Insulin analog preparations and their use in children and adolescents with type 1 diabetes mellitus.

Standard or 'traditional' human insulin preparations such as regular soluble insulin and neutral protamine Hagedorn (NPH) insulin have shortcomings in terms of their pharmacokinetic and pharmacodynamic properties that limit their clinical efficacy. Structurally modified insulin molecules or insulin 'analogs' have been developed with the aim of delivering insulin replacement therapy in a more physiological manner. In the last 10 years, five insulin analog preparations have become commercially available for clinical use in patients with type 1 diabetes mellitus: three 'rapid' or fast-acting analogs (insulin lispro, aspart, and glulisine) and two long-acting analogs (insulin glargine and detemir). This review highlights the specific pharmacokinetic properties of these new insulin analog preparations and focuses on their potential clinical advantages and disadvantages when used in children and adolescents with type 1 diabetes mellitus. The fast-acting analogs specifically facilitate more flexible insulin injection timing with regard to meals and activities, whereas the long-acting analogs have a more predictable profile of action and lack a peak effect. To date, clinical trials in children and adolescents have been few in number, but the evidence available from these and from other studies carried out in adults with type 1 diabetes suggest that they offer significant benefits in terms of reduced frequency of nocturnal hypoglycemia, better postprandial blood glucose control, and improved quality of life when compared with traditional insulins. In addition, insulin detemir therapy is unique in that patients may benefit from reduced risk of excessive weight, particularly during adolescence. Evidence for sustained long-term improvements in glycosylated hemoglobin, on the other hand, is modest. Furthermore, alterations to insulin/insulin-like growth factor I receptor binding characteristics have also raised theoretical concerns that insulin analogs may have an increased mitogenic potential and risk of tumor development, although evidence from both in vitro and in vivo animal studies do not support this assertion. Long-term surveillance has been recommended and further carefully designed prospective studies are needed to evaluate the overall benefits and clinical efficacy of insulin analog therapy in children and adolescents with type 1 diabetes.

Guidance of collective cell migration by substrate geometry.

Collective behavior refers to the emergence of complex migration patterns over scales larger than those of the individual elements constituting a system. It plays a pivotal role in biological systems in regulating various processes such as gastrulation, morphogenesis and tissue organization. Here, by combining experimental approaches and numerical modeling, we explore the role of cell density ('crowding'), strength of intercellular adhesion ('cohesion') and boundary conditions imposed by extracellular matrix (ECM) proteins ('constraints') in regulating the emergence of collective behavior within epithelial cell sheets. Our results show that the geometrical confinement of cells into well-defined circles induces a persistent, coordinated and synchronized rotation of cells that depends on cell density. The speed of such rotating large-scale movements slows down as the density increases. Furthermore, such collective rotation behavior depends on the size of the micropatterned circles: we observe a rotating motion of the overall cell population in the same direction for sizes of up to 200 μm. The rotating cells move as a solid body, with a uniform angular velocity. Interestingly, this upper limit leads to length scales that are similar to the natural correlation length observed for unconfined epithelial cell sheets. This behavior is strongly altered in cells that present a downregulation of adherens junctions and in cancerous cell types. We anticipate that our system provides a simple and easy approach to investigate collective cell behavior in a well-controlled and systematic manner.