Biomedical subjects

F Q Nuttall

Publications and source records attributed to F Q Nuttall.

At least 91 records · Page 5Linked to original sources

PubMed1986

Regulation of liver glycogen synthase phosphatase activity by ATP-Mg.

The kinetics of a synthase phosphatase reaction inhibited by ATP-Mg in a liver glycogen particle preparation were complex. In the presence of a physiological concentration of ATP-Mg, synthase phosphatase activity in the glycogen particle follows a biphasic course. Initially, the reaction was inhibited but later the reaction rate accelerated. The reaction was inhibited but the rate was constant in the presence of ATP-Mg with the addition of a physiological concentration of glucose 6-phosphate (Glc 6-P). Therefore, in most subsequent experiments Glc 6-P was added. The concentration of ATP-Mg at which 50% maximal inhibition (I0.5) occurred was approximately 0.1 mM in preparations obtained from rats given glucagon prior to being killed. In preparations from animals given glucose, the I0.5 was increased to 2.0 mM. The maximum inhibition was little changed in preparations from glucose- or glucagon-treated animals. Thus, administration of glucose in vivo reduced the sensitivity of the synthase phosphatase to ATP-Mg inhibition. Complexes of ATP with paramagnetic ions such as Co2+ and Mn2+ were less inhibitory than complexes with diamagnetic ions, including Ca2+ and Mg2+. Magnesium complexes of adenosine tetraphosphate and 5'-adenylimidodiphosphate also were inhibitory. Inhibition was independent of phosphorylase a and not a nonspecific, polyvalent anion effect. The best explanation for the distinctive effects of ATP-Mg in preparations from glucagon- and glucose-treated animals is that the respective treatments promote and stabilize different forms of synthase D or possibly synthase phosphatase with different affinities for ATP-Mg. These forms are interconvertible, as previously suggested, in studies employing EDTA (20).

Adenine Nucleotides↗

PubMed1986

The serum insulin and plasma glucose responses to milk and fruit products in type 2 (non-insulin-dependent) diabetic patients.

The plasma glucose and serum insulin responses were determined in untreated Type 2 (non-insulin-dependent) diabetic patients following the ingestion of foods containing sucrose, glucose, fructose or lactose in portions that contained 50 g of carbohydrate. The results were compared to those obtained following the ingestion of pure fructose, sucrose, glucose + fructose and lactose. The objectives were to determine 1) if the glucose response to naturally occurring foods could be explained by the known carbohydrate content, and 2) whether the insulin response could be explained by the glucose response. The glucose response was essentially the same whether the carbohydrate was given as a pure substance, or in the form of a naturally occurring food. The glucose response to each type of carbohydrate was that expected from the known metabolism of the constituent monosaccharides. The glucose areas following the ingestion of the foods were: Study 1: glucose 11.7, orange juice 7.3, sucrose 5.2, glucose + fructose 6.3, and fructose 0.7 mmol X h/l; Study 2: glucose 14.6, orange juice 7.3, apples 5.5, and apple juice 4.7 mmol X h/l; Study 3: glucose 12.6, ice cream 8.1, milk 3.7, and lactose 4.1 mmol X h/l. The insulin response was greater than could be explained by the glucose response for all meals except apples. Milk was a particularly potent insulin secretagogue; the observed insulin response was approximately 5-fold greater than would be anticipated from the glucose response. In summary, the plasma glucose response to ingestion of fruits and milk products can be predicted from the constituent carbohydrate present. The serum insulin response cannot.

Adult↗

PubMed1986

The effect of protein ingestion on the metabolic response to oral glucose in normal individuals.

Eight normal subjects were given 50 g protein, 50 g glucose, or 50 g protein + 50 g glucose. Plasma glucose, insulin, C-peptide, glucagon, alpha-amino nitrogen (AAN), and nonesterified fatty acid (NEFA) responses were then determined over 4 h. Protein stimulated only a modest insulin rise and the area above fasting baseline was only 28% of that after glucose. The sum of the serum insulin area following protein ingestion and that following glucose ingestion was 100.4% of the combination meal. C-peptide changes confirmed the insulin response. The addition of glucose to the protein meal resulted in a 60 min delay in glucagon and AAN rise compared to the protein meal alone. Subsequently AAN and glucagon increased to levels greater than or equal to those observed after protein ingestion alone. In summary, protein is a much less potent secretagogue for insulin than is glucose in normal individuals, and the effect on insulin secretion is not synergistic. Addition of glucose to a protein meal results in a delayed rise in AAN and glucagon concentrations in normal subjects.

