# Patent

## Title
Combination of dopamine agonists plus first phase secretagogues for the treatment of metabolic disorders

## Abstract

The present invention is directed to a method of treating a metabolic disorder or key elements of a metabolic disorder such method comprising the use of an agent(s) that increases central dopaminergic activity plus a first-phase insulin secretagouge.

## Background
This application is a U.S. National Phase Application under 35 U.S.C. §371 of PCT application number PCT/US2010/037605 which was filed on Jun. 7, 2010, and which claims the benefit of the priority of U.S. Provisional Patent Application No. 61/217,906 filed on Jun. 5, 2009, the disclosure of each of which is incorporated herein by reference in its entirety for all purposes.


BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is directed to agents that increase central dopaminergic activity plus first phase insulin secretagouges for the treatment of metabolic disorders.
2. Description of the Related Art
Type 2 diabetes (T2D) is characterized by both an ineffectiveness of insulin to maintain normal plasma glucose levels because of resistance of the body to its normal action to induce removal of glucose from the circulation into insulin sensitive tissues when glucose is abnormally high such as after consumption of a meal and also by beta cell failure to secrete appropriate amounts of insulin particularly following a meal/glucose challenge. This insulin resistance coupled with beta cell failure results in abnormally high circulating plasma glucose levels and is coupled with a myriad of other metabolic disorders such as dyslipidemia and hypertension that collectively predispose to cardiovascular disease, the leading cause of death in the T2D patient. Type 2 diabetes is now a global pandemic with more than 200 million people affected with the disease and the World Health Organization estimates that by 2030 there will be approximately 300 million people with the disease world-wide. Additionally, a condition termed pre-diabetes is also growing globally with approximately twice the number of affected individuals as type 2 diabetes. The definition of pre-diabetes varies among health organizations but is generally classified as Impaired Fasting Glucose (IFG) (fasting glucose levels between 110-125 mg/dl) or Impaired Glucose Tolerance (IGT) (2-hour post oral glucose load (75 g) plasma glucose greater than 140 to 199 mg per dL (7.8 to 11.0 mmol)) and is accompanied by an increased risk for the development of frank T2D. IFG and IGT are distinct metabolic abnormalities (Abdul-Ghani M A et al, Diabetes 55:1430-35, 2006). It now appears that the 1-hour post glucose load plasma glucose level is a better predictor of future T2D onset than IFG or IGT (Abdul-Ghani M A et al, Diabetes Care 32:281-86, 2009). Indeed in subjects with fasting hyperglycemia and a normal 2-hour post-glucose load plasma glucose level, it is the 1-hour plasma glucose that is most predictive of future T2D onset (Abdul-Ghani M A et al, Diabetes Care 33:557-561, 2010). Insulin secretory response to an oral glucose load is typically composed of a first-phase and second phase response. Insulin is released from the pancreas in a biphasic manner in response to a square-wave increase in arterial glucose concentration. The first phase consists of a brief spike lasting  ̃10 min followed by the second phase, which reaches a plateau at 2-3 h. It is widely thought that diminution of first-phase insulin release is the earliest detectable defect of β-cell function in individuals destined to develop type 2 diabetes and that this defect largely represents β-cell exhaustion after years of compensation for antecedent insulin resistance. Subjects with IGT are characterized by impaired first and second phase insulin secretory response while subjects with IFG are characterized mainly by impaired first phase insulin secretory response (Abdul-Ghani M A et al, Eur J Clin Invest in press; Ferrannini E et al, Diabetologia 46: 1211-1219, 2003). Subjects with T2D have impairments in both phases of insulin secretion. Subjects with IFG, IGT and T2D all have insulin resistance. Postprandial glucose dysmetabolism (elevated postprandial glucose levels; postprandial hyoperglycemia) has been identified as a risk factor not only for progression to T2D but also for cardiovascular disease (CVD) (Bonora E et al, Diabetologia 44:2107-14, 2001; Ceriello A et al, Nutr Metab Cardiovasc Dis 16:453-6, 2006; Di Filippo C et al, Curr Diabetes Rev 3:268-73, 2007). Therefore postprandial hyperglycemia is important to correct in the prediabetes and T2D subjects alike to improve overall metabolic and cardiovascular health. Little attention has been given to methods of treating postprandial insulin resistance however and little is known of what controls this postprandial insulin response in the muscle and liver. There are currently no methods of treatment available that improve postprandial insulin resistance and first phase insulin secretory response in subjects with prediabetes or T2D. The ability to correct both of these abnormalities would likely lead to better postprandial glucose control and health outcomes in subjects with IFG, IGT and T2D. What is needed is a simple method of treating both postprandial insulin resistance and first-phase insulin secretion as a method of improving IFG, IGT and T2D.
