Previous studies of insulin resistance indicate that the modern human pathology of metabolic syndrome is not majorly a result of a “genetic defect” but more so of an environmentally induced (eg, adverse diet, stress, disrupted sleep-wake architecture) alteration of circadian neuroendocrine regulation of metabolism.

 

Learning From Nature

Studies of animals in the wild indicate that seasonal insulin resistance evolved as a survival benefit during periods of low food and glucose availability (winter in temperate zones). During this time, insulin resistance potentiates a hyperinsulinemia response that functions to increase lipid synthesis and storage (fattening), which is ultimately used as a fuel in peripheral tissues. This increased use of fat as an energy source by peripheral tissues coupled with increased liver production of glucose better provides plasma glucose for the brain, keeping it in good health during long periods (months) of low or no glucose supply in the environment. Remarkably, when the low food season is over, the obese, insulin-resistant condition subsides on its own without any dietary, exercise, or pharmacotherapy intervention.

This annual seasonal cycle of metabolism phenomenon is observed across representative species of all the major vertebrate classes spanning over 400 million years of evolution, including humans. By studying the clock mechanisms in the brain that participate in the development and reversal of this seasonal insulin resistant condition, it has been discovered that the circadian rhythm of brain dopaminergic activity is one important regulator of the body’s biological clock system (the suprachiasmatic nucleus in the hypothalamus), which along with other neuronal signals, functions to modulate the clock system control over metabolism. The circadian peak of dopaminergic activity (usually at the time of daily awakening) becomes diminished at the onset of the insulin-resistant season and is actually a signal to the clock system in the brain to change its control of biochemical physiology throughout the body. These mechanisms, which act to resist insulin action and stimulate hyperinsulinemia, include over-activation of the sympathetic nervous system and the hypothalamic-pituitary-adrenal (cortisol) axis, as well as the induction of leptin resistance, among others. Contrariwise, in the spring, a re-instatement of the circadian peak of brain dopaminergic activity at the clock occurs naturally and facilitates the reversal of this insulin-resistant state.

 

Modern Man’s Dilemma

The dilemma is that in modern man, several aspects of the westernized lifestyle—including high-fat and -sugar diets, psychosocial stress, and altered sleep/wake cycle architectures—all reduce brain dopamine activity. This is resultantly perceived by the brain clock system as the “impending stress” signal to move the individual into the “survival” state of insulin resistance. Interestingly, most antipsychotic medications carry dopamine antagonist activity and are often associated with increased risk for obesity, glucose intolerance, type 2 diabetes, or a combination of all of these. Because these westernized lifestyle stresses can persist throughout the year, year after year, the dopamine-clock system is set in a default mode of inducing insulin resistance long term, not just for a season. Consequently, subsequent pathology can develop—such as type 2 diabetes and cardiovascular disease risk—from sustained reduction in brain dopamine activity.

Certain in vivo studies of brain neurochemistry of humans with obesity, insulin resistance, or both suggest that low brain dopamine activity associates with, and could contribute to, insulin resistance. In a variety of animal models of type 2 diabetes, appropriate circadian-timed re-instatement of the circadian peak dopamine signal systemically or directly at the brain clock center is sufficient to reverse the insulin-resistant/glucose-intolerant condition. Similarly, circadian-timed administration (within 2 hours of waking) of the uniquely formulated dopamine agonist, bromocriptine-QR, has been demonstrated to improve postprandial glucose metabolism without increasing plasma insulin in patients with type 2 diabetes. This increased “dopamine signal” to the brain at the appropriate time of day with pharmacotherapy can reduce over-activation of the sympathetic nervous system and thereby help reduce insulin resistance.