Effects of RAS inhibition on insulin sensitivity and IGF-I bioactivity

The prevalence of type 2 diabetes mellitus is rising rapidly worldwide, and
interventions to prevent or delay its onset are becoming increasingly
important. Previous studies have shown that the incidence of new-onset diabetes
was reduced by inhibitors of the renin-angiotensin system (RAS), suggesting
active positive effects of these drugs on long-term glucose metabolism.
However, the exact mechanisms involved are still unclear.

The GH/IGF-I system is important in the maintenance of glucose homeostasis, and
might thus play a protective role in the development of glucose intolerance.
Improvement of the disturbed GH/IGF-I system (that is reduced levels of IGF-I
and the GH hypersecretion) in patients with insulin resistance and type 2
diabetes mellitus might be one of the mechanisms through which RAS inhibitors
could improve insulin sensitivity and thereby interfere in the development of
type 2 diabetes. It was previously hypothesised that production of IGF-I is
reduced by angiotensin II, which is reversed by the angiotensin-receptor
antagonist losartan. Furthermore, in a former small study, we have observed
that short-term losartan treatment reduced insulin resistance in patients with
impaired fasting glucose, which was close to significantly correlated to an
increase in serum levels of free IGF-I.

Recently, an IGF-I kinase receptor activation assay (IGF-I KIRA) was developed
and validated, now providing a highly sensitive and specific method for
measuring IGF-I bioactivity in human serum. Also normative data for the IGF-I
KIRA have become available. It has been suggested that the IGF-I KIRA method
can provide information about the IGF-I system that in part differs from
measures obtained from the classic immunoassays, and especially in the
pathophysiology of insulin resistance.

In this single centre pilot intervention study, we will investigate the effects
of short-term administration of the angiotensin-receptor antagonist losartan on
insulin sensitivity (assessed by using the homeostasis model assessment of
insulin resistance (HOMA)), as well as on total IGF-I and IGF-I bioactivity in
patients with impaired fasting glucose and/or impaired glucose tolerance.

In this randomised, controlled, open-label pilot study, 40 patients with
impaired fasting glucose and/or impaired glucose tolerance will be included. 20
patientes will receive losartan tablets, 100 mg once daily, for 8 weeks, and
the controlgroup of 20 patients will not receive medication. Before and after
the treatment period, insulin sensitivity will be assessed using homeostasis
model assessment of insulin resistance (HOMA). Also, the effects of short-term
losartan treatment on the IGF-I system, including IGF-I bioactivity measured by
IGF-I KIRA, will be investigated.

Baseline: 3 fasting blood samples are taken at 5 minutes interval for
measurement of:
- t=0: total IGF-I, IGF-I bioactivity, insulin, glucose
- t=5: insulin, glucose
- t=10: insulin, glucose
The three baseline samples are averaged for the mean levels of glucose and
insulin for HOMA score calculations. HOMA uses mathematical modelling of
fasting plasma glucose and insulin levels to estimate insulin resistance:
fasting serum insulin (*U/ml) x fasting plasma glucose (mmol/l) / 22.57. -
After this, patients receive 8 weeks of treatment with the angiotensin-receptor
antagonist losartan, 100mg orally, once daily.
During the first visit renal function and elektrolytes will be measured. The
blood pressure, height and weight will also measured.

After 8 weeks of losartan treatment, again 3 fasting blood samples are taken at
5 minutes interval for measurement of:
- t=0: total IGF-I, IGF-I bioactivity, insulin, glucose
- t=5: insulin, glucose
- t=10: insulin, glucose
HOMA scores will again be calculated from these measurements.
Renal function, elektrolytes, weight and blood pressure will be measured again.

Burden:

- Patients have to come twice to the outpatient clinic. The visit will take
about 30 minutes
- Patient will have a venipuncture at both visits, 15 cc of blood will be drawn
- Patients have tot take a tablet, once a day, for 8 weeks

Risks:

Losartan treatment can cause adverse events, which are extensively described in
the patient information form

Benefits:

There is no expected direct benefit for the individual patient. Results from
this study might be beneficial for patients with impaired fasting glucose
and/or impaired glucose tolerance in the future.