Perspective in the treatment of insulin resistance
AJ.Scheen
Division of Diabetes, Nutrition and Metabolic Diseases, Department of Medicine,
CHU Sail Tilman (B35), B-4000 Liege 1, Belgium
Introduction
Insulin resistance plays a significant role in numerous and frequent conditions (Reaven, 1988;
Human Reproduction Volume 12 Supplement 1 1997
Ferrannini, 1993; Moller, 1993), various physiological states (puberty, elderly, sedentarity, etc.),
important pathological entities (obesity, diabetes
mellitus, essential hypertension, dyslipidaemias,
etc.), and several pharmacological treatments
(corticoids, some antihypertensive agents, oral contraceptives, etc.). More particularly, resistance to
insulin is a key element of the so-called syndrome
X which plays a major role in the development of
atherosclerotic cardiovascular diseases (Reaven,
1988; DeFronzo and Ferrannini, 1991; Lefebvre,
1993; Scheen, 1996a). Furthermore, insulin resistance plays a significant role in women and human
reproduction since decreased insulin sensitivity has
been described during pregnancy, in polycystic
ovary syndrome (PCOS) (Poretsky, 1991), after
menopause (Khaw, 1992), as well as during treatment with various contraceptive pills (Gaspard and
Lefebvre, 1990; Godsland et al, 1993b; Godsland
and Crook, 1994). It is thus crucial not only to
have adequate methods to measure insulin action
(Scheen et al., 1994b; Scheen and Lefebvre, 1996),
but also to develop new strategies to improve
insulin sensitivity (Vialettes and Silvestre, 1992;
Scheen and Lefebvre, 1993; Donnelly and Morris,
1994; Lefebvre and Scheen, 1995).
The purpose of the present review is to describe
the main approaches currently used for the treatment of insulin resistance in humans, as well as to
consider two gynaecological potential applications,
i.e. PCOS and menopause.
Non-pharmacological approaches
Several easy and inexpensive non-pharmacological
approaches may result in significant improvement
in insulin action (Figure 1; Sharma, 1992).
European Society for Human Reproduction & Embryology
63
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Improving the action of insulin is a relatively
new concept in therapy. It should, however,
become more and more important because of
the rapid expansion of the insulin resistance
syndrome (including upper body adiposity, glucose intolerance, hypertension, dyslipidaemia,
etc.) in industrialized countries and its dramatic
consequences for public health. Insulin sensitivity can be improved by non-pharmacological
means, essentially reduction of excessive body
weight, promotion of regular physical activity
and modification of dietary habits, as well as,
possibly, cessation of smoking and correction
of subclinical magnesium deficiency. Currently
available pharmacological means mainly
include the biguanide compound metformin and
possibly anti-obesity agents, such as (d-) fenfluramine, fluoxetine and benfluorex. New compounds aiming at improving the action of insulin
are in development, especially the thiazolidinedione derivatives (e.g. troglitazone), known as
insulin sensitizers'. Treatment of insulin resistance may have important gynaecological
applications, essentially in polycystic ovary syndrome and, possibly, after menopause. Hopefully, improving insulin sensitivity could
ameliorate the cardiovascular prognosis of
numerous individuals having some or all components of insulin resistance syndrome.
Key words: diabetes/insulin sensitivity/menopause/
obesity/polycystic ovary syndrome/syndrome X
A.J.Scheen
Glycerol
Free Fatty Acids
/
(METFORMIN)
BIGUANEDES
(BENFLUOREX)
INSULIN
DIET
J«
WEIGHT
LOSS
(TROGLITAZONE)
PLASMA
GLUCOSE
ADIPOSE
TISSUE
BENFLUOREX
METFORMIN
TROGLITAZONE
INSULIN
EXERCISE
Glucose \
Utilization \
Free Fatty Acids
/
/
MAGNESIUM
SEROTONINERGIC
AGENTS
MUSCLE
Figure 1. Sites of action of various therapeutic approaches of insulin resistance. Insulin action on metabolism can be improved
in the liver, skeletal muscle and adipose tissue. Subsequent reduction of hepatic glucose production and increase of peripheral
glucose utilization will result in improvement of glucose tolerance and reduction of compensatory hyperinsulinaemia.
