It is increasingly apparent that not only is a cure for the current worldwide diabetes epidemic required, but also for its major complications, affecting both small and large blood vessels. These complications occur in the majority of individuals with both type 1 and type 2 diabetes. Among the most prevalent microvascular complications are kidney disease, blindness, and amputations, with current therapies only slowing disease progression. Impaired kidney function, exhibited as a reduced glomerular filtration rate, is also a major risk factor for macrovascular complications, such as heart attacks and strokes. There have been a large number of new therapies tested in clinical trials for diabetic complications, with, in general, rather disappointing results. Indeed, it remains to be fully defined as to which pathways in diabetic complications are essentially protective rather than pathological, in terms of their effects on the underlying disease process. Furthermore, seemingly independent pathways are also showing significant interactions with each other to exacerbate pathology. Interestingly, some of these pathways may not only play key roles in complications but also in the development of diabetes per se. This review aims to comprehensively discuss the well validated, as well as putative mechanisms involved in the development of diabetic complications. In addition, new fields of research, which warrant further investigation as potential therapeutic targets of the future, will be highlighted.

Mechanisms of Diabetic Complications

Tea is the most consumed drink in the world after water. Green tea is a 'non-fermented' tea, and contains more catechins, than black tea or oolong tea. Catechins are in vitro and in vivo strong antioxidants. In addition, its content of certain minerals and vitamins increases the antioxidant potential of this type of tea. Since ancient times, green tea has been considered by the traditional Chinese medicine as a healthful beverage. Recent human studies suggest that green tea may contribute to a reduction in the risk of cardiovascular disease and some forms of cancer, as well as to the promotion of oral health and other physiological functions such as anti-hypertensive effect, body weight control, antibacterial and antivirasic activity, solar ultraviolet protection, bone mineral density increase, anti-fibrotic properties, and neuroprotective power. Increasing interest in its health benefits has led to the inclusion of green tea in the group of beverages with functional properties. However, although all the evidence from research on green tea is very promising, future studies are necessary to fully understand its contributions to human health, and advise its regular consumption in Western diets, in which green tea consumption is nowadays limited and sporadic.

Beneficial Effects of Green Tea—A Review

Sleep-induced apnea and disordered breathing refers to intermittent, cyclical cessations or reductions of airflow, with or without obstructions of the upper airway (OSA). In the presence of an anat...

Pathophysiology of Sleep Apnea

Herein, we review mechanisms regulating cerebral blood flow (CBF), with specific focus on humans We revisit important concepts from the older literature and describe the interaction of various mechanisms of cerebrovascular control We amalgamate this broad scope of information into a brief review, rather than detailing any one mechanism or area of research The relationship between regulatory mechanisms is emphasized, but the following three broad categories of control are explicated: (1) the effect of blood gases and neuronal metabolism on CBF; (2) buffering of CBF with changes in blood pressure, termed cerebral autoregulation; and (3) the role of the autonomic nervous system in CBF regulation With respect to these control mechanisms, we provide evidence against several canonized paradigms of CBF control Specifically, we corroborate the following four key theses: (1) that cerebral autoregulation does not maintain constant perfusion through a mean arterial pressure range of 60–150 mmHg; (2) that there is important stimulatory synergism and regulatory interdependence of arterial blood gases and blood pressure on CBF regulation; (3) that cerebral autoregulation and cerebrovascular sensitivity to changes in arterial blood gases are not modulated solely at the pial arterioles; and (4) that neurogenic control of the cerebral vasculature is an important player in autoregulatory function and, crucially, acts to buffer surges in perfusion pressure Finally, we summarize the state of our knowledge with respect to these areas, outline important gaps in the literature and suggest avenues for future research

