Variations in erythrocyte volume [mean corpuscular volume (MCV)] were evaluated during exercise and heat stress to determine the influence on calculated plasma volume and content changes. The results of this study on 17 men indicate that the human red blood cell can increase, decrease, or remain constant in volume during physical stress depending on the combined interactions of plasma osmolality and blood pH. Shrinking of MCV can occur when the increase in plasma osmolality is larger than 5 mosmol/kg H2O and the blood pH remains within 0.1 pH units of its resting value. Erythrocyte swelling is usually noticed with maximal exercise when the blood pH is less than 7.10, in spite of 20 mosmol/kg H20 increments in plasma osmolality. The regression equations indicate that during 30 min of exercise in a cool environment the plasma shifts calculated by either the hematocrit or the hematocrit + hemoglobin method fall within 1% of each other, but during resting heat exposure the hematocrit technique under-estimates the fluid shift by 2.5-3.0%. Application of these considerations to the calculation of plasma content changes during stress made it clear that the pattern of plasma potassium content is quite different with maximal as compared with submaximal exercise.

GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) is a 36-center unmasked, parallel treatment group, randomized controlled trial evaluating four diabetes medications added to metformin in people with type 2 diabetes (T2DM). We report baseline characteristics and compare GRADE participants to a National Health and Nutrition Examination Survey (NHANES) cohort. RESEARCH DESIGN AND METHODS Participants were age ‡30 years at the time of diagnosis, with duration of T2DM <10 years, HbA 1c 6.8-8.5% (51-69 mmol/mol), prescribed metformin monotherapy, and randomized to glimepiride, sitagliptin, liraglutide, or insulin glargine. RESULTS At baseline, GRADE's 5,047 randomized participants were 57.2 6 10.0 years of age, 63.6% male, with racial/ethnic breakdown of 65.7% white, 19.8% African American, 3.6% Asian, 2.7% Native American, 7.6% other or unknown, and 18.4% Hispanic/ Latino. Duration of diabetes was 4.2 6 2.8 years, with mean HbA 1c of 7.5 6 0.5% (58 6 5.3 mmol/mol), BMI of 34.3 6 6.8 kg/m 2 , and metformin dose of 1,944 6 204 mg/day. Among the cohort, 67% reported a history of hypertension, 72% a history of hyperlipidemia, and 6.5% a history of heart attack or stroke. Applying GRADE inclusion criteria to NHANES indicates enrollment of a representative cohort with T2DM on metformin monotherapy (NHANES cohort average age, 57.9 years; mean HbA 1c , 7.4% [57 mmol/mol]; BMI, 33.2 kg/m 2 ; duration, 4.2 6 2.5 years; and 7.2% with a history of cardiovascular disease). CONCLUSIONS The GRADE cohort represents patients with T2DM treated with metformin requiring a second diabetes medication. GRADE will inform decisions about the clinical effectiveness of the addition of four classes of diabetes medications to metformin. The optimal medication management of hyperglycemia in type 2 diabetes (T2DM) is not established. In addition to lifestyle intervention, metformin is the recommended initial medication in T2DM due to its glycemic effectiveness, lack of associated hypoglycemia or weight gain, low cost, and evidence of long-term benefit and safety