Abstract:Bromocriptine, a potent dopamine D(2) receptor agonist, has been shown to reduce insulin resistance, glucose intolerance and hyperlipidaemia in both numerous animal studies and in Phase II studies. Bromocriptine has been used worldwide for over 20 years to treat Parkinson's disease, macroprolactinoma and other disorders; it has been found to be generally safe. We therefore investigated the possible beneficial effects of Ergoset(R) (Ergo Science Corp.), a new quick release formulation of bromocriptine, on glyca… Show more
“…Bromocriptine-QR therapy reduced mean postprandial glucose levels from 135 ± 5 mg/dl to 117 ± 3 mg/dl (P < 0.05) and fasting and postprandial plasma insulin levels from 27 ± 6 μU/ml and 99 ± 13 μU/ml to 15 ± 2 μU/ml and 50 ± 7 μU/ml, respectively (P < 0.05) (Figure 7). The above study of bromocriptine-QR impact on mealtime glucose and insulin was reconducted in T2DM subjects naïve to any anti-diabetes drug treatment [161,162]. Average study population baseline demographics included a percent-glycated HbA1c of 8.9, BMI of 31.5, duration of diabetes of 3.9 years (however, the study was conducted at a time when a fasting glucose level of 140 mg/dl was used as a diagnosis of T2DM so dysglycemia likely was present for a longer period of time), and age of 55 years.…”
Section: Clinical Effects Of Bromocriptine-qr Therapy In the Treatmenmentioning
confidence: 99%
“…Subsequent clinical studies investigated the possible beneficial effects of bromocriptine-QR on glycemic control in obese T2DM subjects whose dysglycemia was poorly controlled on SU and/or metformin therapies. One such study investigated the impact of morning administration (8 a.m.) of bromocriptine-QR (1.6-4.8 mg/day; titrated up at a rate of 0.8 mg/week until a maximum tolerated dose of 1.6-4.8 mg/day was achieved) or placebo upon glycemic control in obese T2DM subjects very poorly controlled on baseline SU therapy (485 subjects) while held on a weight maintaining diet for 24 weeks (the SU add-on study) [161]. Average population baseline demographics included a percent-glycated HbA1c level of 9.4, BMI of 32.1, duration of disease of 6.3 years (the study was conducted at a time when a fasting glucose level of 140 mg/dl was used as a diagnosis of T2DM so dysglycemia likely was present for a longer period of time) and age of 55 years.…”
Section: Clinical Effects Of Bromocriptine-qr Therapy In the Treatmenmentioning
confidence: 99%
“…These studies indicate that such bromocriptine administration reduces plasma TG and FFA levels by reducing TG synthesis and secretion in liver and TG mobilization from adipose tissue. Therefore, the SU add-on study also investigated the impact of bromocriptine-QR therapy upon diurnal plasma TG and FFA levels [161,162]. Diurnal TG levels were assessed from 0700 to 1900 hours including 1 h before and 1 and 2 h after each of breakfast, lunch, and dinner standardized meals, before and 24 weeks after treatment.…”
Section: Effect Of Bromocriptine-qr On Dyslipidemia In T2dm Subjectsmentioning
An extended series of studies indicate that endogenous phase shifts in circadian neuronal input signaling to the biological clock system centered within the hypothalamic suprachiasmatic nucleus (SCN) facilitates shifts in metabolic status. In particular, a diminution of the circadian peak in dopaminergic input to the peri-SCN facilitates the onset of fattening, insulin resistance and glucose intolerance while reversal of low circadian peak dopaminergic activity to the peri-SCN via direct timed dopamine administration to this area normalizes the obese, insulin resistant, glucose intolerant state in high fat fed animals. Systemic circadian-timed daily administration of a potent dopamine D2 receptor agonist, bromocriptine, to increase diminished circadian peak dopaminergic hypothalamic activity across a wide variety of animal models of metabolic syndrome and type 2 diabetes mellitus (T2DM) results in improvements in the obese, insulin resistant, glucose intolerant condition by improving hypothalamic fuel sensing and reducing insulin resistance, elevated sympathetic tone, and leptin resistance. A circadian-timed (within 2 hours of waking in the morning) once daily administration of a quick release formulation of bromocriptine (bromocriptine-QR) has been approved for the treatment of T2DM by the U.S. Food and Drug Administration. Clinical studies with such bromocriptine-QR therapy (1.6 to 4.8 mg/day) indicate that it improves glycemic control by reducing postprandial glucose levels without raising plasma insulin. Across studies of various T2DM populations, bromocriptine-QR has been demonstrated to reduce HbA1c by -0.5 to -1.7. The drug has a good safety profile with transient mild to moderate nausea, headache and dizziness as the most frequent adverse events noted with the medication. In a large randomized clinical study of T2DM subjects, bromocriptine-QR exposure was associated with a 42% hazard ratio reduction of a pre-specified adverse cardiovascular endpoint including myocardial infarction, stroke, hospitalization for congestive heart failure, revascularization surgery, or unstable angina. Bromocriptine-QR represents a novel method of treating T2DM that may have benefits for cardiovascular disease as well.
