Preferred Treatment of Type 1.5 Diabetes

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 islet cell autoantibody 512 (IA 2 Ab).

These patients, autoantibody positive [Ab(+)] Type 2 or Type 1.5 diabetes, were 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 came in for a baseline visit. The nature of the study
was explained and informed consent obtained. A fasting blood sample was obtained for
autoantibodies, glucose, C peptide of proinsulin molecule (C-peptide), glycosylated
hemoglobin (HbA1c), genetic typing, and T lymphocyte (T cell) responses to islet antigens.
The beta cell function test was performed. Patients were then randomized to either
rosiglitazone or glyburide.

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

The rosiglitazone treatment group commenced therapy with 4 milligram (mg) once per day and
increased to twice per day if adequate glycemic control was not achieved. For glyburide,
therapy was initiated with 2.5 mg in the morning or the patient was maintained on the dose
they had been receiving prior to starting the study. The starting dose was 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%, was not achieved on glyburide or rosiglitazone
monotherapy, metformin was added and the dose gradually increased as needed and tolerated to
a maximum of 1000 mg twice daily. If necessary, acarbose was also used up to a maximum dose
of 100 mg thrice daily as needed and tolerated.

After initiation of the study, patients were seen at 1 month and then every 3 months for up
to 3 years. Those patients randomized to rosiglitazone had the liver enzyme alanine
transaminase (ALT) monitored every 2 months. In addition, telephone contact was utilized to
achieve and maintain glycemic goals. Each participant was followed for up to 3 years. Drs.
Chiu and Palmer coordinated the study. If the patient and his/her private physician prefer,
the treatment protocol was 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.