Estudo comparativo entre os análogos de insulina de ação prolongada e insulina NPH humana no Diabetes Mellitus Tipo 1 / Comparative study between long-acting insulin analogues and human NPH insulin in Type 1 Diabetes Mellitus

RESUMO O Diabetes Mellitus do tipo 1 é uma doença de base autoimune com grande impacto econômico sobre a saúde pública mundial. O tratamento é baseado na aplicação subcutânea de insulina, visando mimetizar a secreção pancreática fisiológica. A reposição é feita com insulinas de ação prolongada (insulina NPH humana e análogos de insulina de ação prolongada) e insulinas de ação rápida. A hipoglicemia é a principal complicação relacionada ao tratamento. Objetivo: comparar os efeitos dos análogos de insulina de ação prolongada e insulina NPH humana sobre o controle glicêmico, episódios de hipoglicemia e hipoglicemia severa. Métodos: estudo observacional, utilizando dados obtidos de prontuários médicos ambulatoriais de pacientes acompanhados por período de 4 meses. Resultados: Não houve diferença entre os grupos em relação ao número total de hipoglicemias e hipoglicemias grau I. O grupo em uso dos análogos de insulina de ação prolongada apresentou número cerca de 50% menor de hipoglicemias clinicamente significativas (grau II). A hemoglobina glicada apresentou discreta melhora no período no grupo em uso de análogos de insulina de ação prolongada. Conclusão: As insulinas de ação prolongada apresentam aparente benefício em relação à insulina NPH humana, em relação a um melhor controle glicêmico e principalmente em relação a hipoglicemias mais graves. Descritores: Diabetes Mellitus tipo 1; Hipoglicemia; Insulina NPH; Insulina de ação prolongada; Insulina ultralenta.

High-resolution powder X-ray data reveal the T(6) hexameric form of bovine insulin.

A series of bovine insulin samples were obtained as 14 polycrystalline precipitates at room temperature in the pH range 5.0-7.6. High-resolution powder X-ray diffraction data were collected to reveal the T6 hexameric insulin form. Sample homogeneity and reproducibility were verified by additional synchrotron measurements using an area detector. Pawley analyses of the powder patterns displayed pH- and radiation-induced anisotropic lattice modifications. The pronounced anisotropic lattice variations observed for T6 insulin were exploited in a 14-data-set Rietveld refinement to obtain an average crystal structure over the pH range investigated. Only the protein atoms of the known structure with PDB code 2a3g were employed in our starting model. A novel approach for refining protein structures using powder diffraction data is presented. In this approach, each amino acid is represented by a flexible rigid body (FRB). The FRB model requires a significantly smaller number of refinable parameters and restraints than a fully free-atom refinement. A total of 1542 stereochemical restraints were imposed in order to refine the positions of 800 protein atoms, two Zn atoms and 44 water molecules in the asymmetric unit using experimental data in the resolution range 18.2-2.7 Å for all profiles.

Local insulin therapy affects fracture healing in a rat model.

A significant number of lower extremity fractures result in mal-union necessitating effective treatments to restore ambulation. Prior research in diabetic animal fracture models demonstrated improved healing following local insulin application to the fracture site and indicated that local insulin therapy can aid bone regeneration, at least within an insulin-dependent diabetic animal model. This study tested whether local insulin therapy could accelerate femur fracture repair in normal, non-diabetic rats. High (20 units) and low (10 units) doses of insulin were delivered in a calcium sulfate carrier which provided sustained release of the exogenous insulin for 7 days after fracture. Histomorphometry, radiographic scoring, and torsional mechanical testing were used to measure fracture healing. The fracture calluses from rats treated with high-dose insulin had significantly more cartilage than untreated rats after 7 and 14 days of healing. After 4 weeks of healing, femurs from rats treated with low-dose insulin had significantly higher radiographic scores and mechanical strength (p < 0.05), compared to the no treatment control groups. The results of this study suggest that locally delivered insulin is a potential therapeutic agent for treating bone fractures. Further studies are necessary, such as large animal proof of concepts, prior to the clinical use of insulin for bone fracture treatment.

Effects of local insulin delivery on subperiosteal angiogenesis and mineralized tissue formation during fracture healing.

Local insulin delivery has been shown to improve osseous healing in diabetic animals. The purpose of this study was to quantify the effects of local intramedullary delivery of saline or Ultralente insulin (UL) on various fracture healing parameters using an in vivo non-diabetic BB Wistar rat model. Quantitation of local insulin levels showed a rapid release of insulin from the fractured femora, demonstrating complete release at 2 days. RT-PCR analysis revealed that the expression of early osteogenic markers (Col1α2, osteopontin) was significantly enhanced with UL treatment when compared with saline controls (p < 0.05). Significant differences in VEGF + cells and vascularity were evident between the treatment and control groups at day 7 (p < 0.05). At day 21, histomorphometric analysis demonstrated a significant increase in percent mineralized tissue in the UL-treated animals compared with controls (p < 0.05), particularly within the subperiosteal region of the fracture callus. Mechanical testing at 4 weeks showed significantly greater mechanical strength for UL-treated animals (p < 0.05), but healing in control animals caught up at 6 weeks post-fracture. These results suggest that the primary osteogenic effect of UL during the early stages of fracture healing (1-3 weeks) is through an increase in osteogenic gene expression, subperiosteal angiogenesis, and mineralized tissue formation.