Adjunctive Metformin Therapy in Double Diabetes

In this 12-month clinical trial, a 3-month run-in period will precede the interventional phase of the study. All patients will be placed on treat-to-target insulin regimen alone during the run-in phase. At the end of the 3-month run-in period, all participants will continue on treat-to-target insulin regimen, and will then be randomized to either of the 2 arms of the study: an experimental arm, consisting of treat-to-target insulin regimen plus metformin, and a control arm consisting of treat-to-target insulin regimen plus placebo. Both the physicians and patients will be blinded to the oral agents being administered to patients.

Inclusion criteria

A. General inclusion criteria

• Ten to 20 years of age.
• Pubertal (Tanner stages 2-5, by examination).
• Hemoglobin A1c level of > 8.0% in the 6 months prior to enrollment.
• All subjects must have access to a computer.

B. Specific inclusion criteria: [Subjects could have either #1, or #2].

• Subjects with clinical and biochemical features of T2DM of > 6mo duration who also have positive T1DM antibodies

• Clinical features: acanthosis nigricans, BMI >85%
• Biochemical: evidence of insulin resistance at diagnosis
• fasting insulin >27 uIU/mL(normal range 6-27) at a fasting blood glucose of ≥ 126 mg/dL, or
• fasting c-peptide level of > 7.1 ng/mL (normal range 0.9 - 7.1), or
• Homeostasis model of insulin resistance of >3.16
• Patients with T1DM of > one yr duration with BMI >85%

• Presentation with ketoacidosis at diagnosis
• C-peptide <0.9 ng/mL (normal range 0.9 - 7.1),or (insulin < 6 uIU/mL) (NR 6-27) at diagnosis (when blood glucose is ≥ 126 mg/dL)
• Can be antibody positive or negative
• Increased insulin requirement (>2 Units/kg/day)

Exclusion criteria

• Subjects on weight altering medications, such as orlistat.
• Subjects with eating disorder
• Subjects on medications other than insulin and or metformin that may affect blood glucose level.
• Subjects with abnormal hepatic function tests.
• Subjects with nephropathy, defined in this case as an overnight albumin excretion rate of >200 mcg/min using a first morning urine sample collection.
• Subjects with recurrent diabetes ketoacidosis (more than 2 episodes in the past 12 months), or recurrent severe hypoglycemia (more than 2 episodes of hypoglycemia with altered level of consciousness, requiring assistance to treat in the past year).
• Pregnant, breast-feeding or the intention of becoming pregnant or not using adequate contraceptive measures.
• Known or suspected allergy to metformin.
• The receipt of any investigational drug within 6 months prior to this trial.
• Active malignant neoplasms.
• No access to a computer.
• Subjects currently taking metformin for clinical purposes are not eligible to be enrolled in this study.