Adult↗

PubMed1986

Mechanism of stimulation of liver glycogen synthesis by fructose in alloxan diabetic rats.

In diabetic animals and humans, stimulation of liver glycogen synthesis has been reported after administration of a large parenteral fructose load. The effects of an oral fructose load have not been examined previously. In the diabetic state, glycogen synthase phosphatase activity is reduced, and synthase D (the inactive form) is a poor substrate for the phosphatase. Thus, activation of synthase to the synthase R and synthase I (R + I) (active) forms by fructose would not be expected. We have determined that oral fructose administration does stimulate glycogen synthesis and have examined the mechanism by which this is accomplished. In 24-h-fasted alloxan diabetic rats, basal liver glycogen was higher than in normal rats (8.3 +/- 1.8 vs. 3.0 +/- 0.5 mg/g wet wt). After fructose (4 g/kg) was given, the initial rate of glycogen synthesis was normal in diabetic rats, but total glycogen synthesis was reduced. By 240 min, liver glycogen increased to 18 +/- 4.0 mg/g wet wt in diabetic rats versus 30.5 +/- 1.5 mg/g wet wt in normal rats. Synthase R + I was low and did not increase significantly (0.063 +/- 0.006 to 0.064 +/- 0.010 U/g wet wt) after fructose administration to the diabetic animals. Phosphorylase a did not decrease significantly during the period of active glycogen synthesis. In the diabetic rats, glucose-6-phosphate increased by 84% (0.103 +/- 0.010 to 0.184 +/- 0.020 mumol/g wet wt) within 10 min and remained elevated above the control level. UDPglucose decreased from 0.336 +/- 0.013 to 0.271 +/- 0.011 mumol/g wet wt at 10 min and remained below the control level.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

In vivo phosphorylation of liver glycogen synthase. Isolation of the 32P-labeled enzyme and studies on the nature of the bound [32P]phosphates.

Our previous study (Tan, A. W. H., and Nuttall, F. Q. (1983) J. Biol. Chem. 258, 9624-9630) indicated that liver synthase D contained a large number of endogenous phosphates, 12 of which were stable and 6 labile to alkali treatment. We wished to investigate the nature of the phosphates on synthase which became isotopically labeled when inorganic [32P]phosphate was given either to intact rats or to isolated liver cells. An antibody against liver synthase D was used for the isolation of synthase. The antibody recognized both the phosphorylated and dephosphorylated form of the enzyme, native as well as partially cleaved species. A large enzyme form, with Mr of 90,000 as well as one with Mr of 73,000 was observed. A 61% decrease in [32P]phosphate was found in synthase when prelabeled liver cells were treated with glucose, whereas a 25% increase was seen in cells treated with glucagon. After [32P]synthase D was converted to synthase I by synthase phosphatase, 95% of the [32P]phosphate was lost. All of the bound [32P]phosphates were found to be labile to alkali. Thus, under the in vivo conditions used, the [32P]phosphates incorporated into synthase were characterized by their fast turnover rate, alkali lability and susceptibility to the action of synthase phosphatase, both in vivo and in vitro. These criteria serve to distinguish them from the slower turning-over, alkali-stable phosphates found previously in both synthases D and I.

Animals↗

PubMed1985

Insulin sensitivity in joggers: evaluation by mini-dose insulin infusion test.

Insulin sensitivity in seven joggers was evaluated by a minidose insulin infusion test. The results were compared to those of 22 healthy nonjoggers with a mean body weight within +/- 115% of ideal body weight. The mean increase over base line of the individual steady-state insulin levels were delta 25 microU/ml (range 15-42 microU/ml) for controls and delta 16 microU/ml (range 11.2-23.4 microU/ml) for the joggers. The smaller incremental rise in insulin concentration most likely is due to an increased insulin turnover. The declines in glucose concentrations from 10 min after the infusion began to a nadir were similar in controls (28 +/- 2.4 mg/dl) and in the joggers (33.7 +/- 3.6 mg/dl). However, the insulin sensitivity index, defined as the rate of plasma glucose decline divided by the increment rise in insulin, was clearly higher in the joggers (0.098 +/- 0.009 vs 0.057 +/- 0.005, P less than 0.05). We conclude that the joggers as a group are more sensitive to insulin. The simplicity of a mini-dose insulin infusion should be useful in longitudinal studies where the effect of physical training on insulin sensitivity may be of interest.

