The Role of Autophagy in Systemic Metabolism and Human-Type Diabetes

Abstract

Autophagy is critical for the maintenance of organelle function and intracellular nutrient environment. Autophagy is also involved in systemic metabolic homeostasis, and its dysregulation can lead to or accelerate the development of metabolic disorders. While the role of autophagy in the global metabolism of model organisms has been investigated mostly using site-specific genetic knockout technology, the impact of dysregulated autophagy on systemic metabolism has been unclear. Here, we review recent papers showing the role of autophagy in systemic metabolism and in the development of metabolic disorders. Also included are data suggesting the role of autophagy in human-type diabetes, which are different in several key aspects from murine models of diabetes. The results shown here support the view that autophagy modulation could be a new modality for the treatment of metabolic syndrome associated with lipid overload and human-type diabetes.

Keywords: amyloid; autophagy; diabetes; inflammasome; metabolism.

Fig. 1. Infiltration of IL-1-producing macrophages into the adipose tissue of Atg7^+/−-ob/ob mice

Paraffin-embedded adipose tissue sections were stained with anti-IL-1β and anti-F4/80 antibodies as the primary antibodies, and confocal microscopy was done (left). The number of IL-1β-producing macrophages in the adipose tissue of Atg7^+/−-ob/ob mice was higher than in the adipose tissue of Atg7^+/+ob/ob mice (right). (HPF, high-power field)

Fig. 2. Accumulation of hIAPP oligomers in hIAPP⁺ mice with β⁻cell autophagy knockout (hIAPP⁺Atg7^Δb-cell mice)

Confocal microscopy after immunofluorescent staining of pancreas sections employing anti-insulin and anti-hIAPP oligomer (I11) antibodies. hIAPP oligomer accumulation was not seen when autophagy is competent, despite transgenic expression of hIAPP (left).

Fig. 3. Proposed model for the development of diabetes with lipid overload or human-type diabetes with autophagy insufficiency

Metabolic stress in the presence of autophagy insufficiency causes increased lipid accumulation due to compromised lipophagy. Autophagy insufficiency leads to delayed clearance of dysfunctional mitochondria, which causes increased inflammasome activation when the cell is challenged with an inflammasome activator, such as lipids (green arrow). Autophagy insufficiency also leads to accumulation of human IAPP (hIAPP) oligomers in pancreatic β-cells, since hIAPP clearance is dependent on autophagy. The combined effects of these three axes and their interactions finally culminates in the development of insulin resistance, β-cell failure and diabetes.