SUMMARY OF THE INVENTION
It has recently been determined that timed once daily administration of centrally acting dopamine agonists (such as bromocriptine) or of compounds that increase central dopaminergic activity particularly at the appropriate time of day when central/hypothalamic dopaminergic activity is high in insulin sensitive non-T2D subjects and low in such subjects, improves postprandial glucose metabolism (FDA Cycloset® package insert 2009) without increasing insulin release. This suggests that such dopamine agonist treatment may improve postprandial insulin resistance. It has now been surprisingly found that if one combines such a method of treating IFG, IGT, or T2D with a first-phase insulin secretagouge, one can produce synergistic effects to reduce these disorders. Additional dopamine agonists useful in the invention include quinpirole, quinerolane, talipexole, ropinirole, apomorphine, lisuride, terguride, fenoldopam, dihydroergotoxine, (hydergine), dihydroergocryptine, and combinations thereof. A most preferred central acting dopamine agonist is bromocriptine.
Cycloset, a quick-release, high absorbing formulation of bromocriptine mesylate, a dopamine agonist, improves glycemic control in type 2 diabetes in large part by improving postprandial responsiveness to insulin. Several drugs that directly or indirectly stimulate an increase in first phase insulin release (termed first phase insulin secretagouges) also produce improvements in glycemic control by lowering postprandial glucose levels in subjects with type 2 diabetes.
We have now found that improved glycemic control in subjects with type 2 diabetes is possible by combining these two different drug classes, e.g., agents that increase central dopamine activity plus first phase insulin secretagouges as defined herein. The combination of such dopamine activity regulating agents and first phase insulin secretagouge has been observed to have advantageous effects. First, the combination produces more than additive, i.e., synergistic, effects on glycemic control. This synergism may also be realized with dopamine agonists, such as Cycloset and short acting insulins. Secondly, the combination permits one to reduce the daily dosages of Cycloset and the insulin secretagouge and get additional benefit on glycemic control when combined at these lower dosages relative to their regular respective single dosage uses. Thirdly, the combination reduces overall side effects of each of these agents. Fourth, the metabolic benefits of improvements in lipid metabolism, blood pressure, and vascular dysfunction, and heart and kidney disease may also be realized in a similar synergistic manner with this agent increasing central dopaminergic activity—first phase insulin secretagouge drug combination. In total, this unique combination allows for synergistic increased effectiveness and simultaneous decreased side effects for treating metabolic disease at lower doses than each drug class is utilized at individually to treat such metabolic disorders.
The combination composition is effective to treat one or more metabolic disorders selected from the metabolic syndrome, Type 2 diabetes, obesity, prediabetes, key elements of any metabolic disorder, insulin resistance, hyperinsulinemia, cardiovascular disease, elevated plasma norepinephrine, elevated cardiovascular-related inflammatory factors or potentiators of vascular endothelial dysfunction, hyperlipoproteinemia, atherosclerosis, hyperphagia, hyperglycemia, hyperlipidemia, hypertension, and high blood pressure. The key elements of a metabolic disorder is selected from the group consisting of impaired fasting glucose, impaired glucose tolerance, increased waist circumference, increased visceral fat content, increased fasting plasma glucose, increased fasting plasma triglycerides, increased fasting plasma free fatty acids, decreased fasting plasma high density lipoprotein level, increased systolic or diastolic blood pressure, increased plasma postprandial triglyceride or free fatty acid levels, increased cellular oxidative stress or plasma indicators thereof, increased circulating hypercoagulative state, arteriosclerosis, coronary artery disease, peripheral vascular disease, congestive heart failure, hepatic steatosis, renal disease including renal insufficiency, and cerebrovascular disease.
