Considerations for Defining Cytokine Dose, Duration, and Milieu That Are Appropriate for Modeling Chronic Low-Grade Inflammation in Type 2 Diabetes.

Craig S Nunemaker

doi:10.1155/2016/2846570

Abstract

Proinflammatory cytokines have been implicated in the pathophysiology of both type 1 diabetes (T1D) and type 2 diabetes (T2D). T1D is an autoimmune disease involving the adaptive immune system responding to pancreatic beta-cells as antigen-presenting cells. This attracts immune cells that surround pancreatic islets (insulitis) and secrete cytokines, such as IL-1beta, IFN-gamma, and TNF-alpha, in close proximity to pancreatic beta-cells. In contrast, there is little evidence for such a focused autoimmune response in T2D. Instead, the innate immune system, which responds to cellular damage and pathogens, appears to play a key role. There are three major sources of proinflammatory cytokines that may impact islet/beta-cell function in T2D: (1) from islet cells, (2) from increased numbers of intraislet macrophages/immune cells, and (3) from increased circulating levels of proinflammatory cytokines due to obesity, presumably coming from inflamed adipose tissue. These differences between T1D and T2D are reflected by significant differences in the cytokine concentration, duration, and milieu. This review focuses on chronic versus acute cytokine action, cytokine concentrations, and cytokine milieu from the perspective of the pancreatic islet in T2D. We conclude that new cytokine models may be needed to reflect the pathophysiology of T2D more effectively than what are currently employed.

Highlights

A century has passed since insulin codiscoverers Frederick Banting and Charles Best observed the first patient to receive insulin therapy in 1922, instantly transforming the prognosis of type 1 diabetes (T1D) from a death sentence to a manageable disease
Proinflammatory cytokines play a prominent role in the pathophysiology of T1D [1,2,3,4,5,6], but increasing evidence suggests a significant role for cytokines in islet dysfunction in type 2 diabetes (T2D) as well [6,7,8]
I address the substantial differences in the inflammatory environment of the pancreatic islet in T1D versus T2D and consider alternative models of cytokine exposure that may more accurately reflect the pancreatic environment in T2D, with particular emphasis on the islet

Summary

Introduction

A century has passed since insulin codiscoverers Frederick Banting and Charles Best observed the first patient to receive insulin therapy in 1922, instantly transforming the prognosis of type 1 diabetes (T1D) from a death sentence to a manageable disease. The root cause of T1D is still not known, but the processes that lead to the destruction of insulin-producing pancreatic beta-cells have been fairly well elucidated. T1D is considered an autoimmune disease that causes the gradual, systematic destruction of pancreatic beta-cells within the islets of Langerhans. Proinflammatory cytokines play a prominent role in the pathophysiology of T1D [1,2,3,4,5,6], but increasing evidence suggests a significant role for cytokines in islet dysfunction in T2D as well [6,7,8]. I address the substantial differences in the inflammatory environment of the pancreatic islet in T1D versus T2D and consider alternative models of cytokine exposure that may more accurately reflect the pancreatic environment in T2D, with particular emphasis on the islet

Cytokines in T1D versus T2D

Result

Considerations for a Model of Cytokine Action Consistent with T2D

Cytokine Susceptibility and Signaling in T2D-Prone Islets

Modeling Inflammation in T2D

Final Thoughts