Skeletal muscle function and standard nutritional assessment parameters were measured in six obese patients. Base-line measurements were made on a weight-maintaining diet, and further measurements after 2 wk of a 400-cal diet, followed by 2 wk of fasting and then after 2 wk of refeeding. The function of the adductor pollicis muscle was assessed by electrical stimulation of the ulnar nerve. The objective parameters of muscle function measured were: 1) force of contraction expressed as a percentage of the maximal force obtained with electrical stimulation at 10, 20, 30, 50, and 100 Hz. 2) Maximal relaxation rate expressed as percentage force loss/10 ms. 3) Endurance expressed as percentage force loss/30 s. Standard nutritional assessment parameters (serum albumin and transferrin, creatinine height index, anthropometry and total body nitrogen and potassium) were also measured. There was a significant increase in the force of contraction at 10 Hz from a base-line of 29.6 +/- 1.0% to 49.0 +/- 2.8% (mean +/- SEM) after 2 wk of a 400-cal diet (p less than 0.01). These was a significant slowing of the maximal relaxation rate from a base-line of 9.8 +/- 0.03% force loss/10 ms to 8.2 +/0 0.3% force loss/10 ms (mean +/- SEM) (p less than 0.01) after 2 wk of a 400-cal diet. After a further 2 wk of fasting these abnormalities in muscle function persisted. There was a significant increase in muscle force loss from a base-line of 3.9 +/- 0.8% force loss/30 s to 13.7 +/- 3.4% force loss/30 s (mean +/- SEM) after fasting (P less than 0.01). After 2 wk of refeeding all aspects of muscle function measured were normal. During the study the standard nutritional assessment parameters did not change significantly.

Hypocaloric dieting and fasting alter the contraction-relaxation characteristics of skeletal muscle and result in low frequency fatigue. We report the metabolic and structural changes in skeletal muscle in five morbidly obese female subjects who had biopsies of the gastrocnemius muscle on a base-line diet (2500 kcal/day) followed by a repeat biopsy after 2 wk of a 400-kcal/day carbohydrate diet. Hypocaloric dieting resulted in a significant increase in the intracellular muscle calcium content (p less than 0.05), which may account for the observed changes in muscle function. There were no significant changes in muscle glycogen, lactate, pyruvate, or free energy stores. There was a significant decrease in muscle enzymes [phosphofructokinase (p less than 0.05), succinate dehydrogenase (p less than 0.02)] and some muscle amino acid levels [glutamine (p less than 0.025), glycine (p less than 0.01), and alanine (p less than 0.02)], while muscle histochemistry showed type II fiber atrophy (p less than 0.025). However, these changes reflect a generalized response to hypocaloric dieting and probably do not explain the specific functional changes. Change in the muscle calcium content is probably an important mediator of the adverse functional effects of malnutrition.

As the result of past metabolic studies, especially those of Henderson and Palmer (12) it is known that the non-volatile acids produced in excess of fixed base by human metabolism are excreted in the urine in two forms, viz., as free acids, and as ammonium salts.Since the kidney is unable to form urine with a pH much lower than 5.0, it can excrete, in significant amounts, free acids of only the weak buffer type. In this class fall acid phosphates and the various organic adds. It appears, however, that free acid excretion may assist also in elimination of strong acids, which can react with buffer salts (e.g., HC + Na2HPO4 = H(NaHPO4) + NaCl), the free buffer acid being excreted in place of the strong acid. Thus Marriott and Howland (19)

