Effects of a VLCD in obese patients with type 2 diabetes and cardiovascular complications

Diabetes Mellitus (DM2) is caused by disturbances in glucose and lipid
metabolism, resulting in progressive atherosclerosis and microangiopathy. In
addition to these vascular effects, the metabolic alterations perse also
directly alter structure and function of different organs, including the heart.
Therefore, the cardiac effects of DM2 involve both metabolic derangements in
cardiomyocytes and ischemic heart disease. Ultimately, these effects of DM2
result in excessive cardiovascular morbidity and mortality. In this proposal,
we focus on the relation between metabolic effects of DM2 on the heart and
cardiac function in advanced DM2.

The pathogenesis of the metabolic alterations in the heart in DM2 involves
complex pathways. An important role is attributed to the pathophysiological
changes induced by increased myocardial availability of free fatty acids (FFA)
arising from insulin resistant adipose tissue, leading to excessive FFA
exposure and uptake in organs, including the heart, which exceeds their
oxidizing capacity. Increased myocardial availability of fatty acid derivatives
is reflected in increased accumulation of myocardial triglycerides (TG).

Studies with proton magnetic resonance (1H-MR) spectroscopy techniques have
shown a concept of myocardial lipotoxicity, associated with myocardial TG
accumulation in healthy humans and patients with DM2. In a number of
experiments we have documented that diet-induced alterations in plasma FFA
availability in healthy subjects are associated with concordant changes in
myocardial TG stores. Moreover, increased myocardial TG stores were associated
with decreased diastolic function in healthy subjects. In uncomplicated DM2
patients without overt cardiac disease, myocardial TG accumulation was an
independent predictor of diastolic dysfunction. In addition, there is
reversibility of increased myocardial TG stores and cardiac dysfunction even in
patients with DM2 and untreatable hyperglycaemia by a 16 week caloric
restriction (450 kcal/day). These studies in healthy subjects and patients with
uncomplicated DM2 prove that myocardial TG stores are flexible depending on
nutritional and metabolic conditions and that increased myocardial TG stores
are associated with diastolic dysfunction. In these previous studies we have
documented the metabolic and functional effects of dietary interventions on the
heart in healthy subjects and patients with DM2 without overt cardiac
complications.

We hypothesize that dietary interventions also decrease myocardial TG stores
and improve cardiac function in patients with DM2 and cardiovascular
complications. This will open perspectives for dietary interventions which
decrease myocardial TG stores and improve myocardial dysfunction in this
category of patients.

Primary:
To investigate the effect of VLCD (very low calorie diet) in obese patients
with type 2 DM and cardiovascular complications on cardiac function, pulse wave
velocity and myocardial triglyceride content

Secondary:
To investigate the effect of VLCD in obese patients with type 2 DM and
cardiovascular complications on
• Glucose tolerance
• Fat distribution

Prospective intervention study with 1 intervention group. There will be 3 study
occasions, the first two separated by a 16 week intervention period. The third
occasion will take place 18 months after the first study day.

All patients will receive a VLCD consisting of 4-6 meal replacements (cold and
warm meal replacements) every day of Prodimed. This diet contains 400-600
kcal/day. Dependent on the amount of weigth loss of the patient, the diet will
be adjusted.

The favourable result of this study will be: weight loss, persisting improved
heart function and reduced/discontinued blood glucose lowering medication. The
most common side effect of the diet is constipation. This is easily solved by
enhancing fluid intake, or if necessary lactulose. Bloodglucose lowering
medication is reduced. From earlier studies it has become clear that this can
be done safely. Blood glucose values can fluctuate a little in the beginning.
During the first MRI Gadolinium (Gd) is administered, to asses cardiac muscle
viability. The incidence of an allergic response to Gd contrast is extremely
low. Contrast induced nephropathy and nephrogenic systemic fibrosis are very
rare and are generally seen at patients with a pre existente nierinsufficiency
(creatinin clearance <=30 ml/min). In this study we don't include patienst with
a creatinine clearance <=60 ml/min.