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

This 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.

People 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.

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High-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.