Diabetes, body fat, skeletal muscle, and hypertension: The ominous chiasmus?

In addition to genetic and environmental factors known to play a role in the development of hypertension, body weight and obesity are highly correlated with hypertension; indeed, there is robust evidence that the prevalence of hypertension increases sharply with increasing body weight.1-4 Importantly, obesity has been shown to shift the secretory profile of the adipose tissue, which in turn contributes to the dysregulation of blood pressure; these phenomena occur through both direct actions of circulating adipokines on the vasculature and indirect actions via other systems, including the renal, central, and peripheral nervous system. For instance, leptin, which is elevated in obesity, increases blood pressure through activation of central nervous system pathways and enhancing the sympathetic nervous system output. Increased expression of pro-inflammatory adipokines in obesity, such as tumor necrosis factor-α (TNF-α), promotes vascular dysfunction through alterations in endothelial function and thickening of the vascular smooth muscle layer. These events, in turn, lead to increased oxidative stress and stiffening of the vascular wall, promoting changes in vessel reactivity. Other adipokines that have been shown to increase blood pressure include chemerin, which increases oxidative stress and impairs vasodilation, and visfatin, which stimulates proliferation of smooth muscle cells.1 In a British study performed in 50 436 individuals, Han and collaborators have demonstrated that, compared with normotensive individuals, body fat is significantly higher and skeletal muscle mass significantly lower in any sub-category of hypertension: undetected, adequately controlled, inadequately controlled, and untreated hypertension, both in men and women.5 Therefore, estimates of both body fat and skeletal muscle mass should be considered when analyzing results from health surveys (also using validated anthropometric prediction equations6, 7 when actual measurements are not possible), rather than relying on body mass index (BMI), which does not discriminate between these two fundamental parameters. Musculoskeletal disorders have been observed in diabetic patients, and abnormal changes in morphological properties in both slow and fast fibers have been reported as well.8 Skeletal muscle insulin resistance is considered a core defect in type 2 diabetes, and hyperinsulinemia has been shown to be not only a compensatory response to insulin resistance but also a self- perpetuating cause of the defect in muscle insulin action.9-11 Additionally, reduced muscle mass may further aggravate metabolic impairment, since the skeletal muscle is the primary site of glucose uptake and deposition. Most recently, diabetes has been associated with reduced mitochondrial function in the skeletal muscle8 , whereas sarcopenia, defined as loss of lean muscle mass,12 has been identified as an actual chronic complication of diabetes mellitus.13 Equally important, a reduced muscular mass has been reported in subjects with metabolic syndrome,14, 15 a cluster of at least three out of five cardiovascular risk factors.16 Muscle loss represents a decrease in the mass of insulin-responsive target tissue. This phenomenon promotes insulin resistance, metabolic syndrome, obesity, and hypertension.17 Seminal clinical studies have shown that the skeletal muscle is a major site of insulin resistance in essential hypertension and that such defect is independent of muscle perfusion18; moreover, insulin triggers an abnormal muscle sympathetic activity in essential hypertension.19 Notably, exercise training has been proved to be the intervention that most comprehensively improves the diverse aspects of mitochondrial function, along with whole-body and skeletal muscle insulin sensitivity.8, 12, 20, 21 Blood pressure is directly associated with body size22; however, total body mass contains two factors that have opposite biological effects: adipose tissue and lean mass.5 Subjects with sarcopenia commonly experience functional impairment and physical disability, which may cause a reduction in muscle contraction-induced factors having anti-inflammatory effects, known as myokines23: the relative paucity of myokines in sarcopenia may increase the risk of cardiovascular disorders, including hypertension.24, 25 Subjects with sarcopenic obesity have a greater risk of hypertension than simply obese or sarcopenic subjects.26 Sarcopenic obesity, defined by appendicular muscle mass/body weight, was found to be more closely associated with metabolic syndrome than either obesity or sarcopenia alone.24, 27 Therefore, sarcopenia and obesity might act synergistically on both metabolic and functional impairments. Indeed, a decreased muscle capacity has been observed in the spontaneously hypertensive rat.28 Moreover, low muscle mass has been recently associated with arterial stiffness and cognitive impairment29 and also with an increased cardiometabolic risk regardless of nutritional status.30 Exercise has been long documented to improve blood pressure, even in obese individuals in absence of weight loss.31, 32 The modulation of the adrenergic system has been shown to be a crucial mechanism underlying the beneficial effects of exercise in hypertensive patients.31, 33-36 Another potential mechanism is the increase in skeletal muscle mass, which has been demonstrated to be modulated by myostatin, a fundamental negative regulator of muscle growth; interestingly, myostatin is upregulated in obesity and downregulated by exercise,37 and preclinical studies have shown that increased muscle mass can reduce blood pressure in obesity, as well as improve glucose tolerance and renoprotection, independent of changes in body weight and/or adiposity.38, 39 Obesity is the major risk factor for the development of pre-diabetes and type 2 diabetes. The National Health and Nutrition Examination Survey (NHANES) has verified that the BMI is positively associated with the prevalence of metabolic syndrome.40 Despite being widely used as a surrogate measure of obesity, BMI underestimates the prevalence of obesity, defined as an excess of body fat.41 Indeed, clinical studies have demonstrated that the actual body fat amount is playing an essential role in the development of insulin resistance and that maintaining normal body fat is significantly more relevant than BMI in preventing diabetes.41-43 Several epidemiological studies have confirmed that BMI alone may lack predictive value for type 2 diabetes due to differences in muscle mass and fat mass (particularly abnormal adiposity) for the same BMI value.41, 44, 45 A significant proportion of people with a normal BMI (18.5-24.9 kg/m2) has been shown to have pre-diabetes, undiagnosed diabetes, and hypertension.46, 47 Moreover, the increase in body fat has been shown to represent an independent risk factor for new-onset diabetes after transplantation,48 a serious metabolic complication that can follow organ transplantation.49, 50 Epidemiological and pathological data indicate that diabetes represents an independent risk factor for cardiovascular disease.51-54 As incident diabetes is more frequent in hypertensive than normotensive subjects,55 the incidence of hypertension is twofold higher in subjects with diabetes relative to aged-matched individuals without diabetes.56, 57 Moreover, uncontrolled blood pressure is associated with a twofold increased risk of incident diabetes in treated hypertensive patients,58 and the presence of hypertensive target organ damage increases the risk of diabetes independent of anti-hypertensive treatment and metabolic profile.59 Insulin has opposing vasodilator and vasoconstrictor actions (eg, simultaneously stimulating both production of nitric oxide and secretion of endothelin-1) such that the net hemodynamic effect of insulin on blood pressure is minimal in healthy humans; for instance, intravenous insulin infusion significantly increases heart rate and cardiac output and decreases total peripheral resistance.35, 60 A strong association between hypertension and sarcopenia has been proven in diabetic patients: in a Korean study, the prevalence of hypertension among elderly diabetic adults was 70.3%, and the risk of hypertension was fourfold higher in diabetic patients with obese sarcopenia relative to patients without.26 Intriguingly, the above-mentioned study by Han and colleagues5 also revealed that diabetic patients had higher body fat and lower muscle mass, calculated as percentage of body weight, than non-diabetic individuals, for any given hypertensive status, as such opening new fields of investigations in order to determine the exact molecular mechanisms underlying these findings. GS is supported by the NIH (DK107895). The authors have no conflicts of interest to declare.