Insulin Action and Its Disturbances in Disease - part 10 ppt

542 THERAPEUTIC STRATEGIES FOR INSULIN RESISTANCE
range, although these levels were lower than those of placebo-treated patients
in some trials. It is therefore recommended the diet should be rich in fruit and
vegetables. In addition to this, NICE has recommended that the patient should
have already lost 2.4 kg by diet and exercise prior to starting orlistat; their
BMI should be above 30 kg/m
2
or 28 kg/m
2
if they have other co-morbidities.
Patients should receive appropriate dietary advice from health professionals.
Continuation of treatment beyond 3 months should be accompanied by a weight
loss of five per cent from the initial body weight and beyond six months by a
loss of 10 per cent.
38, 39
Sibutramine
Sibutramine is an orally administered, centrally acting weight management
agent. It is apparently devoid of amphetamine-like abuse potential. The primary
(BTS 54 505) and secondary (BTS 54 354) amine metabolites of sibutramine
are pharmacologically active and are thought to induce the natural processes
leading to the enhancement of satiety and thermogenesis by inhibiting serotonin
and noradrenaline re-uptake.
The pharmacological activity of sibutramine does not appear to be a result
of increased serotonin release; this differentiates it from the action of dexfen-
fluramine, which predominantly causes the release of serotonin and dexamphe-
tamine, which predominantly releases dopamine and noradrenaline. This may
account for the lack of abuse potential with sibutramine.
40
The drug undergoes
first pass metabolism to form pharmacologically active primary (M1) and sec-
ondary (M2) metabolites. In trials steady state plasma metabolite concentrations

were maintained throughout treatment.
41
Plasma concentrations of sibutramine
and its metabolites are unaffected by the presence of renal dysfunction.
42
However,
sibutramine is contraindicated in patients with significant hepatic dysfunction.
In most trials sibutramine was administered with a reduced calorie diet and
activity advice. Trial data has shown weight loss in up to 77 per cent of patients
treated with sibutramine 10 mg/day and a 600 kcal/day deficit diet. There was
also sustained weight loss in patients continuing therapy for 2 years.
43
At higher
doses (up to 30 mg/day), greater initial weight loss has been reported.
44
Patients
receiving 10–20 mg/day lost 5.0–7.5 kg of body weight over an 8–12 week
period, compared with placebo recipients, who lost between 1.5 and 3.5 kg.
In individuals with type 2 diabetes, weight loss of more than 10 per cent was
achieved by a third of subjects on sibutramine, and this weight loss was associ-
ated with improvements in both metabolic control and quality of life.
45
However,
in the UK, the NICE guidelines state that sibutramine should only be prescribed
as part of an overall treatment plan for the management of nutritional obesity
in people aged 18–65 years who have either a BMI of >27.0 kg/m
2
in the
presence of co-morbidities or >30 kg/m
2

without associated co-morbidities.
The recommended starting dose of sibutramine is 10 mg o.d. with or without
food. Sibutramine should be used in conjunction with a reduced calorie diet.
SURGICAL MANAGEMENT OF OBESITY 543
If a weight loss of 1.8 kg is not achieved within the first 4 weeks of therapy,
either an increase in the dose to 15 mg o.d. or discontinuation of sibutramine
should be considered. Dosages higher than 15 mg are not recommended. The
most commonly reported adverse effects include headache, dry mouth, anorexia,
insomnia and constipation. Statistically significant increases in blood pressure
and heart rate (compared with placebo) were observed in obese patients without
hypertension who received sibutramine. Blood pressure monitoring is therefore
required before, and at regular intervals during, therapy. Treatment with sibu-
tramine is not recommended for individuals whose blood pressure before the
start of therapy is >145/90 mm Hg. It should be discontinued if it rises above
this level or if the increase is greater than 10 mm Hg.
38
Sibutramine should
not be given to patients with poorly controlled hypertension, and it is also con-
traindicated for patients with coronary heart disease, congestive cardiac failure,
arrhythmia, stroke or severe renal or hepatic impairment.
40
18.7 Surgical management of obesity
Surgery as a treatment for obesity is not new. Techniques such as jaw wiring
and stapled gastroplasty have been used for some time with variable results and
complications. In some carefully selected patients newer surgical techniques
(performed by a surgeon with experience in this field) can achieve a weight loss
of up to 60 per cent. There are two approaches, either restrictive or malabsorptive
surgical techniques. Many procedures involve a combination of these.
Techniques to restrict intake include the stapled gastroplasty, an operation
devised by Mason in 1982. It involves dividing the stomach by a line of staples

into a small upper pouch with a capacity of about 15 ml, which communicates with
the main body of the stomach via a stoma about 9 mm in diameter (Figure 18.2).
When the patient eats or drinks, the pouch rapidly fills and stops further ingestion.
This procedure is effective at limiting intake of solid food, but liquids can be taken
fairly easily. Over time the pouch tends to stretch, thus allowing more intake. The
procedure is relatively safe because the bowel is not cut open and food is nor-
mally digested and absorbed. The average weight loss at 1 year is 28.8 kg. More
recently, extra-gastric banding has been used. Again this restricts the capacity of
the stomach but it is achieved by wrapping an inextensible material around the
outside. This can be done by either open or laproscopic techniques. In a multi-
centre study of 70 consecutive patients the excess weight loss in morbidly obese
patients was 59 per cent (pre-op mean BMI = 45.2 kg/m
2
).
46
This approach to
weight loss has been shown to have associated improvement in insulin sensitivity
and β-cell function. In a series of 254 patients who underwent adjustable gas-
tric banding paired data from pre-operative and 1 year follow-up biochemistry
showed marked improvement in insulin resistance.
47
Malabsorptive procedures include the gastric bypass, bilio-pancreatic diver-
sion and jejuno-ileal bypass. The current gold standard is the Roux en Y gastric
544 THERAPEUTIC STRATEGIES FOR INSULIN RESISTANCE
Figure 18.2 Cartoons show the principles of the bilio-pancreatic bypass and lap-band pro-
cedures for bariatric surgery (illustrations kindly supplied by Robert, E. Brolin, M. D., New
Jersey Bariatrics, www.njbariatricspc.com
)
bypass (Figure 18.2). This can have results of greater than 50 per cent weight
loss in over 80 per cent of patients, corresponding to a fall of 15 BMI units

