RESUMO
ABSTRACT: There exists no cure for acute, recurrent acute or chronic pancreatitis and treatments to date have been focused on managing symptoms. A recent workshop held by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) focused on interventions that might disrupt or perhaps even reverse the natural course of this heterogenous disease, aiming to identify knowledge gaps and research opportunities that might inform future funding initiatives for NIDDK. The breadth and variety of identified active or planned clinical trials traverses the spectrum of the disease and was conceptually grouped for the workshop into behavioral, nutritional, pharmacologic and biologic, and mechanical interventions. Cognitive and other behavioral therapies are proven interventions for pain and addiction, but barriers exist to their use. Whilst a disease specific instrument quantifying pain is now validated, an equivalent is lacking for nutrition - and both face challenges in ease and frequency of administration. Multiple pharmacologic agents hold promise. Ongoing development of Patient Reported Outcome (PRO) measurements can satisfy Investigative New Drug (IND) regulatory assessments. Despite multiple randomized clinical trials demonstrating benefit, great uncertainty remains regarding patient selection, timing of intervention, and type of mechanical intervention (endoscopic versus surgery). Challenges and opportunities to establish beneficial interventions for patients were identified.
Assuntos
Diabetes Mellitus , Pancreatite Crônica , Humanos , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/terapia , National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) , Dor , Pancreatite Crônica/terapia , Pancreatite Crônica/tratamento farmacológico , Estados UnidosRESUMO
Catecholamine neurotransmitters dopamine (DA) and norepinephrine (NE) are essential for a myriad of functions throughout the central nervous system, including metabolic regulation. These molecules are also present in the pancreas, and their study may shed light on the effects of peripheral neurotransmission on glycemic control. Though sympathetic innervation to islets provides NE that signals at local α-cell and ß-cell adrenergic receptors to modify hormone secretion, α-cells and ß-cells also synthesize catecholamines locally. We propose a model where α-cells and ß-cells take up catecholamine precursors in response to postprandial availability, preferentially synthesizing DA. The newly synthesized DA signals in an autocrine/paracrine manner to regulate insulin and glucagon secretion and maintain glycemic control. This enables islets to couple local catecholamine signaling to changes in nutritional state. We also contend that the DA receptors expressed by α-cells and ß-cells are targeted by antipsychotic drugs (APDs)-some of the most widely prescribed medications today. Blockade of local DA signaling contributes significantly to APD-induced dysglycemia, a major contributor to treatment discontinuation and development of diabetes. Thus, elucidating the peripheral actions of catecholamines will provide new insights into the regulation of metabolic pathways and may lead to novel, more effective strategies to tune metabolism and treat diabetes.
Assuntos
Antipsicóticos , Ilhotas Pancreáticas , Catecolaminas/metabolismo , Antipsicóticos/efeitos adversos , Antipsicóticos/metabolismo , Controle Glicêmico , Norepinefrina/metabolismo , Dopamina/metabolismo , Ilhotas Pancreáticas/metabolismo , Neurotransmissores/metabolismoRESUMO
In contrast to the skin and the gut, where somatic stem cells and their niche are well characterized, a definitive pancreatic multipotent cell population in the adult pancreas has yet to be revealed. Of particular interest is whether such cells may be endogenous in patients with diabetes, and if so, can they be used for therapeutic purposes? In the current study, we used two separate reporter lines to target Cre-recombinase expression to the Lgr5- or glucagon-expressing cells in the pancreas. We provide evidence for the existence of a population of cells within and in the proximity of the ducts that transiently express the stem-cell marker Lgr5 during late gestational stages. Careful timing of tamoxifen treatment in Lgr5EGFP-IRES-CreERT2 ;R26 Tomato mice allowed us to show that these Lgr5-expressing progenitor cells can differentiate into α-cells during pregnancy. Furthermore, we report on a spontaneous lineage conversion of α- to ß-cells specifically after parturition. The contribution of Lgr5 progeny to the ß-cell compartment through an α-cell intermediate phase early after pregnancy appears to be part of a novel mechanism that would counterbalance against excessive ß-cell mass reduction during ß-cell involution.
Assuntos
Linhagem da Célula , Células Secretoras de Glucagon/citologia , Células Secretoras de Insulina/citologia , Pâncreas/citologia , Período Pós-Parto/metabolismo , Receptores Acoplados a Proteínas G/fisiologia , Células-Tronco/citologia , Animais , Apoptose , Diferenciação Celular , Feminino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Pancreatic ß-cell loss and dysfunction are critical components of all types of diabetes. Human and rodent ß-cells are able to proliferate, and this proliferation is an important defense against the evolution and progression of diabetes. Transforming growth factor-ß (TGF-ß) signaling has been shown to affect ß-cell development, proliferation, and function, but ß-cell proliferation is thought to be the only source of new ß-cells in the adult. Recently, ß-cell dedifferentiation has been shown to be an important contributory mechanism to ß-cell failure. In this study, we tie together these two pathways by showing that a network of intracellular TGF-ß regulators, smads 7, 2, and 3, control ß-cell proliferation after ß-cell loss, and specifically, smad7 is necessary for that ß-cell proliferation. Importantly, this smad7-mediated proliferation appears to entail passing through a transient, nonpathologic dedifferentiation of ß-cells to a pancreatic polypeptide-fold hormone-positive state. TGF-ß receptor II appears to be a receptor important for controlling the status of the smad network in ß-cells. These studies should help our understanding of properly regulated ß-cell replication.