Acute and chronic effects of dexfenfluramine on glucose and insulin response to intravenous glucose in diabetic and non-diabetic obese subjects.
Fenfluramine improves glucose tolerance in obese subjects independently of its anorectic effect. Increased insulin action has been reported, but such an effect may be secondary to reduced hyperglycemia following augmented insulin secretion. For this reason, we investigated whether the dextro-enantiomer of fenfluramine (dexfenfluramine, dF) has a direct effect on insulin secretion using the glucose infusion test, a technique that can also be used to indirectly evaluate insulin action. Ten lean controls (BMI 21 +/- 0.4 kg/m2), 9 non-diabetic obese subjects (BMI 32.3 +/- 1.1) and 10 obese mild non-insulin dependent diabetics (BMI 36 +/- 2.6, fasting plasma glucose (FPG) 7.9 +/- 0.9 mmol/l) were studied with a random, double blind cross-over protocol. Each subject received 15 mg dF (or placebo) twice daily for 3 days prior to glucose infusion; 30 mg dF (or placebo) were given 90 min before the test. Obese control and diabetic subjects continued treatment with either dF or placebo for one month after which they were retested. There was no significant change in weight or fasting plasma glucose or insulin in any group. Biphasic insulin secretion was demonstrated in both non-diabetic groups, whereas a complete lack of first-phase and a delayed and reduced second phase insulin response was demonstrated in the diabetic subjects. There was no acute or chronic (obese subjects) effect of dF on insulin secretion in any group. In lean control subjects, plasma glucose curves during glucose infusion were unchanged by dF, whereas in non-diabetic obese subjects the glucose slope was improved after both acute and chronic dF, implying augmented glucose disposal. In diabetic patients, no significant acute or chronic effect of dF on glucose response was registered. When all obese subjects were re-grouped according to fasting plasma insulin levels (FPI) and not glucose tolerance, those with relative fasting hyperinsulinemia (> 100 pmol/l, mean +/- SE = 144 +/- 12 pmol/l) showed significant improvement of insulin action after dF, whereas those with low FPI (< 100 pmol/l, mean +/- SE = 65 +/- 7 pmol/l) did not. These findings, together with previously published results of improved insulin action in diabetics during hyperinsulinemic clamps, suggest that dF-mediated improvement in glucose clearance may require substantial plasma insulin concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)
Glaser
B
B
Department of Endocrinology and Metabolism, Hebrew University Hadassah Medical Center, Jerusalem, Israel.
Raveh
Y
Y
Norynberg
C
C
Berry
E
E
Lavielle
R
R
Nathan
C
C
Cerasi
E
E
D000328:Adult; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000097:blood*; D004311:Double-Blind Method; D006801:Humans; D007328:Insulin / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology; D000078790:Insulin Secretion; D007700:Kinetics; D008875:Middle Aged; D009765:Obesity / Q000097:blood*; D011897:Random Allocation; D012016:Reference Values; D013997:Time Factors
D001786:Blood Glucose; D007328:Insulin