Diazoxide-mediated insulin suppression in obese men: a dose-response study.
BACKGROUND
It has been suggested that diazoxide (DZX)-mediated insulin suppression may be useful to promote weight loss in obese subjects.


OBJECTIVE
To assess the DZX-dose range that is safe to use in obese hyperinsulinaemic men.


METHODS
Assessment of DZX efficacy and safety was based on plasma glucose and insulin responses to a standardized 500-kcal breakfast, taken on the sixth day of treatment. Basic information regarding the potential efficacy of DZX treatment was first evaluated in an open-label study in five non-obese men. Subsequently, a double-blind, randomized, placebo-controlled study was performed in 12 obese but otherwise healthy men, comparing placebo treatment with DZX in doses of 50, 75 and 100 mg three times daily for 6 days.


RESULTS
In non-obese subjects, DZX 50 mg decreased peak insulin levels by +/-28% and raised peak glucose concentration from 7.1 +/- 0.6 to 7.8 +/- 0.6 mmol/l (p < 0.05). DZX 100 mg reduced peak insulin levels by 45% and caused a rise in peak glucose levels from 7.1 +/- 0.6 to 9.0 +/- 0.9 mmol/l (p < 0.05). In obese men, the 50 and 75 mg doses had no significant effects on glucose or insulin levels. DZX 100 mg reduced the peak insulin levels and insulin area under the curve by +/-20% (p < 0.05) but did not affect fasting or postprandial glucose levels. The relatively limited insulin-suppressive effects in obese subjects were attributed to the low plasma DZX levels that were achieved in this group. For comparable doses, plasma DZX levels were about 30% lower in obese than in non-obese men. Plasma DZX levels were highly dependent on dose (p < 0.001) and body weight (p < 0.001). Ninety-two percent of the total variability in DZX levels was explained by these two parameters.


CONCLUSIONS
DZX-mediated insulin suppression is dose dependent in normal and in obese men. However, the efficacy of DZX is much less in obese than in non-obese subjects. This is attributed to weight-dependent differences in distribution volume that lead to markedly lower plasma DZX levels in obese subjects. Weight-adjusted doses will be needed to achieve biologically effective plasma DZX levels. Extrapolation of the data suggests that effective insulin suppression in obese men will at least require a daily dose of 3.2-4.2 mg/kg.
Schreuder
T
T
Department of Internal Medicine, Ziekenhuis Rijnstate, Wagnerlaan 55, 6800 TA Arnhem, The Netherlands.
Karreman
M
M
Rennings
A
A
Ruinemans-Koerts
J
J
Jansen
M
M
de Boer
H
H
D000328:Adult; D019540:Area Under Curve; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D003864:Depression, Chemical; D003981:Diazoxide / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use; D004232:Diuretics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D007328:Insulin / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D019518:Postprandial Period; D049993:Sodium Chloride Symporter Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use
D001786:Blood Glucose; D004232:Diuretics; D007328:Insulin; D049993:Sodium Chloride Symporter Inhibitors; D003981:Diazoxide