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.

• Drug: rosiglitazone
• Drug: glyburide

• Active Comparator: Rosiglitazone is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity. 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.
• Active Comparator: Glyburide is a sulfonylurea. 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 in the evening and further up to a maximum of 10 mg twice a day if necessary to achieve desired glycemic control.

• Lampeter EF, Homberg M, Quabeck K, Schaefer UW, Wernet P, Bertrams J, Grosse-Wilde H, Gries FA, Kolb H. Transfer of insulin-dependent diabetes between HLA-identical siblings by bone marrow transplantation. Lancet. 1993 May 15;341(8855):1243-4.
• DeFronzo RA. Pathogenesis of type 2 (non-insulin dependent) diabetes mellitus: a balanced overview. Diabetologia. 1992 Apr;35(4):389-97. Review. No abstract available.
• Porte D Jr. Banting lecture 1990. Beta-cells in type II diabetes mellitus. Diabetes. 1991 Feb;40(2):166-80. Review.
• Zimmet PZ, Tuomi T, Mackay IR, Rowley MJ, Knowles W, Cohen M, Lang DA. Latent autoimmune diabetes mellitus in adults (LADA): the role of antibodies to glutamic acid decarboxylase in diagnosis and prediction of insulin dependency. Diabet Med. 1994 Apr;11(3):299-303.
• Tuomi T, Groop LC, Zimmet PZ, Rowley MJ, Knowles W, Mackay IR. Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease. Diabetes. 1993 Feb;42(2):359-62.
• Zimmet PZ. The pathogenesis and prevention of diabetes in adults. Genes, autoimmunity, and demography. Diabetes Care. 1995 Jul;18(7):1050-64. Review. No abstract available.
• Groop LC, Bottazzo GF, Doniach D. Islet cell antibodies identify latent type I diabetes in patients aged 35-75 years at diagnosis. Diabetes. 1986 Feb;35(2):237-41.
• Groop L, Miettinen A, Groop PH, Meri S, Koskimies S, Bottazzo GF. Organ-specific autoimmunity and HLA-DR antigens as markers for beta-cell destruction in patients with type II diabetes. Diabetes. 1988 Jan;37(1):99-103.
• Kobayashi T, Tamemoto K, Nakanishi K, Kato N, Okubo M, Kajio H, Sugimoto T, Murase T, Kosaka K. Immunogenetic and clinical characterization of slowly progressive IDDM. Diabetes Care. 1993 May;16(5):780-8.
• Kobayashi T. Subtype of insulin-dependent diabetes mellitus (IDDM) in Japan: slowly progressive IDDM--the clinical characteristics and pathogenesis of the syndrome. Diabetes Res Clin Pract. 1994 Oct;24 Suppl:S95-9. Review.
• Kobayashi T, Nakanishi K, Sugimoto T, Itoh T, Murase T, Kosaka K, Tsuji K. Maleness as risk factor for slowly progressive IDDM. Diabetes Care. 1989 Jan;12(1):7-11.
• Kobayashi T, Itoh T, Kosaka K, Sato K, Tsuji K. Time course of islet cell antibodies and beta-cell function in non-insulin-dependent stage of type I diabetes. Diabetes. 1987 Apr;36(4):510-7.
• Nakanishi K, Kobayashi T, Sugimoto T, Murase T, Itoh T, Kosaka K. Predictive value of insulin autoantibodies for further progression of beta cell dysfunction in non-insulin-dependent diabetics. Diabetes Res. 1988 Nov;9(3):105-9.
• Hao W, Li L, Mehta V, Lernmark A, Palmer JP. Functional state of the beta cell affects expression of both forms of glutamic acid decarboxylase. Pancreas. 1994 Sep;9(5):558-62.
• Mehta V, Hao W, Brooks-Worrell BM, Palmer JP. The functional state of the beta cell modulates IL-1 and TNF-induced cytotoxicity. Lymphokine Cytokine Res. 1993 Aug;12(4):255-9.
• Gotfredsen CF, Buschard K, Frandsen EK. Reduction of diabetes incidence of BB Wistar rats by early prophylactic insulin treatment of diabetes-prone animals. Diabetologia. 1985 Dec;28(12):933-5.
• Atkinson MA, Maclaren NK, Luchetta R. Insulitis and diabetes in NOD mice reduced by prophylactic insulin therapy. Diabetes. 1990 Aug;39(8):933-7.
• Keller RJ, Eisenbarth GS, Jackson RA. Insulin prophylaxis in individuals at high risk of type I diabetes. Lancet. 1993 Apr 10;341(8850):927-8.
