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

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.