Adult↗

PubMed1985

Plasma glucose and insulin profiles in normal subjects ingesting diets of varying carbohydrate, fat, and protein content.

The 12-hr profiles of plasma glucose and insulin concentrations in 26 normal subjects ingesting a diet high in carbohydrate, protein, or fat have been determined. The diets were isocaloric and were given as three identical meals 4 hrs apart. In males the high carbohydrate diet resulted in glucose profiles similar to those obtained with the standard diet. In females the peak glucose concentration also was not increased but the glucose concentration remained elevated longer after each meal. In both groups the insulin curves followed the glucose curves. The post-meal glucose and insulin areas were significantly increased in the female group. The high protein diet resulted in only a small post-meal glucose rise particularly later in the day in both males and females. However, there was a sharp rise in insulin concentration after each meal. The total insulin area after each meal was nearly as great as with the standard diet. The high fat diet, which contained approximately the same carbohydrate content as the high protein diet, induced a clear increase in glucose concentration after each meal in the female group. However, the peak was progressively delayed with each meal. The insulin curves followed the glucose curves. In males a small, prolonged post-meal increase in glucose was observed after each meal. The insulin concentration increased modestly after the first meal and then remained elevated and changed little after the subsequent meals. These data help to define the glucose and insulin responses to meals varying greatly in protein, carbohydrate, and fat content and further indicate the need to consider the response of males and females separately.

Adult↗

PubMed1985

Effect of insulin administration on cardiac glycogen synthase and synthase phosphatase activity in rats fed diets high in protein, fat or carbohydrate.

Rats were fed a 70% carbohydrate, 70% protein, 70% fat, or a standard purified diet for 7 d to determine the effect of the diet on heart glycogen synthase response to an acute insulin challenge. Rats fed the high protein or the high fat diets, i.e., the carbohydrate-free diets, exhibited insulin resistance as evidenced by higher plasma glucose levels following insulin administration when compared to rats fed high carbohydrate or standard diet. The diets had no effect on the initial proportion of synthase in the active or I form. Insulin injection resulted in an increase in the proportion of synthase in the active form in rats fed the standard, high carbohydrate or high protein diets, but not in rats fed the high fat diet. Synthase phosphatase activity was similar in rats fed one of the four diets compared to rats fed a nonpurified diet. Thus the lack of synthase response to insulin in fat-fed rats was not due to diminished synthase phosphatase activity. Neither the diets nor insulin administration had any effect on the proportion of phosphorylase in the active or a form. Cardiac glycogen was significantly lower in rats fed the high fat diet than in those fed the standard diet. The latter was a surprising observation since the high fat diet was used to simulate a starved state and cardiac glycogen concentrations increase with starvation.

Animals↗

PubMed1984

The synergistic action of caffeine or adenosine on glucose stimulation of liver glycogen synthase phosphatase activity.

Recent studies indicate that glucose directly stimulates synthase phosphatase activity in vitro but only at high, non-physiological concentrations. Present results demonstrate that at a physiological concentration glucose can be stimulatory, provided that an appropriate second effector is present. Caffeine and adenosine are examples of such effectors which act synergistically with glucose to enhance synthase phosphatase activity. Caffeine but not adenosine enhances glucose stimulation of phosphorylase phosphatase activity. In the absence of glucose, caffeine but not adenosine stimulates both synthase and phosphorylase phosphatase reactions. Thus, glucose regulation of glycogen synthase activation in vivo could require a second effector. Neither the identity nor source of such an effector is known. The putative regulator could be a mediator for a hormone such as insulin. The present work suggests that the chemical nature of the effector might be that of a derivatized purine of which nucleosides are an example.

Adenine↗

PubMed1984

Direct glucose stimulation of glycogen synthase phosphatase activity in a liver glycogen particle preparation.

In glycogen particle suspensions prepared from fed rats given either glucagon or glucose in order to increase or decrease the phosphorylase a concentration, respectively, glucose stimulation of synthase phosphatase activity was observed. In preparations from glucagon-treated rats, addition of glucose stimulated synthase and phosphorylase phosphatase simultaneously and not sequentially. