Rationale:
People with diabetes have an increased risk of malfunctioning of the small blood vessels,
e.g. in the eye and kidney, which can lead to blindness and kidney failure. These are
serious complications, but to date there are no options to improve specifically the
function of the small blood vessels. But why do people with diabetes have such an
increased risk of dysfunction of the small blood vessels? The investigators have shown
that a high glucose concentration in the blood plays an important role in the dysfunction
of, particularly, the small blood vessels. A possible explanation for this dysfunction is
an increased production of methylglyoxal, which arises from the breakdown of glucose.
Methylglyoxal is a small but highly reactive molecule that can damage various organs and
tissues. In several studies, the investigators found that methylglyoxal is increased in
type 1 and type 2 diabetes and that methylglyoxal is associated with dysfunction of the
smaller blood vessels. In our previous research in small laboratory animals, The
investigators have shown that methylglyoxal directly causes damage of the small blood
vessels. Because of these potentially harmful effects of methylglyoxal, the investigators
have tried to reduce circulating methylglyoxal. In small laboratory animals, the
investigators have found that the vitamin B6 isoform pyridoxamine inhibits the formation
and accumulation of methylglyoxal, and improves vascular function. In a clinical trial in
people with overweight, the investigators found that supplementation of pyridoxamine is
safe and that methylglyoxal levels can be reduced, and the investigators found
indications of an improvement of vascular function.
Objective:
Primary objective: to study whether pyridoxamine supplementation in type 2 diabetes
improves microvascular function in the eye, kidney and skin, and reduces markers of
endothelial dysfunction and glycation.
Secondary objective: to study whether pyridoxamine supplementation in type 2 diabetes
improves glucose metabolism, advanced glycation endproduct (AGE) concentrations in blood
plasma and skin, methylglyoxal, glyoxal and 3-deoxyglucose concentrations in blood
plasma, adipokines and inflammatory markers in blood plasma, markers of dicarbonyl stress
and oxidative stress in urine, liver fat, blood pressure, heart rate/ECG and body
composition.
Study design:
The study will be conducted in a randomized, double blind, placebo-controlled manner.
This intervention study includes two intervention periods of 8 weeks in a crossover
design with a washout period of 4 weeks.
Study population:
Adult individuals (>18 years old) with type 2 diabetes, and with generalized
microvascular dysfunction, i.e. an estimated glomerular filtration rate (eGFR) of 30-60
mL/min/1.73m2, and/or microalbuminuria of (albumin-creatinine ratio) 3-30 mg/mmol, and/or
retinopathy (not proliferative), and/or neuropathy (any).
Intervention:
The daily dosage (300 mg) pyridoxamine or placebo will be supplied as three capsules of
100mg each per day, and are taken shortly before or during the meal.
Main study parameter:
The main study parameter is microvascular function in the eye, skin, plasma, and kidney
measured by means of retinal funduscopy, adaptive optics funduscopy, optical coherence
tomography (OCT), dynamic vessel analyser, skin laser doppler flowmetry, markers of
endothelial function in the blood plasma, urinary albumin, and estimated glomerular
filtration rate.
Nature and extent of the burden and risks associated with participation, benefit and
group relatedness:
The number of measurements during each visit in this study is quite substantial.
Nonetheless, the investigators expect that the burden for the subjects is limited since
all measurements, except blood withdrawal, are non-invasive, and are performed while
sitting or in a supine, relaxed, and comfortable position. Additionally, potential
benefits of participating in this study are directly related to the possible beneficiary
effects of pyridoxamine as showed in a previous clinical trial. Moreover, pyridoxamine
supplementation in this previous clinical trial did not result in serious adverse
effects.
