Glucose stimulated insulin secretion GSIS

Glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells is biphasic, and suppression of the first-phase GSIS is one of the most characteristic findings of β-cell dysfunction in type 2 diabetes (). Consistently, decreased early insulin response is associated with post-prandial hyperglycemia (), and improvement in the first-phase GSIS has been proposed as a strategy for better glycemic control in type 2 diabetes. However, at present, little is known on the mechanism underlying diabetes-related dysregulation of first-phase GSIS. In this issue of , Kume and colleagues have identified a novel role of hypothalamic AMPK in the regulation of first-phase GSIS in the pancreas (). They focused on the relationship between fasting-dependent decrease in the first-phase GSIS and β-cell dysfunction in type 2 diabetes. Their study used human- and animal-based experiments to reveal that prolonged fasting reduces first-phase GSIS by signaling via the brain-sympathetic nerve-β-cell axis. Reduced first-phase GSIS after prolonged fasting decreased and increased glucose redistribution to peripheral tissues and brain, respectively, thereby increasing the possibility to maintain glucose supply to the order salvinorin a at time of refeeding after prolonged fasting. Interestingly, excitation of the hypothalamic AMPK-β-cell neural axis impaired first-phase GSIS in both fasted rats and a rat model of type 2 diabetes. Furthermore, surgical denervation of the pancreas dramatically improved first-phase GSIS, glycemic control, and β-cell survival in a murine diabetic model. Decreased first-phase GSIS may be a common insulin secretion pattern during times of scarcity and type 2 diabetes. In this study, the authors suggested an interesting hypothesis that beta cells in diabetic individuals mistakenly sense that they are under conditions that mimic prolonged fasting. This so-called “starvation diabetes” was first observed in 1960s (), and Kume et al. have now solidified the notion that starvation mechanism is closely associated with the pathogenesis of type 2 diabetes (). During evolution, mammals may have developed a well-organized system to regulate blood glucose levels and to avoid serious hypoglycemia during starvation. These mechanisms may be involved in the pathogenesis of type 2 diabetes. Therefore, identifying the mechanism(s) underlying starvation diabetes may facilitate a better understanding of type 2 diabetes. In the context of translation to clinical practice, the authors have highlighted the therapeutic potency of pancreatic denervation for type 2 diabetes (). Surprisingly, this surgical approach not only improved glycemic control but also prevented future β-cell loss. This suggests a novel possibility that hyperactivation of hypothalamic AMPK by fasting leads to both acute and chronic impairment of pancreatic β cell function, even though the mechanism of diabetes prevention by pancreatic denervation remains to be determined. It also remains to be determined whether the present findings can translate to the management of type 2 diabetes. Interestingly, similar approaches are currently approved as therapeutic interventions in other diseases, including bariatric surgery for severe obesity () and renal denervation for hypertension (). If pancreatic denervation can be technically applied to human type 2 diabetic patients, this surgical approach may become a novel therapeutic strategy to improve glycemic control by improving β-cell function and survival. Again, the increasing incidence of type 2 diabetes is a global public health problem. We hope that we will be able to combat type 2 diabetes by continued efforts to fully understand disease pathogenesis. Disclosure
In 1955, Christian de Duve discovered a novel organelle packaged with hydrolytic enzymes for which he coined the terminology ‘lysosome’ (). Two decades later, he received the Nobel prize for this work and more than six decades later, our knowledge of the lysosome as an organelle for end-point degradation has expanded enormously to one that plays a central role in cellular metabolism, implicated not only in rare lysosomal storage diseases but also in common and complex diseases such as Parkinson\'s disease, dementia, and cancer (). In this issue of , () presented novel findings on progranulin (PGRN), a growth factor with anti-inflammation properties, that also functions as a co-chaperone with the heat shock protein HSP70 disaggregation system. During stress, PGRN-HSP70 prevents the aggregation of lysosomal glucocerebrosidase (GCase) and lysosomal integral membrane protein LIMP2 in the cytoplasm, and facilitates their trafficking to the lysosome. These findings have implications in Gaucher disease (GD), an autosomal recessively inherited and most prevalent lysosomal storage disease, and demonstrate the myriad of important cellular physiological functions of the lysosome, in addition to serving as the cell\'s ‘waste bin’.