Increased incidence of type 2 diabetes and cardiovascular disease in Hindostani as compared to Caucasians: role of intracellular pathways leading to glucose uptake and mitochondrial function on ectopic fat storage.

Study 1

People of South-Asian descent, such as the Surinamese Indo-Asian (Hindostani)
population in the Hague, develop type 2 diabetes and associated cardiovascular
complications at a younger age and BMI as compared to the Caucasian population.
The cause of these differences is unknown but might be related to body fat
distribution and/or ectopic fat storage with resulting organ dysfunction and
insulin resistance (if situated in liver or muscle). Impaired fatty acid
beta-oxidation in muscle and/or adipose tissue mitochondria might be the cause
of ectopic fat storage. Recent studies have identified the nutrient- and
energy-sensing mammalian target of rapamycin (mTOR) pathway as modulator of
both insulin sensitivity and mitochondrial function. We hypothesize that
changes in the activity of mTOR between the 2 ethnicities in skeletal muscle
biopsies may underly/contribute to skeletal muscle insulin sensitivity and/or
even mitochondrial function. This could then lead to (an increased
susceptibility to) ectopic lipid accumulation with subsequent organ-specific
dysfunction.



Study 2 (addendum)

People of South-Asian descent, such as the Surinamese Indo-Asian (Hindostani)
population in the Hague, develop type 2 diabetes and associated cardiovascular
complications at a younger age and BMI as compared to the Caucasian population.
The cause of these differences is unknown.
Preliminary results of study 1 show that young, healthy Hindostani men have
significantly higher insulin levels then Caucasians during an oral glucose
tolerance test (OGTT), while they have similar glucose levels, suggesting a
decrease in insulin sensitivity. This pattern is also seen in patients with
prediabetes. In these patients the higher levels of insulin can lead to
reactive hypoglyceamia 3 to 5 hours after a glucose load (36,37). In the
previous study blood samples were only drawn until 120 minutes after the
glucose load. Therefore, we want to perform a prolonged OGTT to confirm the
observations from study 1 and to investigate whether the higher (stimulative)
insulin levels during the OGTT will lead to reactive hypoglyceamia in the
Hindostani subjects.
Furthermore, to elucidate the cause of the higher insulin levels in young
Hindustani men, we want to investigate the GLP-1 response during an OGTT in the
same population. GLP-1 is secreted by entero-endocrine L cells in the distal
ileum and colon and has a glucose dependent effect on insulin secretion.
Because GLP-1 is rapidly inactivated by DPP4, GLP-1 can only be measured
correctly when DPP4-inhibitor is added to the blood sample immediately after it
is drawn (38) (something we had not done in study 1).
Therefore, we want to perform a prolonged OGTT in an additional group of
healthy male Caucasians and Hindostani.


AD ADDENDUM SEPTEMBER 2012 (STUDIE 3):
People of South-Asian descent, such as the Surinamese Indo-Asian (Hindostani)
population in the Hague, develop type 2 diabetes and associated cardiovascular
complications at a younger age and BMI as compared to the Caucasian population.
In study 1, the original main study, we looked if the cause of these
differences might be related to an impaired mitochondrial function, so that the
modern Western high fat/high caloric diet is not burned properly, resulting in
ectopic fat storage leading to organ dysfunction and insulin resistance (if
situated in liver or muscle).
In this addendum, study 3, we investigate if there is a role for brown adipose
tissue (BAT). Recently, BAT has been shown to have an important function in
energy expenditure, it burns triglycerides and glucose to generate heat. In
neonates, large amounts of BAT are present that have an important role in the
production of heat for maintenance of body temperature. BAT decreases with
ageing. Until recently it was thought that the amount of BAT is fully
disappeared in adulthood. However, it has recently been shown with 18F-FDG
PET-CT scans that BAT is still present and active in adults. Interestingly, BAT
is absent in severely obese individuals, while lean individuals have more
functional BAT. Because BAT uses mainly lipids and glucose as an energy source
for the production of heat, a low BAT activity not only leads to overweight,
but also to accumulation of triglycerides and glucose in the blood. This
eventually induces hypertriglyceridemia and insulin resistance, which, together
with obesitas, is precisely the metabolic phenotype shown by Hindostani already
at a young age.

