Lipectomy in obese hyperglycemic mice (ob-ob)

Mature, female obese-hyperglycemic mice ($\text{ob}\text{ob}$) were subjected to partial ablation of abdominal adipose tissue. Between operation and sacrifice, the amount of body fat gained by these mice was significantly greater than that of the “sham-operated” animals. It is not known whether the restoration of body fat to normal in the lipectomized animals was achieved by hypertrophy of the remaining adipose tissue or by compensatory expansion of adipocyte number. The data suggest that the total body fat rather than the fat per adipocyte is the regulated variable in $\text{ob}\text{ob}$.     

Brain tryptophan, plasma free tryptophan and distribution of plasma neutral amino acids.

Although rat brain tryptophan is strikingly elevated following portacaval shunt, plasma total tryptophan is unchanged and plasma free tryptophan is not elevated to the same degree as brain tryptophan. Investigation of the concentrations of the neutral amino acids (phenylalanine, tyrosine, methionine, threonine, leucine, isoleucine, and valine) revealed that their distribution and the sum of their concentrations were altered following portacaval shunt, and that this pattern was similar to that seen in humans with cirrhosis of the liver. It is suggested that both the elevation in plasma free tryptophan and the decrease in the competing neutral amino acids, act together to increase the transport of tryptophan into brain when portal blood is diverted around the liver. The implications of these findings in therapy of hepatic coma is discussed.     

Protein and energy sparing of glucose added in hypocaloric amounts to peripheral infusions of amino acids.

After abdominal surgery, patients were given peripheral infusions of amino acids alone for 4 days followed by amino acids plus glucose for 4 days, or the same solutions in the reverse order. Although there was a wide variation in the response of individual subjects, the typical effect of glucose under these conditions was to reduce both nitrogen excretion (average of 2.8 g N/day) and resting metabolic expenditure (average of 110 kcal/day).     

Metabolism of protein, amino acids, and glucose and their response to insulin in atria and cardiac myocytes of traumatized rats

Soft tissue injury to one hindlimb of rats was used to test the metabolic response of atrial and ventricular muscle to trauma. Effects of insulin on muscle metabolism were also studied. In myocytes and atria from normal animals, insulin increased protein synthesis and decreased protein degradation. For myocytes of rats at one and two days after trauma, this effect of insulin on proteolysis could not be detected. Over the next two days, the inhibitory effect returned to normal. Insulin also did not increase protein synthesis on day 1, but did thereafter. In atria, in contrast to heart cells, the inhibitory effect of insulin on proteolysis was enhanced at two and three days after trauma, and its stimulation of protein synthesis was unaltered. Insulin increased carbohydrate metabolism in both myocytes and atria of normal rats and traumatized rats after 2 days, and trauma did not alter this response. In myocytes, but not atria, trauma led to a faster oxidation of leucine and a significant rise in the production of alanine. Production of glutamine and glutamate was not affected in either tissue. These results show that the metabolic responses to trauma of atrial and ventricular muscle differ considerably.     

Relationship of free fatty acids and magnesium in ethanol withdrawal in dogs

A group of dogs was conditioned to drink 4-6 g ethanol/kg/day for long periods. Ethanol ingestion was interrupted at monthly intervals in order to study some metabolic changes of the withdrawal period. Plasma long chain free fatty acids (FFA) increased by a maximum mean of 1.4 meq/liter (threefold), and magnesium (Mg) decreased by a maximum mean of 0.4 meq/liter (75% of control during the first 24 hr of simple ethanol withdrawal. Because magnesium salts of FFA are very insoluble, these divergent changes of Mg and FFA suggest that lipolysis may be responsible for the hypomagnesemia that occurs in ethanol withdrawal. In order to control lipolysis, glucose-insulin, glucose alone, and fructose alone were given intravenously for a 4-hr period beginning 14 hr after withdrawal. FFA fell by a maximum of 65% or 0.44 meq/liter and Mg fell by a maximum of 0.31 meq/liter during the glucose-insulin infusions. Nicotinic acid (10-20 mg/kg) in saline produced an identical drop in FFA and a slight rise in Mg. After stopping the nicotinic acid infusion, a sharp rebound rise in FFA and a sharp fall in Mg occurred similar to the simple withdrawal experiments. The sharp divergent changes in FFA and Mg after cessation of nicotinic acid infusion support the prime role of FFA-effecting movements of Mg and the thesis that FFA bind Mg. Control of lipolysis is theoretically sound in therapy of the ethanol withdrawal syndrome.     

