The purpose of this research is to test whether one treatment is superior over another in the management of type 1.5 diabetes. Specifically we are testing recently diagnosed antibody positive type 2 diabetic patients to determine whether treatment with rosiglitazone results in greater preservation of beta cell function compared to treatment with glyburide.

Type 1 diabetes and Type 2 diabetes have different underlying pathophysiologic processes. The disease process in classical Type 1 diabetes is an autoimmune destruction of the pancreatic beta cells. In contrast, the disease process in classical Type 2 diabetes is not autoimmune in nature, a decreased sensitivity to insulin action is central to the disease process, and a poorly understood but non-inflammatory beta cell lesion occurs which diminishes insulin secretion. In clinical practice, the diagnosis of Type 1 versus Type 2 diabetes is made phenotypically using variables such as age at onset, apparent abruptness of onset of hyperglycemia, presence of ketosis, degree of obesity (especially central and intra abdominal), prevalence of other autoimmune diseases, and apparent need for insulin replacement. This clinical distinction of Type 1 versus Type 2 diabetes is recognized to be imperfect.

There is also a third group of individuals, who phenotypically are usually like classic Type 2 diabetics but who are positive for one or more of the autoantibodies commonly seen in the Type 1 disease process, namely islet cell antibodies (ICA) and/or insulin autoantibodies (IAA) and/or autoantibodies to glutamic acid decarboxylase (GAD Ab) and/or autoantibodies to the tyrosine phosphatase IA 2 (IA 2 Ab). These patients, Ab(+) Type 2 or Type 1.5 diabetes, are the focus of our study. Compared to antibody negative Type 2 diabetics, patients with Type 1.5 diabetes have a more rapid decline in beta cell function, fail sulfonylurea therapy and require insulin therapy earlier (4-13).

Hypothesis: Rosiglitazone treatment will ameliorate or slow the underlying disease process in antibody positive Type 2 diabetes.

Patients meeting the inclusion criteria will come in for a baseline visit. The nature of the study will be explained and informed consent obtained. A fasting blood sample will be obtained for autoantibodies, glucose, C-peptide, HbA1c, genetic typing, and T cell responses to islet antigens. The beta cell function test will be performed. Patients will then be randomized to either rosiglitazone or glyburide.

All patients will be encouraged to perform self blood glucose monitoring twice per day, before breakfast and before dinner. The treatment goals for all patients will be the same: before breakfast and before dinner blood sugar levels between 90-130 mg/dI and HbA1c of less then 7% without severe hypoglycemia. Patients unable to reach goal with monotherapy will have metformin (initially) or acarbose (secondarily) added, as there is no evidence to suggest that either affect beta-cell function.

The rosiglitazone treatment group will commence therapy with 4 mg once per day and increase to twice per day if adequate glycemic control is not achieved. For glyburide, therapy will be initiated with 2.5 mg in the morning or the patient will be maintained on the dose they had been receiving prior to starting the study. This starting dose will be raised by 2.5 mg in the evening and further up to a maximum of 10 mg twice a day if necessary to achieve desired glycemic control.

If adequate control, HbA1c less than 7%, is not achieved on glyburide or rosiglitazone monotherapy, metformin will be added and the dose gradually increased as needed and tolerated to a maximum of 1000 mg twice daily. If necessary, acarbose will also be used up to a maximum dose of 100 mg thrice daily as needed and tolerated.

After initiation of the study, patients will be seen at 1 month and then every 3 months for up to 3 years. Those patients randomized to rosiglitazone will have the liver enzyme ALT monitored every 2 months. In addition, telephone contact may be utilized to achieve and maintain glycemic goals. Each participant will be followed for up to 3 years. Drs. Chiu and Palmer will coordinate the study. If the patient and his/her private physician prefer, the treatment protocol can be implemented by the patient's private physician.

Inclusion Criteria:

• Age at onset of diabetes - 35-69 years old.
• No history of ketonuria or ketoacidosis.
• Not requiring insulin to achieve glycemic control.
• Not receiving more than two oral hypoglycemic agents.
• Not taking a thiazolidinedione agent.
• HbA1c in established patients (on an oral hypoglycemia agent for over 4 months) of greater than 6% and under 10%.
• Fasting c-peptide greater than or equal to 0.8 ng/ml.
• Women must be either post-menopausal or on adequate birth control (i.e. oral contraceptives, tubal ligation, hysterectomy, condoms, or diaphragm) or use abstinence.

Exclusion Criteria:

• Patients with history of chronic pancreatitis or other secondary causes of diabetes.
• Patients receiving systemic corticosteroids.
• Patients with severe systemic illness (e.g. recent MI, CHF or cerebral vascular disease).
• Creatinine greater than 1.4 or liver enzymes greater than 2 times the upper limits of normal.
• Not able to adhere to the protocol.