Insulin: a sweet deal for human baroreflex function

The pancreatic hormone insulin is a metabolic ‘hormone of abundance’. Following postprandial absorption of nutrients, insulin stimulates glucose and amino acid uptake into skeletal muscle and enhances hepatic and adipose tissue glycogen and fatty acid synthesis. However, its actions are considerably more far-reaching. Pancreatic insulin accumulates in the brain via active transport from plasma across the impermeable blood–brain barrier (Banks, 2004). Once in the brain, it binds to insulin receptors present in multiple discrete sites throughout the central nervous system (Banks, 2004). Its central actions include effects on energy balance, such as suppression of food intake and hepatic glucose production. Central insulin also modulates the cardiovascular system via actions on the autonomic nervous system. In humans and animals alike, increases in brain insulin due to, for example, ingestion of a meal trigger increases in muscle sympathetic outflow (Straznicky et al. 2010). This sympathoexcitation is considered teleogically beneficial, since it contributes to arterial pressure maintenance at a time when the splanchnic circulation is dilating to accommodate and disperse absorbed nutrients. Animal studies show that insulin also enhances the function of the major short-acting blood pressure regulation system, the baroreceptor reflex, by increasing baroreflex sensitivity or gain. Increased baroreflex gain in turn allows for even tighter arterial pressure control during postprandial hypotensive challenges. Remarkably, however, whether insulin exerts a similar effect on the baroreflex in humans was uncertain until now. In a recent issue of The Journal of Physiology, Young et al. (2010) address this question in healthy young male subjects. Gain of arterial baroreflex control of muscle sympathetic nerve activity (MSNA) was assessed using measurements of spontaneous baroreflex sensitivity, in which sequences of spontaneously occurring ramps in diastolic blood pressure are correlated to evoked changes in MSNA or heart rate. A particular strength of the study was that insulin was elevated within the physiological range using two approaches. Consumption of a mixed meal elicited endogenous insulin release, and exogenous insulin was infused i.v. while clamping plasma glucose levels at basal levels. In both instances, within 30 min of the increment in insulin, MSNA baroreflex gain nearly doubled. Since the hyperinsulinaemic euglycaemic clamp also quantified insulin sensitivity, these studies further revealed that those individuals with the highest insulin sensitivity also exhibited the greatest increase in MSNA baroreflex gain when insulin levels were raised. The strong correlation between insulin sensitivity and baroreflex gain observed by Young et al. in healthy men suggests an important mechanistic link with pathophysiological implications. Interestingly, several insulin-resistant conditions, such as obesity, hypertension, heart failure, type 2 diabetes mellitus, and pregnancy, are also associated with baroreflex impairment. In humans with obesity or type 2 diabetes, strategies that improve insulin sensitivity, such as weight loss, exercise, or gastric bypass surgery before weight loss, also normalize baroreflex function (Madden et al. 2010; Perugini et al. 2010; Straznicky et al. 2010). However, a major question lurks behind these associations: is insulin a master regulator of baroreflex function? Does insulin resistance contribute to baroreflex impairment in all these conditions? Other questions naturally follow. First, is brain insulin the link between insulin sensitivity and baroreflex function? Obesity is known to impair insulin transport into the brain, causing brain insulin levels to fall (Banks, 2004). But whether the fall in brain insulin contributes to the parallel drop in baroreflex gain in insulin-resistant conditions has not been established in animals or humans. Second, how does insulin resistance suppress transport of insulin into the brain? Third, where and how does insulin in the brain enhance baroreflex function? Fourth, insulin and leptin have divergent sex-specific central effects on food intake (Clegg et al. 2003); is insulin's prominent baroreflex gain-enhancing action observed by Young et al. in men also present in women? With the finding of Young et al. that insulin enhances baroreflex gain in humans, the answers to these questions become more critical, especially when considering the deleterious effects of decreases in baroreflex function. A key issue is an inability to maintain arterial pressure during acute hypotensive challenges. Indeed, pregnant women are at risk for orthostatic hypotension, and peripartum haemorrhage is a major cause of maternal mortality. In addition, impaired baroreflex sensitivity and decreased heart rate variability have been identified as risk factors for subsequent deleterious cardiovascular events in patients with type 2 diabetes mellitus or following myocardial infarction (Head, 2002; Okada et al. 2010). If decreased brain insulin is a common mechanism, then standard of care could include strategies for increasing it in insulin-resistant individuals. Thus, brain insulin may be more than an appetite-suppressing hormone; increased brain insulin could also be a sweet deal for maintenance of normal human baroreflex function.