Decades of work investigating animals in the wild that undergo marked annual cycles of metabolism revealed that seasonal shifts from the obese, insulin resistant condition to the lean, insulin sensitive state are driven by shifts in the circadian phase relations of specific hypothalamic neurophysiological events.
By mimicking this neurophysiological shift by pharmacological interventions it is possible to effectuate the predicted shift in seasonal metabolism in either direction, to or from the insulin sensitive state. Similar approaches in a variety of genetic and diet-induced animal models of Type 2 Diabetes have produced similar results.
Animals in the wild under natural conditions express a marked annual cycle of metabolism, shifting between insulin sensitive, lean and insulin resistant, obese states at specific times of year. Seasonal insulin resistance imparts the ability to withstand long periods of ensuing low food availability and this seasonal mechanism appears to have evolved as a survival strategy to circumvent such an environmental stress. Among the very many examples of such seasonal variations in metabolism, are bear hibernation, bird migration, and squirrel overwintering.
Available evidence indicates that this seasonal mechanism evolved and has persisted over at least 400 million years. Neuroendocrine and neurophysiological studies of seasonal animals among all the major vertebrate classes have implicated an important role for circadian dopaminergic input to the hypothalamus and specifically to the mammalian biological pacemaker (the suprachiasmatic nuclei, SCN) therein in the regulation of whole-body fuel metabolism.
Seasonal insulin sensitive animals have a pronounced daily rhythm of dopamine release at the SCN, loss of the peak of which (either by expression of a natural annual cycle of decreased dopamine release at the area of the SCN or experimental neurotoxin destruction of dopamine neurons at the area of the SCN) induces a rapid and sustained insulin resistant metabolic syndrome. An increase in central (hypothalamic) dopaminergic tone in insulin resistant animals to mimic the normal daily rise in central dopaminergic tone in insulin sensitive animals produces improvements in insulin resistance. Rapid pulsed delivery of dopamine agonists, at the appropriate time of day to insulin resistant animals in an effort to increase low hypothalamic (SCN) dopaminerigc tone ameliorates the metabolic syndrome in a variety of animal model systems of the disorder. This timed dopamine agonist effect upon insulin resistance is manifested in part by reducing an increased hypothalamic drive for sympathetic tone, hypothalamic-pituitary adrenal axis and counter glucoregulatory activation. These effects in turn reduce postprandial hepatic glucose and lipid output, adipose lipolysis and increase insulin-stimulated glucose disposal via a series of concurrent biochemical events at the liver, adipose and muscle (Cincotta 2002).