https://physoc.onlinelibrary.wiley.com/doi/epdf/10.1113/jphysiol.2013.268953

Integrative regulation of human brain blood flow

Obstructive sleep apnoea syndrome (OSAS) is a common clinical condition in which the throat narrows or collapses repeatedly during sleep, causing obstructive sleep apnoea events. The syndrome is particularly prevalent in middle-aged and older adults. The mechanism by which the upper airway collapses is not fully understood but is multifactorial and includes obesity, craniofacial changes, alteration in upper airway muscle function, pharyngeal neuropathy and fluid shift towards the neck. The direct consequences of the collapse are intermittent hypoxia and hypercapnia, recurrent arousals and increase in respiratory efforts, leading to secondary sympathetic activation, oxidative stress and systemic inflammation. Excessive daytime sleepiness is a burden for the majority of patients. OSAS is also associated with cardiovascular co-morbidities, including hypertension, arrhythmias, stroke, coronary heart disease, atherosclerosis and overall increased cardiovascular mortality, as well as metabolic dysfunction. Whether treating sleep apnoea can fully reverse its chronic consequences remains to be established in adequately designed studies. Continuous positive airway pressure (CPAP) is the primary treatment modality in patients with severe OSAS, whereas oral appliances are also widely used in mild to moderate forms. Finally, combining different treatment modalities such as CPAP and weight control is beneficial, but need to be evaluated in randomized controlled trials. For an illustrated summary of this Primer, visit: http://go.nature.com/Lwc6te.

Obstructive sleep apnoea syndrome

Rationale: Impaired endothelium-dependent vasodilation has been documented in patients with sleep apnea. This impairment may result in blood flow dysregulation during apnea-induced fluctuations in arterial blood gases. Objectives: To test the hypothesis that hypoxic and hypercapnic vasodilation in the forearm and cerebral circulation are impaired in patients with sleep apnea. Methods: We exposed 20 patients with moderate to severe sleep apnea and 20 control subjects, to isocapnic hypoxia and hyperoxic hypercapnia. A subset of 14 patients was restudied after treatment with continuous positive airway pressure. Measurements and Main Results: Cerebral flow velocity (transcranial Doppler), forearm blood flow (venous occlusion plethysmography), arterial pressure (automated sphygmomanometry), oxygen saturation (pulse oximetry), ventilation (pneumotachograph), and endtidal oxygen and carbon dioxide tensions (expired gas analysis) were measured during three levels of hypoxia and two levels of hypercapnia. Cerebral vasodilator responses to hypoxia (20.65 6 0.44 vs. ‐1.02 6 0.72 [mean 6 SD] units/% saturation; P 5 0.03) and hypercapnia (2.01 6 0.88 vs. 2.57 6 0.89 units/mm Hg; P 5 0.03) were smallerinpatientsversuscontrolsubjects.Hypoxicvasodilationinthe forearm was also attenuated (20.05 6 0.09 vs. 20.10 6 0.09 unit/% saturation; P 5 0.04). Hypercapnia did not elicit forearm vasodilation in either group. Twelve weeks of continuous positive airway pressure treatment enhanced hypoxic vasodilation in the cerebral circulation (20.83 6 0.32 vs. 20.46 6 0.29 units/% saturation; P 5 0.01) and forearm (20.19 6 0.15 vs. 20.02 6 0.08 units/% saturation; P 5 0.003), and hypercapnic vasodilation in the brain showed a trend toward improvement (2.24 6 0.78 vs. 1.76 6 0.64 units/mm Hg; P 5 0.06). Conclusions: Vasodilator responses to chemical stimuli in the cerebral circulation and the forearm are impaired in many patients with

/pdf/impaired-vascular-regulation-in-patients-with-obstructive-2pt5114w11.pdf

Impaired vascular regulation in patients with obstructive sleep apnea: effects of continuous positive airway pressure treatment.

Obstructive sleep apnea (OSA) is a recognized cause of secondary hypertension. OSA episodes produce surges in systolic and diastolic pressure that keep mean blood pressure levels elevated at night. In many patients, blood pressure remains elevated during the daytime, when breathing is normal. Contributors to this diurnal pattern of hypertension include sympathetic nervous system overactivity and alterations in vascular function and structure caused by oxidant stress and inflammation. Treatment of OSA with nasal continuous positive airway pressure (CPAP) abolishes apneas, thereby preventing intermittent arterial pressure surges and restoring the nocturnal "dipping" pattern. CPAP treatment also has modest beneficial effects on daytime blood pressure. Because even small decreases in arterial pressure can contribute to reducing cardiovascular risk, screening for OSA is an essential element of evaluating patients with hypertension.