First phase insulin secretagouges include but are not limited to a glucagon-like peptide-1 (GLP-1) or mimetic thereof, insulin and/or a meglitinide, repaglinide, nateglinide or a dipeptidyl peptidase inhibitor.
Multiple circadian central neural oscillations govern the regulation and coordination of multiple physiological (e.g., metabolic) events in the periphery as a function of their circadian (timing) phase relationship, described in U.S. Pat. No. 5,468,755 and herein incorporated in entirety by reference. One such circadian rhythm governing metabolic status is the central (hypothalamic) circadian rhythm of dopaminergic activity. It has previously been observed that phase shifts in the circadian rhythm of central dopaminergic activities influenced the status of obesity or diabetes. However, it has now been surprisingly found that phase shifts away from the healthy normal circadian rhythm of central or hypothalamic dopaminergic activity by environment, diet, stress, genetics and/or other factors are somehow also operative in a much different and broader physiological regulatory system and potentiate and lead to the multiple complex metabolic pathologies of and associated with metabolic syndrome as described herein. Furthermore, it has now been found that resetting these aberrant central dopaminergic circadian rhythms back towards that of the healthy normal state results in simultaneous improvements in the multiple complex pathologies of and associated with metabolic syndrome as described herein. As described above, metabolic syndrome and its associated pathologies represent a different pathology from diabetes or obesity, the cause of which is unknown. However, subjects with metabolic syndrome have much greater risk of developing cardiovascular disease than subjects without the syndrome. Inasmuch as obesity and type 2 diabetes are not always associated with metabolic syndrome and vice versa, it is clear that this major health risk represents a separate and unique metabolic state with unique characteristics. Adjusting the circadian rhythm of central dopaminergic activities by various means may be employed to reduce the many pathologies of and associated with this syndrome, for example aberrant vascular tone, vascular health, endothelial function, glucose and lipid metabolism, immune system functions specifically influencing the vasculature, insulin action, and blood coaguability. This same circadian dopaminergic resetting methodology may also be utilized to treat cardiometabolic risk, a cluster of physiological pathologies of common or discordant origin that converge to increase risk of cardiovascular disease. These risk factors include those of metabolic syndrome, but also inflammation, endothelial dysfunction, hypercholesterolemia, diabetes, obesity, smoking, gender, and age. Rather than just increasing dopaminergic activity with central dopamine agonists to improve metabolic syndrome, cardiometabolic risk and their associated pathologies, one may better influence these conditions by timing the administration of such dopamine agonists to coincide with the daily peak in central dopaminergic activities of healthy subjects of the same species to derive maximal benefit from such dopamine agonist therapy in treating these conditions.
In further accordance with this invention, the use of dopamine agonists to treat the Metabolic Syndrome (obesity, insulin resistance, hyperlipidemia, and hypertension), non-metabolic pathologies associated with MS (a pro-inflammatory state, a pro-coagulative state, pro-oxidant state, and/or endothelial dysfunction), arteriosclerosis, and/or cardiovascular disease, all in subjects with or without Type 2 diabetes, is applied during specific daily intervals to maximize the effectiveness of such treatment. Use of such centrally acting dopamine agonists for treatment of the metabolic and non-metabolic vascular disorders described herein may be potentiated by their administration at the appropriate time(s) of day. Circadian rhythms of dopaminergic activity within the central nervous system, and particularly the phase relations of these dopaminergic neuronal rhythms with other circadian neuronal activities such as serotonergic neuronal activities have been demonstrated to regulate peripheral glucose and lipid metabolism in a manner dependent upon the phase of the daily peak in circadian central dopaminergic activity. Consequently, increases in dopaminergic activity at particular times of day versus others produce maximal effectiveness in improving metabolic diseases and disorders such as type 2 diabetes, obesity, pre-diabetes, metabolic syndrome, cardiometabolic risk, hypertension, dyslipidemia, insulin resistance, hyperinsulinemia, hepatic steatosis, renal disease, cardiovascular disease, cerebrovascular disease, and peripheral vascular disease and biomarkers of impending vascular disease. As such, maximized successful treatment of these aforementioned pathologies and abnormalities