Role and mechanism of pancreatic β-cell death in diabetes: The emerging role of autophagy

Abstract

Pancreatic β-cell failure resulting from decreased β-cell mass or dysfunction is the ultimate step towards most types of diabetes. Even if insulin resistance exists, diabetes does not develop unless pancreatic β-cell function or its adaptation is compromised. Classically, two types of cell death (apoptosis and necrosis) have been studied in the diabetes field. Recently, a third type of cell death (autophagy, sometimes called type 2 programmed cell death in comparison with apoptosis, type 1 programmed cell death) and its pathophysiological role have been recognized and are being investigated. In the present review, we will discuss the role of various types of cell death in the development of type 1 and type 2 diabetes. Specifically, we will briefly cover recent progress regarding the role of autophagy in diabetes, which is becoming a hot topic in diabetes and metabolism. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.0054.x, 2010).

Keywords: Autophagy; Diabetes; β‐cell death.

Figure 1

Effector cytokines and signal transduction in β‐cell death of type 1 diabetes. Both interleukin‐1β (IL‐1β) + interferon‐γ (IFN‐γ) and tumor necrosis factor‐α (TNF‐α) + IFN‐γ synergisms have been implicated in β‐cell death of type 1 diabetes. STAT1 is a common signal transducer in both cytokine synergism models. Nuclear factor (NF)‐κB is activated by both IL‐1β and TNF‐α. However, NF‐κB activation by IL‐1β is likely to play a pro‐apoptotic role by enhancing inducible nitric oxide synthase (iNOS) expression and producing nitric oxide (NO), whereas TNF‐α‐induced NF‐κB activation might have an anti‐apoptotic function by inducing expression of anti‐apoptotic molecules, such as X‐linked inhibitor of apoptosis protein (XIAP).

Figure 2

Morphological and functional changes in β‐cells of Atg7^Δβ‐cell mice. (a) Hematoxylin–eosin staining showing variable‐sized vacuolated cells in pancreatic islets of Atg7^Δβ‐cell mice (arrows). Some vacuolated cells stained positive for insulin. (b) Paraffin‐embedded pancreatic sections were subjected to insulin immunohistochemistry, and relative β‐cell area was determined by point counting (*P < 0.05 vs Atg7^F/F and Atg7^F/W; Cre⁺ mice; n = 9 each). (c) Combined insulin immunohistochemistry and TUNEL staining was carried out to count apoptotic β‐cell number/islet (*P < 0.05 vs Atg7^F/F and Atg7^F/W; Cre⁺ mice; n = 9 each). Representative apoptotic β‐cells are shown on the right (arrow heads). (d) Double immunohistochemistry for insulin and BrdU after intraperitoneal injection of BrdU was carried out to evaluate β‐cell proliferation (P < 0.05 by anova; *P < 0.05 vs Atg7^F/F mice by post‐hoc analysis; n = 9 each). (e) Pancreatic insulin was extracted by acid‐ethanol, and insulin content was measured by radioimmunoassay (*P < 0.001 vs Atg7^F/W; Cre⁺ mice; n = 8 each). (f) Insulin secretion ex vivo. Pancreatic islets from 20‐week‐old mice (n = 3 each) were incubated in KRBB containing 3.0 mmol/L glucose for 1 h and then in KRBB containing 16.7 mmol/L glucose for 1 h. Buffer was collected for insulin radioimmunoassay. Results are representative of two independent experiments carried out in triplicate (*P < 0.05 vs Atg7^F/F and Atg7^F/W; Cre⁺ mice; ^#P < 0.05 vs Atg7^F/F mice). (g) Glucose‐induced Ca²⁺ transients in isolated islets (n = 5 each). [Ca²⁺]_c was determined in Tyrode solution containing 3.0 or 16.7 mmol/L glucose (36°C). In panels (b)–(f), error bars represent SEM. Reproduced from the original paper in Cell Metabolism 2008; 8: 318–325.