An emerging body of evidence supports a role for autophagy in the pathophysiology of type 1 and type 2 diabetes mellitus. Persistent high concentrations of glucose lead to imbalances in the antioxidant capacity within the cell resulting in oxidative stress-mediated injury in both disorders. An anticipated consequence of impaired autophagy is the accumulation of dysfunctional organelles such as mitochondria within the cell. Mitochondria are the primary site of the production of reactive oxygen species (ROS), and an imbalance in ROS production relative to the cytoprotective action of autophagy may lead to the accumulation of ROS. Impaired mitochondrial function associated with increased ROS levels have been proposed as mechanisms contributing to insulin resistance. In this article we review and interpret the literature that implicates a role for autophagy in the pathophysiology of type 1 and type 2 diabetes mellitus as it applies to β-cell dysfunction, and more broadly to organ systems involved in complications of diabetes including the cardiovascular, renal and nervous systems.

: Objective.  The major function of the circadian system is the internal cycling of physiological and metabolic events. The present study sought to explore the effect of rotating shift work schedule on leucocyte count and its relationship with risk factors of metabolic syndrome (MS).Design and participants.  From a population‐based design, 1351 men of self‐reported European ancestry were included in a cross‐sectional study: 877 day workers were compared with 474 rotating shift workers. Medical history, health examination including anthropometric and arterial blood pressure measurements, a questionnaire on health‐related behaviours and biochemical determinations was given to all participants.Results.  In comparison with day workers, rotating shift workers had elevated (mean ± SE) body mass index (27.1 ± 0.3 vs. 26.3 ± 0.2, P < 0.0154), waist‐hip ratio (0.95 ± 0.01 vs. 0.93 ± 0.01, P < 0.00024), diastolic arterial blood pressure (78 ± 1 vs. 76 ± 1, P < 0.033), fasting insulin (65.5 ± 2.9 vs. 55.9 ± 1.9 pmol L⁻¹, P < 0.017), Homeostasis Model Assessment index (2.12 ± 0.11 vs. 1.77 ± 0.07, P < 0.0027), triglycerides (1.71 ± 0.1 vs. 1.5 ± 0.1 mmol L⁻¹, P < 0.002), uric acid (292.7 ± 2.8 vs. 282 ± 3.4 μmol L⁻¹, P < 0.01) and leucocyte count (7030 ± 84 vs. 6730 ± 58, P < 0.0094). In multiple regression analysis, leucocyte count was correlated with rotating shift work independently of age, smoking, education and components of MS.Conclusion.  The odds ratio for MS in rotating shift workers compared with day workers was 1.51 (95% CI 1.01–2.25), independently of age and physical activity. Increased leucocyte count, a biological marker of systemic inflammation, was associated with rotating shift work.

Autophagy is a degradation process of cytoplasmic cellular constituents, which serves as a survival mechanism in starving cells, and it is characterized by sequestration of bulk cytoplasm and organelles in double-membrane vesicles called autophagosomes. Autophagy has been linked to a variety of pathological processes such as neurodegenerative diseases and tumorigenesis, which highlights its biological and medical importance. We have previously characterized the vacuole membrane protein 1 (VMP1) gene, which is highly activated in acute pancreatitis, a disease associated with morphological changes resembling autophagy. Here we show that VMP1 expression triggers autophagy in mammalian cells. VMP1 expression induces the formation of ultrastructural features of autophagy and recruitment of the microtubule-associated protein 1 light-chain 3 (LC3), which is inhibited after treatment with the autophagy inhibitor 3-methiladenine. VMP1 is induced by starvation and rapamycin treatments. Its expression is necessary for autophagy, because VMP1 small interfering RNA inhibits autophagosome formation under both autophagic stimuli. VMP1 is a transmembrane protein that co-localizes with LC3, a marker of the autophagosomes. It interacts with Beclin 1, a mammalian autophagy initiator, through the VMP1-Atg domain, which is essential for autophagosome formation. VMP1 endogenous expression co-localizes with LC3 in pancreas tissue undergoing pancreatitis-induced autophagy. Finally, VMP1 stable expression targeted to pancreas acinar cell in transgenic mice induces autophagosome formation. Our results identify VMP1 as a novel autophagy-related membrane protein involved in the initial steps of the mammalian cell autophagic process.

Autophagy has recently elicited significant attention as a mechanism that either protects or promotes cell death, although different autophagy pathways, and the cellular context in which they occur, remain to be elucidated. We report a thorough cellular and biochemical characterization of a novel selective autophagy that works as a protective cell response. This new selective autophagy is activated in pancreatic acinar cells during pancreatitis-induced vesicular transport alteration to sequester and degrade potentially deleterious activated zymogen granules. We have coined the term “zymophagy” to refer to this process. The autophagy-related protein VMP1, the ubiquitin-protease USP9x, and the ubiquitin-binding protein p62 mediate zymophagy. Moreover, VMP1 interacts with USP9x, indicating that there is a close cooperation between the autophagy pathway and the ubiquitin recognition machinery required for selective autophagosome formation. Zymophagy is activated by experimental pancreatitis in genetically engineered mice and cultured pancreatic acinar cells and by acute pancreatitis in humans. Furthermore, zymophagy has pathophysiological relevance by controlling pancreatitis-induced intracellular zymogen activation and helping to prevent cell death. Together, these data reveal a novel selective form of autophagy mediated by the VMP1-USP9x-p62 pathway, as a cellular protective response.