in morbidly obese patients (BMI > 40 kg/m
2
) and 20 BMI units in super-obese
patients (BMI > 50 kg/m
2
).
48
An ongoing intervention study, the Swedish Obe-
sity Study (SOS), enrolled over 2000 surgically treated patients and a similar
number of matched controls. After 2 years follow-up the surgically treated
patients had lost an average of 28 kg and the incidence of diabetes was reduced
by 90 per cent.
49
Complications from surgery in this high risk group include
immediate cardiorespiratory complications with pulmonary embolus accounting
for the majority of deaths. Abdominal wall complications occur in 6–10 per
cent. Later complications include pouch dilation/erosion of the bands or staple
line disruption, diarrhoea and the dumping syndrome. Nutritional complications
are very common after bypass techniques and many patients require iron, folate
and B12 supplementation.
50
18.8 Pharmacological treatment of insulin resistance
Metformin
Metformin is the only biguanide available for clinical use. Although metformin
has a small effect as a peripheral insulin sensitizer, it primarily works by
PHARMACOLOGICAL TREATMENT OF INSULIN RESISTANCE 545
reducing hepatic gluconeogenesis and hepatic glycogenolysis, and by enhancing
insulin-stimulated glucose uptake and glycogenesis by skeletal muscle.
51
This

effect may be mediated through stimulation of AMP-activated protein kinase.
52
It
does not cause hypoglycaemia or weight gain, which is extremely advantageous
for many patients with associated obesity. Following the results of metformin in
the United Kingdom Prospective Diabetes Study (UKPDS), it has become the
first line pharmacological treatment for type 2 diabetes in overweight individu-
als in the United Kingdom.
53
Beneficial effects for metformin in patients with
insulin resistance but without type 2 diabetes have also been shown.
Although not a true insulin sensitizer, metformin treatment lower plasma insulin
levels and corrects many of the non-traditional cardiovascular risk factors associ-
ated with the insulin resistance syndrome. Various studies have used metformin
in patients with polycystic ovarian syndrome with positive effects both on weight
and sex-hormone-binding globulin, androgens and insulin resistance above that
of diet alone.
54, 55
Patients with acanthosis nigricans given metformin have also
shown a reduction in hyperinsulinaemia, body weight and fat mass and improved
insulin sensitivity.
56
Patients with impaired glucose tolerance but not overt dia-
betes have been treated with metformin and diet in various studies. It has been
shown that metformin also improves insulin resistance in these individuals and in
some studies there appears to be an anti-obesity effect.
57, 58
However, the use of
metformin does not appear to alter the long term susceptibility of developing type
2 diabetes above the use of diet and lifestyle modifications alone.

19
Side-effects in the gut include bloating, flatulence, diarrhoea and epigastric
discomfort, which are common at the start of therapy. These can be minimized
by starting at a low dose of 500 mg once or twice daily with meals. These
side-effects resolve with time in many patients and the dose can be increased
to a therapeutic level of 1 g twice daily. The drug is contraindicated in patients
with renal impairment as it is excreted unchanged in the urine and excess accu-
mulation causes hyperlactataemia and the risk of the rare complication of lactic
acidosis. Other conditions leading to tissue hypoxia, for example severe heart
failure or advanced liver disease, also exclude the use of metformin.
Thiazolidinediones
Thiazolidinediones (TZDs) are novel compounds chemically and functionally
unrelated to other oral blood-glucose-lowering agents. The antihyperglycaemic
effects of TZDs were noticed by actions of ciglitazone on obese and diabetic
animals in the early 1980s. Many agents in this class have followed, including
troglitazone, pioglitazone and rosiglitazone. A thiazolidine-2-4-dione structure
is common to all agents of this class, but they possess different side-chains that
influence their pharmacological actions and potential for adverse effects. Trogli-
tazone was introduced for clinical use in 1997 in Japan, the United States and
United Kingdom, but its use was voluntarily suspended in the United Kingdom
546 THERAPEUTIC STRATEGIES FOR INSULIN RESISTANCE
Troglitazone
Pioglitazone
Rosiglitazone
O
O
S
N
CH
3

HO
H
3
C
CH
3
CH
3
O
O
N O
S
N
O
O
Et
N O
S
N
O
O
N
CH
3
Figure 18.3 Structure of rosiglitazone and pioglitazone as distinct from troglitazone
in December 1997 following reports of side-effects on the liver and subsequently
it was withdrawn worldwide due to problems with idiosyncratic hepatotoxicity.
It is the α-tocopherol moiety on the side-chain of troglitazone that was thought
to be implemented in hepatotoxicity (Figure 18.3).
Thiazolidinediones (TZDs) have emerged as an important therapeutic drug

class in the management of type 2 diabetes mellitus. Administration of a thi-
azolonedione results in increased insulin sensitivity in insulin-resistant mam-
mals.
59–61
This is thought to be associated with increased insulin gene expression
in both skeletal muscle and adipose tissue and increased intrinsic activity of glu-
cose transporters.
62
The actions of the TZDs are mediated through binding and
activation of the peroxisome proliferator-activated receptor (PPAR) γ, a nuclear
receptor that has a regulatory role in the differentiation of cells, particularly
adipocytes.
63, 64
Since TZDs mediate their effects via gene transcription, the
maximal therapeutic effect is seen 6–8 weeks after start of therapy.
PPAR-γ is expressed mainly in white and brown adipocytes, where it is
complexed to the retinoid X receptor (RXR) within the nucleus. Being lipophilic,
TZDs enter the cells and bind to PPAR-γ with high affinity. This causes a
conformational change in the PPAR-γ–RXR complex, which displaces a co-
repressor and allows activation of regulatory sequences of DNA, which in turn
controls expression of specific genes. Thus, increased expression of insulin-
sensitive genes, through the activation of PPAR-γ, is perceived as the main
mechanism by which TZDs reduce insulin resistance. At least some of these
PHARMACOLOGICAL TREATMENT OF INSULIN RESISTANCE 547
genes are also controlled by insulin, and TZDs amplify or mimic certain genomic
effects of insulin on adipocytes.
Activation of PPAR-γ is associated with control of the production, transport
and utilization of glucose. The increased glucose transport has been attributed to
increased production of the glucose transporter isoforms GLUT1 and GLUT4,
and translocation of GLUT4 into the plasma membrane. Increased glucose trans-

