Effect of d-fenfluramine on basal glucose turnover and fat-feeding-induced insulin resistance in rats.
There is evidence that fenfluramine improves insulin action independently of its anorectic and weight-loss-inducing properties. Chronic d-fenfluramine also reduces hypothalamic noradrenergic tone, which correlates highly with hepatic glucose output. We report that chronic d-fenfluramine (5 mg.kg-1.day-1) ameliorates insulin resistance induced by high-fat feeding. Insulin action was assessed in adult male rats at basal insulin levels and at hyperinsulinemia (approximately 140 mU/L with the euglycemic clamp technique). Hepatic glucose production, peripheral glucose disposal, and individual tissue glucose metabolism were determined from bolus injections of [3H]-2-deoxyglucose and [14C]glucose. Food intake was matched between groups. Basal glucose turnover was reduced 28% (P less than .05) in fat-fed rats receiving d-fenfluramine (fat + fen). The glucose infusion rate to maintain euglycemia was 22.0 +/- 1.1 mg.kg-1.min-1 in the high-carbohydrate-fed rats, 8.2 +/- 1.0 in fat-fed rats, and 15.1 +/- 0.5 in the fat + fen group. Peripheral glucose disposal, reflecting measured skeletal muscle changes, was reduced by fat feeding (from 23.5 +/- 1.0 to 13.8 +/- 0.6 mg.kg-1.min-1) but was improved by d-fenfluramine (16.9 +/- 0.5, P less than .05 vs. fat fed). Impaired suppression of hepatic glucose output by insulin, caused by fat feeding, was totally reversed by d-fenfluramine. Thus, d-fenfluramine counteracted diet-induced insulin resistance, with the predominant effect on the liver. We hypothesize that d-fenfluramine improves insulin action by reducing hypothalamic noradrenergic tone, which in turn reduces the neural drive to hepatic glucose output and improves the hepatic response to insulin.
Storlien
L H
LH
Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, Australia.
Thorburn
A W
AW
Smythe
G A
GA
Jenkins
A B
AB
Chisholm
D J
DJ
Kraegen
E W
EW
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004040:Dietary Carbohydrates / Q000494:pharmacology; D004041:Dietary Fats / Q000494:pharmacology*; D005277:Fenfluramine / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000097:blood*; D007332:Insulin Infusion Systems; D007333:Insulin Resistance; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009132:Muscles / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D051381:Rats
D001786:Blood Glucose; D004040:Dietary Carbohydrates; D004041:Dietary Fats; D007328:Insulin; D005277:Fenfluramine; D005947:Glucose