Therefore, the hypothesis for this addendum is that an impaired function of BAT
might underlie the disadvantageous metabolic phenotype and susceptibility for
DM2 of the Hindostani population (representing the South Asian population
forming one fifth of the world population).

Study 1

1. To determine whether or not there are differences, at baseline, in mTOR
activity, between Caucasians and Hindostani, 18-25 years old and healthy on the
one hand and middle-aged (40-50 years) with abdominal adiposity on the other
hand
2. To investigate whether possible differences in mTOR activity are related to
mitochondrial function and insulin sensitivity of liver, muscle and/or adipose
tissue
3. To study if there are, at baseline, differences in body fat distribution
(coupled to organ function, with emphasis on the muscle, pancreas [OGTT] and
visceral fat) and plasma adipokine profile between the 2 ethnicities at
different ages
4.To study if there are differences in insulin secretion between the 2
ethinicities at different ages, this will only be measured at baseline
5.With respect to mTOR activity, mitochondrial function, insulin sensitivity,
insulin secretion and body fat distribution we want to investigate whether the
response to high-fat/high-caloric feeding (HFHC) in healthy young males and
caloric restriction (CR) in middle-aged men with abdominal adiposity, differs
between the 2 ethnicities



Study 2 (addendum)

- Differences in GLP-1 response to glucose between Caucasians and Hindostani
- Differences in glucose and insulin levels during prolonged OGTT between
Caucasians and Hindostani

AD ADDENDUM SEPTEMBER 2012 (STUDIE 3):
To assess if Hindostani and Caucasians differ in volume and/or activity of BAT
using a cold-induced 18F-FDG PET-CT scan, in subjects who participated in study
1.

Prospective non-randomised, controlled observational intervention study

Study 1

1 week highcaloric/hig fat feeding in the young group: 140% of energy needs
(calculated with the Harris-Benedict equation) with the extra 40% in the form
of 2 snacks per day amounting 50%, 40% and 10% of energy of fat, carbohydrate
and protein respectively.
1 week low caloric diet in the middle-aged men consisting of Modifast (450
kcal/day)


Study 2 (addendum)
-


AD ADDENDUM SEPTEMBER 2012 (STUDY 3):
-

Study 1

1 week diet, 2 study days (on which 2 muscle and fat biopsies will be taken)
and 2 MRI's . We have extensive expercience and never had complications. The
benefit would be early detection of insulin resistance/diabetes with early
intervention. In addition for the Hindostani population at large our findings
can have important consequences for the detection, prevention and treatment of
DM2




Study 2 (addendum)

1 study day with a prolonged OGTT.


AD ADDENDUM SEPTEMBER 2012 (STUDY 3):
The total effective radiation dose from the low dose CT-scan (2 mSv), injected
18F-FDG (2.66 mSv) and the Dexa scan (negligible) will be approximately 4.66
mSv, which is comparable to a standard CT-thorax. According to the risk
categorization based on ICRP-62 an effective dose of 4.66 mSv comes within
category IIb, which involves risks to the irradiated individual in the order of
one in ten thousand. The degree of benefit to society from studies in this
category should be *moderate*; the benefit would be expected to be *aimed
directly at the diagnosis, cure or prevention of disease*.

With respect to benefit:
If this study shows that BAT is indeed less present and/or active in
Hindostani, new therapies could possibly be developed, that increase the
activity of BAT, so that more triglycerides and glucose will be burned. This
may prevent the development of diabetes on the long term. This is relevant not
only for people of South Asian ethnicity, but also for people of e.g. Caucasian
ethnicity this could lead to important leads for the prevention and treatment
of diabetes. Therefore, we believe that our study proposal meets the above
mentioned criterium, and that the expected outcome of this study absolutely
justifies the radiation dose. The Dutch Diabetes Foundation has recognized the
importance of this study as well with a pilot grant.