Apoptosis, autophagy & endoplasmic reticulum stress in diabetes mellitus

Abstract

The prevalence of diabetes mellitus (DM) is increasing secondary to increased consumption of food and decreased physical activity worldwide. Hyperglycaemia, insulin resistance and hypertrophy of pancreatic beta cells occur in the early phase of diabetes. However, with the progression of diabetes, dysfunction and loss of beta cells occur in both types 1 and 2 DM. Programmed cell death also named apoptosis is found to be associated with diabetes, and apoptosis of beta cells might be the main mechanism of relative insulin deficiency in DM. Autophagic cell death and apoptosis are not entirely distinct programmed cell death mechanisms and share many of the regulator proteins. These processes can occur in both physiologic and pathologic conditions including DM. Besides these two important pathways, endoplasmic reticulum (ER) also acts as a cell sensor to monitor and maintain cellular homeostasis. ER stress has been found to be associated with autophagy and apoptosis. This review was aimed to describe the interactions between apoptosis, autophagy and ER stress pathways in DM.

Fig. 1

Mechanisms of apoptosis. In the mitochondrial pathway, pro- and antiapoptotic Bcl-2 proteins control cytochrome c release from mitochondria. Cytochrome c binds to APAF-1, which forms a complex with procaspase-9. Thereafter, caspase-9 becomes activated. In the death receptor pathway, the binding of a ligand to its death receptor recruits an adaptor protein that in turn activates procaspase-8. FasL binds to Fas that activates FADD. FADD activates caspase-8. Caspases-8 and -9 in turn activate caspase-3. Caspase-3 plays a crucial role in the promotion of apoptotic cell death. APAF-1, apoptosis protease-activating factor 1; FADD, Fas-associated death domain; FasL, Fas ligand.

Fig. 2

Molecular machinery of autophagy. Proteins encoded by autophagy-related genes (ATGs), ATG5, ATG12, ATG16 and LC3-II are responsible for initiation, formation, and maturation of autophagosomes, which subsequently fuse with lysosomes for hydrolysis or degradation of enwrapped materials through the process of autophagy. LC3, light chain 3.

Fig. 3

Downstream pathways of inositol requiring enzyme 1α (IRE1α) and PKR-like eukaryotic inhibition factor 2a kinase (PERK) in endoplasmic reticulum stress. UPR- unfolded protein response; ASK1, apoptosis signal-regulating kinase 1; CHOP, C/EBP homologous protein; XBP-1, X box binding protein 1; ERO1α, endoplasmic reticulum oxidase 1alpha; eIF-2α, eukaryotic translation initiation factor-2α; JNK, janus kinase; NF-κB, nuclear factor kappa β; GADD34, growth arrest and DNA damage-inducible protein-34; Bcl2, B-cell lymphoma 2; BIM, Bcl 2-interacting mediator of cell death.

Fig. 4

Relationship between endoplasmic reticulum (ER) stress, autophagy and apoptosis. In diabetes mellitus, various effectors including hyperglycaemia, increased free fatty acids (FFAs), islet amyloid polypeptide (IAPP), chronic low-grade ongoing inflammation and oxidative stress can induce protein misfolding, mammalian target of rapamycin 1 (mTORC1) and decreased lysosomal degradation process. Thereafter, protein (for instance, proinsulin) misfolding induces ER stress and eventually β-cell death occurs via apoptosis. Activation of mTORC1 inhibits autophagy. mTORC1 inhibitors such as rapamycin might stimulate autophagy and prevent ER-stress activated β-cell apoptosis. Eventually, there is a decrease in proinsulin and insulin biosynthesis. PERK, PKR-like eukaryotic inhibition factor 2a kinase; inositol requiring enzyme 1alpha (IRE1α); ATF6, activating transcription factor 6.