Metformin lowers blood glucose by reducing hepatic glucose output and improving insulin sensitivity without requiring an increase in circulating insulin concentration. We hypothesized that metformin could be used adjunctively with insulin to improve glycemic control in type 1 diabetes mellitus (DM). We conducted a 6-month open-label pilot study in 10 adolescents and young adults with type 1 DM, 19.1 +/- 3.4 years, 4 males, 6 females, and body mass index 26.3 +/- 3.1 kg/m2. Patients started metformin at a dose of 250 mg b.i.d.; the dose was increased until blood glucose was within an optimal target range or a maximum of 2,500 mg/d was reached. Insulin dose was reduced as needed to prevent hypoglycemia. Seven patients had an average decrease in HbA(1c) of 11% from pretreatment. These responders had no change in insulin dose, BMI or lipid levels during the study. Three patients had no improvement of HbA(1c) on therapy. We conclude that some patients with type 1 DM will have improved glycemic control on adjunctive metformin therapy. Evaluation of the long-term benefit and safety of adjunctive therapy in patients with type 1 DM is warranted.

CD1d presents lipid antigen to a conserved population of natural killer (NK) T cells, which participate in host immune defense, tumor cell rejection and suppression of autoimmunity. The levels of human CD1d expression vary significantly between individuals. To understand such variation, we sequenced the region up to 1.7 kb 5' upstream of the translation start site and partially through exon 2 in 44 white Americans. We also studied two tagged single nucleotide polymorphisms (SNP) in 112 white Americans, 60 African-Americans, 88 Europeans, and 84 Chinese people from the region. Six SNP present in the region (-836C-->T, -773C-->T, -764C-->G, -713A-->T, -365A-->G and +363A-->G) were found to be in a complete linkage disequilibrium and comprised three haplotypes. Haplotype 1 had -836C, -773C, -764C, -713A, -365A and +363A. Haplotype 2 had -836C, -773T, -764C, -713A, -365A and +363A. Haplotype 3 had -836T, -773C, -764G, -713T, -365G and +363G. -773C-->T and -764C-->G can serve as the tagged SNP to differentiate the three haplotypes. The frequency of haplotype 1 was significantly higher in African Americans than in the other three ethnic groups, whereas the frequency of haplotype 3 was significantly higher in the Chinese people than those in the other three groups. The finding of the three haplotypes provides a genetic marker for CD1d and facilitates the study of the functional role of the genetic variations in human CD1d expression and regulation.