Effects of dietary substitution of mixed amino acids for glucose on the splanchnic metabolism of plasma triglycerides, cholesterol, carbohydrates, and amino acids in conscious fed baboons

Splanchnic metabolism was studied in the fed state during prolonged constant intravenous administration of tracer amounts of [9,10]-3H palmitic acid and the calculated isocaloric intraduodenal administration (13 mg/min X kg body wt0.75) of either (1) glucose, (2) 15% mixed amino acids and 85% glucose or (3) 45% mixed amino acids and 55% glucose to conscious, restrained female baboons that had been maintained on a similar diet (supplemented in essential nutrients) for the previous 9 days. Secretion of plasma triglycerides from the splanchnic region was quantified from splanchnic flow and radiochemical measurements of transsplanchnic gradients of 3H-labeled free fatty acids and triglycerides. Mean splanchnic secretion of plasma triglycerides increased significantly as the proportion of dietary calories derived from amino acids was varied from 0 to 15 to 45% (mean values 1.1 +/- 0.1, 2.6 +/- 0.2 and 4.2 +/- 0.3 mumol/min kg body wt0.75, respectively, p less than 0.05). Increased triglyceride secretion was attributable to both significantly higher rates of esterification of free fatty acids taken up in the splanchnic region to triglycerides released into hepatic venous blood plasma (mean values 10 +/- 1, 16 +/- 2 and 34 +/- 5%, respectively) and to significantly higher rates of secretion of triglycerides derived from precursors other than free fatty acids. Higher intake of amino acids was also associated with both higher plasma concentrations of cholesterol and higher values for hepatic oxidation of cholesterol to bile acids.(ABSTRACT TRUNCATED AT 250 WORDS)     

Some metabolic effects of fat infusions in depleted patients

Severely depleted surgical patients were given total parenteral nutrition, providing an average of 34.6 kcal and 266 mg nitrogen/kg body weight. Two diets were used, one with glucose as sole source of nonprotein energy, the other with a fat emulsion, Liposyn 10%, substituted isocalorically for one-third of the glucose. The two diets were given alternately, for 1 wk at a time, to each patient. N balance, at zero energy balance, was estimated to average 50 mg nitrogen/kg, indicating that energy intake in excess of expenditure is not required to restore lean body mass in depleted patients. Nitrogen (N) balance was equally good with either diet. Respiratory quotients and carbohydrate oxidation were lower, and fat oxidation was higher with the fat-containing diet. Amino acids and glucose were infused continuously over each 24-hr period and fat was given for only 6--8 hr. During the period of fat infusion, fat oxidation was significantly higher, and carbohydrate oxidation and RQ were lower than at other times of day.     

Factors affecting plasma amino acid concentrations in control subjects

Plasma amino acid concentrations were determined in groups of normal control subjects under fasting and postprandial conditions. Differences were observed that were found to be, to a considerable extent, sex-related. Fasting females had lower concentrations than fasting males of several amino acids, although postprandial differences in concentrations between the sexes were not significant. Under the dietary conditions normal for a British population, no significant diurnal variation of plasma amino acid concentrations was found. Reducing the dietary protein by 30% failed to affect plasma amino acid concentrations; however, increasing the dietary protein by 50% resulted in a significant increase in the plasma concentrations of several amino acids, and induced a significant degree of variation throughout the day in six, proline, half-cystine, methionine, valine, leucine, and isoleucine. The importance of these results with regard to the interpretation of population mean values and disease diagnosis is discussed.     

Diet,pregnancy, and lactation: Effects on adipose tissue,lipoprotein lipase,and fat cell size

Adipose tissue fat cell size and lipoprotein lipase (LPL) activity were determined in the retroperitoneal and subscapular depots of nonpregnant, pregnant, and postpartum rats fed either a standard laboratory diet or a high-fat diet containing 55% fat by wieght. High-fat feeding for 20 days increased, in nonpregnant rats, fat cell size and LPL activity two-to threefold in both depots. In pregnant rats at term, fat cell size was increased and LPL activity was depressed in both dietary groups. Twenty days postpartum, both retroperitoneal fat cell size and LPL activity were decreased in proportion to the size of the litter. Rats not allowed to lactate had fat cell sizes and LPL activity that were not significantly different than in nonpregnant controls. Fat cell size and LPL activity in rats nursing four pups were reduced to 77% and 36% of control, respectively. Those nursing a normal-sized litter of eight pups demonstrated a further reduction of fat cell size to 38% and of LPL activity to 2% of nonpregnant control values. High-fat feeding and obesity did not prevent the fat loss and decreased LPL activity associated with lactation; fat cell size was decreased to 61% and LPL activity to 3% of control values. Values for the subscapular depot followed essentially the same pattern as that observed for the retroperitoneal depot. Mammary LPL activity was increased more than tenfold in animals nursing four or eight pups compared with values at term, whereas no activity was detected in rats not allowed to lactate.     

