Elucidating the high cardiovascular disease risk in South Asians: focus on monocyte phenotype and incretin hormones

The worldwide increasing incidence of type 2 diabetes mellitus (T2DM) and
cardiovascular diseases (CVD) has significant health and economic implications.
Interestingly, the vulnerability to develop CVD is higher in Dutch South Asians
(from here on called: South Asians) than in Dutch Europids. Several factors are
suspected to contribute to this high CVD risk in South Asians, including higher
prevalence of central obesity, insulin resistance and dyslipidemia as well as
lifestyle factors such as lower amount of exercise and consumption of a diet
high in ultra-processed foods.The higher susceptibility to develop central
obesity and insulin resistance in the South Asian population would fit with
increased sensitivity of the glucocorticoid receptor (GR) compared with
Europids, resulting in increased activity of the glucocorticoid system.
Furthermore, dyslipidemia and inflammation are central risk factors for the
development of atherosclerosis, the most important driver of CVD. Levels of
C-reactive protein (CRP), a non-specific marker for low-grade inflammation in
the body, were shown to be higher in South Asians compared to Dutch Europids
already just after birth. The fact that CRP levels are already higher in South
Asian neonates suggests that genetic susceptibility may underlie the
pro-inflammatory phenotype of South Asians. Up till now, only little is known
about the regulation of the immune system of South Asians. Moreover, the
phenotype of monocytes, the immune subset that plays a central role in
atherosclerosis development, has also not been studied in South Asians so far.
In addition, the underlying cause for the more proinflammatory phenotype is
currently unknown in South Asians. Since this susceptibility further aggravates
their high CVD risk, it is important to be further uncovered. Incretin hormones
(glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic
polypeptide (GIP)), secreted by intestinal cells following a meal, have direct
anti-inflammatory effects and the incretin system has not been studied in
detail in South Asians compared to Europids. Considering their high CVD risk,
we hypothesize that Dutch South Asians have a relatively pro-inflammatory
balanced immune system including more pro-inflammatory monocytes compared with
Dutch Europids and a lower release of anti-inflammatory incretin hormones
following a meal, further contributing to their proinflammatory phenotype.

Unravel the working of the immune system in South Asians, specifically the
monocytes. We will also study whether the release of incretin hormones (GLP-1
and GIP) following a meal is lower in South Asians compared to Europids. The
latter we will study with a mixed meal test followed by several blood
withdrawals to study blood GLP-1 and GIP levels. In addition, we will study the
sensitivity of the stress hormone receptor (glucocorticoid receptor) in both
ethnicities by performing in vitro measurements in polymorphonuclear cells of
both ethnicities.
We hope this study will give us more insight in the causes of the high
cardiovascular disease risk in South Asians. Eventually, this may contribute to
development of novel treatments to prevent cardiovascular diseases in this
vulnerable population, targeting the immune system and/or incretin hormones.

This study is a cross-sectional study carried out at the Leiden University
Medical Centre (LUMC). The study encompasses one screening phone call and half
a study day that takes approximately 4.5 hours per participant. We will first
study height, weight and body composition. Then, 3 questionnaires are taken.
Then, blood is withdrawn for measurement of components of the immune system.
Next, participants will consume a meal drink and blood is drawn at several time
points afterwards to assess e.g. incretin hormones (GLP-1 and GIP) and hunger
and satiety hormones (e.g. ghrelin, PYY), insulin, glucose and lipids in blood.

Participants will neither directly nor personally benefit from participating in
this research project. At the same time, no large side effects are expected
when taking part in this study. After informed consent, anthropometric measures
will be taken, venous blood (130.5 mL) will be drawn for investigating the
above-mentioned objectives and an MMTT will be performed to assess release of
incretin hormones and insulin sensitivity. All measurements will be done in one
study day that takes approximately 4.5 hours per participant.