Reduction of excessive weight
Obesity is a major cause of insulin resistance
(Scheen et al, 1995c). Non-pharmacological
means of reducing excessive body weight include
dietary counselling, psychological and behavioural
approaches, very low calorie diets and, in some
extreme cases, bariatric surgery (Scheen et al,
1994a). A few studies have investigated the effects
of these procedures on insulin sensitivity (Letiexhe
et al, 1994b; Lefebvre and Scheen, 1995; Scheen
et al, 1995c). In absence of non-insulin-dependent
diabetes, only dramatic weight losses similar to
those obtained after gastroplasty induce clear-cut
improvement (Letiexhe et al, 1994a) or even
normalization (Letiexhe et al, 1995) of insulin
sensitivity. Nevertheless, reducing excessive body
weight is a major target in the management of
insulin resistance of obese subjects.
Promotion of physical activity
Several studies have suggested that regular exercise
may significantly improve insulin sensitivity and
64
glucose tolerance (Sharma, 1992; Kriska and
Bennett, 1992; Gudat et al, 1994). However,
exercise-improved insulin sensitivity is usually of
short duration (several days) or may require heavy
and sustained training programmes that can be
assumed to be difficult for many patients to accept
(Lefebvre and Scheen, 1995).
Modification of dietary habits
There is substantial evidence indicating that
changes in diet composition can have a significant
effect on glucose tolerance and insulin sensitivity
in man (Sharma, 1992). However, several of these
studies are confounded by changes in body weight
or physical activity, by differences in the source
and composition of the macronutrients, and by
sparse information on concomitant changes in
dietary micronutrients or lifestyle (Sharma, 1992).
Nevertheless, it appears that a diet low in fat but
high in carbohydrates and fibre may be best suited
to improve insulin sensitivity and glucose tolerance
in insulin-resistant states (Sharma, 1992; Smith,
1994).
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ANTIOBESITY
AGENTS
THIAZOLIDINEDIONES
Glucose \
/
Production \/
Treatment of insulin resistance
Cessation of cigarette smoking
It has been reported that insulin-mediated glucose
uptake is significantly reduced in cigarette smokers
compared with appropriately matched non-smoker
controls, and that smokers are also hyperinsulinaemic and dyslipidaemic (Facchini et al, 1992).
However, the effect of smoking on insulin sensitivity appears to be rapidly reversible, over 10-12 h
(Nilsson et al., 1995). It remains to be demonstrated
that cigarette smoking cessation does in fact
increase the sensitivity to insulin.
development. They have been essentially evaluated
in obese diabetic patients, but may be also effective
in insulin-resistant individuals, in absence of overt
diabetes (Figure 1).
Pharmacological approaches
First of all, when prescribing drugs, the clinician
must always consider the possibility that some of
them may adversely affect insulin sensitivity and,
consequently, prefer those that are either neutral
or, better, improve the sensitivity to insulin (Lithell,
1991; Pandit et al, 1993; Lefebvre and Scheen,
1995). This is particularly the case in the field of
gynaecology, where, for instance, progestagen with
high androgenic properties should be avoided and
replaced by progestagens with low androgenic
properties, in combination with low rather than
high doses of oestrogens (Gaspard and Lefebvre,
1990; Godsland et al, 1993b; Godsland and Crook,
1994). As recently reviewed (Vialettes and
Silvestre, 1992; Scheen and Lefebvre, 1993; Donnelly and Morris, 1994; Lefebvre and Scheen,
1995), several drugs specifically increase insulin
sensitivity and numerous compounds are still in
Antiobesity agents
Several studies have shown that serotoninergic
anorectic agents, such as fenfluramine or dexfenfluramine (Davis and Faulds, 1996) and fluoxetine
(O'Kane et al, 1994), improve glucose control in
obese diabetic subjects independently of weight
loss, which suggests a direct effect on insulin
sensitivity (Scheen and Lefebvre, 1993). This has
been confirmed using the classical euglycaemic
hyperinsulinaemic clamp technique with the anorectic drug dexfenfiuramine (Scheen et al, 1991)
or the antidepressant compound fluoxetine (Potter
van Loon et al, 1992). Serotoninergic agents may
therefore prove to be a useful adjunct to diet or
classical oral hypoglycaemic agents in obese Type
2 diabetic subjects (Scheen and Lefebvre, 1993).
