Therapeutic Potential of Alpha-1 Antitrypsin in Type 1 and Type 2 Diabetes Mellitus.

Sangmi S. Park,Itsaso Garcia-Arcos,Patrick Geraghty,Cormac McCarthy,Christina W. Agudelo,Brais Perez Gandara,Romy Rodriguez Ortega,Jessica Perez Perez

doi:10.3390/medicina57040397

Abstract

Alpha-1 antitrypsin (AAT) has established anti-inflammatory and immunomodulatory effects in chronic obstructive pulmonary disease but there is increasing evidence of its role in other inflammatory and immune-mediated conditions, like diabetes mellitus (DM). AAT activity is altered in both developing and established type 1 diabetes mellitus (T1DM) as well in established type 2 DM (T2DM). Augmentation therapy with AAT appears to favorably impact T1DM development in mice models and to affect β-cell function and inflammation in humans with T1DM. The role of AAT in T2DM is less clear, but AAT activity appears to be reduced in T2DM. This article reviews these associations and emerging therapeutic strategies using AAT to treat DM.

Highlights

Alpha-1 antitrypsin (AAT) has established anti-inflammatory and immunomodulatory effects that go beyond its anti-protease activity, which are well documented in the pathogenesis of emphysema [1]
Immune dysregulation and inflammation play a significant role in type 1 diabetes mellitus (T1DM) and is a subject of intense study for more than 100 years when Schmidt in 1902 described a peri-islet cellular infiltrate in the pancreas of a deceased 10-year-old child with diabetes [6,7,8,9]
There is some mechanistic evidence suggesting that AAT could have a role in type 2 DM (T2DM), with an imbalance between AAT and neutrophil elastase (NE) contributing to the development of obesity and insulin resistance in mice [78]

Summary

Introduction

Alpha-1 antitrypsin (AAT) has established anti-inflammatory and immunomodulatory effects that go beyond its anti-protease activity, which are well documented in the pathogenesis of emphysema [1]. Multiple roles of AAT beyond its anti-protease capacity have emerged [1,39], including activation of phosphatases [40], inhibition of caspase activity [41] and nitric oxide production [42], subduing HIV type 1 [43] and rhinovirus infectivity [44], reducing endoplasmic reticulum stress responses [45,46], regulating neutrophil degranulation [47,48], modifying dendritic cell maturation and promoting regulatory T cell (Treg) differentiation [49], increasing IL-10 and IL-1Ra release [50], minimizing epithelial barrier damage, and regulating IL-8-mediated neutrophil chemotaxis [51]. There is some mechanistic evidence suggesting that AAT could have a role in T2DM, with an imbalance between AAT and neutrophil elastase (NE) contributing to the development of obesity and insulin resistance in mice [78] This was observed in NE knockout (Ela2−/− ) mice and AAT transgenic mice, as they were resistant to high-fat diet-induced body weight gain, insulin resistance, inflammation, and fatty liver [78]. AAT regulated the AMP-activated protein kinase (AMPK) responses, fatty acid oxidation, and energy expenditure [78]

The Potential Use of AAT to Treat Diabetes

Design

Findings

Conclusions