The relationship between obstructive sleep apnea (OSA) and endocrine and metabolic disease is unequivocal. OSA, which is characterized by intermittent hypoxia and sleep fragmentation, leads to and exacerbates obesity, metabolic syndrome, and type 2 diabetes (T2D) as well as endocrine disturbances, such as hypothyroidism and Cushing syndrome, among others. However, this relationship is bidirectional with endocrine and metabolic diseases being considered major risk factors for the development of OSA. For example, polycystic ovary syndrome (PCOS), one of the most common endocrine disorders in women of reproductive age, is significantly associated with OSA in adult patients. Several factors have been postulated to contribute to or be critical in the genesis of dysmetabolic states in OSA including the increase in sympathetic activation, the deregulation of the hypothalamus-pituitary axis, the generation of reactive oxygen species (ROS), insulin resistance, alteration in adipokines levels, and inflammation of the adipose tissue. However, probably the alterations in the hypothalamus-pituitary axis and the altered secretion of hormones from the peripheral endocrine glands could play a major role in the gender differences in the link between OSA-dysmetabolism. In fact, normal sleep is also different between men and women due to the physiologic differences between genders, with sex hormones such as progesterone, androgens, and estrogens, being also connected with breathing pathologies. Moreover, it is very well known that OSA is more prevalent among men than women, however the prevalence in women increases after menopause. At the same time, the step-rise in obesity and its comorbidities goes along with mounting evidence of clinically important sex and gender differences. Metabolic and cardiovascular diseases, seen as a men's illness for decades, presently are more common in women than in men and obesity has a higher association with insulin-resistance-related risk factors in women than in men. In this way, in the present manuscript, we will review the major findings on the overall mechanisms that connect OSA and dysmetabolism giving special attention to the specific regulation of this relationship in each gender. We will also detail the gender-specific effects of hormone replacement therapies on metabolic control and sleep apnea.

Insulin resistance is a complex condition in which the body does not respond adequately to insulin, a hormone secreted by the pancreas with an essential role in the regulation of blood sugar levels

The association between obstructive sleep apnea (OSA) and metabolic disorders is well-established; however, the underlying mechanisms that elucidate this relationship remain incompletely understood. Since the liver is a major organ in the maintenance of metabolic homeostasis, we hypothesize that liver dysfunction plays a crucial role in the pathogenesis of metabolic dysfunction associated with obstructive sleep apnea (OSA). Herein, we explored the underlying mechanisms of this association within the liver. Experiments were performed in male Wistar rats fed with a control or high fat (HF) diet (60% lipid-rich) for 12 weeks. Half of the groups were exposed to chronic intermittent hypoxia (CIH) (30 hypoxic (5% O₂) cycles, 8 h/day) that mimics OSA, in the last 15 days. Insulin sensitivity and glucose tolerance were assessed. Liver samples were collected for evaluation of lipid deposition, insulin signaling, glucose homeostasis, hypoxia, oxidative stress, antioxidant defenses, mitochondrial biogenesis and inflammation. Both the CIH and HF diet induced dysmetabolism, a state not aggravated in animals submitted to HF plus CIH. CIH aggravates hepatic lipid deposition in obese animals. Hypoxia-inducible factors levels were altered by these stimuli. CIH decreased the levels of oxidative phosphorylation complexes in both groups and the levels of SOD-1. The HF diet reduced mitochondrial density and hepatic antioxidant capacity. The CIH and HF diet produced alterations in cysteine-related thiols and pro-inflammatory markers. The results obtained suggest that hepatic mitochondrial dysfunction and oxidative stress, leading to inflammation, may be significant factors contributing to the development of dysmetabolism associated with OSA.

Epidemiological studies showed that chronic caffeine intake decreased the risk of type 2 diabetes. Previously, we described that chronic caffeine intake prevents and reverses insulin resistance induced by hypercaloric diets and aging, in rats. Caffeine has several cellular mechanisms of action, being the antagonism of adenosine receptors the only attained with human coffee consumption. Here, we investigated the subtypes of adenosine receptors involved on the effects of chronic caffeine intake on insulin sensitivity and the mechanisms and sex differences behind this effect. Experiments were performed in male and female Wistar rats fed either a chow or high-sucrose (HSu) diet (35% of sucrose in drinking water) during 28 days, to induce insulin resistance. In the last 15 days of diet the animals were submitted to DPCPX (A₁ antagonist, 0.4 mg/kg), SCH58261 (A_2A antagonist, 0.5 mg/kg), or MRS1754 (A_2B antagonist, 9.5 μg/kg) administration. Insulin sensitivity, fasting glycaemia, blood pressure, catecholamines, and fat depots were assessed. Expression of A₁, A_2A, A_2B adenosine receptors and protein involved in insulin signaling pathways were evaluated in the liver, skeletal muscle, and visceral adipose tissue. UCP1 expression was measured in adipose tissue. Paradoxically, SCH58261 and MRS1754 decreased insulin sensitivity in control animals, whereas they both improved insulin response in HSu diet animals. DPCPX did not alter significantly insulin sensitivity in control or HSu animals, but reversed the increase in total and visceral fat induced by the HSu diet. In skeletal muscle, A₁, A_2A, and A_2B adenosine receptor expression were increased in HSu group, an effect that was restored by SCH58261 and MRS1754. In the liver, A₁, A_2A expression was increased in HSu group, while A_2B expression was decreased, being this last effect reversed by administration of MRS1754. In adipose tissue, A₁ and A_2A block upregulated the expression of these receptors. A₂ adenosine antagonists restored impaired insulin signaling in the skeletal muscle of HSu rats, but did not affect liver or adipose insulin signaling. Our results show that adenosine receptors exert opposite effects on insulin sensitivity, in control and insulin resistant states and strongly suggest that A₂ adenosine receptors in the skeletal muscle are the majors responsible for whole-body insulin sensitivity.

Accumulating evidence suggests the existence of a strong link between metabolic syndrome and neurodegeneration. Indeed, epidemiologic studies have described solid associations between metabolic syndrome and neurodegeneration, whereas animal models contributed for the clarification of the mechanistic underlying the complex relationships between these conditions, having the development of an insulin resistance state a pivotal role in this relationship. Herein, we review in a concise manner the association between metabolic syndrome and neurodegeneration. We start by providing concepts regarding the role of insulin and insulin signaling pathways as well as the pathophysiological mechanisms that are in the genesis of metabolic diseases. Then, we focus on the role of insulin in the brain, with special attention to its function in the regulation of brain glucose metabolism, feeding, and cognition. Moreover, we extensively report on the association between neurodegeneration and metabolic diseases, with a particular emphasis on the evidence observed in animal models of dysmetabolism induced by hypercaloric diets. We also debate on strategies to prevent and/or delay neurodegeneration through the normalization of whole-body glucose homeostasis, particularly via the modulation of the carotid bodies, organs known to be key in connecting the periphery with the brain.