porter production and translocation into the plasma membrane in skeletal muscle
and fat will contribute to improved glucose disposal and reduce glucose toxic-
ity. Glucose toxicity will be further reduced by increased glucose disposal and
decreased hepatic glucose production.
The PPAR-γ receptor is also expressed in several other tissues, including
vascular tissue. TZDs lower circulating triglyceride and non-esterified fatty acid
concentrations, which may also contribute to improved insulin sensitivity
65
via
the glucose fatty acid (Randle) cycle. Because free fatty acids are involved
in lipid metabolism and also have deleterious effects on the vasculature, this
reduction in plasma free fatty acids may have a beneficial effect on cardio-
vascular disease. The lipid-lowering effect of TZDs appears to be independent
of their glucose-lowering and their insulin-lowering effects,
66
and this effect
has been attributed to decreased hepatic very low density lipoprotein (VLDL)
synthesis and increased peripheral clearance, together with reduced lipolysis. It
is important to note that TZDs have effects on numerous other genes, which
may also be related to the effects seen on glycaemic control and insulin resis-
tance. For example, they reduce circulating TNF-α , which may be related to
the development of obesity-linked insulin resistance. TZDs also reduce serum
leptin, but increase the circulating levels of the antidiabetic, anti-inflammatory
and anti-atherogenic agent adiponectin.
Rosiglitazone
Rosiglitazone (Figure 18.3) is rapidly absorbed and food does not affect absorp-
tion significantly.
67
It is highly bound to plasma proteins (99.8 per cent) and
metabolized by the liver. It is given in doses of 4–8 mg as single or divided

doses. There is virtually no unchanged drug secreted in the urine or faeces. In
the UK it is licensed for use as monotherapy, or in combination with a sulfony-
lurea or metformin. Rosiglitazone is contraindicated for use in patients with
heart failure, and with insulin therapy in the UK, but is used in combination
with insulin in the USA. It is also contraindicated in patients with impaired liver
function (ALT > 2.5 × normal). Monitoring of liver enzymes is recommended,
every two months for the first year and periodically thereafter. Adverse effects
related to rosiglitazone therapy include significant increase in body weight (see
below) and a decrease in haemoglobin and haematocrit.
In controlled clinical trials with rosiglitazone given as monotherapy, dose-
dependent reduction in fasting plasma glucose and glycated haemoglobin have
548 THERAPEUTIC STRATEGIES FOR INSULIN RESISTANCE
been reported;
68–72
study duration varied in these studies from 8 to 52 weeks.
Drug-na
¨
ıve patients show a better response to therapy than those previously
treated with other oral agents.
70
A study of combination treatment of sulfony-
lureas with either 2 or 4 mg of rosiglitazone has been published.
73
In a study
of 574 subjects, patients were randomized to continuing sulfonylurea therapy or
the addition of either 2 or 4 mg of rosiglitazone to their therapy. Rosiglitazone,
at both doses, in combination with sulfonylurea was associated with significant
reduction in HbA
1c
from baseline. Furthermore, the percentage of patients who

achieved HbA
1c
reduction of >0.7 per cent was 19 per cent in the control group
versus 60 per cent in those receiving 4 mg of rosiglitazone with sulfonylurea.
In addition to sulfonylureas, rosiglitazone has also been studied in combination
with metformin. Fonseca et al., reported a mean reduction of 0.56–0.78 per
cent in HbA
1c
from baseline after 26 weeks of rosiglitazone therapy in combi-
nation with metformin.
74
During this period there was a 0.45 per cent increase
in HbA
1c
from baseline in those receiving metformin alone.
In addition to improving glycaemic parameters, rosiglitazone improves endo-
genous insulin secretion and significantly reduces NEFA levels.
73, 74
Insulin
resistance, measured using homeostasis model assessment (HOMA), was shown
to be significantly reduced in patients with type 2 diabetes taking rosiglita-
zone 4–8 mg/day monotherapy over 12–52 weeks. There was no significant
change in patients taking placebo or glibenclamide.
75
Similarly, rosiglitazone
2–8 mg/day in combination with a sulfonulurea or metformin for 26 weeks
resulted in significant reductions in insulin resistance (HOMA) versus no sig-
nificant changes with sulfonylurea or metformin alone.
76
Rosiglitazone may

reduce insulin-resistance-related cardiovascular disease risk in type 2 diabetes
patients.
77
Euglycaemic clamp data substantiate these results: the insulin sen-
sitivity index was significantly increased (by 78 per cent from baseline) in 33
patients with type 2 diabetes mellitus receiving rosiglitazone 8 mg/day.
78
These
effects appear to be sustained with continued treatment for at least 24 months.
79
Indeed, rosiglitazone has also been shown to improve β-cell function by up
to 94 per cent as assessed by mathematical modelling of fasting glucose and
insulin data (HOMA).
80
Furthermore, it is reported that open-label extension
studies indicate no deterioration of glycaemic control in patients taking rosigli-
tazone during the 2 years of follow-up. If confirmed, this could prove to be a
major advantage in the treatment of type 2 diabetes and insulin resistance as the
progression of this disease is characterized by failing β-cell function.
Pioglitazone
Pioglitazone (Figure 18.3), like rosiglitazone, mediates its effects through im-
proved peripheral glucose disposal and reduced hepatic glucose production.
81
Pioglitazone absorption from the gut is delayed when taken with food but with-
out alteration of its clinical efficacy.
73
Pioglitazone undergoes extensive hepatic
PHARMACOLOGICAL TREATMENT OF INSULIN RESISTANCE 549
metabolism via the CYP2C8 system. Secondary pathways include CYP3A4,
CYP2C9 and CYP1A1/2.

