Differentiating Between Type 1 and Type 2 Diabetes

Raymond A. Plodkowski, MD; Stanley Shane, MD


February 27, 2003


While serving on an internal medicine inpatient consult service, I encountered several patients with new-onset diabetes whose conditions were difficult to characterize (based on initial history, physical examination, and lab values) as type 1 or type 2. After the management of acute issues, what are the recommendations for differentiating between type 1 and type 2 diabetes?

Vidur Mahadeva, MD

Response from Raymond A. Plodkowski, MD and Stanley Shane, MD

The clinical presentations of type 1 and type 2 diabetes have become blurred. In the past, it was often assumed that children and adolescents who presented in diabetic ketoacidosis had autoimmune destruction of their insulin-producing pancreatic beta cells. These youngsters were classified as type 1 diabetics. Middle-aged adults with diabetes were assumed to have insulin resistance that resulted in glucose intolerance, and they were classified as type 2 diabetics.

Unfortunately, obesity has become rampant in the adolescent population, and now there are many young people with insulin resistance and type 2 diabetes. In contrast, occasionally there are adults who have autoimmune-mediated destruction and failure of their beta cells. It is important to determine the type of diabetes so that appropriate therapy can be initiated. Patients who are insulinopenic due to beta-cell failure must be managed with insulin. Patients who have insulin resistance can be managed with oral therapies including thiazolidinediones, metformin, and/or sulfonylureas.

The process responsible for type 1 diabetes is destruction of insulin-secreting pancreatic islet cells. This is manifested by a mononuclear infiltrate and beta-cell lysis in the islets.[1] The underlying defect that causes type 2 diabetes is insulin resistance. People with type 2 diabetes have an underlying genetic predisposition towards insulin resistance. There are 3 factors that cause insulin resistance to worsen and lead to diabetes: getting older, gaining weight, and becoming more sedentary. Normally, insulin acts as a signal to promote glucose uptake and metabolism in the muscle. However, in people with type 2 diabetes, the muscle is resistant to this signal. Therefore, the pancreatic beta cells have to increase insulin production and secretion to signal the defective muscle to metabolize glucose. As the patient's insulin resistance becomes more severe over time, the beta cells are not able to fully compensate. Then, blood glucose levels rise and diabetes is diagnosed.

Response from Raymond A. Plodkowski, MD and Stanley Shane, MD

Although many people consider type 1 autoimmune diabetes to be a disease that begins in childhood, it can actually occur at any age. Approximately 50% of patients develop the disorder before the age 40. The remainder develop the disease as older adults.[2] There are several autoimmune diseases associated with type 1 diabetes. Celiac disease is the most common, with a 5% incidence for patients with type 1 diabetes. The others are Graves' disease, hypothyroidism, adrenal insufficiency, and pernicious anemia. There is also a genetic predisposition. If an individual has a parent, sibling, or child with type 1 diabetes, he or she has approximately a 5% lifetime chance of developing type 1 diabetes.[2]

Response from Raymond A. Plodkowski, MD and Stanley Shane, MD

There are certain ethnic groups that are at greater risk for type 2 diabetes, including Native Americans, African Americans, Pacific Islanders, and Hispanics. Women who have a previous history of gestational diabetes also have a higher risk for type 2 diabetes. Patients at risk for type 2 diabetes often have features of the metabolic syndrome due to underlying insulin resistance. The criteria for the metabolic syndrome include abdominal obesity, which is defined as a waist circumference > 40 inches in men and > 35 inches in women. There are also lipid abnormalities, including triglycerides ≥ 150 mg/dL, and HDL cholesterol < 40 mg/dL in men and < 50 mg/dL in women. Additional criteria include blood pressure ≥ 130/85 mmHg and fasting blood glucose > 110 mg/dL. The Third National Health and Nutrition Examination Survey used these criteria and classified patients with any 3 as having the metabolic syndrome. The prevalence of the metabolic syndrome was 21.8% in this cross-sectional population aged 20 years and older.[3]

