Cellular Ions in NIDDM: Relation of Calcium to Hyperglycemia and Cardiac Mass

Abstract

OBJECTIVE To investigate the role of hyperglycemia in mediating the clinical association of NIDDM with hypertension and left ventricular dysfunction and hypertrophy. RESEARCH DESIGN AND METHODS Since hyperglycemia elevates cytosolic free calcium (Cai) both in myocardial and vascular smooth muscle cells, we utilized nuclear magnetic resonance (NMR) spectroscopy to measure erythrocyte Cai levels and compared them with serum ionized calcium (Caio), glucose, and insulin values before and following an oral glucose tolerance test (OGTT) and with previously obtained cardiac structural indexes in normotensive and hypertensive NIDDM (n = 32) and normal control subjects (n = 35). RESULTS Compared with control subjects, normotensive NIDDM subjects had higher Cai (31.5 ± 2.3 vs. 24.3 ± 1.9 nmol/l, P = 0.05), lower intracellular free magnesium (Mgi) (200 ± 10 vs. 225 ± 7 μumol/l, P = 0.05), and greater posterior wall thickness (0.98 ± 0.04 vs. 0.86 ± 0.03 cm, P = 0.05). Hypertensive NIDDM subjects exhibited a further increase in Cai (43.1 ± 4.4 nmol/l, P = 0.05 vs. control subjects) and left ventricular mass (LVM) (201.5 ± 12.2 vs. 155.8 ± 7.7 g, P = 0.05 vs. control subjects). For all subjects, significant relationships were observed between Cai and fasting blood glucose (r = 0.510, P < 0.01), HbA1c (r = 0.389, P < 0.05), and the glycemic response to OGTT (the area under the curve [AUC] for glucose; r = 0.519, P < 0.01) and to systolic (r = 0.504, P < 0.01) and diastolic (r = 0.624, P < 0.01) blood pressure. Left ventricular mass index (LVMI) was related to fasting glucose levels (r = 0.406, P < 0.01) and the AUC for glucose (r = 0.380, P < 0.01), but not to fasting insulin or insulin responses to an OGTT. The LVMI was best related to Cai (r = 0.516, P < 0.01), while being inversely related to Caio (r = −0.486, P < 0.01). Multivariate regression indicated the contribution of glucose to LVMI was independent of age, BMI, insulin, and blood pressure but demonstrated a significant interaction with Cai. CONCLUSIONS Altogether, these data suggest that glucose-related excess Cai is a fundamental lesion in diabetes that contributes to the elevated blood pressure and cardiac mass in this disease.