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Insulin resistance in Dutch males of Hindostanian origin vs. Dutch males of Caucasian origin.


- candidate number8336
- NTR NumberNTR2473
- ISRCTNISRCTN wordt niet meer aangevraagd.
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR13-aug-2010
- Secondary IDsP09-143 METC LUMC
- Public TitleInsulin resistance in Dutch males of Hindostanian origin vs. Dutch males of Caucasian origin.
- Scientific TitleIncreased incidence of type 2 diabetes and cardiovascular disease in Hindostani as compared to Caucasians: role of intracellular signaling pathways involved in glucose uptake and mitochondrial function on ectopic fat accumulation.
- ACRONYM
- hypothesisPeople of South-Asian/Indian descent, such as the Hindostani population in The Hague, develop DM2 at a much younger age and lower BMI as compared to Caucasian controls of the same age and BMI. Moreover, the incidence and seriousness of cardiovascular disease is much higher in Hindostani compared to Caucasians. The susceptibility to DM2 and atherogenic diseases of South-Asians might be causally related to body fat distribution and/or fatty acid handling. Impaired fatty acid beta-oxidation in muscle and/or adipose tissue mitochondria might be the cause of ectopic fat storage in, for example, skeletal muscle. The resulting excess intermediates of fatty acid metabolism will accumulate in the cells and disturb metabolic processes and thus organ function.
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 Hindostani and Caucians in skeletal muscle and adipose tissue biopsies, before and after high-fat-high-calorie-feeding (HFHC) or calorie-restriction (CR), may underly/contribute to skeletal muscle insulin sensitivity and/or even mitochondrial function. This could then lead to ectopic lipid accumulation with subsequent organi-specific dysfunction.
CR improves carbohydrate metabolism, while a HFHC-diet induces carbohydrate intolerance in high risk subjects. Because mTOR is a nutrient-sensing pathway it is likely we hypothesize that, if a dysfunction in this pathway underlies the early development of DM2 in Hindostani, the diets (HFHC and CR) will elicit different responses in the Hindostani as compared to the Caucasians.
- Healt Condition(s) or Problem(s) studiedCardiovascular disease, Diabetes Mellitus Type 2 (DM type II), Insulin resistance, Ectopic fat accumulation, Mitochondrial dysfunction
- Inclusion criteriaWe will study:
1. Young, healthy male Caucasians and Hindostani before and after 5 days of high-fat-high-calorie diet on the one hand, and;
2.Middle-aged male Caucasians and Hindostani with abdominal adiposity before and after 8 days of caloric restriction on the other hand.

Young men:
1. Male healthy volunteers, 12 Hindostani and 12 Caucasians, born in the Netherlands;
2. Age >= 18 years and <= 25 years;
3. BMI >= 19 and <= 25;
4. 1 parent or grandparent with DM2 and >= relative.

Middle-aged men:
1. Male volunteers, 12 Hindostani and 12 Caucasians, born in the Netherlands;
2. Age 40 - 50 years;
3. Waist circumference > 94 cm for Caucasians and > 90 cm for Hindostani;
4. BMI >= 25 and <= 30;
5. 1 parent or grandparent with DM2 and >= 1 other relative.
- Exclusion criteria1. Diabetes mellitus as defined by ADA criteria;
2. Any significant chronic disease;
3. Renal, hepatic or endocrine disease;
4. Clinical cardiovascular disease, including complaints of angina pectoris or intermittent claudication;
5. Smoking;
6. Use of medication known to influence glucose and/or lipid metabolism;
7. Recent weight changes or attemps to lose weight (> 3 kg weight gain or loss, within the last 3 months);
8. Difficulties to insert an intravenous catheter;
9. Severe claustrophobia;
10. Contra-indications for MRI;
11. Recent blood donation (within the last 3 months);
12. Recent participation in other research projects (within the last 3 months), participation in 2 or more projects in one year.
- mec approval receivedyes
- multicenter trialno
- randomisedno
- groupParallel
- Type2 or more arms, non-randomized
- Studytypeobservational
- planned startdate 1-feb-2010
- planned closingdate31-jan-2013
- Target number of participants48
- InterventionsHigh-fat-high-calorie-diet (HFHC) (young group):
Consisting of a subject's normal diet plus 375 cc cream per day, providing 150% of energy demands and consisting of 50% fat. Duration of HFHC diet: 5 days.