Their usefulness in non-diabetic insulin-resistant
obese subjects, however, remains to be proven in
further studies.
Benfluorex, which is structurally related to fen65
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Magnesium supplements
Several studies have suggested that decreased
plasma and cellular magnesium levels may contribute to the insulin resistance of patients with Type
2 diabetes and that this defect in insulin action can
be partially reverted by magnesium supplements
(Paolisso et al, 1990; Lefebvre et al, 1994a,b).
Further studies are definitely needed to determine
to what extent subclinical magnesium depletion
contributes to the abnormal glucose metabolism in
diabetes (American Diabetes Association Consensus Statement, 1995) and to evaluate the possible role of decreased magnesium content on
impaired insulin sensitivity in some non-diabetic
subjects.
Metformin
Metformin, the only biguanide compound still
available, reduces insulin resistance in non-insulindependent diabetes and is now considered as the
drug of choice in obese diabetic patients (Bailey,
1992; Andreani and Lefebvre, 1995; Bailey and
Turner, 1996). Such an effect on insulin sensitivity
may also be present in obese subjects with only
impaired glucose tolerance (Scheen et al., 1995a,b).
The main site of action (liver, skeletal muscles or
even intestinal tract) remains, however, controversial (Bailey, 1992; Andreani and Lefebvre, 1995;
Scheen et al, 1995b). Besides its positive effects on
glucose metabolism, metformin exerts favourable
actions on associated disorders, such as high triglyceride values, low high density lipoprotein
(HDL) cholesterol concentrations and high
plasminogen activator inhibitor-I concentrations,
frequently seen in insulin-resistant subjects (Bailey,
1992; Andreani and Lefebvre, 1995; Scheen et al,
1995b; Bailey and Turner, 1996; Fontbonne
et al, 1996).
A.J.Scheen
fluramine, is a known hypolipidaemic agent with
possible glucose-lowering effects (review in
Reaven, 1993). Benfiuorex has been shown to
improve glucose tolerance and lipid metabolism
in obese Type 2 diabetic patients by increasing
sensitivity to insulin (at the liver and/or muscle
site), without directly stimulating insulin secretion
(Bianchi et al, 1993; Reaven, 1993).
Gynaecological applications
Diminished insulin sensitivity is clearly present in
the polycystic ovary syndrome (PCOS) and, to a
lesser extent, in some post-menopausal women.
Reduction of insulin resistance may help treating
associated metabolic or endocrine disorders in such
conditions.
