Misdiagnosed with type 2 diabetes
Despite adhering to lifestyle modifications, a woman’s glycemic control remains inadequate.
Ms. W, 50 years old, was seen for ongoing care of type 2 diabetes, diagnosed five years earlier. In addition to being evaluated by a nutritionist, she had attended diabetes-education classes and was adhering to dietary guidelines. She exercised 30-45 minutes three or more times a week. In spite of receiving maximal doses of metformin and a sulfonylurea, she remained hyperglycemic. Her hemoglobin A1c level (9.2%) revealed inadequate control.
Ms. W weighed 166 lb and was 68 in tall, for a BMI of 25.2. Her waist was 34 in, BP 120/80 mm Hg, LDL 160 mg/dL, triglycerides 148 mg/dL, and HDL 48 mg/dL. Physical examination revealed no acanthosis or skin tags. However, she was already manifesting background retinopathy with microaneurysms and reduced deep tendon reflexes of the lower extremities. When the patient expressed concern over poor glycemic control to her previous provider, she was told that she had type 2 diabetes (obvious by her lack of ketoacidosis) and would not need insulin.
Laboratory studies revealed C peptide 1 ng/mL (normal fasting range 0.78-1.89) and glutamic acid decarboxylase antibodies (GADab).
Normal C-peptide levels indicate some degree of beta-cell function, i.e., insulin is still being released by the pancreas, which would be unexpected in type 1 diabetes. In type 2 diabetes, C-peptide levels are usually well above normal. A positive GADab is a well-recognized sensitive and specific marker of autoimmune beta-cell destruction and predictive of declining beta-cell function and eventual failure.
The absence of obesity and/or metabolic syndrome, lack of acanthosis or skin tags, relatively normal triglyceride and HDL levels, early presence of microvascular complications, and inability to achieve optimal glycemic control despite maximal doses of hypoglycemic agents led to a reconsideration of the diagnosis. In all probability, this patient had latent autoimmune diabetes of adulthood (LADA).
Clearing up the confusion
LADA, a slowly progressive form of type 1 diabetes, is a frequently missed diagnosis. Patients who develop diabetes mellitus as adults are routinely misdiagnosed with type 2 diabetes. In many of these cases, re-evaluation could result in a diagnosis of LADA.
The confusion stems from the fact that patients with LADA have numerous manifestations of both type 1 and 2 diabetes. A defining feature of LADA is that, similar to patients with type 1 diabetes, positive testing for pancreatic autoantibodies is commonly manifest (identifying the autoimmune pathology of the disease). Understandably, patients with LADA are frequently misdiagnosed with type 2 diabetes after responding to oral hypoglycemic agents early in their disease trajectory. These patients may have a more rapid progression to insulin dependency than a typical type 2 diabetic, in spite of maximal therapy with oral agents and optimal lifestyle behaviors.
Immune-mediated destruction of beta cells occurs in both type 1 diabetes and LADA. However, beta-cell destruction is much slower in LADA (although the pathology is similar). Slower—but continuing—beta-cell destruction is believed to result in later age of onset and gradual progression toward insulin dependency.
LADA is definitively diagnosed by an elevation of pancreatic autoantibodies in patients with newly diagnosed diabetes who do not require insulin.1 Patients with low C-peptide levels have more beta-cell destruction and are less likely to benefit from oral agents that stimulate insulin release. Patients with type 2 diabetes have normal or high levels of C peptide; those with LADA have below-normal levels.
While it may not be cost-effective to test for antibodies in all type 2 diabetes patients, it is efficacious to select individuals who have an elevated probability of LADA. Suspicion for LADA should be raised by low levels of C peptide, an absence of metabolic syndrome, poor glycemic control even with maximal doses of oral agents, and presence of other autoimmune diseases.2,3
Typically, a patient with LADA will have slow and insidious onset of hyperglycemia compared with type 1 diabetics and will not require insulin immediately at the onset of symptomatology.4 LADA patients do not manifest ketoacidosis at the time of diagnosis. Insulin dependency occurs at an earlier stage than in type 2 diabetes; it is important to realize that once a patient becomes insulinopenic, he is at risk for ketoacidosis.
