly defined as T1D that develops later in life and has some distinguishing characteristics from classic T1D, which normally presents with diabetic ketoacidosis (DKA) in childhood. LADA has a different clinical presentation that is often missed by health care providers (HCPs) because of the older age and absence of DKA. Beta cell destruction is much slower so DKA typically does not occur and the patient may actually respond somewhat to oral antidiabetic drug (OADs), especially sulfonylurea (SFUs). In a relatively short period of time, the patient usually will require insulin therapy. Patients with LADA do not have some of the associated conditions and physical stigmata of type 2 diabetes (T2D), in that they do not have hypertension, dyslipidemia, or central obesity. Since islet cell antibody (ICA) titers drop off after the diagnosis of T1D, use of anti- glutamic acid decarboxylase (GAD) antibodies is the best test to determine if a patient has LADA, since these antibodies can be detected for many years after the diagnosis.

Type 2 Diabetes Mellitus

Type 2 diabetes (T2D) is the most common type of diabetes, accounting for 90% to 95% of all diagnosed cases in the United States and is more prevalent among various non-Caucasian ethnic/racial populations, such as American Indians, African Americans, Pacific Islanders and Hispanics. A strong genetic basis exists for T2D (approximately 70% of patients with T2D have a positive family history of this disorder). In addition, identical-twin studies have revealed a 60% to 90% concordance for diabetes. An absence of antibodies and ketosis are two of the primary features that distinguish T2D from T1D, although it is possible to have ketonemia and acidosis with T2D.

Patients with T2D can vary considerably in their ability to secrete insulin. Insulin secretion, however, is inadequate to overcome the insulin resistance associated with this type of diabetes. Defects of insulin action (insulin resistance) are pathognomonic of T2D.

Obesity is frequently present in T2D. Approximately 90% of people with T2D have obesity (20% over ideal body weight), and the chances of developing T2D double for every 20% increase in body weight in susceptible individuals. However, T2D also can develop in individuals without obesity; this is more commonly observed in older patients. The incidence of T2D increases with age and obesity in part because people tend to gain weight and especially develop visceral or central abdominal obesity.

T2D usually is diagnosed after the age of 30, although it is being diagnosed more frequently at a younger age (e.g., at age 20 or below) in certain ethnic groups prone to developing diabetes. The age at onset for T2D is progressively decreasing and now develops in children and adolescents as well as in young adults. Initially, patients are often asymptomatic and only occasionally display the classic symptoms of hyperglycemia (polydipsia, polyuria, polyphagia, weight loss). Because T2D can go unrecognized for many years, the early stages of microvascular disease and frank macrovascular complications may be present by the time a diagnosis is made.

Gestational Diabetes Mellitus

Glucose intolerance that is diagnosed during the second or third trimester of pregnancy is classified as GDM. Excluded from this group are women who had diabetes before conception. GDM occurs in approximately 4.6% to 9.2% of pregnant women and is more common in women who are older, of high-risk ethnic groups, or have obesity or a family history of diabetes. This condition is important to identify because of the increased risk of fetal morbidity and mortality with GDM.

Pregnant women with risk factors for T2D should be screened by either a one-step or two-step oral glucose tolerance test (OGTT). The one-step test employs a 75-g OGTT, with plasma glucose measurement during fasting and at 1 and 2 hours. Diagnosis of GDM is made if any of the fasting, 1-hour, or 2-hour PG values meet or exceed 95 mg/dL, 180 mg/dL, or 153 mg/dL, respectively. The two-step test first utilizes a nonfasting 1-hour 50-g glucose load test (GLT). If the PG values is ≥140 mg/dL 1 hour after the 50-g load, then it is followed by a fasting 100-g OGTT. Diagnosis of GDM is made if two or more of the fasting, 1-, 2-, or 3-hour PG levels meet or exceed 95 mg/dL, 180 mg/dL, 155 mg/dL, or 140 mg/dL, respectively. Both tests are performed between the 24^th to 28^th weeks of pregnancy. Women at high risk for GDM should undergo glucose testing as soon as possible. Approximately 90% to 95% of women with GDM return to normal glucose tolerance after delivery. However, women who have had GDM are at increased risk for developing T2D, with approximately 35% to 60% developing T2D within 5 to 10 years following pregnancy.