ARTICLE HISTORY
“…Bromocriptine-QR therapy reduced mean postprandial glucose levels from 135 ± 5 mg/dl to 117 ± 3 mg/dl (P < 0.05) and fasting and postprandial plasma insulin levels from 27 ± 6 μU/ml and 99 ± 13 μU/ml to 15 ± 2 μU/ml and 50 ± 7 μU/ml, respectively (P < 0.05) (Figure 7). The above study of bromocriptine-QR impact on mealtime glucose and insulin was reconducted in T2DM subjects naïve to any anti-diabetes drug treatment [161,162]. Average study population baseline demographics included a percent-glycated HbA1c of 8.9, BMI of 31.5, duration of diabetes of 3.9 years (however, the study was conducted at a time when a fasting glucose level of 140 mg/dl was used as a diagnosis of T2DM so dysglycemia likely was present for a longer period of time), and age of 55 years.…”
Section: Clinical Effects Of Bromocriptine-qr Therapy In the Treatmenmentioning
confidence: 99%
“…Subsequent clinical studies investigated the possible beneficial effects of bromocriptine-QR on glycemic control in obese T2DM subjects whose dysglycemia was poorly controlled on SU and/or metformin therapies. One such study investigated the impact of morning administration (8 a.m.) of bromocriptine-QR (1.6-4.8 mg/day; titrated up at a rate of 0.8 mg/week until a maximum tolerated dose of 1.6-4.8 mg/day was achieved) or placebo upon glycemic control in obese T2DM subjects very poorly controlled on baseline SU therapy (485 subjects) while held on a weight maintaining diet for 24 weeks (the SU add-on study) [161]. Average population baseline demographics included a percent-glycated HbA1c level of 9.4, BMI of 32.1, duration of disease of 6.3 years (the study was conducted at a time when a fasting glucose level of 140 mg/dl was used as a diagnosis of T2DM so dysglycemia likely was present for a longer period of time) and age of 55 years.…”
Section: Clinical Effects Of Bromocriptine-qr Therapy In the Treatmenmentioning
confidence: 99%
“…These studies indicate that such bromocriptine administration reduces plasma TG and FFA levels by reducing TG synthesis and secretion in liver and TG mobilization from adipose tissue. Therefore, the SU add-on study also investigated the impact of bromocriptine-QR therapy upon diurnal plasma TG and FFA levels [161,162]. Diurnal TG levels were assessed from 0700 to 1900 hours including 1 h before and 1 and 2 h after each of breakfast, lunch, and dinner standardized meals, before and 24 weeks after treatment.…”
Section: Effect Of Bromocriptine-qr On Dyslipidemia In T2dm Subjectsmentioning
An extended series of studies indicate that endogenous phase shifts in circadian neuronal input signaling to the biological clock system centered within the hypothalamic suprachiasmatic nucleus (SCN) facilitates shifts in metabolic status. In particular, a diminution of the circadian peak in dopaminergic input to the peri-SCN facilitates the onset of fattening, insulin resistance and glucose intolerance while reversal of low circadian peak dopaminergic activity to the peri-SCN via direct timed dopamine administration to this area normalizes the obese, insulin resistant, glucose intolerant state in high fat fed animals. Systemic circadian-timed daily administration of a potent dopamine D2 receptor agonist, bromocriptine, to increase diminished circadian peak dopaminergic hypothalamic activity across a wide variety of animal models of metabolic syndrome and type 2 diabetes mellitus (T2DM) results in improvements in the obese, insulin resistant, glucose intolerant condition by improving hypothalamic fuel sensing and reducing insulin resistance, elevated sympathetic tone, and leptin resistance. A circadian-timed (within 2 hours of waking in the morning) once daily administration of a quick release formulation of bromocriptine (bromocriptine-QR) has been approved for the treatment of T2DM by the U.S. Food and Drug Administration. Clinical studies with such bromocriptine-QR therapy (1.6 to 4.8 mg/day) indicate that it improves glycemic control by reducing postprandial glucose levels without