74, 80
Time to peak plasma concentration is 2.5 h for
15 mg/day and 3 h for 30 mg/day, with an elimination half-life of 3.3 and 4.9 h,
respectively. Pioglitazone can be administered once daily at a dose of 15–45 mg.
Clinical trials have examined its effects during monotherapy and in combination.
Clinical efficacy in terms of reducing HbA
1c
levels was shown in a double-
blind dose-ranging study in which 399 patients were randomized to receive
pioglitazone (7.5, 15, 30 or 45 mg/day) or placebo for 26 weeks. Mean HbA
1c
levels decreased significantly (p<0.05 versus placebo) with pioglitazone 15, 30
or 45 mg/day in both previously treated and untreated patients.
81
In another ran-
domized double-blind study, involving 197 patients with type 2 diabetes mellitus,
pioglitazone 30 mg/day for 16 weeks significantly reduced mean HbA
1c
(adjusted
change versus placebo =−1.37 per cent; p<0.05), and fasting plasma glucose
and triglyceride levels.
82
Similar effects on glycaemic control using pioglitazone
as monotherapy have been reported by others.
83
In a double-blind study of 560 patients with poorly controlled type II dia-
betes mellitus on sulfonylurea therapy,
84
addition of pioglitazone therapy (15
or 30 mg/day) for 16 weeks significantly decreased HbA

1c
levels (by 0.9 and
1.3 per cent, respectively; p<0.05) and fasting blood glucose levels (by 2.2
and 3.2 mmol/l respectively; p<0.05), relative to sulfonylurea plus placebo.
Furthermore, combination treatment of pioglitazone (30 mg/day) and metformin
(>2 g/day in 40 per cent of patients) for 16 weeks significantly decreased HbA
1c
and fasting glucose levels in a double-blind study in 328 patients with type 2
diabetes.
85
Administration of pioglitazone 30 mg/day has no significant affects on the
pharmacodynamic characteristics of warfarin, glipizide, metformin or digoxin.
74
Lack of induction or inhibition of hepatic enzyme systems was also indicated by
data showing no statistically or clinically significant effect of pioglitazone on the
pharmacokinetics of ethinyloestradiol/norethindrone or ethinyloestradiol/oestrone
as used in oral contraceptive or hormone replacement therapy regimens.
1
How-
ever, adverse effects reported include headache, sinusitis, myalgia, tooth disorders
and pharyngitis.
2
In the UK, although licensed for use as monotherapy as an alternative to
metformin (if intolerant of metformin) and also in combination with metformin
or sulfonylurea, their use is restricted within the National Health Service by
current guidelines. It has been recommended that their use is confined to those
patients inadequately controlled on oral monotherapy and who are unable to
tolerate or have contraindications to conventional drug combination therapy
of metformin and a sulfonylurea. These guidelines seriously limit the current
clinical use of TZDs in the UK. Several studies have clearly shown an advantage

for the glitazones in drug-na
¨
ıve type 2 diabetic patients.
69, 70
The same research
shows the complementary effect of the three major classes of oral hypoglycaemic
agents. Their effects are synergistic and particularly effective in combination
550 THERAPEUTIC STRATEGIES FOR INSULIN RESISTANCE
therapy.
84
The combination of TZDs with insulin in insulin-resistant patients is
a logical strategy but under current guidelines it is not recommended because
of potential problems, including fluid retention.
Thiazolidinediones and weight gain
Weight gain is associated with both thiazolidinediones. There were initial con-
cerns that weight gain with TZD use may have an adverse impact on glycaemic
control, and that the increase in the absolute number of fat cells may lead to
refractory obesity. However, increases in body weight with TZD use are posi-
tively correlated with reductions in HbA
1c
and weight gain appears to stabilize
after the initial reductions in HbA
1c
. Significant variability in the adipose tis-
sue distribution of PPAR-γ may be responsible for the observation that TZDs
have a site-specific effect on differentiation of human preadipocytes, with the
effect being markedly enhanced in subcutaneous fat, with less effect in visceral
fat.
86, 87
Several studies have attempted to elucidate the mechanisms behind the

apparent paradox of TZDs improving insulin sensitivity while simultaneously
causing weight gain. These include increased appetite and a decrease in serum
leptin,
88
although not all studies have shown this effect. Fat redistribution may
also explain the weight gain seen with TZDs.
Fat redistribution may be explained by induced remodelling of abdominal fat
tissue, characterized by differentiation of preadipocytes into small fat cells in
subcutaneous fat depots and apoptosis of differentiated large adipocytes (hyper-
trophic adipocytes) in visceral and/or subcutaneous fat depots. Indeed, several
studies have demonstrated that the weight gain with TZDs is associated with an
increase in subcutaneous adipose tissue and a concomitant decrease in visceral
fat content. This altered fat distribution also improves insulin sensitivity. Carey
et al.
89
reported that 16 weeks therapy with rosiglitazone (8 mg daily), in patients
with type 2 diabetes, increased subcutaneous fat by eight per cent (p = 0.02
versus placebo) and decreased intrahepatic fat by 45 per cent (p = 0.04 versus
placebo). In another study by Kelley et al.,
90
rosiglitazone improved insulin sen-
sitivity and led to a 10 per cent reduction in visceral fat. These beneficial effects
of fat redistribution have also been seen with pioglitazone.
91
Fluid retention is another potential mechanism by which TZDs lead to weight
gain, although the precise cause remains unclear. Peripheral oedema is particu-
larly a problem when TZDs are used in combination with insulin,
2
and this is one
reason why TZDs are not licensed for use in combination with insulin in the UK,