may be accomplished by appropriately timed daily administration of centrally acting dopamine agonist(s). Because such dopamine agonist therapy attacks a root cause of these metabolic disorders (central dysregulation of global peripheral metabolism) it is possible to effectuate improvements in several metabolic pathologies in a simultaneous fashion that is not generally achievable by other conventional means that attack particular specific symptoms of metabolic disease for example hypertension or high cholesterol or hyperglycemia by acting at specific downstream peripheral targets such as biochemical pathways within liver or muscle. Such a treatment effect is currently lacking in the general armamentarium of therapeutics for metabolic diseases. Moreover, central dopamine agonist therapy may be coupled to direct or indirect peripheral acting therapeutic agents such as anti-diabetes agents, antihypertensive agents, cholesterol lowering agents, anti-inflammatory agents, or anti-obesity agents to produce additive improvements in metabolic disease such as obesity or type 2 diabetes or particular aspects of metabolic disease such as hypertension associated with obesity or type 2 diabetes. Details of the timing aspects of the invention can be found in copending International Patent Application Publications WO 2008/150480 and WO 2008/121258.
The novel treatment for metabolic disorders, including the metabolic syndrome (obesity, insulin resistance, hyperlipidemia, and hypertension), Type 2 diabetes, obesity, and/or prediabetes including key elements of metabolic disorders consists of administering to a mammalian species in need of such treatment a pharmaceutical composition that simultaneously stimulates an increase in central dopaminergic neuronal activity level (particularly within neurons innervating the hypothalamus and the hypothalamus itself) and a decrease in central noradrenergic neuronal activity level (particularly within the brain stem region that innervates the hypothalamus and the hypothalamus itself). It has been unexpectedly discovered that increasing the ratio of dopaminergic neuronal to noradrenergic neuronal activity within the central nervous system, particularly the hypothalamus of the central nervous system reduces metabolic disorders and improves the conditions associated with metabolic syndrome, type 2 diabetes, obesity, and/or prediabetes and key elements thereof. As defined herein, “neuronal activity” refers to either an increase or decrease in the action potential of a neuron. More specifically, as defined herein, “neuronal activity” refers to either an increase or decrease in the synaptic neurochemical signal transmission of a neuron to another thereby affecting action potential. More narrowly yet, as defined herein, “neuronal activity” refers to the biochemical communication to a (secondary [e.g., post-synaptic]) neuron from either the neurochemical signal transmission of another (primary [e.g., pre-synaptic]) neuron (e.g., as via an endogenous neurotransmitter) or from any neuromodulatory compound (e.g., an exogenous neurotransmitter receptor modulator such as a pharmaceutical agent) thereby affecting action potential or neurotransmitter release of the secondary neuron. As such, an increase in dopaminergic neuronal activity would be characterized by a) an increase in release of dopamine molecules from a dopamine producing (primary) neuron, an increase in dopamine molecules within the synapse by any mechanism, and/or increase in dopamine-mimetic compound(s) from any source (e.g., pharmaceutical) resulting in increased binding to dopaminergic receptor sites of other (secondary) neuron(s) that affect said other neuron(s)' action potential or neurotransmitter release in a manner consistent with increased dopamine ligand-dopamine receptor binding signal transduction (e.g., post-synaptic dopamine receptor agonist) and/or b) an increase in sensitivity or responsiveness of said “other (secondary)” neuron(s) to such dopamine or dopamine-mimetic compound(s)' ability to affect action potential or neurotransmitter release in said “other (secondary)” neuron (e.g., as an increase in dopamine receptor number or affinity or responsiveness). Contrariwise, dopamine-mimetic binding to dopamine-producing neurons (i.e., presynaptic dopamine neurons) and/or increased sensitivity or responsiveness of dopamine producing neurons to respond to neurotransmitters or neuromodulators that thereby reduces dopamine release would be considered an activity leading to a decrease in dopaminergic neuronal activity [and, when considered in and of itself, is an undesirable aspect of dopaminergic activity respecting this invention]. For the sake of clarity, post-synaptic dopamine receptor agonists include dopamine D1, D2, D3, D4, and D5 receptor agonists and post-synaptic norepinephrine receptor antagonists include alpha 2bc and alpha1 antagonists.


