A Receptor Story: Insulin Resistance Pathophysiology and Physiologic Insulin Resensitization's Role as a Treatment Modality

Stanley T Lewis; Frank Greenway; Tori R Tucker; Michael Alexander; Levonika K Jackson; Scott A Hepford; Brian Loveridge; Jonathan R T Lakey

doi:10.3390/ijms241310927

A Receptor Story: Insulin Resistance Pathophysiology and Physiologic Insulin Resensitization's Role as a Treatment Modality

Int J Mol Sci. 2023 Jun 30;24(13):10927. doi: 10.3390/ijms241310927.

Authors

Stanley T Lewis¹, Frank Greenway², Tori R Tucker³, Michael Alexander⁴, Levonika K Jackson⁵, Scott A Hepford⁵, Brian Loveridge⁵, Jonathan R T Lakey^{4

6}

Affiliations

¹ Eselle Health, La Jolla, CA 92037, USA.
² Clinical Trials Unit, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA 77808, USA.
³ Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA 92617, USA.
⁴ Department of Surgery, University of California Irvine, Orange, CA 92686, USA.
⁵ Well Cell Global, Medical and Scientific Advisory Board, Houston, TX 77079, USA.
⁶ Department of Biomedical Engineering, University of California Irvine, Irvine, CA 92868, USA.

Abstract

Physiologic insulin secretion consists of an oscillating pattern of secretion followed by distinct trough periods that stimulate ligand and receptor activation. Apart from the large postprandial bolus release of insulin, β cells also secrete small amounts of insulin every 4-8 min independent of a meal. Insulin resistance is associated with a disruption in the normal cyclical pattern of insulin secretion. In the case of type-2 diabetes, β-cell mass is reduced due to apoptosis and β cells secrete insulin asynchronously. When ligand/receptors are constantly exposed to insulin, a negative feedback loop down regulates insulin receptor availability to insulin, creating a relative hyperinsulinemia. The relative excess of insulin leads to insulin resistance (IR) due to decreased receptor availability. Over time, progressive insulin resistance compromises carbohydrate metabolism, and may progress to type-2 diabetes (T2D). In this review, we discuss insulin resistance pathophysiology and the use of dynamic exogenous insulin administration in a manner consistent with more normal insulin secretion periodicity to reverse insulin resistance. Administration of insulin in such a physiologic manner appears to improve insulin sensitivity, lower HgbA1c, and, in some instances, has been associated with the reversal of end-organ damage that leads to complications of diabetes. This review outlines the rationale for how the physiologic secretion of insulin orchestrates glucose metabolism, and how mimicking this secretion profile may serve to improve glycemic control, reduce cellular inflammation, and potentially improve outcomes in patients with diabetes.

Keywords: T2D; carbohydrate metabolism; diabetes; insulin resistance; physiologic insulin resensitization (PIR).

Publication types

Review

MeSH terms

Blood Glucose / metabolism
Diabetes Mellitus, Type 2* / metabolism
Humans
Insulin / metabolism
Insulin Resistance*
Insulin, Regular, Human
Ligands

Substances

Insulin
Ligands
Insulin, Regular, Human
Blood Glucose

Grants and funding

This manuscript was supported in part by 1 U54 GM104940 from the National Institute of General Medical Sciences of the National Institutes of Health, which funds the Louisiana Clinical and Translational Science Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors also acknowledge the support and assistance of the Department of Surgery at the University of California Irvine.