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A New Paradigm in the Understanding and Treatment of the Metabolic Syndrome: Targeting Alterations within the Biological Clock System

Evolutionary Selection for Insulin Resistance in a Cyclic Environment:  Brain Clocks and Control of Peripheral Fuel Metabolism

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The prevalence of obesity and insulin resistance syndrome, rare only a century ago in most geographic locals of the world are now disorders whose prevalence represents the majority of humans in westernized countries on planet Earth.    This simple observation strongly suggests that factors other than or in addition to genetic mutations/alterations are facilitating this rapid onset in disease occurrence world wide.  While studies of genetic mutations associated with metabolic disease have identified critical biochemical and physiological pathways in the regulation of metabolism, these studies have unveiled only a few genes that collectively may account for a very small fraction of the metabolic disease prevalence in the world today.  It appears that physiological regulation of gene expression rather than heritable alteration/loss of gene function is a dominant component to metabolic status.  Although the insulin resistance syndrome is viewed by the medical community as a defect of normal physiology, a plethora of available evidence indicates that the insulin resistant condition evolved among vertebrates as a survival strategy to enable increased survivability of ensuing, predictable seasons of low/no food (including glucose) availability.

Studies of animals under natural environmental conditions that all vertebrates, including humans, evolved within indicate that biological clocks and organismal level pacemaker systems within the central nervous system are strong modulators of systemic fuel metabolism.    Animals in the wild exposed to a seasonal fluctuation in flora and fauna food stuffs exhibit seasonal changes in body fat store levels and insulin sensitivity wherein the onset of insulin resistance and subsequent fattening precedes and overlaps the ensuing season of low food availability (e.g., winter).  In an environment absent of or in scarce supply of food and sugar, the obese/insulin resistant state allows for increased endogenous hepatic glucose output into the circulation that due to peripheral insulin resistance is better shunted to the brain, which has a near absolute requirement for glucose as an energy source.  The increased fat stores in adipose and muscle potentiate insulin resistance in peripheral tissues when coupled with increased muscle utilization of such fat stores as an energy source and the animal survives the environmental stress of low food availability generally and low glucose supply specifically.  With the subsequent emerging season of increased food availability (e.g., spring) the obese/insulin resistant state recedes and vanishes.  That is, as the seasonal famine comes to an end, so to does the insulin resistant condition, amidst an environment of food plenty.  This annual cycle of metabolism is expressed equally well in hibernating, migrating and over-wintering animals.  This annual cycle of insulin sensitivity is expressed under laboratory conditions even when the animals’ dietary composition and consumption amount remain constant through the year.  Moreover, the effects of a high fat diet to induce insulin resistance are much greater during the insulin resistant season than during the insulin sensitive season, when such diets are minimally effective in inducing insulin resistance.   It is not merely the ability to become obese and insulin resistant that is the survival advantage selected for by evolution but rather the ability to become obese and insulin resistant at precisely the correct time of the year.  Since this obese/insulin resistant state is relatively short-lived, pathology does not develop.  However, it may be reasonable to assume that much may be learned of the regulation of metabolism and dysmetabolism among humans from the study of the natural evolution of vertebrate metabolic physiology preserved over the past 400 million years.  Such annual cycles of metabolism are pervasive among all vertebrate species and have been documented in humans as well.   Such observations beg the obvious question of what is the nature of this well preserved physiological timing mechanism to control fuel metabolism independent of food consumption.

A series of studies conducted initially and primarily by the laboratory of Dr. Albert H. Meier and his colleagues at Louisiana State University in Baton Rouge, LA, between the years of the early 1960s to the late 1980s and subsequently to date by the laboratories of Anthony H. Cincotta, have shed light on the essence of vertebrate biological timing mechanisms responsible for control of seasonal peripheral fuel metabolism.  To concisely summarize the half century findings of these laboratories, it was found that the annual cycle of metabolism in vertebrates was itself the manifestation of changing circadian phase (temporal) relationships of circadian neuronal oscillations in the brain that input to the biological clock pacemaker system (centered at the suprachiasmatic nucleus1 of the hypothalamus).  This information is then processed and responded to by the SCN (suprachiasmatic nucleus) that then directs metabolic functions through direct communication with the neuroendocrine axis.  The SCN clock system sends strong regulatory signals to the preautonomic fibers in the hypothalamus, to higher brain centers regulating autonomic function, and to the entire neuroendocrine system.  A long series of studies led to the postulate that the changing phase relations of circadian dopaminergic and serotonergic neuronal input signals into the pacemaker clock system in the hypothalamus (centered at the suprachiasmatic nuclei) regulate the output signals from the clock that in turn regulate neuroendocrine programming of metabolism.  For example, a circadian peak of dopaminergic input activity to the SCN at 12 hours after the circadian peak of serotonergic input activity to the SCN is coupled to one seasonal condition (obese/insulin resistant state) while a circadian dopaminergic input activity to the SCN at 0 hours after the circadian peak in serotonergic input activity to the SCN is coupled to another seasonal condition (lean/insulin sensitive state) (Figure 1)

