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Pancreatic [beta]-cell mass is dynamic and is regulated by [beta]-cell proliferation, neogenesis, and apoptosis. Under physiological conditions, apoptosis is tightly regulated with a slow, net rise in [beta]-cell mass over time. Excessive [beta]-cell apoptosis is an important contributor to both type 1 and type 2 diabetes development. Therefore, much effort has been given recently to better understand the mechanisms of apoptosis that occur both during physiological homeostasis and during the course of both types of diabetes. Caspases are the executioners of apoptosis that ultimately result in cell suicide. In mammals, there are 14 caspases, of which many participate in the apoptotic pathways. Genetic mouse models have been important tools for elucidation of the specific apoptotic pathways that play an essential role in [beta]-cell apoptosis under physiological and pathological conditions. This review focuses on the diverse roles of each of the specific caspases and their regulators, unveiling both the classical apoptotic roles as well as emerging nonapoptotic roles. caspases; diabetes doi: 10.1152/ajpendo.00696.2009.

The Goto Kakizaki (GK) rat is a widely used animal model to study defective glucose-stimulated insulin release in type-2 diabetes (T2D). As in T2D patients, the expression of several proteins involved in [Ca.sup.2+]-dependent exocytosis of insulin-containing large dense-core vesicles is dysregulated in this model. So far, a defect in late steps of insulin secretion could not be demonstrated. To resolve this apparent contradiction, we studied [Ca.sup.2+]-secretion coupling of healthy and GK rat [beta] cells in acute pancreatic tissue slices by assessing exocytosis with high time-resolution membrane capacitance measurements. We found that [beta] cells of GK rats respond to glucose stimulation with a normal increase in the cytosolic [Ca.sup.2+] concentration. During trains of depolarizing pulses, the secretory activity from GK rat [beta] cells was defective in spite of upregulated cell size and doubled voltage-activated [Ca.sup.2+] currents. In GK rat [beta] cells, evoked [Ca.sup.2+] entry was significantly less efficient in triggering release than in nondiabetic controls. This impairment was neither due to a decrease of functional vesicle pool sizes nor due to different kinetics of pool refilling. Strong stimulation with two successive trains of depolarizing pulses led to a prominent activity-dependent facilitation of release in GK rat [beta] cells, whereas secretion in controls was unaffected. Broad-spectrum inhibition of PKC sensitized [Ca.sup.2+]-dependent exocytosis, whereas it prevented the activity-dependent facilitation in GK rat [beta] cells. We conclude that a decrease in the sensitivity of the GK rat [beta]-cell to depolarization-evoked [Ca.sup.2+] influx is involved in defective glucose-stimulated insulin secretion. Furthermore, we discuss a role for constitutively increased activity of one or more PKC isoenzymes in diabetic rat [beta] cells.

Inflammatory injury to the pancreas results in regeneration of normal tissue and formation of metaplastic lesions of a ductal phenotype. These metaplastic ductal lesions (MDL) are called tubular complexes (TC), mucinous metaplasia, or pancreatic intraepithelial neoplasia. Because they are regularly found in chronic pancreatitis and pancreatic cancer, their formation is thought to represent a step in inflammation-mediated carcinogenesis. Despite these lesions' ductal character, their origin is controversial. All known pancreatic cell lineages have been suggested as the origin. In vitro studies suggest that differentiated cells in the pancreas remain highly plastic and can transdifferentiate as a mechanism of regeneration and metaplasia. In vivo studies suggest that islets, specifically [beta] cells, may be the cell of origin. However, in vitro studies are subject to ductal cell contamination, and previous in vivo studies interpret static data rather than direct evidence. Using genetic lineage tracing in vivo, we investigate whether transdifferentiation of [beta] cells contributes to regeneration or metaplasia in pancreatitis. RIP-CreER;Z/AP mice were used to heritably tag [beta] cells in the adult pancreas. Injury by cerulein pancreatitis resulted in regeneration of normal tissue and metaplasia with formation of two distinct types of TC and mucinous lesions. Lineage tracing revealed that none of these MDL are of [beta] cell origin; nor do [beta] cells contribute to regeneration of normal acinar and ductal tissue, which indicates that the plasticity of differentiated pancreatic islet cells, suggested by earlier static and in vitro studies, plays no role in regeneration, metaplasia, and carcinogenesis in vivo. metaplasia | pancreatitis | pancreatic intraepithelial neoplasia