Evidence of increased visceral obesity and reduced physical fitness in healthy insulin-resistant first-degree relatives of type 2 diabetic patients.
OBJECTIVE
First-degree relatives (FDR) of type 2 diabetic patients are often insulin resistant. Visceral obesity is closely linked to both insulin resistance and type 2 diabetes. We therefore hypothesized that the inheritance of an increased tendency to store fat in visceral fat depots may be a characteristic phenotypic feature in FDR contributing to their insulin resistance.


METHODS
We measured fat distribution in 20 FDR and 14 age-, gender- and body mass index (BMI)-matched controls employing dual energy X-ray absorbtiometry (DEXA)- and computed tomography (CT)-scanning. Insulin-stimulated glucose uptake (ISGU) was determined by a hyperinsulinemic clamp and maximal aerobic work capacity (VO2 max) by a bicycle ergometer test. Baseline lipolysis was measured using [3H]palmitate. The activity level of the hypothalamic-pituitary-adrenal axis was assessed as the 24 h urinary (u)-cortisol/creatinine ratio.


RESULTS
All subjects had a normal oral glucose tolerance test (OGTT), but FDR were insulin resistant (ISGU: 6.64+/-0.48 vs 9.12+/-0.98 mg/kg ffm/min, P=0.01). Despite similar BMI (25.2+/-0.5 vs 24.8+/-0.7 kg/m2, P=0.61) and overall fat mass (26.4+/-1.6 vs 24.2+/-2.1%, P=0.41) in FDR vs controls, the amount of visceral adipose tissue was substantially increased (65.9+/-10.0 vs 40.1+/-11.3 cm2, P<0.05) and VO2 max was reduced (52.2+/-3.1 vs 63.3+/-3.9 ml/kg ffm/min, P<0.05) in FDR. Visceral adiposity was inversely correlated with ISGU (FDR: r=-0.52, P<0.05; controls: r=-0.65, P<0.01) and in multiple regression analysis visceral adiposity (P<0.01), VO2 max (P<0.001) and a family history of type 2 diabetes (P<0.05) (r2=0.64) all significantly and independently contributed to the level of ISGU. Baseline palmitate appearance (145+/-10 vs 139+/-15 micromol/min, P=0.74) and the 24 h u-cortisol/creatinine ratio ((24.9+/-1.3 vs 27.4+/-2.0).10(-6), P=0.28) were both comparable in the two groups.


CONCLUSIONS
Healthy but insulin-resistant FDR have enhanced visceral obesity and reduced VO2 max compared with people without a family history of diabetes, despite similar BMI and overall fat mass. Both the visceral adiposity and reduced aerobic fitness are strongly associated with and may contribute to their insulin resistance.
Nyholm
Birgit
B
Department of Medicine M (Endocrinology and Diabetes), Aarhus Kommunehospital, University Hospital of Aarhus and Department of Clinical Pharmacology, University of Aarhus, Aarhus, Denmark. bnyholm@dadlnet.dk
Nielsen
Michael F
MF
Kristensen
Kurt
K
Nielsen
Søren
S
Østergård
Torben
T
Pedersen
Sten B
SB
Christiansen
Thomas
T
Richelsen
Bjørn
B
Jensen
Michael D
MD
Schmitz
Ole
O
D000273:Adipose Tissue / Q000502:physiology*; D000328:Adult; D001786:Blood Glucose / Q000235:genetics / Q000378:metabolism*; D001823:Body Composition / Q000235:genetics / Q000502:physiology*; D003404:Creatinine / Q000652:urine; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism*; D005080:Exercise Test; D005260:Female; D020022:Genetic Predisposition to Disease; D015309:Glucose Clamp Technique; D006801:Humans; D006854:Hydrocortisone / Q000652:urine; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008297:Male; D016555:Matched-Pair Analysis; D010809:Physical Fitness / Q000502:physiology; D010913:Pituitary-Adrenal System / Q000502:physiology; D012016:Reference Values; D012044:Regression Analysis; D014781:Viscera
D001786:Blood Glucose; D003404:Creatinine; D006854:Hydrocortisone