.cincotta-chart-1Figure 1. Click image to enlarge.

Figure 1. Circadian organization of the annual cycle of metabolism of a representative mammalian species.

Seasonal changes in insulin sensitivity/body fat store levels are consequences of changes in day length (i.e., photoperiodism) coupled with seasonal alternations in responsiveness to daily photoperiod length (seasonality: scotosensitive [sensitive to the neurophysiologic effects of short daily photoperiod, e.g. <10hrs] and scotorefractory [refractory to the neurophysiologic effects of short daily photoperiod, e.g. <10hrs] responsive conditions). Scotosensitive animals become sensitive to the insulin resistance and fattening effects of short daily photoperiod lengths (<12 hours of light per day; Oct—Feb) that occur naturally during the fall-winter seasons. After ~20 weeks of short daily photoperiods, the animals spontaneously become scotorefractory (unresponsive to the stimulatory effects of short daily photoperiods to induce insulin resistance) so that insulin sensitivity ensues and body fat stores are depleted and animals remain so while retained on short daily photoperiods (artificially in lab) (Feb- May). Long daily photoperiods for 8–10 weeks, occurring naturally during summer (Jun- Sep), are required to reinitiate scotosensitivity to short daily photoperiods. Daily photoperiod length coupled with seasonality establishes the phase relationships of two or more circadian neural oscillations that input to and modulate biological clock neural output activities via the autonomic and neuroendocrine axes to produce either the insulin sensitive or insulin resistant states by way of a temporal synergism of their circadian expressions (i .e., different phase relationships of different circadian activities in the CNS generate different phase relationships of different circadian activities in the peripheral tissues that thus regulate metabolic activities in those tissues as a function of their circadian phase relationships). One such important regulator of the clock circadian output activity is the circadian rhythm of dopaminergic input to the clock.

Copyright 1996 American Diabetes Association From Diabetes Reviews®, Vol. 4, 1996; 464487

Modified with permission from The American Diabetes Association.

Meier and Cincotta [51] with permission.

Importantly, merely mimicking the phase relationship of circadian dopaminergic and serotonergic input signals to the clock as observed at a particular season by appropriately circadian timed daily injections of their precursors (L-DOPA and 5HTP, respectively) produce that seasonal physiology irrespective of the actual time of year of such treatment.  That is to say, it is possible to shift animals back and forth between the seasonal insulin sensitive and resistant states by such treatment even when made at any time of year.    The circadian neuroendocrine output signals from the clock function to create circadian stimulus (humoral hormone, neurotransmitter) and response (cellular hormone and neurotransmitter signal transduction apparatus) rhythms in peripheral tissues to synchronize metabolic activities within the organ systems of the body and keep the organism in sync with its cyclic environment.  A simple example of such an organization is the peak in the daily rhythm of hepatic lipogenic responsiveness to insulin synchronized with the daily peaks in insulin release from the pancreas and feeding.  In obese animals these rhythms are all in phase and the amplitudes of the insulin stimulus and response rhythms are elevated relative to lean animals wherein the peaks in the insulin stimulus and response rhythms are out-of-phase and diminished (Figure 2).

cincotta-chart-2Figure 2. Click image to enlarge.