Effect of various oral glucose doses on plasma neutral amino acid levels

Six healthy, nonobese, fasting subjects each received, on different days 0, 6, 12.5, 25, or 50 g of glucose (Glucola) in a total volume of 100 ml. Blood was taken at intervals and assayed for plasma levels of the branched-chain amino acids (valine, isoleucine and leucine); the other major large neutral amino acids (LNAA) (methionine, phenylalanine, tyrosine and tryptophan); and, in some cases, insulin and glucose. Insulin levels were significantly elevated 30 min after consumption of 12.5, 25, or 50 g of glucose, and were higher after the 50 g dose than after 12.5 g. Changes in plasma glucose concentrations were small and did not correlate with glucose dose. Mean percent reductions of LNAA tended to exhibit dose-dependence, most clearly observed after 120 min. In some subjects as little as 6 g of glucose transiently decreased LNAA concentrations. Branched-chain amino acids were most sensitive, decreasing by 35%-41% after 50 g of glucose. Plasma tryptophan concentrations fell only by 23%, hence the ratio of plasma tryptophan to other plasma LNAA (which affects brain serotonin synthesis) increased significantly.     

Comparison of free fatty acid and glyceride--fatty acid uptake by human adipose tissue

A comparison has been made of the uptake of palmitate and triglyceride into human adipose tissue. Both substrates are converted into tissue lipid at similar rates over an incubation period of 2 hr; the uptake of triglyceride is proportional to the amount of tissue in the incubation medium. The assimilation of triglyceride by human adipose tissue requires preincubation of the triglyceride emulsion with serum; depends on the presence of glucose in the incubation medium; and radioactivity from glyceryl-tripalmitin-T is incorporated in preference to ¹⁴C-glyceryl-tripalmitin. Fasting reduced both the uptake of triglyceride into tissue lipid and the esterification of palmitate by the tissue. Fluoride (20 mM) significantly inhibits the esterification of palmitate by human adipose tissue without altering the incorporation of triglyceride. At higher concentrations of fluoride (80 mM) there is some inhibition of triglyceride uptake.     

Metabolic effects of hypothalamic hyperphagia

In order to test the hypothesis that the enhanced gluconeogenesis of hypothalamic obesity remains responsive to changed in food intake, we have measured gluconeogenesis in two modes of hypothalamic obesity under both hyperphagic and normophagic conditions. The results show that hyperphagia partially decreases gluconeogenesis and fully restores liver glycogen in both modes. The discussion section relates our present findings to the enhanced glucose utilization previously noted after VMH destruction and to the recent hypothesis that hyperphagia is a response to body protein depletion.     

Increased plasma norepinephrine concentrations and metabolic rates following glucose ingestion in man

The effects of glucose ingestion on plasma levels of norepinephrine (NE), epinephrine (E), immunoreactive insulin (IRI), and glucose, and the resting metabolic rate (RMR) were examined in six normal males. Ingestion of the glucose (100 g) solution significantly increased all of these measures except E levels, compared with changes observed during a control experiment in which an equal volume of water was ingested. The initial (0–60 min) increase in plasma NE levels and the increase in the RMR following glucose was significantly greater than the smaller increases that occurred during the control experiment. Plasma IRI and glucose levels peaked 30–60 min after glucose consumption, then declined toward basal values. These data show that glucose intake causes an elevation of the RMR and sympathetic nervous system activity greater than that caused by other aspects of the testing solution, and are consistent with the possibility that the increase in RMR following glucose ingestion is related to elevated sympathetic nervous system activity.     

Insulin deficiency and insulin resistance interaction in diabetes: estimation of their relative contribution by feedback analysis from basal plasma insulin and glucose concentrations.

The liver and beta cells function in a negative feedback loop, which appears to have a predominant role in regulating both the basal plasma glucose and insulin concentrations. The degree of basal hyperglycemia in diabetes probably provides a bioassay of both the effect of a reduction in insulin secretory capacity and the degree of insulin resistance. A mathematic model of the interaction of insulin deficiency and insulin resistance has been constructed, based on the known response characteristics of the beta cells to glucose, and of plasma glucose and insulin control of hepatic and peripherpal glucose flux. The degree to which beta cell deficiency increases basal plasma glucose reflects the hyperbolic shape of the normal insulin secretory response to different glucose concentrations. The height of basal plasma insulin is a function of the degree of insulin resistance. From the basal plasma insulin and glucose concentrations, the model provides an estimate of the degree to which both beta cell deficiency and insulin resistance contribute to diabetes. The predictions arising from the model are in accord with experimental data in man and in animals. In normal-weight diabetics who do not have increased insulin resistance, the model predicts that more than 85% of beta cell function has to be lost for the basal plasma glucose to rise to 6 mmol/liter, but a further 5%--10% loss increases the basal plasma glucose to over 10 mmol/liter. In a third of a consecutive series of 65 newly presenting, uncomplicated diabetics, both normal weight and obese, the analysis from the model suggested that insulin resistance, rather than beta cell deficit, was the predominant feature.     