Polycystic ovary syndrome
Frequent coexistence of insulin resistance and
ovarian hyperandrogenism is a well known phenomenon. In PCOS, hyperinsulinism appears to
66
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Thiazolidinedione derivatives
Thiazolidinediones represent a new structural class
of antidiabetic compounds which act as 'insulin
sensitizers' by enhancing post-binding events
mediating insulin actions on the peripheral target
tissues (Hofmann and Colca, 1992). Thiazolidinediones appear to act as agonists of the peroxisome
proliferator activator (PPAR)-y, a nuclear receptor
expressed in adipocytes that regulates expression
of adipocyte-specific fatty acid enzymes (Saltiel
and Olefslky, 1996). Several studies have demonstrated the efficacy of these drugs in patients with
Type 2 diabetes and in obese subjects with impaired
glucose tolerance (Suter et al, 1992; Nolan et al,
1994; Saltiel and Olefsky, 1996). Interestingly
enough, several components of the insulin resistance syndrome, e.g. lipid abnormalities and arterial
hypertension, appeared also to be improved by the
most extensively studied compound, troglitazone
(Saltiel and Olefsky, 1996). Ongoing clinical
studies will reveal more precisely whether thiazolidinediones can provide a safe and effective means
for treating Type 2 diabetes, as well as related
non-diabetic syndromes associated with insulin
resistance.
induce hyperandrogenism, which then leads to
gonadotrophin secretory abnormalities and anovulation (Poretsky, 1991). The contribution to
hyperinsulinaemia in women with PCOS may be
due to both increased pancreatic secretion and
reduced removal of insulin (Fulghesu et al, 1995a),
as also shown in control obese women (Letiexhe
et al, 1994a, 1995). Two recent studies (Fulghesu
et al, 1995a; Lanzone et al, 1995) demonstrated
that chronic pharmacological inhibition of opioid
tone by naltrexone could reduce insulin plasma
concentrations, mainly by improving liver metabolism of the hormone (Fulghesu et al, 1995a), and
reduce the LH response to GnRH (Lanzone et al,
1995) in hyperinsulinaemic women with PCOS.
The same group further demonstrated the existence
of a functional linkage between exaggerated insulin
and LH-stimulated secretion by showing that octreotide, a long-lasting somatostatin analogue, can
normalize these alterations and reduce ovarian
androgen secretion of hyperinsulinaemic women
with PCOS (Fulghesu et al, 1995b).
Weight loss is generally associated with an
improvement of insulin sensitivity and a reduction
in circulating plasma insulin concentrations in
obese women (Letiexhe et al, 1994a,b, 1995).
Intensive dietary intervention with adequate weight
loss has also been shown to restore insulin sensitivity (Andersen et al, 1995; Holte et al, 1995),
change an unfavourable atherothrombogenic risk
profile (Andersen et al, 1995), decrease insulin
and androgen concentrations and cause ovulation
in women with PCOS (Bates and Whitworth, 1982;
Kiddy et al, 1992; Table I). It has been recently
demonstrated that leptin, a protein hormone produced by adipocytes, increases energy expenditure,
decreases appetite and influences the reproductive
axis in animal models (Caro et al, 1996; Scheen,
1996b). Recent observations have shown abnormally excessive serum leptin concentrations when
compared to body weight in about one third of
women with PCOS; such results suggest that
abnormalities in leptin signalling to the reproductive system may be involved in certain cases of
PCOS (Brzechffa et al, 1996). Diet-induced reduction of fat mass, by reducing serum leptin concentrations, may correct such abnormalities in the
control of the reproductive axis in women with
PCOS.