raising plasma insulin. Across studies of various T2DM populations, bromocriptine-QR has been demonstrated to reduce HbA1c by -0.5 to -1.7. The drug has a good safety profile with transient mild to moderate nausea, headache and dizziness as the most frequent adverse events noted with the medication. In a large randomized clinical study of T2DM subjects, bromocriptine-QR exposure was associated with a 42% hazard ratio reduction of a pre-specified adverse cardiovascular endpoint including myocardial infarction, stroke, hospitalization for congestive heart failure, revascularization surgery, or unstable angina. Bromocriptine-QR represents a novel method of treating T2DM that may have benefits for cardiovascular disease as well.
ARTICLE HISTORY
“…However in these studies, fasting plasma glucose reductions in response to such treatment varied from not at all to moderate depending upon the prevailing glucose level. In Type 2 Diabetes Mellitus (T2DM) subjects, such once daily (morning) treatment with bromocriptine-QR, a Food and Drug Administration (FDA) approved quick release formulation of bromocriptine for the treatment of T2DM, reduced postprandial glucose across the three meals of the day and, these postprandial glucose reductions were larger than those observed in the pre-prandial (intermeal) state [5,6]. Collectively these findings suggest that the plasma glucose disposal/glucose homeostasis effects of timed bromocriptine administration may be more potent during the postprandial versus fasting state and that such bromocriptine treatment may potentially act as a unique postprandial "weighted" insulin sensitizer.…”
Background: Postprandial glucose metabolism is deranged in insulin resistant states typified by increased hepatic glucose output and reduced peripheral and hepatic glucose deposition despite elevated plasma insulin levels. And, mounting evidence suggests that postprandial hyperglycemia may potentiate cardiovascular disease. Time-of-day pulsed bromocriptine (a dopamine D2 receptor agonist) administration to insulin resistant animals and humans improves impaired glucose tolerance and post-meal hyperglycemia without raising the plasma insulin level when assayed many hours after bromocriptine has been removed from the circulation. The bromocriptine response of glucose lowering is more prominent after a meal than just before the meal suggesting a "weighted" effect on postprandial glucose metabolism. However, this supposition has never been evaluated under controlled physiological glucose-insulin clamp conditions to verify the existence of such a unique phenomenon.
Findings:This study therefore investigated the effects of daily bromocriptine or vehicle administration for 2 weeks on hepatic glucose output and total body glucose disposal during such hyperglycemic versus euglycemic insulin clamp conditions in insulin resistant, glucose intolerant Syrian hamsters. Bromocriptine treatment improved fasting insulin sensitivity (HOMA-IR) by 38% P < 0.04 and both total body glucose disposal and hepatic glucose output during the euglycemic clamp by 21% and 26%, P < 0.03 respectively, relative to vehicle treated animals. Importantly, the incremental increase in total body glucose disposal and inhibition in hepatic glucose output under hyperglycemic versus euglycemic conditions was greater (73% vs. 40%, P < 0.001) and markedly stronger (30% vs. no change, P < 0.002), respectively, in bromocriptine versus vehicle treated animals, respectively.
Conclusions:These findings indicate a unique hyperglycemic environment "weighted" effect of bromocriptine on improving glucose homeostasis in insulin resistant animals that is independent of plasma insulin level.
“…[21] A 24 weeks randomized controlled trial by Cincotta et al in 1999 showed a significant reduction in plasma free fatty acids and triglycerides after administration of bromocriptine mesylate in obese T2DM patients. [22] …”
Section: Bromocriptine and Lipid Profilementioning
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