although they are in the USA. Fluid retention and the potential precipitation of
congestive cardiac failure in patients with underlying heart disease represent the
major concern of most health care providers. Because of increases in plasma
volume, rosiglitazone and pioglitazone should be used cautiously in patients
with signs of impaired cardiac function, such as peripheral oedema. Although
in animal studies TZDs have been reported to cause cardiac hypertrophy, in
INSULIN SENSITIZERS AND CARDIOVASCULAR RISK FACTORS 551
echocardiographic clinical studies (a 52 week study using rosiglitazone, and a
26 week study with pioglitazone) in patients with type 2 diabetes no deleterious
alterations in cardiac structure or function were observed.
92, 93
Apart from fluid retention, lack of compliance with diet is another factor that
contributes to weight gain. In addition, weight gain appears to be greatest when
TZDs are used in combination with insulin or sulphonylureas and least when
used as monotherapy or in combination with metformin. Therefore, previous
glycaemic control and type of concomitant therapy may prove to be to the bases
for predicting which patients are most likely to gain weight. Education about
diet and exercise at time of prescription, low-calorie diets and concomitant use
of metformin are strategies to minimize weight gain in individuals given TZDs.
18.9 Insulin sensitizers and cardiovascular risk factors
Most patients with obesity and the insulin resistance syndrome exhibit a spec-
trum of clinical abnormalities (Table 18.1) that play an important role in the
pathogenesis of atherosclerosis (Figure 18.1). It has therefore been proposed
that drugs that directly improve insulin sensitivity, such as metformin and the
TZDs, may correct other abnormalities of the insulin resistance syndrome in
addition to improving hyperglycaemia. Thus, treatment of patients with type 2
diabetes with these agents may confer benefits beyond the lowering of glucose.
Metformin
Metformin is frequently perceived as a drug that induces weight loss. However,
data from the UKPDS showed no change in the weight of patients taking met-

formin throughout the study.
53
In the Diabetes Prevention Program,
18
metformin
did not cause a greater weight loss than that seen with placebo, and there was
a minimal change in weight during the 4 years of the study. This contrasted
with the lifestyle-change group, in which participants lost an average of 5.6 kg.
Thus, metformin appears to be weight neutral in the long term.
To date, metformin is the only drug that has been shown to decrease car-
diovascular events in patients with type 2 diabetes, independently of glycemic
control.
53
More importantly, the UKPDS demonstrated that patients who were
obese and randomized to receive metformin had a significantly reduced rate
(30 per cent reduction) of cardiovascular disease events and mortality compared
with those receiving conventional therapy when analysed on an intention-to-
treat basis.
53
Although the reason for this difference is not clear, it may be
related to moderate effects exerted by metformin on the insulin resistance syn-
drome; metformin treatment lowers plasma insulin levels and corrects many of
the non-traditional risk factors associated with the insulin resistance syndrome.
94
Metformin has a favorable, albeit modest, effect on plasma lipids, particularly
lowering levels of triglycerides and LDL cholesterol; however, it has little if any
552 THERAPEUTIC STRATEGIES FOR INSULIN RESISTANCE
effect on HDL cholesterol levels.
95
Although TZDs were not included in the

UKPDS, several long term trials, including A Diabetes Outcome Progression
Trial (ADOPT), Diabetes Reduction Approaches with Ramipril and Rosiglita-
zone Medications (DREAM) and the Action to Control Cardiovascular Risk in
Diabetes (ACCORD) Trial, are ongoing to evaluate their effect on prevention
of cardiovascular events in patients with type 2 diabetes.
Thiazolidinediones
Because of their beneficial effects on hyperinsulinaemia and insulin resistance,
the cardiovascular effect of thiazolidinediones is a subject of considerable re-
search interest (Table 18.4). Several studies have observed beneficial effects of
the thiazolidinediones on lipid metabolism. With rosiglitazone therapy, changes
in serum lipids included the increase in HDL cholesterol and total cholesterol,
but the LDL:HDL cholesterol ratio did not change.
72, 73
Serum triglycerides
increased slightly.
73
Clinical trials suggest that pioglitazone has more impressive
effects, compared with rosiglitazone, on serum lipids,
84, 85, 96
with significant
decrease in mean fasting serum triglyceride levels and significant increases in
fasting HDL cholesterol levels. Caution needs to be exercised in comparing
rosiglitazone and pioglitazone, as no head-to-head study has been conducted.
In addition, the differences between the thiazolidinediones with respect to their
lipid effects may reflect the fact that populations with different baseline values
have been studied, and therefore a randomized comparative trial is needed to
determine whether a true difference exists.
Several studies have noted that TZDs can reduce blood pressure in nor-
motensive and hypertensive animals, without any obvious correlation with either
Table 18.4 Impact of TZDs on traditional and non-traditional cardio-

vascular risk factors
Risk factor Effects
Lipids ↓ LDL oxidation
↑ HDL levels
↓ Triglyceride levels
Vascular effects ↓ blood pressure
↓ vascular contraction
↓ vascular smooth muscle cell migration
↓ intima–media thickness
↑ cardiac output
Microalbuminuria ↓ microalbuminuria
Coagulation ↓ plasma activator inhibitor-1 (PAI-1)
↓ fibrinogen
Inflammation ↓ C-reactive protein
↓ interleukin-6
Endothelial function ↓ cell adhesion molecules
↓ PAI-1
CONCLUSIONS 553
the glucose-lowering or insulin-lowering effects.
97
Improving insulin sensitiv-
ity has the potential to lower blood pressure in patients with insulin resistance
and/or diabetes. A study of 24 hypertensive patients without diabetes treated
with rosiglitazone demonstrated that rosiglitazone treatment that was added on
to the patient’s usual antihypertensive medication resulted in a decrease in both
systolic and diastolic blood pressure and improved insulin resistance.
98
Piogli-
tazone in normotensive and hypertensive patients with diabetes has been shown
to decrease systolic blood pressure.