Treatment of insulin resistance
Table I. Metabolic and endocrine effects of various
therapeutic approaches in women with PCOS (see text for
references)
Diet-induced weight loss
Improvement of insulin sensitivity
Reduction of plasma insulin and androgen concentrations
Improvement of atherogenic risk profile
Restoration of ovulation and fertility
Drugs improving insulin sensitivity
Troglitazone
Improvement of metabolic and reproductive abnormalities
(one recent study)
Gynaecological hormonal treatments
Gonadotropin-releasing hormone agonists
No effects on plasma insulin concentrations
No or inconsistent effects on insulin sensitivity
Anti-androgen therapy (flutamide, spironolactone)
Controversial effects on insulin sensitivity
Oral contraceptives
Further deterioration of insulin sensitivity
Several studies have investigated the possibility
of improving insulin sensitivity of women with
PCOS using gonadotropin-releasing hormone
agonists. Most results were negative as no reduction
in hyperinsulinaemic response during an oral glucose tolerance test (Dale et al, 1992) and no
improvement of peripheral or hepatic insulin resistance evaluated during a euglycaemic hyperinsulinaemic clamp (Dunaif et al, 1990) were observed
(Table I). Only one study (Elkind-Hirsch et al,
1993b) reported a significant improvement in the
insulin sensitivity index Sj during an intravenous
glucose tolerance test analysed with the minimal
model (Scheen et al, 1994b) in six mildly insulinresistant women with PCOS; however, such a
favourable effect was not observed in six women
with more severe insulin resistance (Elkind-Hirsch
et al, 1993b). Similarly, anti-androgen therapy
with flutamide did not result in any significant
increase of insulin-mediated glucose disposal in
both lean and obese women with PCOS (DiamantiKandarakis et al, 1995). However, in contrast to
Menopause
The observation that oral contraceptive steroids
may be associated with an impairment of glucose
67
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Metformin
Improvement of insulin sensitivity, endocrine milieu and
fertility (one study)
No additional effect independently of weight loss (two
studies)
all these negative results, a recent study demonstrated that various antiandrogen treatments, spironolactone, flutamide, or the GnRH agonist
buserelin, can partially reverse insulin resistance
(evaluated during a euglycaemic hyperinsulinaemic
clamp) in women with hyperandrogenism (hirsutism and/or PCOS), suggesting that androgens
impair insulin action in those women (Moghetti
etal, 1996).
If hyperandrogenism is secondary to insulin
resistance rather than the primary event, one may
speculate a positive influence of classical pharmacological means improving insulin sensitivity
(Table I). Metformin has been shown to improve
insulin sensitivity in women with PCOS, and,
remarkably enough, most of the metabolic abnormalities of PCOS could be reversed by metformin
with the additional benefit of enough normalization
of the endocrine milieu to allow regular menstrual
menses, reversal of infertility, and spontaneous
pregnancy (Velazquez et al, 1994). However, such
favourable results were not confirmed in two recent
studies which were unable to demonstrate any
significant improvement of hyperinsulinaemia and
androgen excess by the administration of metformin in obese non-diabetic women with PCOS
(Crave et al, 1995; Ehrmann et al, 1997). Interestingly, it has been shown that the new thiazolidinedione derivative troglitazone improves insulin
resistance and reproductive abnormalities in
women with PCOS (Dunaif et al, 1996). Such
encouraging results should be confirmed in further
studies before considering that insulin-sensitizing
agents may provide a novel therapy for PCOS.
Although oral contraceptives are often instituted
to regulate menses and suppress hyperandrogenism
in women with PCOS, their use has been postulated
to cause a deterioration in insulin sensitivity and
to adversely affect circulating lipids. A recent
study confirmed that short-term (3 months) therapy
with a triphasic oral contraceptive results in a
further decline in insulin sensitivity index in
women with PCOS, however without inducing
additional adverse effects on lipids (Korytkowski
et al, 1995).
AJ.Scheen
68
but higher doses might attenuate this benefit, and
progestins might cause a decrease in insulin sensitivity. The independent effects on insulin sensitivity
of the three most prevalent conjugated equine
oestrogens of Premarin® have been recently evaluated by measuring the plasma glucose disappearance after i.v. insulin injection (Wilcox et al,
1997); some improvement of insulin action was
observed with the various oestrogens, highest with
equilin sulphate, intermediate with oestrone
sulphate and least (results not significantly different) with 17oc-dihydroequilin sulphate. In contrast,
a prospective randomized cross-over study comparing the effects of oral and transdermal oestrogen on
glucose tolerance (during an oral glucose tolerance
test) and insulin sensitivity (evaluated during a
classical euglycaemic hyperinsulinaemic clamp) in
post-menopausal women led to negative results;
no significant effects on carbohydrate metabolism
were demonstrated after 10 weeks of treatment,
whatever the route of oestrogen replacement therapy (O'Sullivan and Ho, 1995). Thus, the effects
of HRT on insulin sensitivity are controversial,
but, if present, they appear to be of small amplitude.