DETAILED DESCRIPTION OF THE INVENTION
Materials and Methods
Animal Studies
Male Syrian hamsters known to develop insulin resistance and glucose intolerance were purchased at 4 weeks of age and kept on rodent diet for 10 weeks at 72 degrees F. and a 14 hr:10 hr daily light:dark cycle. When animals were 14 weeks of age on this daily photoperiod (known to be insulin resistant and glucose intolerant under these conditions), bromocriptine mesylate was administered intraperitoneally (IP) for 2 weeks at 4 mg/kg per hamster 13 hours after light onset to half of the animals, while the other half received vehicle injections for 2 weeks.
After 2 weeks of treatment both Bromocriptine and vehicle groups were divided into two groups for a total of 4 groups: 1. Vehicle for 2 weeks and Vehicle at initiation of a glucose tolerance test (GTT); 2. Vehicle for 2 weeks and Exendin-4 at initiation of the GTT; 3. Bromocriptine for 2 weeks and Vehicle at GTT; 4. Bromocriptine for 2 weeks and Exendin-4 at GTT.
Glucose tolerance test was performed among all 4 study groups on Day 15 of the study by challenge with 3 g/kg body weight of glucose at 7 hours after light onset among each of the 4 treatment groups—(bromocriptine or vehicle treatment for 2 weeks and with IP injection of either vehicle or 4 μg/kg of Exendin-4, a GLP-1 analog [Sigma Chemical, St Louis, Mo.] dissolved in saline) at the GTT. Also, an additional group of hamsters treated with vehicle for 2 weeks received Exendin-4 on the day of GTT at 8 μg/kg. Blood was drawn from the jugular vein and blood glucose level was measured every 30 minutes for 2 hours after the glucose load administration.
In a similarly designed experiment among 4 groups of animals, insulin was injected IP at 240 ng/kg in place of Exendin-4 as the first phase insulin secretagouge (FPIS).
Human Studies
494 obese Type 2 diabetes subjects who were poorly controlled on a sulphonylurea dose that was stable for at least 60 days prior to study initiation were enrolled in a multicentre study, with 244 randomized to treatment with Cycloset plus a stabilized dose of currently used sulphonylurea, and 250 randomized to treatment with placebo plus a stabilized dose of currently used sulphonylurea. Subjects were admitted to a clinical research center one week prior and 24 weeks after the start of Cycloset administration and administered standardized meals at breakfast lunch and dinner. One-hour postprandial plasma insulin and glycated hemoglobin A1c (HbA1c) (a measure of glycemic control) were measured one week prior and 24 weeks after the start of Cycloset administration. Cycloset induced improvements in HbA1c relative to placebo were analyzed as a function of the baseline 1-hour postprandial insulin level in the study subjects.
Results
Animal Studies
Timed Bromocriptine administration for 2 weeks did not statistically significantly reduced blood glucose Area Under Curve (AUC) during the GTT over two hours after glucose administration (21% reduction, P<0.09). Likewise Exendin-4 immediately prior to glucose administration at either 4 ug/kg or 8 ug/kg did not statistically significantly reduced blood glucose Area Under Curve (AUC) during the GTT over two hours after glucose administration (19% and 27% reduction, P=0.23 and P=0.13 respectively). However, in animals that were treated both with bromocriptine for 2 weeks and received Exendin-4 at 4 ug/kg prior to GTT initiation a statistically significant decrease of Glucose AUC of 60% was observed (P<0.0002). Thus no statistically significant effect of either the dopamine agonist treatment or of the first-phase insulin secretagouge on glucose intolerance was observed, yet the combination of the two produced a marked improvement in glucose intolerance, the numerical value of which was 50% greater than the addition of the two drug effects separately and also more than double the effect of doubling the dose of exendin-4 (P=0.05). Even when viewed in these terms, a 50% reduction in the GTT AUC represents a robust improvement in relative glucose intolerance (Ceriello A et al Nutr Metab Cardiovasc Dis 16:453-6, 2006; Abdul-Ghani M A et al, Diabetes Care 32: 281-86, 2009). This synergistic effect of these agents (0+0=marked effect) allows for the lowering of the first-phase insulin secretagouge (FPIS) dose and yet to achieve better results when combined with a centrally acting dopamine agonist (as evidence d by the result that 2× the Exendin-4 dose did not produce any benefit to glucose intolerance and was not even half the numerical effect of the dopamine agonist/half FPIS dose on glucose intolerance). The lowering of the FPIS allows for reducing its side effects and strain on the beta cell (beta cell exhaustion) which is beneficial to the treated subject.