Very-low-calorie-diet (VLCD) (middle-aged group):
Consisting of 3 sachets of Modifast per day, providing approximately 450 kcal/day. Duration of VLCD diet: 8 days.
- Primary outcomeDifference in all of the following study endpoints between Caucasians and Hindostani at baseline and after a dietary intervention; HFHC in the young group and VLCD in the middle-aged men:
1. Whole body glucose disposal determined by [6,6-2H2] glucose infusion and a two-step hyperinsulinaemic euglycaemic clamp;
2. EGP determined by [6,6-2H2] glucose infusion and a two-step hyperinsulinaemic euglycaemic clamp;
3. Glucose and lipid oxidation as determined by indirect calorimetry;
4. Body fat distribution: Hepatic and myocardial triglyceride content, visceral/subcutaneous abdominal fat and cardiac function, assessed by MRI/MRS;
5. Insulin signalling pathway in skeletal muscle and adipose tissue as assessed by expression and activation of IRS1-associated PI3K, PKB, AS160, GLUT4;
6. mTOR nutrient sensing pathway in skeletal muscle: mTOR, S6K1, PRAS40, raptor;
7. Muscle and adipose tissue mitochondrial function (mRNA levels of PGC-1á, mitochondrial enzymes, including the complexes of the electron transport chain/oxidative phosphorylation, uncoupling protein 3 [UCP3], mitochondrial copy number, and activity of mitochondrial enzymes (citrate synthase and cytochrome C oxidase));
8. Intramyocellular lipid content (Oil-red-O staining) and ceramide, acyl-co-enzyme A and triacylglycerol, and diacylglycerol levels;
9. Pancreatic function (first and second phase insulin response) as assessed by OGTT (only measured before the intervention);
10. Adipocyte function before the intervention: Plasma FFA’s, resistin, adiponectin, leptin, inflammatory mediators;
11. Calorie intake and daily activities as determined by a 3-day diary.
- Secondary outcomeN/A
- TimepointsN/A
- Trial web sitegeen
- statusopen: patient inclusion
- CONTACT FOR PUBLIC QUERIESMD. PhD. Leontine E.H. Bakker
- CONTACT for SCIENTIFIC QUERIESMD. PhD. Leontine E.H. Bakker
- Sponsor/Initiator Leiden University Medical Center (LUMC)
- Funding
(Source(s) of Monetary or Material Support)
Roba
- PublicationsN/A
- Brief summaryThis study investigates why Hindostani compared to Caucasian people develop type 2 diabetes and cardiovascular diseases at a younger age and lower BMI. The cause of thse differences is unkonw but might be related to body fat distribution and/or fatty acid handling. South Asians have a much smaller subcutaneous fat depot and relatively more visceral fat compared to Caucasians. Visceral fat is presumed to be more deleterious. Impaired fatty acid beta-oxidation in muscle and/or adipose tissue mitochondria might be the cause of ectopic fat storage. The resulting excess intermediates of fatty acid metabolism will accumulate in the cells and disturb metabolic processes (e.g. the insulin signaling pathway and insulin secretion). The mTOR pathway is a modulator of both insulin sensitivity and mitochondrial function. We hypothesize that changes in the activity of mTOR between Hindostani and Caucasian in skeletal muscle and adipose tissue biopsies, may underly/contribute to skeletal muscle insulin sensitivity and/or even mitochondrial function.
We will investigate healthy young males with a normal BMI and healthy middle-aged males with abdominal adiposity. Both groups will be studied before and after a diet. The young group after a high-fat-high-calorie-diet; and the middle-aged group after a very-low-calorie-diet.
Measurements which will be done are: hyperinsulinemic, euglycemic clamp; muscle biopsies; fat biopsies; indirect calorimetry; MRI/MRS, anthropometric measurements and blood samples.
- Main changes (audit trail)Hypothesis of addendum:
Brown adipose tissue (BAT) is importantly involved in energy expenditure by dissipating glucose and triglycerides into heat. Only recently, BAT has been shown to be present and active in humans. There are two forms of BAT: brown fat pads, which are mainly located along the great vessels and in the supraclavicular area, and single brown fat cells that lie scattered in peripheral tissues, such as white adipose tissue and muscle. The latter are called ‘peripheral brown fat cells’. Both types of brown fat cells importantly contribute to total energy expenditure. Interestingly, there is an inverse correlation between BAT activity and BMI. Therefore, a very likely hypothesis is that in the South Asian population a disturbed BAT function might underlie both the frequent unfavorable metabolic phenotype and the increased risk for DM2 development. Indeed, we have previously shown that after a high fat high calorie (HFHC) diet, South Asian adolescents display decreased energy expenditure, which could point to BAT dysfunction. To explore this hypothesis further, we will determine BAT activity and volume by 18F-FDG PET-CT scan after mild cold induction in the available cohorts of study 1, as a measure for the activity of the brown fat pads. Furthermore, in the collected muscle and white fat biopsies of study 1 we will measure BAT-specific mRNA expression (e.g. UCP-1, Cidea, Pgc1α, PRDM16) as a measure of peripheral brown fat cell activity. This study will provide more insight into the association of BAT activity and functionality with ethnicity and different metabolic disease states, such as dyslipidemia and insulin resistance. If impaired BAT function indeed appears to be the cause of the diseased metabolic phenotype of the South Asian population, therapies might be developed that specifically increase the activity of BAT in an early stage of the development of metabolic disturbances. This might be an innovative therapy to prevent the development of DM2, in the South Asian as well as the general population, in the future. Since BAT is importantly involved in total energy expenditure and clearance of glucose and triglycerides from the blood, we hypothesize that a low BAT activity might underlie the disadvantageous metabolic phenotype and susceptibility for DM2 of South Asian subjects.

