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

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).

Figure 1

Insulin Resistance Pathophysiology. Insulin resistance can be initiated by obesity with an increase in visceral fat, inactivity, genetics, diet, and environmental factors. Insulin resistance leads to hyperinsulinemia with down regulation of the insulin receptors and a further increase in insulin resistance. Diabetes is a progressive disease with beta-cell dysfunction and loss of insulin pulses. Diabetes leads to diabetes complications, cardiovascular disease, metabolic syndrome, and is associated with neurodegenerative diseases [26,40,41,42].

Figure 2

Cellular glucose uptake and ATP production [51,52]. Glucose is brought into the pancreatic beta cell by the GLUT-2 transporter and converted to glucose-6-phosphate by glucokinase initiating the glycolytic pathway and resulting in the generation of pyruvate. Pyruvate is transported into the mitochondria where ATP is generated through the electron transport chain. ATP depolarizes the ATP-sensitive potassium channel causing depolarization of the voltage dependent calcium channel, which causes prepackaged insulin granules to fuse with the cell membrane and release insulin into the blood stream (Image used under license from: https://support.shutterstock.com/s/article/Can-I-use-Images-on-my-website?language=en_US#:~:text=Shutterstock%20Photos%20Are%20Royalty%2DFree,multiple%20ways%20on%20multiple%20applications, accessed on 20 June 2023).