• [No authors listed] Effect of intensive therapy on residual beta-cell function in patients with type 1 diabetes in the diabetes control and complications trial. A randomized, controlled trial. The Diabetes Control and Complications Trial Research Group. Ann Intern Med. 1998 Apr 1;128(7):517-23.
• [No authors listed] Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med. 2002 May 30;346(22):1685-91.
• Kobayashi T, Nakanishi K, Murase T, Kosaka K. Small doses of subcutaneous insulin as a strategy for preventing slowly progressive beta-cell failure in islet cell antibody-positive patients with clinical features of NIDDM. Diabetes. 1996 May;45(5):622-6.
• Kobayashi T, Maruyama T, Shimada A, Kasuga A, Kanatsuka A, Takei I, Tanaka S, Yokoyama J. Insulin intervention to preserve beta cells in slowly progressive insulin-dependent (type 1) diabetes mellitus. Ann N Y Acad Sci. 2002 Apr;958:117-30. Review.
• Kumar S, Boulton AJ, Beck-Nielsen H, Berthezene F, Muggeo M, Persson B, Spinas GA, Donoghue S, Lettis S, Stewart-Long P. Troglitazone, an insulin action enhancer, improves metabolic control in NIDDM patients. Troglitazone Study Group. Diabetologia. 1996 Jun;39(6):701-9. Erratum in: Diabetologia 1996 Oct;39(10):1245.
• Antonucci T, Whitcomb R, McLain R, Lockwood D, Norris RM. Impaired glucose tolerance is normalized by treatment with the thiazolidinedione troglitazone. Diabetes Care. 1997 Feb;20(2):188-93. Erratum in: Diabetes Care 1998 Apr;21(4):678.
• Nolan JJ, Ludvik B, Beerdsen P, Joyce M, Olefsky J. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med. 1994 Nov 3;331(18):1188-93.
• Nakanishi K, Kobayashi T, Miyashita H, Ohkubo M, Sugimoto T, Murase T, Kosaka K, Inouye K, Kono M. Relationships among islet cell antibodies, residual beta-cell function, and metabolic control in patients with insulin-dependent diabetes mellitus of long duration: use of a sensitive C-peptide radioimmunoassay. Metabolism. 1990 Sep;39(9):925-30.
• Nakanishi K, Kobayashi T, Inoko H, Tsuji K, Murase T, Kosaka K. Residual beta-cell function and HLA-A24 in IDDM. Markers of glycemic control and subsequent development of diabetic retinopathy. Diabetes. 1995 Nov;44(11):1334-9.
• Sjoberg S, Gunnarsson R, Gjotterberg M, Lefvert AK, Persson A, Ostman J. Residual insulin production, glycaemic control and prevalence of microvascular lesions and polyneuropathy in long-term type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1987 Apr;30(4):208-13.
• [No authors listed] The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993 Sep 30;329(14):977-86.
• Juneja R, Hirsch IB, Naik RG, Brooks-Worrell BM, Greenbaum CJ, Palmer JP. Islet cell antibodies and glutamic acid decarboxylase antibodies, but not the clinical phenotype, help to identify type 1(1/2) diabetes in patients presenting with type 2 diabetes. Metabolism. 2001 Sep;50(9):1008-13.
• Brooks-Worrell BM, Juneja R, Minokadeh A, Greenbaum CJ, Palmer JP. Cellular immune responses to human islet proteins in antibody-positive type 2 diabetic patients. Diabetes. 1999 May;48(5):983-8.
• Gleichmann H, Zorcher B, Greulich B, Gries FA, Henrichs HR, Betrams J, Kolb H. Correlation of islet cell antibodies and HLA-DR phenotypes with diabetes mellitus in adults. Diabetologia. 1984 Jul;27 Suppl:90-2.
• Hagopian WA, Karlsen AE, Gottsater A, Landin-Olsson M, Grubin CE, Sundkvist G, Petersen JS, Boel E, Dyrberg T, Lernmark A. Quantitative assay using recombinant human islet glutamic acid decarboxylase (GAD65) shows that 64K autoantibody positivity at onset predicts diabetes type. J Clin Invest. 1993 Jan;91(1):368-74.
• Rowley MJ, Mackay IR, Chen QY, Knowles WJ, Zimmet PZ. Antibodies to glutamic acid decarboxylase discriminate major types of diabetes mellitus. Diabetes. 1992 Apr;41(4):548-51.

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.

• Seattle Institute for Biomedical and Clinical Research
• GlaxoSmithKline