Response from Raymond A. Plodkowski, MD and Stanley Shane, MD

People with type 1 diabetes often present in diabetic ketoacidosis. Unfortunately, some patients with type 2 diabetes can also present with diabetic ketoacidosis, so it is not a completely specific finding.Confusion can also occur because patients with type 1 diabetes can have a "honeymoon period." These individuals with type 1 diabetes still have a small amount of beta cells that can transiently respond to sulfonylurea therapy, and the diagnosis can be confused with type 2 diabetes. However, progressive islet destruction occurs and the patient will eventually develop absolute insulinopenia and require exogenous insulin. As mentioned above, type 1 diabetes is associated with other autoimmune diseases. Therefore, a preexisting diagnosis of an autoimmune disease may suggest an autoimmune cause for diabetes.Patients with type 2 diabetes can have a darkening of the skin at the neck and in skin folds (acanthosis nigricans). These skin changes only occur in type 2 diabetics because of insulin resistance. Insulin resistance is also the underlying problem in female patients with polycystic ovary syndrome (PCOS). Therefore, patients with PCOS have an elevated incidence of type 2 diabetes.

Response from Raymond A. Plodkowski, MD and Stanley Shane, MD

Specific autoantibodies to islet cells, insulin, and glutamic acid decarboxylase help identify patients with autoimmune type 1 diabetes. Antibodies to glutamic acid decarboxylase 65 (GAD65) are considered by many diabetologists to be the most specific antibodies. Seventy to eighty percent of type 1 diabetics have GAD antibodies prior to or at the onset of disease. GAD65 is detected in less than 3% of control subjects.[4] Islet cell antibodies (ICA) are also present in the serum of patients with type 1 diabetes. When the autoantibody assay for ICA is added to GAD65, it increases autoimmune disease detection to greater than 90%.[5] Insulin autoantibodies can also be ordered. However, this must be done before the patient has any exposure to exogenous insulin. Recently, the tyrosine phosphatase-like autoantigen IA-2 has been identified as a potentially useful marker of autoimmune islet disease.

C-peptide can be measured to determine if endogenous insulin production is present. Proinsulin consists of insulin peptide and c-peptide portions. When the c-peptide is removed from the proinsulin peptide, it yields a fully active insulin molecule. C-peptide has no known biologic activity. The presence of c-peptide indicates endogenous insulin production. The normal values vary by laboratory. If c-peptide is not present at the time of diagnosis, then total beta-cell failure has occurred, suggesting type 1 diabetes. If c-peptide is present, then 2 situations could be present. First, the patient might be a type 1 diabetic early in the course of autoimmune beta-cell destruction with some residual insulin secretion. Or, more commonly, the patient might be a type 2 diabetic who is still producing endogenous insulin.

The gold standard to determine if a patient has insulin resistance consistent with type 2 diabetes is via a "glucose clamp" procedure. This procedure usually takes several hours and requires concurrent insulin and dextrose intravenous infusions. The procedure makes it possible to quantify how efficiently a patient disposes of the infused glucose. A patient with type 2 diabetes has decreased glucose disposal compared with a control patient. Unfortunately, the procedure is very time- and labor-intensive and is usually only used in research settings.

Response from Raymond A. Plodkowski, MD and Stanley Shane, MD

It is important to differentiate between autoimmune beta-cell destruction and an insulin-resistant state. Type 1 diabetics require insulin to prevent ketoacidosis. In contrast, patients with type 2 diabetes can be treated with oral therapy once the initial glucose toxicity resolves. Type 2 patients will benefit greatly from therapies that target insulin resistance (ie, thiazolidinediones) and suppress hepatic gluconeogenesis (ie, biguanides). These 2 medications are the preferred agents in early type 2 diabetes. Sulfonylureas are also useful in type 2 diabetes if the former 2 agents are not sufficient to control blood glucose levels. By employing family history, clinical clues, and lab tests, including autoantibodies, clinicians can make an educated decision regarding the etiology of a patient's diabetes and the appropriate treatment can be prescribed.


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