LADA carries a risk for cardiovascular disease comparable with that of type 2 diabetes.5 Nevertheless, hyperglycemia is a stronger risk factor for cardiovascular disease in patients with LADA. These patients have the same risk for microvascular complications (i.e., retinopathy, nephropathy, and neuropathy) as those with type 2 diabetes.5 However, a study showed that patients with LADA may have an increased occurrence of retinopathy compared with type 2 diabetes patients.6 This may be because patients with LADA more commonly have inadequate glycemic control.
The primary focus when managing a patient with LADA is controlling hyperglycemia and minimizing complications. A secondary goal is to intervene in ways that will foster beta-cell preservation. The rationale for this is the slow or insidious onset of LADA. Preservation of beta-cell function may yield a more optimal level of glycemic control, which in turn may slow or reduce the degree of proliferative retinopathy.7
Although some LADA patients may be insulin-resistant, the benefits from metformin are still being researched. These benefits (facilitating the sensitivity of the liver to insulin and slowing the destruction of beta-cell function) have not been clearly supported in animal models.8
Thiazolidinediones (i.e., rosiglitazone [Avandia] and pioglitazone [Actos]) have been found to have an anti-inflammatory effect and are the first-line drugs of choice for beta-cell preservation in all forms of diabetes mellitus.9 Due to the slower rate of beta-cell destruction in LADA, many clinicians and researchers believe that early initiation of insulin therapy may actually preserve beta-cell function.9
Patients with LADA typically lack the dyslipidemias (i.e., hypertriglyceridemia and low HDL) normally seen with metabolic syndrome or frank type 2 diabetes. These patients may manifest elevated LDL levels and may benefit from statins to reach LDL goals. Often, patients with LADA will have been previously diagnosed with other autoimmune diseases or exhibit a family history of similar patterns of diabetes or autoimmune diseases. LADA treatment strategies differ from those of type 2 diabetes. Although therapy is initially focused on the management of hyperglycemia and complications, proper interventions may restore beta-cell function.
Ms. W was started on a long-acting insulin detemir 10 units every night and Actos 15 mg daily (to preserve beta-cell funcion). She was also referred to an ophthalmologist.
Dr. Appel is a board-certified acute care and family nurse practitioner and associate professor at the University of Alabama at Birmingham School of Nursing.
1. Torn C, Landin-Olsson M, Ostman J, et al. Glutamic acid decarboxylase antibodies (GADA) is the most important factor for prediction of insulin therapy within 3 years in young adult diabetic patients not classified as type 1 diabetes on clinical grounds. Diabetes Metab Res Rev. 2000;16:442-447.
2. Bell DS, Ovalle F. The role of C-peptide levels in screening for latent autoimmune diabetes in adults. Am J Ther. 2004;11:308-311.
3. Fourlanos S, Perry C, Stein MS, et al. A clinical screening tool identifies autoimmune diabetes in adults. Diabetes Care. 2006;29:970-975.
4. Pozzilli P, Di Mario U. Autoimmune diabetes not requiring insulin at diagnosis (latent autoimmune diabetes of the adult): definition, characterization, and potential prevention. Diabetes Care. 2001;24:1460-1467.
5. Isomaa B, Almgren P, Henricsson M, et al. Chronic complications in patients with slowly progressing autoimmune type 1 diabetes (LADA). Diabetes Care. 1999;22:1347-1353.
6. Balme M, McAllister I, Davis WA, et al. Retinopathy in latent autoimmune diabetes of adults: the Fremantle Diabetes Study. Diabet Med. 2002;19:602-605.
7. Nakanishi K, Kobayashi T, Inoko H, et al. Residual beta-cell function and HLA-A24 in IDDM. Markers of glycemic control and subsequent development of diabetic retinopathy. Diabetes. 1995;44:1334-1339.
8. Beales PE, Giorgini A, Annovazzi A, et al. Metformin does not alter diabetes incidence in the NOD mouse. Horm Metab Res. 1997;29:261-263.9. Beales PE, Pozzilli P. Thiazolidinediones for the prevention of diabetes in the non-obese diabetic (NOD) mouse: implications for human type 1 diabetes. Diabetes Metab Res Rev. 2002;18:114-117.