99
Similar results were also seen in those
without diabetes who were obese.
100
Elevated plasma plasminogen activator–inhibitor type 1 (PAI-1) is asso-
ciated with increased risk of atherosclerosis and cardiovascular disease, and
PAI-1 levels are elevated both in patients with diabetes and in those who are
insulin resistant without diabetes. Increased PAI-1 levels are now recognized
as an integral part of the insulin resistance syndrome and correlate signifi-
cantly with plasma insulin. Studies with rosiglitazone
101
and pioglitazone
102
have demonstrated a decrease in plasma PAI-1 levels in patients with diabetes,
suggesting that PAI-1 reduction may well be a class effect of the insulin sensitiz-
ers. Other non-traditional cardiovascular risk factors, such as C-reactive protein
and interleukin-6, have been shown to decrease with TZD therapy. Microal-
buminuria, widely considered as a marker of impaired vascular integrity, is a
recognized marker of cardiovascular disease. Rosiglitazone has been recently
shown to significantly reduce urinary albumin excretion in patients with type II
diabetes,
103
adding to the beneficial effects of TZDs.
Carotid intima–media complex thickness, which is an indicator for early
atherosclerosis and a surrogate marker for atherosclerotic events, is associ-
ated with insulin resistance. Treatment with pioglitazone was shown to sig-
nificantly decrease intima–media thickness in patients with type 2 diabetes.
104
Furthermore, endothelial dysfunction is a complication of the insulin resistance
syndrome, and improvement of vascular reactivity in insulin-resistant obese sub-

jects without diabetes after treatment with rosiglitazone has been reported.
105
This improvement was associated with beneficial changes in several markers
of inflammation and endothelial activation. Recently, metformin also has been
shown to improve endothelial function.
106
Because metformin does not stimu-
late PPARs, other mechanisms are likely to be involved in the pathogenesis of
endothelial dysfunction in insulin resistance. It is possible, therefore, that these
effects of the thiazolidinediones are direct cellular effects on the atherosclerotic
process that are not linked to their effects on insulin resistance.
18.10 Conclusions
The prevalence of the metabolic syndrome is increasing and reaching epi-
demic proportions. Obesity plays a pivotal role in the development of insulin
resistance and its complications. Strategies to manage body weight should be
554 THERAPEUTIC STRATEGIES FOR INSULIN RESISTANCE
part of the treatment plan for obese insulin-resistant patients, and will include
a multidisciplinary approach with dietetic input, exercise and anti-obesity ther-
apeutic intervention. However, many of these strategies will not be able to
have a major and lasting effect on insulin sensitivity, and there is therefore
a need for ‘insulin-sensitizing’ drugs using metformin and/or TZDs. Because
many cardiovascular risk factors are linked with insulin resistance, treatment
with insulin sensitizers has the potential to modulate these traditional and non-
traditional cardiovascular risk factors favourably, including a favourable redis-
tribution of fat. Finally, although weight gain may occur with TZD therapy,
it is not inevitable and can be controlled with dietary methods; the addition of
metformin also mitigates additional weight gain and may have an additive effect
on insulin sensitivity.
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19
Drug Therapy for Insulin
Resistance – a Look at the
Future
Bei B. Zhang and David E. Moller
19.1 Introduction
Type 2 diabetes is a complex metabolic disorder characterized by abnormal
insulin secretion caused by impaired β-cell function and insulin resistance in
target tissues.
1, 2
The worldwide prevalence of type 2 diabetes is reaching epi-
demic proportions, with an expected total of 221 million cases by the year
2010.
3
The single most important risk factor for the pathogenesis of diabetes
is obesity and its associated insulin resistance. Indeed, insulin resistance per se
and type 2 diabetes are components of the more complex ‘metabolic syndrome’
that also encompasses impaired glucose tolerance, obesity, hypertension and
dyslipidaemia.
3
Insulin is essential for maintaining glucose homeostasis and regulating car-
bohydrate, lipid and protein metabolism.
2
The hormone elicits a diverse array of
biological responses by binding to its specific receptor
4, 5
(Figure 19.1). Exten-
sive studies have indicated that the ability of the receptor to autophosphorylate
and to phosphorylate intracellular substrates is essential for its mediation of the

complex cellular responses of insulin.
6–9
Insulin receptors trans-phosphorylate
several immediate substrates (on Tyr residues) including insulin receptor sub-
strate (IRS) proteins 1–4, Shc and Gab 1, each of which provides specific
docking sites for other signalling proteins containing Src homology 2 (SH2)
domains.
10
These events lead to insulin-mediated activation of glucose transport
and glycogen synthesis through activation of downstream signalling molecules
including phosphatidylinositol-3-kinase (PI-3-kinase) and Akt (or PKB).
11, 12
Insulin Resistance. Edited by Sudhesh Kumar and Stephen O’Rahilly
 2005 John Wiley & Sons, Ltd ISBN: 0-470-85008-6
562 DRUG THERAPY FOR INSULIN RESISTANCE – A LOOK AT THE FUTURE
SHC
PI-3 K
p70S6k
Akt
PP1
GSK3
Hexokinase
G-6-P
UGP-
glucose
Oxidative
glucose
metabolism
Glycogen
synthase

Insulin
receptor
Glucose
transporter
(GLUT-4)
Signal transduction
Glucose utilization
Glycogen/lipid/protein synthesis
Glycogen
PTP 1B
Grb2
IRS1/2/3/4
SOS/Ras
MEK
MAP kinase
Gene expression
Growth regulation
PDK
aPKC
PTEN
SHIP2
Cbl/CAP
complex
P
P
P
P
JNK
IKK
β

Figure 19.1 Diagram of insulin signal transduction pathways
Mice lacking the insulin receptor (IR) gene via targeted disruption die within
the first week after birth due to severe diabetic ketoacidosis.
13–15
Decreased
cellular responses to insulin or perturbation of the insulin signalling pathways
are associated with a number of pathological states. Mutations in the IR gene
that lead to alterations of receptor synthesis, degradation and function have been
described in patients with several uncommon syndromes associated with severe
insulin resistance.
16
Several studies have also shown modest decreases in insulin
receptor number, attributed to downregulation in response to hyperinsulinaemia,
in tissues or cells from type 2 diabetes patients.
17, 18
Substantial decreases in
insulin-stimulated receptor tyrosine kinase activity have been reported. More
importantly, substantial defects affecting the insulin signal transduction pathway,
including receptor-mediated IRS phosphorylation or phosphatidylinositol (PI)-3
kinase activation, have been described using samples of tissue (e.g. muscle or
fat) derived from rodents or human subjects with type 2 diabetes.
19–22
However,
the detailed molecular basis for insulin resistance that precedes, or is associated
with, common forms of type 2 diabetes remains poorly understood.
As discussed in earlier chapters, a number of agents are currently being used
as therapies for insulin resistance. Notably, PPARγ ligands appear to princi-
pally target this aspect of the pathogenesis of type 2 diabetes. However, the
diabetes and metabolic syndrome epidemic is growing at an alarming rate and
current therapies are clearly suboptimal with respect to net efficacy and their