Inclusion criteria:
Same cohorts as in study 1.

Exclusion criteria:
Same as in study 1.

MEC approval received:
yes

Study design:
Prospective case-controlled observational intervention

Intervention:
none

Primary outcome:
We want to study potential differences on the following parameters:
- volume and activity of BAT using cold-induced 18F-FDG PET-CT scan
- peripheral BAT activity, measuring mRNA expression of BAT specific genes in skeletal muscle and white adipose tissue biopsies of study 1.
- Energy expenditure, thermoneutral and cold-induced using indirect calorimetry
- Glucose and triglyceride clearance by determining glucose and triglyceride levels in a fasted and cold-induced blood sample.
- Thermoregulation by measuring core body temperature and skin temperature in thermoneutral and cold-induced conditions
Secondary outcome:
none

Funding:
Dutch Diabetes Research Foundation (grant 2012.11.1500).

Brief summary:
Brown adipose tissue (BAT) is importantly involved in energy expenditure by dissipating glucose and triglycerides into heat. Only recently, BAT has been shown to be present and active in humans. There are two forms of BAT: brown fat pads, which are mainly located along the great vessels and in the supraclavicular area, and single brown fat cells that lie scattered in peripheral tissues, such as white adipose tissue and muscle. The latter are called ‘peripheral brown fat cells’. Both types of brown fat cells importantly contribute to total energy expenditure. Interestingly, there is an inverse correlation between BAT activity and BMI. Therefore, a very likely hypothesis is that in the South Asian population a disturbed BAT function might underlie both the frequent unfavorable metabolic phenotype and the increased risk for DM2 development. Indeed, we have previously shown that after a high fat high calorie (HFHC) diet, South Asian adolescents display decreased energy expenditure, which could point to BAT dysfunction. To explore this hypothesis further, we will determine BAT activity and volume by 18F-FDG PET-CT scan after mild cold induction in the available cohorts of study 1, as a measure for the activity of the brown fat pads. Furthermore, in the collected muscle and white fat biopsies of study 1 we will measure BAT-specific mRNA expression (e.g. UCP-1, Cidea, Pgc1α, PRDM16) as a measure of peripheral brown fat cell activity. This study will provide more insight into the association of BAT activity and functionality with ethnicity and different metabolic disease states, such as dyslipidemia and insulin resistance. If impaired BAT function indeed appears to be the cause of the diseased metabolic phenotype of the South Asian population, therapies might be developed that specifically increase the activity of BAT in an early stage of the development of metabolic disturbances. This might be an innovative therapy to prevent the development of DM2, in the South Asian as well as the general population, in the future.

Study procedure: all subjects will have one study day after an overnight fast. Anthropometric measurements will be performed first, followed by 1) a DEXA scan to determine body composition, 2) indirect calorimetry, to measure basal energy expenditure, and 3) a blood sample to determine glucose and triglyceride levels. Then a personalized cooling procedure will be started using a cooling device. After approximately 30 minutes the subject will have reached the right temperature (environmental temperature will be around 16°C) at which he does not shiver and the official cooling time starts. One hour after cold exposure 18F-FDG will be infused intravenously. After 75 minutes of cooling a second, cold-induced, indirect calorimetry will be performed, followed by a second, cold-induced blood sample. Then, after 2 hours, a PET-CT scan will be performed to measure the volume and activity of BAT after mild cold induction (16°C). When the PET-CT scan is finished, after circa 30 minutes, subjects will have a meal and can go home.
- RECORD13-aug-2010 - 29-jul-2013


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