Evidence That the Sympathetic Nervous System Elicits Rapid, Coordinated, and Reciprocal Adjustments of Insulin Secretion and Insulin Sensitivity During Cold Exposure

Abstract

Dynamic adjustment of insulin secretion to compensate for changes of insulin sensitivity that result from alteration of nutritional or metabolic status is a fundamental aspect of glucose homeostasis. To investigate the role of the brain in this coupling process, we used cold exposure as an experimental paradigm because the sympathetic nervous system (SNS) helps to coordinate the major shifts of tissue glucose utilization needed to ensure that increased thermogenic needs are met. We found that glucose-induced insulin secretion declined by 50% in rats housed at 5°C for 28 h, and yet, glucose tolerance did not change, owing to a doubling of insulin sensitivity. These potent effects on insulin secretion and sensitivity were fully reversed by returning animals to room temperature (22°C) for 4 h or by intravenous infusion of the α-adrenergic receptor antagonist phentolamine for only 30 min. By comparison, insulin clearance was not affected by cold exposure or phentolamine infusion. These findings offer direct evidence of a key role for the brain, acting via the SNS, in the rapid, highly coordinated, and reciprocal changes of insulin secretion and insulin sensitivity that preserve glucose homeostasis in the setting of cold exposure.

Glucoregulatory responses to hypothalamic preoptic area cooling

“…During insulin-resistant conditions such as obesity (Buchanan et al, 1990; Kahn et al, 1993; Moran et al, 1999), for example, preservation of normal glucose tolerance requires a proportionate increase of insulin secretion while conversely, states of increased insulin sensitivity (e.g., exercise, weight loss or cold exposure) (Bukowiecki, 1989) require a compensatory reduction of insulin secretion to avert hypoglycemia. Consistent with this concept, the relationship between insulin secretion and insulin sensitivity is hyperbolic across multiple species including humans (Kahn et al, 1993), dogs (Stefanovski et al, 2011), and rats (Morton et al, 2017). Consequently, the product of the two (referred to as the Disposition Index (DI), a measure of insulin-mediated glucose disposal) tends to remain constant in normal individuals, such that glucose tolerance remains unchanged even in the face of conditions that strongly impact tissue glucose utilization.…”

“…Our recent work demonstrates that relative to those housed at room temperature, rats exposed to at 5°C for 28 h (without access to food, to avoid the confounding effects on food intake) exhibited a marked increase of insulin sensitivity, yet glucose tolerance remained unchanged owing to a precisely calibrated compensatory decrease of insulin secretion (Morton et al, 2017). As a first step to investigate the time-course over which these responses to cold exposure are mounted, we compared measurements of blood glucose and plasma insulin levels in fasted rats that were either exposed to cold (5°C) or housed at room temperature for 4, 8 or 28 h. As expected, blood glucose levels declined steadily in both groups as a result of the increased duration of fasting.…”

“…Specifically, maintenance of core body temperature in a cold environment depends upon increased heat production (Morrison, 2016) that in turn is coupled to marked increases of insulin sensitivity and glucose uptake into thermogenic tissues (Smith et al, 1986), with glucose tolerance remaining unchanged owing to a compensatory reduction of insulin secretion (Morton et al, 2017; Vallerand et al, 1983). Moreover, the effect of cold exposure to elicit these rapid, potent and reciprocal changes of insulin sensitivity and insulin secretion appears to depend upon increased sympathetic nervous system (SNS) outflow, since the effects are rapidly reversed by intravenous infusion of the alpha-adrenergic receptor antagonist, phentolamine (Morton et al, 2017). Taken together, these findings implicate the brain in adaptive changes of insulin secretion and insulin sensitivity that preserve normal glucose tolerance during cold exposure.…”

“…Accordingly, we reasoned that if the potent effect of cold exposure on insulin secretion and insulin sensitivity is coordinated by POA neurocircuits, these responses should be elicited by direct cooling of this brain area. We therefore developed and validated a water-circulating thermode with which to cool the POA of rats, and utilized this approach to determine whether cold- induced activation of POA neurocircuits is sufficient to recapitulate the effect of cold exposure on determinants of glucose tolerance (Morton et al, 2017). …”

Study of Modified Oral Minimal Model using n-Order Decay Rate of Plasma Insulin for the Oral Glucose Tolerance Test in Subjects with Normal, Impaired and Diabetic Glucose Tolerance

“…The estimation of the S I and S G index of glucose ingestion had been an interesting research in present years with a number of different models developed for the study of this situation. Mari et al (2002) proposed a comparison of several OGTT-based methods, including one in which the glucose clearance was not described by the minimal model (Kim et al, 2014;Morton et al, 2017). Dalla Man et al (2002) proposed a glucose tracer method to validate the S I and S G index from the OGTT methods.…”