In a similarly designed experiment as above but replacing the FPIS from exendin-4 to exogenous insulin itself, glucose AUC over two hours after such glucose administration was not significantly reduced by 2 weeks of treatment with bromocriptine (28% reduction, P=0.23) or by insulin administration immediately prior to glucose administration (P=0.64). However, animals that were both treated with Bromocriptine for 2 weeks and received insulin prior to the GTT exhibited a decrease of Glucose AUC of 55% (P=0.014). Once again, the combination of a FPIS (insulin) plus a central acting dopamine agonist produces an effect much greater than the sum of the individual treatments as each were ineffective in producing any beneficial result. Once again, even when viewed in numerical terms irrespective of statistical significance, the combination produced a reduction in glucose intolerance of 50% greater than the addition of each therapy alone which as stated above is a marked improvement in glucose intolerance with demonstrable health benefits.
The observation that this synergism is achieved with 2 markedly different FPIS molecules that share only the ability to increase plasma insulin level after a meal when administered prior to the meal indicates that this is a class phenomenon and not something particular to the FPIS agents employed. Previously it has been demonstrated that various agents that increase central dopaminergic activity all improve metabolic disorders, again indicating that the phenomenon, in a general sense, is not molecule specific, but rather a class effect. Therefore, this synergism may be fully expected to be a class interaction synergism.
Inasmuch as meals for humans are typically 3 times per day, it is possible to reduce this combination synergistic therapeutic for metabolic disorders to a once-daily dosing by preparing long acting FPIS with short acting agents that increase central dopaminergic activity at specific time of day only in unique dosage forms. Such dosage forms provide the benefit of the synergism, allow for the maximal effect of the dopamine stimulation by timing it to the appropriate time of day, and provide for convenience of use (only a single administration per day). Such dosage forms may take the form of non-oral or oral routes of administration.
Human Studies
The average 1-hour postprandial plasma insulin level was 50 μU/ml in both Cycloset and Placebo treated groups at the start of the study; incoming HbA1C was 9.4% and 9.5% respectively. In the Cycloset treated group HbA1C was reduced by 0.3% over 24 weeks of treatment, while HbA1C went up by 0.26% in the Placebo arm (P<0.0001). For subjects with incoming 1-hour postprandial insulin<30 uU/ml there was no effect of Cycloset on HbA1c, for subjects with incoming 1-hour postprandial>30 uU/ml and <50 uU/ml the Cycloset effect was −0.57 (P<0004) and among subjects with incoming 1-hour postprandial insulin>50 μU/ml the Cycloset effect on HbA1C was −0.79 (P<0.0001).
These results indicate that the effect of the dopamine agonist to improve glycemic control in T2D subjects is positively correlated with 1-hour postprandial insulin level in the subjects supporting the concept that the combination of an agent that increases central dopaminergic activity with a FPIS will produce synergistic improvements in glucose metabolism. Moreover the collective results of these animal and human studies indicate that pharmaceutical agents that preserve pancreatic beta cell function per se, i.e., retard the loss of appropriate beta cell insulin responsiveness to meal glucose (and as such improve postprandial insulin secretory response to glucose) such as thiazolidinediones and glucagon like peptide 1 analogs, will also synergize with agents that increase central dopaminergic activity to improve metabolic disorders and produce long lasting benefit on glycemic control (e.g., for a year or more). This combination of therapies for the treatment of metabolic disorders is also envisioned by this invention as well.
Exendin-4
Exendin-4, a 39 amino acid peptide, originally isolated from Heloderma suspectum (Gila monster lizard) venom, activates GLP-1 (glucagon-like peptide-1) receptors to increase intracellular cAMP in pancreatic acinar cells. Synthetic Exendin-4 is also known as Exenatide, or Byetta; its molecular weight is: 4187
GLP-1 is a gastrointestinal hormone, which regulates blood glucose primarily by stimulating glucose-dependent insulin release (first phase insulin secretion). Exendin-4 is a high affinity glucagon-like peptide 1 (GLP-1) receptor agonist (Kd=136 pM). Exendin-4 is a long-acting agonist of the GLP-1 receptor. Exenatide has comparable potency to GLP-1 and is resistant to degradation by DPP-IV. Exenatide improves glycemic control primarily by reducing postprandial hyperglycemia.
Exendin-4 dose used in this study is comparable to the dose used in the studies reported by Strauss et al., 2008 and Nachnani et al., 2010
REFERENCES


