POLYMORPHISM OF THE GLYCOGEN-SYNTHASE GENE IN HYPERTENSIVE AND NORMOTENSIVE SUBJECTS

Hypertension and non-insulin-dependent diabetes mellitus (NIDDM) are c haracterized by a strong genetic component and impaired ability to sto re glucose as glycogen in skeletal muscle. Impaired insulin activation and altered genetic control of muscle glycogen synthase, the rate-lim iting enzyme for glucose storage in skeletal muscle, could provide an explanation for this insulin resistance. We examined whether there is an association between the glycogen synthase gene (Xba I polymorphism) and hypertension in 304 nondiabetic subjects. We examined glucose tol erance with an oral glucose tolerance test and glucose storage in skel etal muscle with the euglycemic insulin clamp technique in combination with indirect calorimetry. The Xba I A(2) allele of the glycogen synt hase gene was enriched in subjects with hypertension and a family hist ory of NIDDM (48%) compared with normotensive subjects without a famil y history of NIDDM (6%, P<.0001). The presence of the A(2) versus the A(1) allele was associated with decreased rates of insulin-stimulated glucose storage in hypertensive subjects (11.2+/-2.3 versus 16.9+/-2.6 mu mol/kg lean body mass per minute, P=.029) but not in normotensive subjects (28.0+/-4.6 versus 29.6+/-3.7 mu mol/kg lean body mass per mi nute). In conclusion, Xba I polymorphism of the glycogen synthase gene identifies a subgroup of hypertensive subjects with a family history of NIDDM. The data suggest that a locus in the glycogen synthase gene region on chromosome 19 may serve as a ''thrifty gene,'' increasing su sceptibility for insulin resistance when exposed to other environmenta l or genetic factors.