Figure 2. Temporal synergism of circadian rhythms of biological activities at the target tissue level regulate metabolism. There are dramatic circadian variations in peripheral tissue responses to many neuronal and hormonal stimuli as well as daily variations in levels of such stimuli. The phase relationships of the stimulus and response rhythms may change to alter the net consequences of such interactions. Temporal coincidence of greatest daily stimulus with greatest daily target tissue responsiveness produces the greatest cumulative effect. Least effect occurs when the stimulus peak coincides with an interval of least responsiveness in the target tissue.
Copyright 1996 American Diabetes Association From Diabetes Reviews®, Vol. 4, 1996; 464487
Modified with permission from The American Diabetes Association
Modified from Meier and Cincotta [51] with permission.

A notable alteration in the naturally occurring shift in brain neurochemistry that is coupled to the onset of seasonal insulin resistance/glucose intolerance is a marked diminution of the circadian peak dopaminergic input signal to the clock at this time of year.  Subsequent studies demonstrated that merely destroying the dopaminergic projections to the clock without altering any other hypothalamic circuitry in seasonally insulin sensitive animals induces a marked insulin resistance and glucose intolerance (4).  Low dopaminergic input to the SCN at the onset of the daily locomotor activity rhythm in rodents is coupled with output signals from the hypothalamus that drive an increase in sympathetic tone and the hypothalamic-pituitary-adrenal axis to the periphery that in turn increase plasma insulin, glucagon, and circadian-dependent cortisol levels, adipose lipolysis, liver lipogenesis and glucose production, fattening and peripheral insulin resistance.  As the “insulin resistance season” ends the circadian peak in dopaminergic input to the SCN returns accompanied by other seasonal changes in circadian inputs to the pacemaker system via an internal timing control mechanism and the insulin resistance subsides (Figure 3).

cincotta-chart-3Figure 3. Click image to enlarge.

Figure 3. Schematic of dopamineclock interactions in the regulation of peripheral fuel metabolism.

Click here to view Figure 3 abbreviations and references.

It is important to realize that it is not simply the presence or absence of some critical level of central dopaminergic activity that regulates the annual cycle of metabolism but rather a critical level at a critical circadian time of day at the SCN that programs its output control of metabolism.  Information from the environment (photoperiod, stress, sleep/wake cycle, endogenous metabolites and humoral factors, neuromodulators [e.g., dopamine and others]) affects the SCN output signals to the endocrine and autonomic nervous systems.  Administration to several animal models of insulin resistance of a dopamine agonist at the appropriate time of day to mimic (i.e., reinstate) the natural circadian peak of dopaminergic activity at the clock (SCN) observed in insulin sensitive animals abrogates the insulin resistance.

Low central dopaminergic tone has now been identified as a hallmark of obese and insulin resistant states in humans (Table 1).  Currently our laboratory is investigating the molecular translational impact of environmental perturbations “perceived” as stress by the pacemaker apparatus such as social and socioeconomic stress, altered sleep-wake cycle, dietary alterations, and/or feedback signals from peripheral metabolism (leptin, FFA, insulin, etc.) upon (dopamine) clock-pacemaker control of peripheral fuel metabolism.   As an initial observation, it appears that all these stresses impact the pacemaker system in a way that facilitates a pacemaker system output inducing insulin resistance.   That is to say, such stresses in humans can “lock” the individual in a seasonal (winter) insulin resistant state all year long, predisposing to pathological consequences.  It appears that the endogenous clock pacemaker system is at the top of a complex hierarchy of neuroendocrine modulatory systems for peripheral metabolism and that “resetting” of  neuronal “insulin resistance signals” emanating from the clock may represent a practical means of long term prevention or improvement of metabolic disease.  Restoring the daily peak in circadian dopamine activity input at the SCN area in insulin resistant states appears to be one such “resetting” mechanism for the diminution of insulin resistance.

•        Brain dopamine and obesity. Wang GJ, et al. Lancet. 2001;357(9253):354-7.•        Similarity between obesity and drug addiction as assessed by neurofunctional imaging: a concept review. Wang GJ, et al. J Addict Dis. 2004;23(3):39-53.•        Activation instead of blocking mesolimbic dopaminergic reward circuitry is a preferred modality in the long term treatment of reward deficiency syndrome (RDS): a commentary.
Blum K, et al. Theor Biol Med Model. 2008 Nov 12;5:24.•        Relation between obesity and blunted striatal response to food is moderated by TaqIA A1 allele.
Stice E, et al. Science. 2008;322(5900):449-52.•        Low dopamine striatal D2 receptors are associated with prefrontal metabolism in obese subjects: possible contributing factors. Volkow ND, et al. Neuroimage. 2008;42(4):1537-43.•        D2 dopamine receptor Taq1A polymorphism, body weight, and dietary intake in type 2 diabetes.
Barnard ND, et al. Nutrition. 2009;25(1):58-65.

