Atherosclerosis 152 2000 229 – 237
Inefficiency of insulin therapy to correct apolipoprotein A-I metabolic abnormalities in non-insulin-dependent diabetes mellitus
Laurence Duvillard , Fre´de´ric Pont, Emmanuel Florentin, Philippe Gambert, Bruno Verge`s
INSERM U
498
-Me´tabolisme des lipoprote´ines humaines et interactions 6asculaires, Faculte´ de Me´decine,
21033
Dijon, France Received 21 May 1999; received in revised form 25 October 1999; accepted 5 November 1999
Abstract
Non-insulin-dependent diabetes mellitus NIDDM is associated with low high density lipoprotein HDL cholesterol and apoA-I, related to an increased apoA-I fractional catabolic rate. This stable isotope kinetic experiment, using
L
-[1-
13
C] leucine, was designed to study the effect of insulin therapy on HDL apoA-I and A-II metabolism in poorly controlled NIDDM patients.
A kinetic study was performed in five control subjects and in six NIDDM patients before and two months after the introduction of insulin therapy. ApoA-I and A-II were modelled using a monoexponential function. Insulin treatment was able to correct
neither the low HDL apoA-I concentration observed in NIDDM patients 1.14 9 0.19 vs. 1.16 9 0.12 g l
− 1
controls: 1.33 9 0.14, nor the HDL apoA-I hypercatabolism 0.39 9 0.11 vs. 0.34 9 0.05 pool d
− 1
, controls: 0.23 9 0.01, P B 0.01. HDL apoA-I production rate was increased in NIDDM patients compared to control subjects and was not modified by insulin
0.45 9 0.12 vs. 0.39 9 0.08 g d
− 1
l
− 1
, controls: 0.31 9 0.04, P B 0.05. HDL apoA-II kinetic parameters were initially not significantly different between NIDDM patients and control subjects, and were not modified by insulin. The decreased insulin
sensitivity, assessed by the insulin suppressive test, was not modified by insulin therapy in NIDDM patients. HDL apoA-I fractional catabolic rate was significantly correlated to HDL triglyceridecholesteryl ester and triglycerideprotein ratios, which
were significantly higher in NIDDM patients than in controls and were not modified by insulin therapy. The persistence of insulin resistance and of high neutral lipid exchanges between triglyceride rich lipoproteins and HDL in insulin-treated NIDDM patients
probably explain the inefficiency of insulin therapy to correct HDL apoA-I metabolic abnormalities. © 2000 Elsevier Science Ireland Ltd. All rights reserved.
Keywords
:
Non-insulin-dependent diabetes mellitus; Insulin; Apolipoprotein A-I; Apolipoprotein A-II; Stable isotope; Kinetic study www.elsevier.comlocateatherosclerosis
1. Introduction
Atherosclerosis is the first cause of morbidity and mortality among non insulin dependent diabetes melli-
tus NIDDM patients. These patients generally exhibit high triglyceride level and low high-density lipoprotein
HDL cholesterol concentration, especially HDL
2
cholesterol [1]. Apolipoprotein A-I, the main apolipo- protein of HDL particles, tends also to be decreased in
NIDDM patients, and the diminution of plasma HDL cholesterol andor apoA-I in these patients has been
associated with an increased risk of macrovascular dis- ease [2 – 4]. The decrease of apoA-I plasma pool size
observed in NIDDM subjects has been related to a major increase of its fractional catabolic rate FCR,
whereas the moderate rise of its production rate PR is not sufficient to compensate the hypercatabolism [5,6].
The same apoA-I metabolism abnormalities have been described in subjects with impaired glucose tolerance
[7]. In these studies, apoA-I FCR was strongly corre- lated with plasma triglycerides, plasma insulin concen-
tration and fasting plasma glucose, indicating that hypertriglyceridaemia, insulin resistance and hypergly-
caemia are likely to be responsible for apoA-I hyper- catabolism in NIDDM or glucose intolerance.
Corresponding author. Present address: Laboratoire de Biochimie des Lipoprote´ines, Hoˆpital du Bocage, BP 1542, 21034 Dijon, France.
Tel.: + 33-3-80293825; fax: + 33-3-80293661. E-mail address
:
laurence.duvillardu-bourgogne.fr L. Duvillard. 0021-915000 - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 0 2 1 - 9 1 5 0 9 9 0 0 4 7 3 - 6
NIDDM patients with poor metabolic control de- spite diet and antidiabetic oral therapy are often treated
by insulin. Insulin therapy generally improves gly- caemic control. Moreover it induces an important de-
crease of
hypertriglyceridaemia and
has been
demonstrated to make apoB-containing lipoprotein metabolism more physiological [8]. Unlike hypertriglyc-
eridaemia, HDL cholesterol level is moderately im- proved, or not improved at all on insulin therapy
[9 – 11]. The reasons for the persistence of low HDL cholesterol level on insulin therapy are not elucidated.
To our knowledge the metabolism of HDL particles has not been investigated in insulin-treated NIDDM
patients. The lack of modification of HDL cholesterol and apo A-I plasma concentrations may indicate that
the metabolism of HDL particles is unchanged by insulin therapy, but also that insulin may induce oppo-
site modifications on production and catabolism of these particles.
In order to get further insight into the persistence of low HDL cholesterol concentration in insulin-treated
NIDDM patients, we compared the kinetic of apolipo- proteins A-I and A-II, the two main apolipoproteins of
HDL particles, in NIDDM patients before and 2 months after the introduction of insulin therapy.
ApoA-I and A-II were endogenously labelled with
L
-[1-
13
C] leucine, a stable isotope, and sample isotopic en- richment
was quantified
by gas
chromatographycombustionisotope ratio mass spec- trometry, the most precise and most accurate technique
known at present [12]. In this article, we report that insulin therapy is unable to correct apoA-I hyper-
catabolism in NIDDM patients, and by analyzing the evolution on insulin therapy of factors likely to be
involved in apoA-I hypercatabolism, we elucidated the reasons for its persistence in insulin-treated NIDDM
patients.
2. Subjects and methods