    Cervera et al., (2008) Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes. Am J Physiol Endocrinol Metab 294: E846-E852.
    Eng, J. et al., (1992) Isolation and characterization of exendin-4 an exendin-3 analogue from Heloderma suspectum venom. J. Biol. Chem. 267, 7402,
    Goke et al (1993) Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting b-cells. J. Biol. Chem. 268 19650
    Nachnani J. et al., (2010) Biochemical and histological effects of exendin-4 (exenatide) on the rat pancreas. Diabetologia 53:153-159
    Thorens et al (1993) Cloning and functional expression of the human islet GLP-1 receptor. Diabetes 42 1678.
    Strauss A. et al., (2008) Exendin-4 improves the oral glucose tolerance in diabetic rats: pancreas regeneration, better function of pancreatic islets, or impaired glucose uptake? Transplantation Proceedings, 40, 533-535

## Claims

1. A method of treating a metabolic disorder or key elements of a metabolic disorder, such method comprising the step of administering to a patient in need of such treatment daily (a) a dopamine receptor agonist; and (b) a first-phase insulin secretagouge selected from the group consisting of glucagon like peptide-1 (GLP-1) or an analog thereof, a dipeptidyl peptidase inhibitor, gastric inhibitory polypeptide (also known as glucose-dependent insulinotropic peptide), a meglitinide, repaglinide, nataglinide and short acting insulin, wherein the dosage of each of said dopamine receptor agonist and first-phase insulin secretagouge in combination, provides a therapeutic effect greater than the additive effect of administering the same dosage of each of said dopamine receptor agonist and first-phase insulin secretagouge alone.

2. The method of claim 1 where the dopamine receptor agonist is selected from the group consisting of bromocriptine, lisuride, hydergene, dihydroergotoxine, and other dopamine D2 receptor agonists with low or no serotonin 2B receptor agonist activity.

3. The method of claim 1 wherein metabolic disorder is selected from the group consisting of pre-diabetes, Impaired Fasting Glucose, Impaired Glucose Tolerance and Type 2 diabetes.

4. The method of claim 1 wherein the metabolic disorder is selected from the group consisting of the metabolic syndrome, Type 2 diabetes, obesity, pre-diabetes, key elements of any metabolic disorder, insulin resistance, hyperinsulinemia, cardiovascular disease, elevated plasma norepinephrine, elevated cardiovascular-related inflammatory factors or potentiators of vascular endothelial dysfunction, hyperlipoproteinemia, atherosclerosis, hyperphagia, hyperglycemia, hyperlipidemia, hypertension, and high blood pressure.

