Bromocriptine: a novel approach to the treatment of type 2 diabetes.
OBJECTIVE
In vertebrates, body fat stores and insulin action are controlled by the temporal interaction of circadian neuroendocrine oscillations. Bromocriptine modulates neurotransmitter action in the brain and has been shown to improve glucose tolerance and insulin resistance in animal models of obesity and diabetes. We studied the effect of a quick-release bromocriptine formulation on glucose homeostasis and insulin sensitivity in obese type 2 diabetic subjects.


METHODS
There were 22 obese subjects with type 2 diabetes randomized to receive a quick-release formulation of bromocriptine (n = 15) or placebo (n = 7) in a 16-week double-blind study. Subjects were prescribed a weight-maintaining diet to exclude any effect of changes in body weight on the primary outcome measurements. Fasting plasma glucose concentration and HbA(1c) were measured at 2- to 4-week intervals during treatment. Body composition (underwater weighing), body fat distribution (magnetic resonance imaging), oral glucose tolerance (oral glucose tolerance test [OGTT]), insulin-mediated glucose disposal, and endogenous glucose production (2-step euglycemic insulin clamp, 40 and 160 mU x min(-1) x m(-2)) were measured before and after treatment.


RESULTS
No changes in body weight or body composition occurred during the study in either placebo- or bromocriptine-treated subjects. Bromocriptine significantly reduced HbA(1c) (from 8.7 to 8.1%, P = 0.009) and fasting plasma glucose (from 190 to 172 mg/dl, P = 0.02) levels, whereas these variables increased during placebo treatment (from 8.5 to 9.1%, NS, and from 187 to 223 mg/dl, P = 0.02, respectively). The differences in HbA(1c) (delta = 1.2%, P = 0.01) and fasting glucose (delta = 54 mg/dl, P < 0.001) levels between the bromocriptine and placebo group at 16 weeks were highly significant. The mean plasma glucose concentration during OGTT was significantly reduced by bromocriptine (from 294 to 272 mg/dl, P = 0.005), whereas it increased in the placebo group. No change in glucose disposal occurred during the first step of the insulin clamp in either the bromocriptine- or placebo-treated group. During the second insulin clamp step, bromocriptine improved total glucose disposal from 6.8 to 8.4 mg x min(-1) kg(-1) fat-free mass (FFM) (P = 0.01) and nonoxidative glucose disposal from 3.3 to 4.3 mg min(-1) x kg(-1) FFM (P < 0.05), whereas both of these variables deteriorated significantly (P < or = 0.02) in the placebo group.


CONCLUSIONS
Bromocriptine improves glycemic control and glucose tolerance in obese type 2 diabetic patients. Both reductions in fasting and postprandial plasma glucose levels appear to contribute to the improvement in glucose tolerance. The bromocriptine-induced improvement in glycemic control is associated with enhanced maximally stimulated insulin-mediated glucose disposal.
Pijl
H
H
University of Texas Health Science Center and Texas Diabetes Institute, San Antonio 78284-7886, USA.
Ohashi
S
S
Matsuda
M
M
Miyazaki
Y
Y
Mahankali
A
A
Kumar
V
V
Pipek
R
R
Iozzo
P
P
Lancaster
J L
JL
Cincotta
A H
AH
DeFronzo
R A
RA
D000005:Abdomen; D000273:Adipose Tissue / Q000033:anatomy & histology; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D001835:Body Weight; D001971:Bromocriptine / Q000627:therapeutic use*; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D003927:Diet, Diabetic; D004311:Double-Blind Method; D005260:Female; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000032:analysis; D006727:Hormone Antagonists / Q000627:therapeutic use; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009765:Obesity; D010919:Placebos; D013997:Time Factors; D014781:Viscera
D001786:Blood Glucose; D001971:Bromocriptine; D006442:Glycated Hemoglobin; D006727:Hormone Antagonists; D007004:Hypoglycemic Agents; D010919:Placebos