Reduced skeletal muscle oxygen uptake and reduced beta-cell function: two early abnormalities in normal glucose-tolerant offspring of patients with type 2 diabetes.
OBJECTIVE
Studies on insulin sensitivity and insulin secretion in subjects with a familial predisposition for type 2 diabetes mellitus (T2DM) traditionally produce inconsistent results. This may be due to small sample size, subject selection, matching procedures, and perhaps lack of a measure of physical fitness.


METHODS
In the present study, we specifically tested the hypothesis that a family history of T2DM is associated with reduced VO(2max), measured by incremental bicycle ergometry, independent of insulin sensitivity estimated from an oral glucose tolerance test (OGTT; n = 424) and measured by a euglycemic-hyperinsulinemic clamp (n = 185). Subjects included in the study were young (34 +/- 10 years), healthy, and normal glucose tolerant with either a first-degree relative (FDR) with T2DM (n = 183), a second-degree relative with T2DM (n = 94), or no family history of T2DM (control subjects, n = 147). BMI, percent body fat, waist-to-hip ratio (WHR), and habitual physical activity (HPA; standard questionnaire) were comparable among groups. FDRs had significantly lower VO(2max) than control subjects: 40.5 +/- 0.6 vs. 45.2 +/- 0.9 ml O(2)/kg lean body mass, P = 0.01 after adjusting for sex, age, BMI, HPA, and insulin sensitivity (euglycemic-hyperinsulinemic clamp).


RESULTS
BMI, percent body fat, waist-to-hip ratio (WHR), and habitual physical activity (HPA; standard questionnaire) were comparable among groups. FDRs had significantly lower VO(2max) than control subjects: 40.5 +/- 0.6 vs. 45.2 +/- 0.9 ml O(2)/kg lean body mass, P = 0.01 after adjusting for sex, age, BMI, HPA, and insulin sensitivity (euglycemic-hyperinsulinemic clamp). Insulin sensitivity per se was not affected by family history of T2DM after adjusting for age, sex, BMI, and percent body fat (P = 0.76). The appropriateness of beta-cell function for the individual insulin sensitivity (disposition index: product of a validated secretion parameter [OGTT] and sensitivity [clamp]) was significantly lower in FDRs (87 +/- 4 units) versus control subjects (104 +/- 6 units, P = 0.02 after adjusting for sex, age, and BMI). Analyses of the larger OGTT group produced essentially the same results.


CONCLUSIONS
In conclusion, these data are compatible with the hypothesis that familial predisposition for T2DM impairs maximal oxygen consumption in skeletal muscle. Because habitual physical activity was not different, genetic factors may be involved. Conceivably, reduced VO(2max) precedes skeletal muscle insulin resistance, providing a partial explanation for discrepancies in the literature.
Thamer
Claus
C
Department of Endocrinology and Metabolism, Eberhard-Karls-University, Tübingen, Germany.
Stumvoll
Michael
M
Niess
Andreas
A
Tschritter
Otto
O
Haap
Michael
M
Becker
Regine
R
Shirkavand
Fatemeh
F
Bachmann
Oliver
O
Rett
Kristian
K
Volk
Annette
A
Häring
Hans
H
Fritsche
Andreas
A
D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D001824:Body Constitution; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000517:prevention & control; D015444:Exercise / Q000502:physiology*; D005080:Exercise Test; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005951:Glucose Tolerance Test; D006801:Humans; D007515:Islets of Langerhans / Q000503:physiopathology*; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D010101:Oxygen Consumption; D010290:Parents; D012044:Regression Analysis
D001786:Blood Glucose