Prediabetes: Impaired Glucose Tolerance (IGT) and Impaired Fasting Glucose (IFG)

Individuals who have plasma glucose or A1C levels that are higher than normal but lower than established diagnostic values for diabetes mellitus are classified as having prediabetes (diagnostic criteria in Table 3-2). IFG is defined as FPG levels of 100-125 mg/dL (5.6-6.9 mmol/L) and IGT is defined as PG levels of 140-199 mg/dL (7.8-11.0 mmol/L) 2 hours after a 75-g oral glucose load. It is reasonable to consider individuals meeting these criteria, as well as those with A1C of between 5.7% and 6.4%, as those with prediabetes. This condition is common (in 2012, approximately 37% of US adults ≥20 years had prediabetes) and is considered a precursor of T2D. Although individuals with prediabetes are more likely to eventually develop diabetes mellitus, only approximately 29% go on to develop T2D. The rate of progression is approximately 5% to 10% per year and can be influenced by:

• Ethnic origin and genetics
• Degree of obesity
• Distribution of body fat
• Sedentary lifestyle
• Aging
• Concomitant medical conditions.

Individuals with prediabetes are more susceptible to develop T2D, heart disease and stroke. Pharmacologic therapies and nonpharmacologic interventions, such as weight reduction, improved diet and increased physical activity through lifestyle modifications, have been shown to prevent the progression of prediabetes to T2D.

Enlarge 

Other Specific Types of Diabetes Mellitus

This category of diabetes mellitus is the least common and includes diabetes related to certain other diseases, conditions, or drugs. Patients are placed in this category if their diabetes has a known or probable cause or is part of a specific condition or syndrome (Table 3-2). Hyperglycemia is present at a level that is diagnostic of diabetes. Treatment of the underlying disorder may ameliorate the diabetes; more frequently, however, it is necessary to treat the diabetes with lifestyle modification, such as diet and exercise, and medication.

Enlarge 

Problems With Classification

Sometimes it is difficult to distinguish between T1D and T2D, especially in younger children, due to the obesity epidemic. Children with features of T2D, such as obesity, may also present with autoantibodies and ketosis. Alternatively, younger patients with T2D who are thin and taking insulin may resemble patients with T1D. In addition, some patients display the characteristics of T2D and are not susceptible to ketoacidosis, yet they are taking insulin. These patients should not be classified as T1D based solely on their insulin regimen, because they are taking insulin for glycemic control rather than as a life-sustaining therapy to prevent ketoacidosis and death.

T2D sometimes is found in children or adolescents who usually are above their ideal body weight and a member of a high-risk ethnic group susceptible to T2D. A unique type of diabetes found in the pediatric and young-adult population is called maturity-onset diabetes of the young (MODY) and is an example of an autosomal-dominant form of inheritance of diabetes. The 2008 best practice guidelines for the diagnosis of MODY include the following criteria: 1) young onset (before 25 years of age in one or more family members); 2) family history of diabetes in at least two consecutive generations; 3) lack of insulin dependence (outside the normal ‘honeymoon’ period); 4) absence of β-cell autoantibodies; 5) glycosuria at blood glucose levels below 10 mmol/L or 180 mg/dL; 6) increased sensitivity to sulfonylureas. Patients with MODY are not typically overweight, which distinguishes it from obesity-associated youth-onset T2D. However, MODY is difficult to distinguish from T1D and T2D based on clinical characteristics alone; correct diagnosis requires genetic testing. Mutations responsible for MODY have been identified in at least 14 different genes to date; the most common is a mutation in the hepatocyte nuclear factor-1α (HNF-1α). In order to assure that these individuals receive optimal treatment, proper genetic diagnosis is important, and can be achieved through genetic testing. Each of the 6 major subtypes and 8 minor subtypes of MODY have characteristic features, largely dependent on the affected gene. For example, MODY 3 (HNF1α-MODY) is characterized by progressive childhood hyperglycemia which develops into diabetes in early adulthood; by contrast, MODY 2 (GCK-MODY) is characterized by mild and often nonprogressive hyperglycemia, and is thus typically asymptomatic. Several MODY subtypes are characterized by additional manifestations, including MODY 5 (HNF1β-MODY; renal abnormalities) and MODY 8 (CEL-MODY; exocrine abnormalities).