Type 2 diabetic patients are at increased risk to develop atherosclerotic v
ascular disease. These patients are often treated with sulphonylurea deriva
tives, and it has been suggested that this treatment might contribute to th
e increased atherosclerotic process. The aim of the present study was there
fore to investigate whether tolbutamide influences lipid metabolism in such
a way that the atherosclerotic process may be promoted. Addition of tolbut
amide (5-500 mg/l) to isolated rat fat adipocytes inhibited the lipoprotein
lipase (LPL) activity in a dose-dependent manner to levels about 50% of th
ose registered in the absence of tolbutamide. This effect was due to inhibi
tion of the activation of the enzyme in the tissue and not to interference
with the interaction of enzyme with its substrate. Addition of tolbutamide
(500 mg/l) also inhibited noradrenaline (100 nM) and isoprenaline (40 nM)-i
nduced lipolysis by 48.1 +/- 7.4% (mean +/- S.E.M.) and 47.3 +/- 5.5%, resp
ectively. The decreased lipolysis in tolbutamide preincubated adipocytes wa
s shown to be the result of an inhibition of the phosphorylation of hormone
sensitive lipase (HSL), Three months of tolbutamide treatment (0.5 g t.i.d
.) in diet treated type 2 diabetic patients did not influence the plasma co
ncentrations of cholesterol, triglycerides, LDL cholesterol, HDL cholestero
l as well as HDL triglycerides and HDL phospholipids, and there were no dif
ferences compared to placebo treated patients. There was a tendency towards
a decrement in the elimination rate of exogenous triglycerides in the tolb
utamide group (P = 0.0801). No differences between the groups and no treatm
ent effects were seen on LPL and hepatic lipase activities. In conclusion,
our in vitro data show that tolbutamide has dual effects on lipid transport
, with impairment of the LPL system, which would tend to decrease plasma li
poproteins by reducing hepatic production of lipoproteins. In vivo, these t
wo effects seem to balance each other and plasma lipoprotein levels remain
unaffected. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.