Amino Acid Nanofibers Improve Glycemia and Confer Cognitive Therapeutic Efficacy to Bound Insulin.

Aejin Lee,Randy J Nelson,Danah Muhanna,Lianbo Yu,Zachary M Weil,Rafael Jiménez-Flores,Mckensie L Mason,Jon R Parquette,A Courtney Devries,Ouliana Ziouzenkova,Devan Kowdley,Yuan Sun,Jacob H Leung,Shashi Bhushan Kumar ,Julie Fitzgerald ,Joana Ortega‐Anaya ,Tzu‐Jung Lin

doi:10.3390/pharmaceutics14010081

Abstract

Diabetes poses a high risk for debilitating complications in neural tissues, regulating glucose uptake through insulin-dependent and predominantly insulin-independent pathways. Supramolecular nanostructures provide a flexible strategy for combinatorial regulation of glycemia. Here, we compare the effects of free insulin to insulin bound to positively charged nanofibers comprised of self-assembling amino acid compounds (AACs) with an antioxidant-modified side chain moiety (AAC2) in both in vitro and in vivo models of type 1 diabetes. Free AAC2, free human insulin (hINS) and AAC2-bound-human insulin (AAC2-hINS) were tested in streptozotocin (STZ)-induced mouse model of type 1 diabetes. AAC2-hINS acted as a complex and exhibited different properties compared to free AAC2 or hINS. Mice treated with the AAC2-hINS complex were devoid of hypoglycemic episodes, had improved levels of insulin in circulation and in the brain, and increased expression of neurotransmitter taurine transporter, Slc6a6. Consequently, treatment with AAC2-hINS markedly advanced both physical and cognitive performance in mice with STZ-induced and genetic type 1 diabetes compared to treatments with free AAC2 or hINS. This study demonstrates that the flexible nanofiber AAC2 can serve as a therapeutic platform for the combinatorial treatment of diabetes and its complications.

Highlights

We described the properties of amino acid compound 2 (AAC2) and demonstrated AAC2dependent mechanisms that increase glucose uptake under insulin-resistant and insulindeficient conditions in vivo [31]
We demonstrated an ability of AAC2 nanofibers to bind insulin on the surface in vitro
Under conditions resembling type 1 diabetes (T1D), the mice treated with the AAC2-human insulin (hINS) complex retained hINS in blood longer without inducing hypoglycemic episodes

Summary

Introduction

Glycemic control has been significantly improved over the last decade through the application of continuous blood glucose monitoring, as well as the ongoing development conditions of the Creative Commons. Pharmaceutics 2022, 14, 81 of nanomaterials that release insulin in response to changes in blood glucose concentrations [2]. Clinical outcomes of continuous glucose monitoring in patients with basal insulin treatment has not reduced the rate of hospitalization of patients with diabetes [3]. Neurodegeneration is a major complication that continues to contribute to hospitalization and mortality in patients with diabetes, which remains as high as cancer deaths [4]. Current strategies to improve control over insulin action follow three major directions:

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Conclusion