Obstructive sleep apnea and hypertension: mechanisms, evaluation, and management.

Sleep-disordered breathing (SDB) is a medical condition that has increasingly recognized adverse health effects. Obesity is the primary risk factor for the development of SDB and contributes to cardiovascular and metabolic abnormalities in this population. However, accumulating evidence suggests that SDB may be related to the development of these abnormalities independent of obesity. Periodic apneas and hypopneas during sleep result in intermittent hypoxemia, arousals, and sleep disturbances. These pathophysiologic characteristics of SDB are likely mechanisms underlying cardiovascular and metabolic abnormalities including hypertension and other cardiovascular diseases, altered adipokines, inflammatory cytokines, insulin resistance, and glucose intolerance. Treatment of SDB with continuous positive airway pressure reverses some but not all of these abnormalities; however, studies to date have demonstrated inconsistent findings. Weight loss strategies, including diet, exercise, medications, and bariatric surgery, have been evaluated as a treatment strategy for SDB. In preliminary studies, dietary intervention and exercise reduced severity of SDB. One study demonstrated improvements in SDB severity using the weight-reducing medication sibutramine. In morbidly obese subjects, bariatric surgery effectively induces weight loss and improvement in SDB severity and symptoms, but long-term benefits remain uncertain. Large randomized trials are required to determine the utility of these strategies as long-term approaches to improving SDB and reducing associated complications.

/pdf/sleep-disordered-breathing-and-obesity-pathophysiology-1ursultqfo.pdf

Sleep-disordered breathing and obesity: pathophysiology, complications, and treatment.

Background: Xanthine oxidase is a major source of superoxide in the vascular endothelium Previous work in humans demonstrated improved conduit artery function following xanthine ox

/pdf/xanthine-oxidase-inhibition-attenuates-endothelial-3njh5w6k9f.pdf

Xanthine oxidase inhibition attenuates endothelial dysfunction caused by chronic intermittent hypoxia in rats.

BACKGROUND Obesity is associated with exaggerated blood pressure and systemic vascular resistance responses to mental stress. OBJECTIVE To test the hypothesis that skin and muscle microvascular dilatation in response to mental stress is blunted in obesity. DESIGN AND METHODS Blood pressure, heart rate and forearm and skin blood flow responses to mental stress were compared in 23 obese and 23 age- and sex-matched lean normotensive individuals. RESULTS Blood pressure was almost identical in both obese (mean 94 +/- 1 mmHg) and lean (93 +/- 2 mmHg) individuals. The increase in blood pressure during mental stress was similar in obese and lean individuals (2.0 +/- 0.9% compared with 3.1 +/- 4.0%; P = 0.8). Forearm vascular resistance decreased during mental stress in both groups, but this decrease was significantly blunted in obese individuals compared with controls (decreases of 14 +/- 4% and 26 +/- 3%; P < 0.01). Skin microcirculatory dilatation was also significantly blunted in obese individuals compared with controls (decreases of 5 +/- 2 and 17 +/- 4%; P = 0.02). CONCLUSIONS Normotensive obese individuals exhibit markedly impaired muscle and skin microcirculatory responses to mental stress. The increased propensity of obese individuals to develop hypertension under conditions of chronic psychosocial stress may underlie obesity-related hypertension and cardiovascular disease.

John M. Dopp

Papers

Impaired vascular regulation in patients with obstructive sleep apnea: effects of continuous positive airway pressure treatment.

Obstructive sleep apnea and hypertension: mechanisms, evaluation, and management.

Sleep-disordered breathing and obesity: pathophysiology, complications, and treatment.

Xanthine oxidase inhibition attenuates endothelial dysfunction caused by chronic intermittent hypoxia in rats.

Impaired skeletal muscle and skin microcirculatory function in human obesity.