potential for adverse effects.
23
These facts underscore the importance of identi-
fying new therapeutic targets for insulin resistance. There is emerging evidence
TARGETING THE INSULIN SIGNALLING PATHWAY 563
suggesting that modulation of specific components of the insulin signal trans-
duction pathways could impact on insulin sensitivity in vivo, thereby presenting
putative targets for amelioration of insulin resistance. Furthermore, since insulin
resistance in association with obesity is likely to be related to excessive levels of
circulating lipids and tissue lipid accumulation (known as ‘lipotoxicity’), selec-
tive modulation of lipid metabolism, apart from engaging PPARγ directly, also
represents a future avenue for the treatment of insulin resistance. In this chapter,
we will discuss potential advantages and concerns that pertain to a number of
newer drug ‘targets’ that have been implicated as being useful in the treatment
of insulin resistance.
19.2 Targeting molecules within the insulin signal
transduction pathway
Insulin receptor
The insulin receptor (IR) is a heterotetrameric protein consisting of two extracel-
lular α-subunits and two transmembrane β-subunits. The binding of the ligand
to the IR α-subunits stimulates the tyrosine kinase activity intrinsic to the
β-subunits. Structural biology studies reveal that the two α-subunits jointly par-
ticipate in insulin binding and that the kinase domains in the two β-subunits
are juxtaposed in order to permit autophosphorylation of tyrosine residues as
the first step of IR activation.
24
The kinase domain undergoes a conformational
change upon autophosphorylation, providing a basis for activation of the kinase
and binding of downstream signalling molecules.
25, 26

The IR is homologous to the insulin-like growth factor 1 receptor (IGF-
1R) with the highest degree of homology in the tyrosine kinase domain.
27, 28
Indeed, hybrid receptors containing α/β-halves of both the IR and IGF-1R have
been identified in mammalian tissues.
29, 30
Another homologous receptor in the
insulin-receptor family is the insulin-receptor-related receptor (IRR).
31
The cog-
nate hormone ligand for and biological function of IRR are yet to be identified.
Since the IR has an important role in the regulation of whole body metabolism
and diabetes pathogenesis, small molecule agents that can activate IRs or poten-
tiate insulin action at the receptor level might prove to be useful as novel
therapeutics for diabetes. In recent years, several small molecule IR activa-
tors have been discovered and shown to activate insulin signalling in cells and
to decrease blood glucose levels in murine models of diabetes when dosed
orally.
32–35
These molecules have also shown insulin-sensitizing effects in cel-
lular and animal models. Although these agents are still in early preclinical
research stages, the identification of such molecules demonstrates, in principle,
the feasibility of an ‘insulin pill’ that could potentially be developed as an insulin
mimetic or sensitizer.
564 DRUG THERAPY FOR INSULIN RESISTANCE – A LOOK AT THE FUTURE
IRS proteins
The four IRS proteins identified to date are highly homologous with overlap-
ping and differential tissue distribution. Studies with genetic deletion in mouse
models and cell lines indicate that IRS proteins serve complementary functions
in different tissues as immediate substrates for IRs and IGF-1Rs.

36–38
Com-
bined heterozygous deletions of IRs and IRS-1 or IRS-2 suggest that IRS-1 has a
prominent role in skeletal muscle and IRS-2 in liver.
39
Since IRS proteins are key
docking proteins that serve to relay signals from IRs, intervention to modulate
the interactions of IRS proteins with other signalling molecules could poten-
tially represent a new avenue for up-regulation of insulin sensitivity. Although
IRS proteins are not considered ‘druggable’ targets, several molecules that may
directly or indirectly affect IRS function are plausible targets (discussed below).
PI3 kinase/Akt pathways
PI3 kinase plays a pivotal role in the metabolic and mitogenic actions of insulin.
PI3K consists of a catalytic subunit and a regulatory subunit. Three distinct genes
encode the regulatory subunit: the p85
α
, p85
β
and p55
γ
genes. The p85
α
gene
also generates two splicing variants, p50
α
and p55
α
.
40–42
All forms of the struc-

turally distinct regulatory subunits are capable of associating with the IRS pro-
teins upon insulin stimulation.
42–44
Activated PI3K specifically phosphorylates
PI substrates to produce PI(3)P, PI(3,4)P2 and PI(3,4,5)P3. Acting as second
messengers, these phospholipids recruit the PI3K-dependent serine/threonine
kinases (PDK1) and Akt from the cytoplasm to the plasma membrane by bind-
ing to the ‘pleckstrin homology domain’ (PH domain) of kinases. Lipid binding
and membrane translocation lead to conformational changes in Akt, which is
subsequently phosphorylated on Thr 308 and Ser 473 by PDK1. Phosphorylation
by PDK1 leads to full activation of Akt.
45–47
Activated Akt phosphorylates and regulates the activity of many downstream
proteins involved in multiple aspects of cellular physiology, including glucose
transporter 4 (GLUT4) complex, protein kinase C (PKC) isoforms and GSK3, all
of which are critical in insulin-mediated metabolic effects.
46–49
Pharmacological
inhibition of PI3K by wortmannin and LY294002 is associated with blockade of
insulin-stimulated translocation of GLUT4 to cell surface and glucose uptake into
cells.
50–53
Overexpression of constitutively active forms of PI3K p110 catalytic
subunit or Akt stimulates,
49, 54, 55
whereas that of dominant-negative p85 regu-
latory subunit constructs blocks, insulin-mediated metabolic effects.
11, 54, 56–58
Although controversy still surrounds the role of Akt in insulin-mediated GLUT4
translocation,

