Cellular ions in NIDDM: Relation of calcium to hyperglycemia and cardiac mass

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 (Ca-i) both in myocardial and vascular smooth muscle cells, we utilized nuclear magnetic resonance (NMR) spectroscopy to measure erythrocyte Ca-i levels and compared them with serum ionized calcium (Ca-io), 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 Ca-i (31.5 +/- 2.3 vs. 24.3 +/- 1.9 nmol/l, P = 0.05), lower intracellular free magnesium (Mg-i) (200 +/- 10 vs. 225 +/- 7 mu mol/l, P = 0.05), and greater posterior nail thickness (0.98 +/- 0.04 vs. 0.86 +/- 0.03 cm, P = 0.05). Hypertensive NIDDM subjects exhibited a further increase in Ca-i (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 Ca-i and fasting blood glucose (r = 0.510, P < 0.01), HbA(1c) (r = 0.389, P < 0.05), and the glycemic response to OGTT (the area under the curve [AUG] 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 Ca-i (r = 0.516, P < 0.01), while being inversely related to Ca-io (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 Ca-i. CONCLUSIONS - Altogether, these data suggest that glucose-related excess Ca-i is a fundamental lesion in diabetes that contributes to the elevated blood pressure and cardiac mass in this disease.