Nanomedicine in the Treatment of Diabetes

Abstract

Nanomedicine could improve the treatment of diabetes by exploiting various therapeutic mechanisms through the use of suitable nanoformulations. For example, glucose-sensitive nanoparticles can release insulin in response to high glucose levels, mimicking the physiological release of insulin. Oral nanoformulations for insulin uptake via the gut represent a long-sought alternative to subcutaneous injections, which cause pain, discomfort, and possible local infection. Nanoparticles containing oligonucleotides can be used in gene therapy and cell therapy to stimulate insulin production in β-cells or β-like cells and modulate the responses of T1DM-associated immune cells. In contrast, viral vectors do not induce immunogenicity. Finally, in diabetic wound healing, local delivery of nanoformulations containing regenerative molecules can stimulate tissue repair and thus provide a valuable tool to treat this diabetic complication. Here, we describe these different approaches to diabetes treatment with nanoformulations and their potential for clinical application.

Keywords: insulin pathway; nanomedicine; nanoparticles; oral formulation; type 1 diabetes mellitus; wound healing.

Figure 1

Schematic representation of the main types of nanoparticles used in the management of diabetes.

Figure 2

Mechanisms of insulin release from nanoparticles in response to increased glucose levels in blood and bodily fluids: (a) Environmental glucose penetrates the polymeric matrix. It links PBA in place of the glucose monomer of the matrix. This generates a loss of the polymeric structure and a consequent insulin release. (b) Environmental glucose penetrates the polymeric matrix. It links ConA in place of the glucose monomer of the matrix. This generates a loss of the polymeric structure and a consequent insulin release. (c) The increased environmental glucose decreases the pH, thus inducing a protonation of the polymeric chains in the nanoparticle matrix. This generates a repulsive forces that disassembles the matrix and allows insulin to be released.

Figure 3

Insulin secretion and body distribution: (a) In physiological conditions, insulin is secreted by pancreatic islets into the portal vein, reaches the liver, and subsequently enters the systemic circulation. (b) With oral administration, insulin is absorbed by the intestinal mucosa capillaries, which transport it to the portal vein and to the liver, from which it reaches the systemic circulation. (c) With subcutaneous administration, insulin is absorbed by the epidermal capillaries and reaches the systemic circulation.

Figure 4

Schematic representation of the main mechanisms of nanoparticle absorption through the intestinal mucosa: Paracellular diffusion occurs between endothelial cells and endocytosis in M-cells (or microfold cells), whose name derives from their particular composition. M-cells are specialized intestinal cells and are part of GALT lymphoid follicles such as Peyer’s patches. Their function is to transport antigens from the luminal side to the sub-epithelium (transcytosis). This is possible due to an exclusive cellular structure, including many basolateral membrane invaginations that enable macrophages and other immune cells to begin an immune response. Transcytosis is also being explored as an intestinal drug and vaccine delivery opportunity.

Figure 5

The basic mechanisms of gene delivery. (a) Non-viral gene delivery: Nanoparticles carrying siRNA or plasmids enter the cells via endocytosis, releasing their content in the cytoplasm. siRNA links homologous mRNA, inducing its degradation and the consequent repression of target proteins. Plasmids translocate to the nucleus and induce specific mRNA transcription, thus increasing target protein production. (b) Viral gene delivery: Viruses carrying specific DNA sequences enter the cells via endocytosis and then release their content in the cytoplasm. DNA translocates to the nucleus, inducing specific mRNA transcription, thus increasing target protein production.