Hepatic glycogenosis (HG) in type 1 diabetes is a underrecognized complication. Mauriac firstly described the syndrome characterized by hepatomegaly with altered liver enzymes, growth impairment, delay puberty and Cushingoid features, during childhood. HG in adulthood is characterized by the liver disorder (with circulating aminotransferase increase) in the presence of poor glycemic control (elevation of glycated hemoglobin, HbA1c levels). The advances in the comprehension of the metabolic pathways driving to the hepatic glycogen deposition point out the role of glucose transporters and insulin mediated activations of glucokinase and glycogen synthase, with inhibition of glucose-6-phosphatase. The differential diagnosis of HG consists in the exclusion of causes of liver damage (infectious, metabolic, obstructive and autoimmune disease). The imaging study (ultrasonography and/or radiological examinations) gives information about the liver alterations (hepatomegaly), but the diagnosis needs to be confirmed by the liver biopsy. The main treatment of HG is the amelioration of glycemic control that is usually accompanied by the reversal of the liver disorder. In selected cases, more aggressive treatment options (transplantation) have been successfully reported.
The metabolic syndrome (MetS) presents an increasing prevalence in elderly people. A significant role in MetS is played by the stress response and cortisol. The hypothalamic-pituitary-adrenal (HPA) axis activity is increased by central (loss of hippocampal glucocorticoid receptors) and peripheral (11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1, hyperactivity) mechanisms. The HPA hyperactivity has been found in chronic diseases affecting the endocrine (abdominal obesity with MetS, type 2 diabetes), cardiovascular (atherosclerosis, essential hypertension), and nervous systems (dementia, depression), in aging. A novel therapeutic approach (11β-HSD1 inhibition) is promising in treating the HPA axis hyperactivity in chronic diseases with MetS. A large-scale national clinical trial (AGICO, AGIng, and COrtisol study) has been proposed by our group to evaluate the role of cortisol and MetS in the main pathologies of aging (vascular and degenerative dementia, cardiovascular diseases, type 2 diabetes, abdominal obesity).
The stress response during chronic conditions increases vulnerability to diseases through the activation of adaptive systems, in particular, the hypothalamus-pituitary-adrenal (HPA) axis. Dysregulation in HPA activity (central and peripheral) has been reported in chronic diseases, like metabolic syndrome, type-2 diabetes mellitus, atherosclerosis-related disease, essential hypertension, dementia, depression, particularly during comorbid conditions. Different targets of anti-glucocorticoid treatment have been proposed, acting at supra-hypothalamic, HPA axis, glucocorticoid receptor and post-receptor levels. The recent promising patents on the therapy against glucocorticoid-mediated damage will be presented and discussed.
The brain controls coping with aversive situations, modulating the activity of the adaptive systems (the nervous, endocrine and immune systems). In this review, we focus the involvement of the hypothalamus-pituitary-adrenal (HPA) axis in the stress response. In the physiological response, the hypothalamic paraventricular nucleus secretes CRH (corticotrophin releasing hormone) that stimulates pituitary ACTH (adrenocorticotropic hormone), through CRH-receptor type 1 (CRH-R1). In turn, ACTH activates adrenal glands to produce cortisol, acting on type-2 melanocortin receptors (MC2-R). The glucocorticoid negative feedback inhibits the HPA axis activity through the glucocorticoid receptor (GR). The hippocampus plays a central role as an important connection between cortex and hypothalamus, and, together with the suprachiasmatic nucleus (SCN), regulates cortisol rhythm. Peripherally, an important regulator of cortisol metabolism in local tissues is 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), that produces cortisol within the splanchnic bed. The stress response during chronic conditions increases vulnerability to diseases through the activation of adaptive systems, in particular, the HPA axis. Increased levels of allostatic load (a measure of stress with multisystem dysregulation) are associated with the development of functional and cognitive decline, frailty and with mortality in high-functioning older adults. Moreover, HPA axis hyperactivity is a feature that can be present in chronic diseases, affecting endocrine (abdominal obesity, type-2 diabetes mellitus), cardiovascular (atherosclerosis, essential hypertension) and nervous system (dementia, depression), particularly during comorbid conditions. In conclusion, the spectrum of molecules interacting at the different levels of HPA axis is exponentially increasing, ranging from supra-hypothalamic targets to post-receptor mechanisms and it includes agents acting on SCN, CRH-R1 receptor, adrenal steroidogenesis, GR and peripheral/central 11β-HSD1 enzyme. This area of research is rapidly advancing in order to develop therapeutic strategies to counteract HPA axis hyperactivity and to reduce the burden of stress-related disorders. The article presented some promising patents on the strategies against glucocorticoid-mediated brain damage.
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