5. The method of claim 1 wherein the key elements of metabolic disorders are selected from the group consisting of impaired fasting glucose, impaired glucose tolerance, increased waist circumference, increased visceral fat content, increased fasting plasma glucose, increased fasting plasma triglycerides, increased fasting plasma free fatty acids, decreased fasting plasma high density lipoprotein level, increased systolic or diastolic blood pressure, increased plasma postprandial triglyceride or free fatty acid levels, increased cellular oxidative stress or plasma indicators thereof, increased circulating hypercoagulative state, arteriosclerosis, coronary artery disease, peripheral vascular disease, congestive heart failure, hepatic steatosis, renal disease including renal insufficiency, and cerebrovascular disease.

6. The method of claim 1 wherein the dopamine receptor agonist is administered at a time and in a manner to increase central dopaminergic activity at the time of day its circadian rhythm naturally peaks in healthy subjects of the same species.

7. The method of claim 1 wherein said dopamine receptor agonist is administered to a human to increase central dopaminergic activity primarily within 4 hours of waking in the morning.

8. The method of claim 1 wherein said dopamine receptor agonist is administered within 2 hours of waking in the morning.

9. The method of claim 1, wherein the dosage of the dopamine receptor agonist is insufficient to effectively treat said disorder or key elements of said disorder without co-administration of the first-phase insulin secretagouge.

10. The method of claim 1, wherein the dosage of the first-phase insulin secretagouge is insufficient to effectively treat said disorder or key elements of said disorder without co-administration of the dopamine receptor agonist.

11. The method of claim 1, wherein the dosage of each of the dopamine receptor agonist and the first-phase insulin secretagouge in combination are effective to treat said disorder or key elements of said disorder.

12. The method of claim 1 where the dopamine receptor agonist is selected from the group consisting of quinpirole, quinerolane, talipexole, ropinirole, apomorphine, terguride, fenoldopam, dihydroergocryptine and combinations thereof.

13. The method of claim 1 wherein the dosage of said first-phase insulin secretagouge effective to treat said disorder when administered with said dopamine receptor agonist is less than the dosage of said secretagouge effective to treat said disorder when administered without said dopamine receptor agonist.

14. The method of claim 1, wherein the dopamine receptor agonist is a combination of a dopamine D1 receptor agonist and a dopamine D2 receptor agonist.

15. A method of treating glucose intolerance or insulin resistance in a mammal in need of such treatment, such method comprising: administering daily to a mammal suffering from glucose intolerance (a) a dopamine D2 receptor agonist selected from the group consisting of bromocriptine, lisuride, hydergene, dihydroergotoxine, and other dopamine D2 receptor agonists with low or no serotonin 2B receptor agonist activity; and (b) a first-phase insulin secretagouge selected from the group consisting of glucagon like peptide-1 (GLP-1) or an analog thereof, a dipeptidyl peptidase inhibitor, gastric inhibitory polypeptide (also known as glucose-dependent insulinotropic peptide), a meglitinide, repaglinide, nataglinide and short acting insulin wherein the dosage of each of said dopamine D2 receptor agonist and first-phase insulin secretagouge in combination, provides a therapeutic effect greater than the additive effect of administering the same dosage of each of said dopamine D2 receptor agonist and first-phase insulin secretagouge alone.

16. The method of claim 15, wherein the mammal suffers from diabetes or pre-diabetes.

17. A method of treating glucose intolerance or insulin resistance in a mammal in need of such treatment, such method comprising: administering daily to a mammal suffering from glucose intolerance or insulin resistance (a) bromocriptine or a pharmaceutically acceptable salt thereof; and (b) a first-phase insulin secretagouge selected from the group consisting of GLP-1 or an analog thereof and insulin wherein the dosage of each of bromocryptine or a pharmaceutically acceptable salt thereof and first-phase insulin secretagouge in combination, provides a therapeutic effect greater than the additive effect of administering the same dosage of each of said bromocriptine or a pharmaceutically acceptable salt thereof and a first-phase insulin secretagouge alone.

18. The method of claim 17, wherein the salt is mesylate.

19. The method of claim 17, wherein the mammal is suffering from type 2 diabetes.