•        Relationship of dopamine type 2 receptor binding potential with fasting neuroendocrine hormones and insulin sensitivity in human obesity. Dunn JP, et al. Diabetes Care. 2012;35:1105–1111.

•        Reduced insulin sensitivity is related to less endogenous dopamine at D2/3 receptors in the ventral striatum of healthy non-obese humans. Caravaggio F, et al. Int J Neuropsychopharmacol. 2015;18(7):pyv014.

Table 1. Low brain dopaminergic activity is associated with insulin resistance syndrome and T2DM in humans


Figures 1, 2,  and 3 are from Philip Raskin & Anthony H. Cincotta (2016) Bromocriptine-QR therapy for the management of type 2 diabetes mellitus: developmental basis and therapeutic profile summary, Expert Review of Endocrinology & Metabolism, 11:2, 113-148.

1 The suprachiasmatic nucleus or nuclei (SCN) is a small  region of the brain in the hypothalamus, situated directly above the optic chiasm. It is a biological circadian clock system of neurons that are responsible for controlling/modulating  the synchronization and temporal organization of circadian rhythms in cells and tissues  throughout the body.

Additional References:

Cincotta AH. Hypothalamic role in insulin resistance and insulin resistance syndrome. Frontiers in Animal Diabetes Research Series. Taylor and Francis. eds. Hansen B. Shafrir E, London. 2002;pp271-312.

Meier AH, Cincotta AH.  Circadian rhythms regulate the expression of the thrifty genotype/phenotype.  Diabetes Reviews. 1996;4(4):464-87. Click here to download free full-text article

Roe ED, Chamarthi B, Raskin P.

Impact of Bromocriptine-QR Therapy on Glycemic Control and Daily Insulin Requirement in Type 2 Diabetes Mellitus Subjects Whose Dysglycemia Is Poorly Controlled on High-Dose Insulin: A Pilot Study.

Journal of Diabetes Research 2015; Volume 2015, Article ID 834903.

Chamarthi B, J. Gaziano JM, , Blonde L, Vinik AI, Scranton R, Ezrokhi M, Rutty D,  Cincotta AH

Timed Bromocriptine-QR Therapy Reduces Progression of Cardiovascular Disease and Dysglycemia in Subjects with Well-Controlled Type 2 Diabetes Mellitus.

Journal of Diabetes Research 2015; Volume 2015, Article ID 157698

Vinik AI, Cincotta AH, Scranton RE, Bohannon N, Ezrokhi M, Gaziano JM.

Effect of bromocriptine-QR on glycemic control in subjects with uncontrolled hyperglycemia on one or two oral anti-diabetes agents.

Endocr Pract. 2012; 18(6):931-43

Gaziano JM, Cincotta AH, Vinik A, Blonde L, Bohannon N, Scranton R.

Effect of Bromocriptine-QR (a Quick-Release Formulation of Bromocriptine Mesylate) on Major Adverse Cardiovascular Events in Type 2 Diabetes Subjects. J Am Heart Assoc. 2012 Oct;1(5):e002279

Florez H, Scranton R, Farwell WR, DeFronzo RA, Ezrokhi M, et al. (2011) Randomized Clinical Trial Assessing the Efficacy and Safety of Bromocriptine-QR when Added to Ongoing Thiazolidinedione Therapy in Patients with Type 2 Diabetes Mellitus. J Diabetes Metab 2:142.

Gaziano JM, Cincotta AH, O’Connor CM, Ezrokhi M, Rutty D, Ma ZJ, Scranton RE.

Randomized clinical trial of quick-release bromocriptine among patients with type 2 diabetes on overall safety and cardiovascular outcomes.

Ezrokhi M, Luo S, Trubitsyna Y, Cincotta AH.

Neuroendocrine and metabolic components of dopamine agonist amelioration of metabolic syndrome in SHR rats.

Diabetology and Metabolic Syndrome 6:104, 2014.

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