Warren and Stead's (1) contention that disturbed renal function secondary to a diminished cardiac output is responsible for the following series of events-salt and water retention, increased blood and extracellular fluid volume, rise in venous pressure, edema-seemed to offer a rational explanation for some of the clinically observed phenomena. We therefore initiated a series of studies on patients with chronic congestive heart failure, using the clearance techniques of Smith and associates (2), in order to evaluate the relationship between the decreased sodium excretion in heart failure (3, 4) and renal blood flow, to determine the nature of the disturbance in renal function and the relationship, if any, between the altered renal dynamics and sodium retention. We later attempted to define some of the variables involved in the tubular transfer system for sodium as it obtains in the normal and in the cardiac patient. Since our studies began, Merrill (5) reported that the renal plasma flow was reduced to as little as 20 per cent and the filtration rate to 33 per cent of normal in chronic congestive failure. We have been able to confirm his findings of a decreased sodium excretion rate due to a diminished load presented to the tubules for reabsorption, and not to enhanced tubular reabsorption as suggested by earlier workers (3). EXPERIMENTAL PROCEDUREPatients with advanced chronic congestive failure due predominantly to rheumatic heart disease were the subjects. All had variable amounts of edema at rest. Members of the resident house staff and patients without heart failure or renal disease served as controls.The subjects were brought to the laboratory in a postabsorptive state. Each patient was given 300 to 600 cc. of water about 30 to 60 minutes before the test period.' This study was aided by a grant from the Martha M. Hall Foundation and the Committee on Scientific Research of the American Medical Association.2 Martha M. Hall Foundation Fellow in Medicine.Five controls were maintained on a special cardiac saltpoor diet (about 1.3 grams of sodium chloride daily), for 4 to 5 days before the studies were made. Most of the patients with congestive heart failure were maintained on the same diet (strict metabolic control was not attempted) and, in addition, all were taking digitalis.

During a total fast in obese subjects, the daily rate of nitrogen excretion undergoes only a small further decline after 2 wk, the excretion rate being about 5 g N/day. At this time, ammonium and urea each constitute about one-half of this excretion. The purpose of this study was to consider two alternative hypotheses: first, that the near plateau in nitrogen excretion represents an irreducible minimum rate of net protein breakdown in order to supply essential organs with calories in the form of glucose; second, that protein breakdown could be further reduced by minimizing the requirement to provide nitrogen for ammonium excretion during the ketoacidosis of fasting. Because ammonium excretion is largely controlled by acid-base balance, 150 mmol of sodium bicarbonate plus 60 mmol of potassium chloride were administered daily to decrease ammonium excretion in eight obese subjects who were totally fasting for more than 14 days. Urine ammonium nitrogen fell with this treatment (from 3.8 +/- 0.4 to 2.0 +/- 0.4 g N/g creatinine). In addition, there was a smaller fall in the rate of urea excretion (from 2.5 +/- 0.2 to 2.1 +/- 0.3 g N/g creatinine) together with a fall in the blood urea nitrogen. Therefore, it appears that ammonium excretion contributes to the negative nitrogen balance of a prolonged total fast, as assessed over a 3-day period of observation, is responsible for about one-third of the net lean body mass loss.

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Many studies suggest that sulfonylureas (SUs) have direct extrapancreatic actions. The action of gliclazide, a new SU, was examined and compared to that of glyburide in L6 myotubes, a model of skeletal muscle. Gliclazide and glyburide increased 2-deoxy-D-glucose (2DG) uptake in a time- and dose-dependent fashion after 24 h to a maximum of 179% and 202% of the basal value, respectively (P < 0.001). Acute (30-min) insulin (10(-7) M) stimulated 2DG uptake to similar levels (203% of basal), but this effect was absent after maximum stimulation by SU. SU action did not require insulin and was not blocked by the protein synthesis inhibitor cycloheximide. To investigate the mechanism of stimulation of 2DG uptake, cells were fractionated, and total plasma membrane and internal membrane levels of glucose transporter (GLUT) isoforms were determined by immunoblotting. Both drugs significantly increased the total content (1.7-fold) and plasma membrane level (1.8-fold) of GLUT1, with no change in internal membrane. Total content and plasma membrane levels of GLUT4 and GLUT3 did not change or showed a small decrease. We conclude that the stimulation of glucose uptake in L6 cells by gliclazide and glyburide is associated not with a redistribution but, rather, with an increase in the total membrane content and plasma membrane level of GLUT1, which is independent of protein synthesis. These data suggest a novel action of SU to stabilize GLUT1 protein at the plasma membrane.

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