Weighted Effects of Bromocriptine Treatment on Glucose Homeostasis during Hyperglycemic versus Euglycemic Clamp Conditions in Insulin Resistant Hamsters: Bromocriptine as a Unique Postprandial Insulin Sensitizer

Abstract

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.

Bromocriptine-QR therapy for the management of type 2 diabetes mellitus: developmental basis and therapeutic profile summary

“…Relative to placebo, bromocriptine-QR therapy resulted in a significant decrease from baseline in postprandial glucose after each meal of the day without altering plasma insulin levels (37 mg/dl average decline of postprandial glucose of all three meals, P < 0.002; Figure 8). Given that the drug is substantially cleared from the circulation by lunch time, yet postprandial effects are observed at lunch and dinner, these results (and those described above in insulin-resistant, nondiabetes subjects) support preclinical data concluding a 'resetting' of hypothalamic nutrient-sensing responsiveness to a meal to improve postprandial insulin sensitivity with this therapy [125].…”

“…Moreover, numerous studies have consistently demonstrated the ability of such circadian-timed daily administration of bromocriptine (systemic or intracerebroventricular) to markedly reduce insulin resistance (particularly during the postprandial state [125,126], in agreement with its ability to improve VMH hypothalamic fuel-sensing mechanisms as described above), hyperinsulinemia and/or glucose intolerance without raising the plasma insulin level, in a variety of animal models of IRS including seasonal insulin-resistant hamsters, SHRs, high-fat fed rats, genetically leptin-deficient ob/ob mice, fattened pigs, and high-fat fed dogs [86,124,[126][127][128][129][130][131][132]. As a composite, these animal studies provide evidence that timed bromocriptine treatment improves dysglycemia by improving (postprandial) insulin action in the liver and/or peripheral insulin-sensitive tissues (e.g.…”

Effect of bromocriptine-QR therapy on glycemic control in subjects with type 2 diabetes mellitus whose dysglycemia is inadequately controlled on insulin

“…Interestingly, this B-QR effect on postprandial hyperglycemia is expressed at meal times across the day [22,23] and well after (e.g. 24 h later) the short pulsed duration of bromocriptine into the circulation following its circadian-timed morning administration [37,38], which supports the preclinical data suggesting a 'resetting' of aberrant neuroendocrine responsiveness to mealtime feeding to improve postprandial insulin sensitivity with this therapy [27][28][29][30][31][32][33][34][35][36]. Mechanistic insights into this metabolic phenomenon can be gained from a series of neurophysiological studies that established a facilitatory role for the circadian peak in dopaminergic input activity to the body pacemaker clock system (suprachiasmatic nuclei [SCN]) in the maintenance of normal insulin sensitivity and glucose tolerance in animal models of insulin resistance [26][27][28][29][30][31][32][33][34] described as follows.…”

“…The preponderance of available evidence from preclinical and clinical mechanistic studies indicates that a majority (but not the total) of the improvement in glycemic control observed with B-QR therapy in T2DM subjects results from a drug-induced improvement in postprandial glucose metabolism and hyperglycemia [21][22][23][35][36][37][38][39]. Interestingly, this B-QR effect on postprandial hyperglycemia is expressed at meal times across the day [22,23] and well after (e.g.…”

“…Available evidence from preclinical and clinical studies suggests that B-QR is a postprandial-weighted insulin sensitizer promoting glucose disposal following a meal [21][22][23][35][36][37][38][39]. Hyperinsulinemic-euglycemic clamp studies indicate that B-QR improves maximally insulin-stimulated glucose disposal [21].…”