Glucocorticoids (GCs) are broadly prescribed for numerous pathological conditions because of their anti-inflammatory, antiallergic and immunosuppressive effects, among other actions. Nevertheless, GCs can produce undesired diabetogenic side effects through interactions with the regulation of glucose homeostasis. Under conditions of excess and/or long-term treatment, GCs can induce peripheral insulin resistance (IR) by impairing insulin signalling, which results in reduced glucose disposal and augmented endogenous glucose production. In addition, GCs can promote abdominal obesity, elevate plasma fatty acids and triglycerides, and suppress osteocalcin synthesis in bone tissue. In response to GC-induced peripheral IR and in an attempt to maintain normoglycaemia, pancreatic β-cells undergo several morphofunctional adaptations that result in hyperinsulinaemia. Failure of β-cells to compensate for this situation favours glucose homeostasis disruption, which can result in hyperglycaemia, particularly in susceptible individuals. GC treatment does not only alter pancreatic β-cell function but also affect them by their actions that can lead to hyperglucagonaemia, further contributing to glucose homeostasis imbalance and hyperglycaemia. In addition, the release of other islet hormones, such as somatostatin, amylin and ghrelin, is also affected by GC administration. These undesired GC actions merit further consideration for the design of improved GC therapies without diabetogenic effects. In summary, in this review, we consider the implication of GC treatment on peripheral IR, islet function and glucose homeostasis.
Alex Rafacho, Henrik Ortsäter, Angel Nadal and Ivan Quesada
Ivan Quesada, Eva Tudurí, Cristina Ripoll and Ángel Nadal
The secretion of glucagon by pancreatic α-cells plays a critical role in the regulation of glycaemia. This hormone counteracts hypoglycaemia and opposes insulin actions by stimulating hepatic glucose synthesis and mobilization, thereby increasing blood glucose concentrations. During the last decade, knowledge of α-cell physiology has greatly improved, especially concerning molecular and cellular mechanisms. In this review, we have addressed recent findings on α-cell physiology and the regulation of ion channels, electrical activity, calcium signals and glucagon release. Our focus in this review has been the multiple control levels that modulate glucagon secretion from glucose and nutrients to paracrine and neural inputs. Additionally, we have described the glucagon actions on glycaemia and energy metabolism, and discussed their involvement in the pathophysiology of diabetes. Finally, some of the present approaches for diabetes therapy related to α-cell function are also discussed in this review. A better understanding of the α-cell physiology is necessary for an integral comprehension of the regulation of glucose homeostasis and the development of diabetes.
Laura Marroqui, Eva Tudurí, Paloma Alonso-Magdalena, Iván Quesada, Ángel Nadal and Reinaldo Sousa dos Santos
Type 2 diabetes is a chronic, heterogeneous syndrome characterized by insulin resistance and pancreatic β-cell dysfunction or death. Among several environmental factors contributing to type 2 diabetes development, endocrine-disrupting chemicals (EDCs) have been receiving special attention. These chemicals include a wide variety of pollutants, from components of plastic to pesticides, with the ability to modulate endocrine system function. EDCs can affect multiple cellular processes, including some related to energy production and utilization, leading to alterations in energy homeostasis. Mitochondria are primarily implicated in cellular energy conversion, although they also participate in other processes, such as hormone secretion and apoptosis. In fact, mitochondrial dysfunction due to reduced oxidative capacity, impaired lipid oxidation and increased oxidative stress has been linked to insulin resistance and type 2 diabetes. Herein, we review the main mechanisms whereby metabolism-disrupting chemical (MDC), a subclass of EDCs that disturbs energy homeostasis, cause mitochondrial dysfunction, thus contributing to the establishment of insulin resistance and type 2 diabetes. We conclude that MDC-induced mitochondrial dysfunction, which is mainly characterized by perturbations in mitochondrial bioenergetics, biogenesis and dynamics, excessive reactive oxygen species production and activation of the mitochondrial pathway of apoptosis, seems to be a relevant mechanism linking MDCs to type 2 diabetes development.
Ana B Ropero, Pablo Juan-Picó, Alex Rafacho, Esther Fuentes, F Javier Bermúdez-Silva, Enrique Roche, Ivan Quesada, Fernando Rodríguez de Fonseca and Angel Nadal
PPARα is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. PPARα is involved in the regulation of in vivo triglyceride levels, presumably through its effects on fatty acid and lipoprotein metabolism. Some nuclear receptors have been involved in rapid effects mediated by non-genomic mechanisms. In this paper, we report the rapid non-genomic effects of PPARα ligands on the intracellular calcium concentration ([Ca2 +]i), mitochondrial function, reactive oxygen species (ROS) generation, and secretion of insulin in freshly isolated mouse islets of Langerhans. The hypolipidemic fibrate PPARα agonist WY-14 643 decreased the glucose-induced calcium oscillations in intact islets. This effect was mimicked by the synthetic agonist GW7647 and the endogenous agonist oleylethanolamide. The WY-14 643 action was rapid in onset (5 min) and was still produced in the presence of protein and mRNA synthesis inhibitors, cycloheximide, and actinomycin-d. This suggests that it is independent of gene transcription. In addition, WY-14 623 impaired mitochondrial function, increased ROS formation and decreased insulin release. PPARα is present in β-cells, mainly in the cytosol and nucleus, with a small subpopulation localized in the plasma membrane. However, the presence of the PPARα ligand effects in mice bearing a disrupted Pparα gene raises the possibility that the rapid effects of the agonists in pancreatic β-cells are independent of the receptor. We conclude that PPARα agonists produce a decrease in glucose-induced [Ca2 +]i signals and insulin secretion in β-cells through a rapid, non-genomic mechanism.
Silvana Y Romero-Zerbo, Alex Rafacho, Adenis Díaz-Arteaga, Juan Suárez, Ivan Quesada, Mónica Imbernon, Ruth A Ross, Carlos Dieguez, Fernando Rodríguez de Fonseca, Rubén Nogueiras, Ángel Nadal and Francisco J Bermúdez-Silva
The cannabinoid CB1 receptor is a well-known player in energy homeostasis and its specific antagonism has been used in clinical practice for the treatment of obesity. The G protein-coupled receptor GPR55 has been recently proposed as a new cannabinoid receptor and, by contrast, its pharmacology is still enigmatic and its physiological role is largely unexplored, with no reports investigating its putative role in metabolism. Thus, we aim to investigate in rats the presence, distribution and putative physiological role of GPR55 in a key metabolic tissue, the endocrine pancreas. We found high Gpr55 mRNA content in pancreatic islets and considerable protein distribution in insulin-secreting β-cells. Activation of GPR55 by the agonist O-1602 increased calcium transients (P<0.01) and insulin secretion (P<0.001) stimulated by glucose. This latter effect was blunted in Gpr55 KO mice suggesting that O-1602 is acting, at least in part, through GPR55. Indeed, acute in vivo experiments showed that GPR55 activation increases glucose tolerance (P<0.05) and plasma insulin levels (P<0.05), suggesting an in vivo physiological relevance of GPR55 systemic stimulation. Taken together, these results reveal the expression of GPR55 receptors in the endocrine pancreas as well as its function at stimulus-secretion coupling of insulin secretion, suggesting a role in glucose homeostasis. In this context, it may also represent a new target for consideration in the management of type 2 diabetes and related diseases.