Modulation of pancreatic exocrine and endocrine secretion

Abstract

Purpose of review Recent advances in the regulation of pancreatic secretion by secretagogues, modulatory proteins and neural pathways are discussed. Recent findings Downstream events involved in secretagogue-stimulation of pancreatic secretion have been have been elucidated through characterization of the Src kinase pathway. An additional mechanism regulating vagus nerve effects on the pancreas involves Group II and III metabotropic glutamate receptors that are located presynaptically on certain vagal pancreas-projecting neurons. Hypothalamic neurons perceive glucose and regulate insulin release by direct communication with islets, and activation of POMC neurons by leptin enhances insulin secretion and modulates glucose but not energy homeostasis. Ghrelin and somatostatin mediate glucose-stimulated insulin secretion by differential receptor signaling that is dependent on the amount of ghrelin and state of receptor heterodimerization. Endoplasmic reticulum (ER) stress and loss-of-function mutations of a key ER stress protein are associated with disruption of membrane translocation and reduction in insulin secretion. The importance of hormones, neuropeptides, amino acids, cytokines and regulatory proteins in pancreatic secretion and the pathophysiology of type 2 diabetes are also discussed. Summary The biomolecular pathways regulating pancreatic secretions are still not fully understood. New secretagogues and mechanisms continue to be identified and this information will aid in drug discovery and development of new and improved therapy for pancreatic disorders.

Amyloidogenic lysozymes accumulate in the endoplasmic reticulum accompanied by the augmentation of ER stress signals

“…Although forced overexpression of the amyloidogenic mutant lysozymes leads to their rapid accumulation in the ER, it is estimated, in the case of human body, that the accumulation of the mutant proteins proceeds slowly, resulting in developing amyloidosis mainly in the 40-50's [5,45]. Several diseases including diabetes II [46] and amyotrophic lateral sclerosis (ALS) [47,48] are known to be brought about by the accumulation of misfolding proteins in the ER. A recent report indicated that, in Saccharomyces cerevisiae, unstable lysozymes may interact with a calnexin homolog, possibly causing their retention in the ER and subsequent elimination via ER-associated degradation [49].…”

Abnormalities of the Exocrine Pancreas in Type 1 Diabetes

“…Exocrine secretion is tightly regulated by the autonomic nervous system in response to a meal and is mediated by numerous hormonal secretagogues and neurotransmitters [8, 9]. One of the most important mediators of exocrine secretion is cholecystokinin (CCK), secreted by I cells in the small intestine and by neurons in the brain [10].…”

“…CCK activates sensory afferent neurons in the duodenal mucosa, which in turn stimulates a vago-vagal reflex and the subsequent release of acetylcholine, ultimately leading to exocrine secretion by acinar cells. Exocrine secretory activity is complex and involves many different molecules and activating/inhibitory pathways that are outside of the focus of this review [7, 8, 11]. …”

Beta Cell Function and the Nutritional State: Dietary Factors that Influence Insulin Secretion

“…These vesicles secrete insulin in proportion to the concentration of glucose in the blood [8]. Despite increased intracellular Ca 2 + being the primary insulin secretary signal, the cAMP signaling-dependent mechanism also plays an important role in augmenting glucose-stimulated insulin secretion (GSIS) [3,9].…”