Changes in phosphodiesterase activity of human subcutaneous adipose tissue during starvation

The phosphodiesterase (PDE) activity, the basal rate of lipolysis and the basal cyclic AMP level in adipose tissue were determined in hypogastric and gluteal specimens obtained from 14 obese healthy subjects before and after one week of starvation. During starvation there was a significant increase in both the tissue level of cyclic AMP and the rate of lipolysis, whereas the apparent values of Vmax of the low and high Km forms of PDE decreased significantly-i.e. by about 50 and 30 percent. respectively. The substrate concentration of cyclic AMP at Vmax of the low Km PDE corresponded to the tissue level of the nucleotide. During, but not before, starvation there was a positive correlation between Vmax of the low Km PDE and the cyclic AMP level (r = 0.7-0.8). The metabolism in the tissues from the two fat depots exhibited similar variations during starvation. The findings suggest that the low Km form of PDE is inhibited during starvation. This may be one factor responsible for the starvation-mediated increase in the cyclic AMP levels and the rate of lipolysis in adipose tissue.     

Comparison of peripheral glucose uptake after oral glucose loading and a mixed meal

Forearm glucose uptake (FGU) and other metabolic responses were studied in six normal men for three hours after a 75-g oral glucose load and a mixed meal containing 75 g carbohydrate. After the meal the rise in arterial glucose levels was considerably less than that following the oral glucose load but the overall insulin responses from 0 to 180 minutes were not statistically different. Although the initial rise in FGU was more gradual after the meal, the subsequent elevation was more sustained and, at the termination of the study, exceeded significantly that seen after the oral glucose load. The rise in GIP levels during the first hour was similar after the meal and the oral glucose load, but thereafter concentrations following the oral glucose load fell while those after the meal continued to rise. When the incremental area (delta) is used as the index of response, the results show that while the glucose response (delta G) after the meal (19.1 +/- 5.3 units) was only 26% of that after oral glucose loading (72.7 +/- 7.0 units), the corresponding increase in FGU (delta FGU) reached 62% (55.0 +/- 12.8 units after the meal, 89.2 +/- 20.0 units after the oral glucose load). Thus, the increase in peripheral glucose uptake relative to the glycemic response (delta FGU/delta G) was significantly greater after the meal than following the oral glucose load alone (P less than 0.05). In conclusion, relative to the rise in arterial glucose levels, peripheral glucose uptake is greater after a meal than after glucose loading with an equivalent carbohydrate challenge. Furthermore, the present data support previous studies emphasizing the failure of GIP alone to explain the entero insular axis.     

Effects of pharmacologic hyperglucagonemia on plasma amino acid concentrations in normal and diabetic man

Four normal and five insulin dependent diabetic men received a 2 h pharmacologic glucagon infusion (50 ng/kg/min) resulting in plasma glucagon levels (4400 pg/ml) similar to those seen in glucagonoma patients. In normal subjects in whom plasma insulin concentrations rose significantly (239 uU/ml) and the blood level of 15 of the 18 amino acids measured fell significantly. In contrast, in the diabetic men who secreted no insulin in response to glucagon (no rise in C-peptide levels), only 10 of 18 amino acid levels fell significantly. The branched chain amino acids valine, leucine and isoleucine, as well as tyrosine and phenylalanine were among the 8 amino acids which showed no change in response to glucagon in the diabetics. Thus, glucagon appears to have no acute affect on branched chain amino acid levels in man.     

The effects of aldose reductase inhibition on nerve sorbitol and myoinositol concentrations in diabetic and galactosemic rats

The interrelationship between sorbitol excess and myoinositol deficiency in the peripheral nerve was examined in acutely diabetic rats. Nerve myoinositol concentration was also studied in galactosemic rats. Polyol pathway blockade with Sorbinil (Pfizer, Connecticut) prevented nerve myoinositol reduction in both groups of animals. This conclusion was independent of alteration in the fluid content of the peripheral nerve. It is likely that myoinositol loss from nerves is causally related to the sorbitol and galactitol accumulation.