The conflicting data may stem from the use of
different dosages and formulations of HRT and the
failure to delineate the individual or combined
effects of oestrogen and progestagen. Nevertheless,
no similar deterioration in insulin sensitivity has
been reported with HRT as that described with
some oral contraceptives (Godsland et al,
1993a,b). Contrasting with the indirect conclusions
of epidemiological studies (Nabulsi et al, 1993),
almost all clinical studies which measured insulin
sensitivity failed to demonstrate a significant
improvement of insulin sensitivity with HRT in
post-menopausal women. Thus, up to now, general
means, such as appropriate diet and regular physical
activity, avoiding weight gain and abdominal adiposity, remain the best tools for improving insulin
sensitivity in post-menopausal women.
Conclusions
Resistance to insulin is a key element of a large
syndrome including upper body obesity, glucose
intolerance, arterial hypertension, dyslipidaemia
and mild fibrinolytic disturbances, all factors leading to an increased risk of cardiovascular diseases.
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tolerance, hyperinsulinaemia, and a reduction in
insulin sensitivity (Gaspard and Lefebvre, 1990;
Godsland etal, 1993b; Godsland and Crook, 1994)
raises the possibility that hormone replacement
therapy (HRT) in post-menopausal women may
result in similar changes in carbohydrate metabolism. To date, the majority of studies on the effects
of HRT on carbohydrate metabolism have concentrated on glucose tolerance, and the results have
been conflicting (Khaw, 1992; O'Sullivan and Ho,
1995). Furthermore, the oral glucose tolerance
test does not give precise information on insulin
sensitivity, even if concomitant plasma insulin
response is measured (Scheen et al, 1994b). Epidemiological studies reported, however, reduced
fasting glucose and insulin plasma concentrations
in post-menopausal women receiving HRT, a finding suggesting improved insulin sensitivity (Nabulsi et al, 1993). The use of oestrogen combined
with progestin appeared to be associated with a
better metabolic profile than the use of oestrogen
alone (Nabulsi et al, 1993).
Unfortunately, few clinical studies have directly
evaluated the influence of HRT on insulin sensitivity. Insulin resistance, secretion, and elimination
were investigated in a large number of postmenopausal women receiving oral or transdermal
HRT (Godsland et al, 1993a). Compared with
baseline values, neither treatment significantly
affected the insulin sensitivity index Sj (estimated
with the minimal model during an i.v. glucose
tolerance test; Scheen et al, 1994b). However,
with the oral treatment, insulin sensitivity was
lower during the combined phase compared with
the oestrogen-only phase. Furthermore, the transdermal regimen had relatively fewer effects on
insulin secretion and metabolism than the oral
treatment (Godsland et al, 1993a). Using the same
technique, a significant reduction of the index
Sj has been reported in six young women with
premature ovarian failure receiving oral HRT, but
the number of subjects was too small to draw any
definite conclusions (Elkind-Hirsch et al, 1993a).
In a study using the i.v. insulin tolerance test, a
possible bimodal effect of oestrogen on insulin
sensitivity has been suspected in post-menopausal
women (Lindheim et al, 1993); a moderate dose
of oestrogen appeared to increase insulin sensitivity
Treatment of insulin resistance
These abnormalities are frequently present in polycystic ovary syndrome and, to a lesser extent, in
some post-menopausal women. Non-pharmacological means should be proposed first in the
treatment of insulin resistance, with the main
objective to correct weight excess. Pharmacological treatments come only second in line, more
particularly metformin and the recently developed
thiazolidinedione derivatives such as troglitazone.
New therapeutic approaches are welcomed by the
clinician who is confronted with many patients with
all or some components of the insulin resistance
syndrome.
69
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