59
recent reports show that Akt2 deficiency but not Akt1 deficiency
in mice is associated with insulin resistance and diabetes, strongly supporting the
notion that Akt is important in insulin action.
60, 61
Surprisingly, recent studies suggest that down-regulation of PI3K regulatory
subunit expression actually improves insulin sensitivity in mice.
62–65
Given the
TARGETING THE INSULIN SIGNALLING PATHWAY 565
positive role of the regulatory subunit in PI3K activation and the essential role of
PI3K in insulin action reported in earlier studies, it is perplexing that a reduction
of regulatory subunit levels resulted in greater insulin sensitivity in a number of
genetically engineered mouse lines. It is possible that the relative abundance of the
regulatory and the catalytic subunits is important in determining net levels of PI3K
activation. Consistent with this notion, excessive amounts of p85 protein, in com-
parison with p110 protein abundance, reportedly occurs in normal cells. Therefore,
inhibition of this molecule might represent a novel therapeutic strategy for treating
insulin resistance. However, several potential pitfalls for such an approach should
be considered. If down-regulation of the regulatory subunit leads to constitutive
activation of PI3K or Akt, one has to be concerned about tumourigenesis as PI3K
is shared by a number of growth factor signal transduction pathways. Moreover,
a more marked decrease in PI3K activity could lead to liver necrosis as occurs in
combined regulatory subunit knockout mice.
63
From a practical standpoint, PI3K
regulatory subunits are not enzymes; thus their inhibition and down-regulation
would require interruption of protein–protein interactions or approaches such as
antisense oligonucleotides to inhibit protein expression. These approaches have
limitations even when current state-of-the-art technologies are applied.

GLUT4 translocation
Insulin promotes glucose uptake by muscle and adipose tissue via stimulation of
glucose transporter (GLUT) 4 translocation from intracellular sites to the plasma
membrane. Attenuated GLUT4 translocation and glucose uptake following insulin
stimulation represents a prime defect in insulin-resistant states.
66
Validation of the
critical role of GLUT4 is derived from numerous studies that examined genetically
engineered mice with partial or complete GLUT4 deficiency
84, 85
and selective
loss of muscle GLUT4 expression.
67
As noted above, the PI3 kinase/Akt pathway has been demonstrated to be
upstream of GLUT4 translocation. However, recent studies have shown that
GLUT4 translocation is also downstream of a PI3-kinase-independent pathway.
68
Insulin stimulates tyrosine phosphorylation of c-Cbl in the metabolically respon-
sive cells. c-Cbl is recruited to complex with IRs via the adaptor protein CAP
(c-Cbl-associated protein).
69
Upon Cbl phosphorylation, the Cbl/CAP complex is
translocated to the plasma membrane domain enriched in lipid rafts or caveolae. In
the lipid rafts, CAP associates with caveolar protein flotillin and forms a complex
with a number of proteins including TC10, CRKII and other accessory proteins
involved in vesicular trafficking and membrane fusion.
70
Expression of a domi-
nant negative CAP mutant completely blocked insulin-stimulated glucose uptake
and GLUT4 translocation. These data suggest that the PI3 kinase/Akt pathway and

the CAP/Cbl complex represent two compartmentalized parallel pathways lead-
ing to GLUT4 translocation. In addition, one can now envisage new approaches
by which selective augmentation of the CAP/Cbl pathway might enhance insulin
566 DRUG THERAPY FOR INSULIN RESISTANCE – A LOOK AT THE FUTURE
sensitivity. Taken together, current knowledge implies that alteration of GLUT4
expression and/or function could contribute to the development of insulin resis-
tance and diabetes. Therefore, agents that stimulate or facilitate GLUT4 translo-
cation may represent new therapeutic approaches for insulin resistance.
GSK3
Insulin action includes key regulatory effects to promote hepatic and muscle
glycogen synthesis. A net increase in liver glycogen synthesis would be predicted
to attenuate excessive hepatic glucose output in diabetic states. Glycogen synthase
kinase 3 (GSK-3) is a cytoplasmic serine/threonine kinase that has key roles in
insulin signal transduction and metabolic regulation.
71–73
This enzyme also has
a key role in Wnt signalling that is critical for determination of cell fates during
embryonic development.
71
In the insulin signalling pathway, GSK-3 is active in
the absence of insulin; it phosphorylates (and thereby inhibits) glycogen synthase
and several other substrates. Insulin binding to the IR activates a phosphorylation
cascade, leading to inhibitory phosphorylation of GSK-3 by Akt. Thus, insulin
activates glycogen synthase, in part, by promoting its dephosphorylation through
the inhibition of GSK-3. Increased GSK-3 activity has been shown to occur in
diabetic animals
74
and human subjects.
75
Lithium and other small molecule inhibitors of GSK-3 have been shown to

promote net activity of glycogen synthase in cells. Importantly, these compounds
have antidiabetic effects in animal models, suggesting that specific inhibitors of
GSK-3 hold potential as novel therapeutics for diabetes.
76
Specifically, a recent
report using novel GSK-3 inhibitors demonstrated improved insulin-stimulated
glucose metabolism via increasing liver glycogen synthesis in Zucker diabetic
fatty (fa/fa)rats.
77
Surprisingly, no significant increase in muscle glycogen syn-
thesis was evident despite increased muscle glycogen synthase activity.
77
Since GSK-3 is a central element in the Wnt-β-catenin pathway, inhibitors of
GSK-3 could potentially cause tumourigenesis via this pathway. Indeed, lithium
has been shown to inhibit GSK-3 and mimic Wnt signalling in intact cells.
78
This
presents a serious issue with implications regarding the approach of GSK-3 inhibi-
tion for chronic treatment. However, significant advancements in the field during
the past 2 years have demonstrated that the insulin and Wnt signalling pathways
differentially regulate GSK-3. The crystal structure of GSK-3β, together with bio-
chemical studies, revealed how GSK3 selectively regulates different downstream
targets according to which signalling pathway is activated.
72, 73
Therefore, it is
now theoretically possible to identify GSK-3 inhibitors that selectively block the
activity of the enzyme towards glycogen synthase for the treatment of diabetes.
Despite these developments, all currently described GSK-3 inhibitors that are
ATP-site competitors are likely to have effects to augment both insulin and Wnt
signalling pathways. Therefore, continued caution is advisable when considering

such compounds.