FOR THE SITAGLIPTIN STUDY 021 GROUP*OBJECTIVE -To examine the efficacy and safety of once-daily oral sitagliptin as monotherapy in patients with type 2 diabetes. RESULTS -Sitagliptin 100 and 200 mg produced significant (P Ͻ 0.001) placebosubtracted reductions in A1C (Ϫ0.79 and Ϫ0.94%, respectively) and fasting plasma glucose (Ϫ1.0 mmol/l [Ϫ17.1 mg/dl] and Ϫ1.2 mmol/l [Ϫ21.3 mg/dl], respectively). Patients with baseline A1C Ն9% had greater reductions in placebo-subtracted A1C with sitagliptin 100 and 200 mg (Ϫ1.52 and Ϫ1.50%, respectively) than those with baseline A1C Ͻ8% (Ϫ0.57 and Ϫ0.65%) or Ն8 to Ͻ9.0% (Ϫ0.80 and Ϫ1.13%, respectively). In a meal tolerance test, sitagliptin 100 and 200 mg significantly decreased 2-h postprandial glucose (PPG) (placebo-subtracted PPG Ϫ2.6 mmol/l [Ϫ46.7 mg/dl] and Ϫ3.0 mmol/l [Ϫ54.1 mg/dl], respectively). Results for the above key efficacy parameters were not significantly different between sitagliptin doses. Homeostasis model assessment of ␤-cell function and proinsulin-to-insulin ratio improved with sitagliptin. The incidence of hypoglycemia was similar, and overall gastrointestinal adverse experiences were slightly higher with sitagliptin. No meaningful body weight changes from baseline were observed with sitagliptin 100 (Ϫ0.2 kg) or 200 mg (Ϫ0.1 kg). The body weight change with placebo (Ϫ1.1 kg) was significantly (P Ͻ 0.01) different from that observed with sitagliptin. RESEARCH DESIGN AND METHODSCONCLUSIONS -In this 24-week study, once-daily sitagliptin monotherapy improved glycemic control in the fasting and postprandial states, improved measures of ␤-cell function, and was well tolerated in patients with type 2 diabetes.

OBJECTIVE—To assess the efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes and inadequate glycemic control on diet and exercise. RESEARCH DESIGN AND METHODS—In a 24-week, randomized, double-blind, placebo-controlled, parallel-group study, 1,091 patients with type 2 diabetes and A1C 7.5–11% were randomized to one of six daily treatments: sitagliptin 100 mg/metformin 1,000 mg (S100/M1000 group), sitagliptin 100 mg/metformin 2,000 mg (S100/M2000 group), metformin 1,000 mg (M1000 group), metformin 2,000 mg (M2000 group) (all as divided doses administered twice daily [b.i.d.]), sitagliptin 100 mg q.d. (S100 group), or placebo. Patients who had an A1C >11% or a fasting glucose value >280 mg/dl after the run-in period were not eligible to be randomized; these patients could participate in an open-label substudy and were treated with S100/M2000 for 24 weeks. RESULTS—The mean baseline A1C was 8.8% in the randomized patients. The placebo-subtracted A1C change from baseline was −2.07% (S100/M2000), −1.57% (S100/M1000), −1.30% (M2000), −0.99% (M1000), and −0.83% (S100) (P < 0.001 for comparisons versus placebo and for coadministration versus respective monotherapies). The proportion of patients achieving an A1C <7% and <6.5% was 66 and 44%, respectively, in the S100/M2000 group (P < 0.001 vs. S100 or M2000). For the open-label cohort (n = 117; baseline A1C 11.2%) treated with S100/M2000, the within-group mean A1C change from baseline was −2.9%. The incidence of hypoglycemia was low (0.5–2.2%) across active treatment groups and not significantly different from that in the placebo group (0.6%). The incidence of gastrointestinal adverse experiences was similar for coadministration therapies compared with their respective metformin monotherapy. CONCLUSIONS—The initial combination of sitagliptin and metformin provided substantial and additive glycemic improvement and was generally well tolerated in patients with type 2 diabetes.

Sitagliptin significantly improved glycaemic control and was well tolerated in patients with type 2 diabetes mellitus who had inadequate glycaemic control on exercise and diet.

Haematopoietic stem cells in umbilical cord blood are an attractive target for gene therapy of inborn errors of metabolism. Three neonates with severe combined immunodeficiency were treated by retroviral-mediated transduction of the CD34+ cells from their umbilical cord blood with a normal human adenosine deaminase complementary DNA followed by autologous transplantation. The continued presence and expression of the introduced gene in leukocytes from bone marrow and peripheral blood for 18 months demonstrates that umbilical cord blood cells may be genetically modified with retroviral vectors and engrafted in neonates for gene therapy.

Human immunodeficiency virus 1 (HIV-1) Nef downregulates surface expression of CD4, an integral component of the functional HIV receptor complex, through accelerated endocytosis of surface receptors and diminished transport of CD4 from the Golgi network to the plasma membrane [1-3]. HIV-1 Nef also diminishes surface expression of major histocompatibility complex (MHC) class I antigens [4]. In the case of HIV-2 and simian immunodeficiency virus 1 (SIV-1) Nef, aminoterminal tyrosine-based motifs mediate the binding of Nef to the AP-1 and AP-2 adaptors and this interaction appears to be required for CD4 downregulation [5,6]. As these tyrosine motifs are not present in the HIV-1 Nef protein, the molecular basis for the presumed interaction of Nef with components of the endocytic machinery is unknown.Here, we identify a highly conserved dileucine motif in HIV-1 Nef that is required for downregulation of CD4. This motif acts as an internalization signal in the context of a CD8-Nef chimera or in a fusion of the interleukin-2 receptor a with an 11-amino-acid region from Nef containing the dileucine motif. Finally, HIV-1 Nef binds to the AP-1 adaptor, both in vitro and in vivo, in a dileucine-dependent manner. We conclude that this conserved dileucine motif in HIV-1 Nef serves as a key interface for interaction with components of the host protein trafficking machinery. Our findings also reveal an evolutionary difference between HIV-1 and HIV-2/SIV in which the Nef proteins utilize structurally distinct motifs for binding cellular adaptors.