Reduced Insulin Sensitivity Is Related to Less Endogenous Dopamine at D2/3 Receptors in the Ventral Striatum of Healthy Nonobese Humans

Abstract

Background:Food addiction is a debated topic in neuroscience. Evidence suggests diabetes is related to reduced basal dopamine levels in the nucleus accumbens, similar to persons with drug addiction. It is unknown whether insulin sensitivity is related to endogenous dopamine levels in the ventral striatum of humans. We examined this using the agonist dopamine D2/3 receptor radiotracer [11C]-(+)-PHNO and an acute dopamine depletion challenge. In a separate sample of healthy persons, we examined whether dopamine depletion could alter insulin sensitivity.Methods:Insulin sensitivity was estimated for each subject from fasting plasma glucose and insulin using the Homeostasis Model Assessment II. Eleven healthy nonobese and nondiabetic persons (3 female) provided a baseline [11C]-(+)-PHNO scan, 9 of which provided a scan under dopamine depletion, allowing estimates of endogenous dopamine at dopamine D2/3 receptor. Dopamine depletion was achieved via alpha-methyl-para-tyrosine (64mg/kg, P.O.). In 25 healthy persons (9 female), fasting plasma and glucose was acquired before and after dopamine depletion.Results:Endogenous dopamine at ventral striatum dopamine D2/3 receptor was positively correlated with insulin sensitivity (r(7)=.84, P=.005) and negatively correlated with insulin levels (r(7)=-.85, P=.004). Glucose levels were not correlated with endogenous dopamine at ventral striatum dopamine D2/3 receptor (r(7)=-.49, P=.18). Consistently, acute dopamine depletion in healthy persons significantly decreased insulin sensitivity (t(24)=2.82, P=.01), increased insulin levels (t(24)=-2.62, P=.01), and did not change glucose levels (t(24)=-0.93, P=.36).Conclusion:In healthy individuals, diminished insulin sensitivity is related to less endogenous dopamine at dopamine D2/3 receptor in the ventral striatum. Moreover, acute dopamine depletion reduces insulin sensitivity. These findings may have important implications for neuropsychiatric populations with metabolic abnormalities.

Bromocriptine-QR therapy for the management of type 2 diabetes mellitus: developmental basis and therapeutic profile summary

“…That is to say, it is the brain's response to the environment, more so that the environment itself, that dictates the full metabolic outcome of environmental changes such as the presentation of the westernized diet. The neurophysiological literature is now replete with studies demonstrating the important roles of several neural circuits that impact peripheral fuel metabolism (reviewed in [32]) including hypothalamic arcuate-alpha melanocortin-stimulating hormone (αMSH) [33][34][35] and arcuate neuropeptide Y (NPY) -paraventricular nuclei (PVN) circuits [36][37][38], the lateral hypothalamic (LH) leptinorexin mesolimbic circuit [39][40][41][42], ventromedial hypothalamic and arcuate leptin autonomic/neuroendocrine circuits [43][44][45][46][47], and the insulin arcuate [48] and dopamine mesolimbic circuits [49,50] to name just a few. Emerging experimental evidence suggests important roles for the biological clock system residing within and around the SCN of the hypothalamus in the integration of these CNS circuits to create an orchestrated organized CNS output signal (program) to the peripheral organs respecting fuel metabolism (see discussion below) [51][52][53][54].…”

“…The annual cycle of metabolism among vertebrates in the wild evolved in synchrony with the annual cycle of food quality supply. Hints of an annual cycle of fuel metabolism exist even in prehistoric man exposed to the Paleolithic diet (reviewed in [50]), which is known to support insulin sensitivity [63][64][65]. The high protein, omega-3 fatty acid, and flavonoid content of the Paleolithic diet was only available seasonally as a result of seasonal changes in the availability of flora and fauna [51].…”

“…Dopamine also functions to inhibit feeding in the perifornical area of the hypothalamus and to inhibit sympathetic nervous system (SNS) activation via its actions at the PVN [52,123]. Moreover, positron emission topography scan studies with radiolabeled dopaminergic receptor ligands in humans have identified a decreased dopaminergic function in obese and insulinresistant individuals [49,50]. However, our recent studies suggest that these non-SCN CNS functions of dopamine that collectively tend to maintain the lean/insulin-sensitive state are actually regulated in part by circadian SNC output signals that, as described herein, are modulated by circadian dopaminergic input signals to the SCN.…”

“…In normal healthy humans, plasma prolactin concentrations peak at night during sleep and are relatively low during the wakeful daylight period of the day (reviewed in [50]), and animal studies indicate this inhibition is due in large part to inhibition from hypothalamic dopaminergic tone [146]. Generally, a large fraction of obese, insulin-resistant humans have diurnal (day-time) plasma prolactin levels that are elevated relative to lean, insulin-sensitive subjects [147][148][149][150][151].…”

Brain-Based Etiology of Weight Regulation

“…Rather, insulin and dopamine interact to alter D2 availability. Elsewhere, insulin sensitivity has been shown to be negatively correlated with D2 binding potential in obese versus lean females (70), and specifically reduced insulin sensitivity has been associated with dopamine depletion in the ventral striatum (71). This is particularly interesting considering that post RYGB insulin sensitivity was improved in as little as six days post operation (72), as well as suggests an important role for dopamine on insulin sensitivity and vice versa.…”