Table 1.
Key differences in β-cell lipotoxicity between humans and rodents.
| Theory of β-cell lipotoxicity | Human (β-cells) | Rodent (β-cells) |
|---|---|---|
| Lipid homeostasis | LC-SFA trafficked to lipid droplets (8, 9, 73). | LC-SFA not trafficked to lipid droplets (9). |
| ER stress | LC-SFA activate the expression of 4 ER stress markers (27, 84). | LC-SFA activate the expression of 9 ER stress markers (26, 81–83). |
| Impaired autophagy | Markers of impaired autophagy in pancreatic sections from T2D donors (85, 91). | Rodent β-cells treated with LC-SFA have alterations in autophagy (87–89) but unclear whether LC-SFA increases or impairs autophagic flux. |
| Human islets treated with LC-SFA have overloaded autophagosomes with a potential reduction in lysosomal fusion (91). | ||
| Mitochondrial dysregulation | In β-cells from individuals with T2D: Increased mitochondrial density (96). Increased UCP-2 expression (96). Impaired hyperpolarisation of the mitochondrial membrane (96). Uncertain whether lipotoxicity is the cause. |
LC-SFA induce mitochondrial permeability transition pore activation leading to rodent β-cell apoptosis (94). |
| LC-SFA induce cardiolipin remodelling leading to rodent β-cell apoptosis (95). | ||
| Oxidative stress | Markers of oxidative damage found in pancreatic biopsies from T2D individuals (103, 104). | Unclear whether ROS (produced as a bi-product of LC-SFA breakdown) from the mitochondria or peroxisomes play a greater role in rodent β-cell lipotoxicity (99). |
| Treating β-cells with LC-SFA causes nitrogen free radicals to accumulate and a change in the expression of ROS scavenger proteins (105, 106). | UCP-2 may act as a protective mechanism against mitochondrial derived ROS (101). | |
| Inflammation | Islets from individuals with T2D display pro-inflammatory mediators (79, 109). | LC-FFA induces pro-inflammatory factors in rodent β-cells (109). |
| LC-SFA increase the expression of pro-inflammatory markers in non-diabetic β-cells (79, 109). |
LC-SFA activates the STING-IRF3 (stimulator of interferon gene stimulator and interferon regulatory factor 3) signalling pathway which initiates inflammatory and apoptotic pathways in rodent β-cells (110, 111). | |
| Proinflammatory cytokines can trigger human β-cell death (10). |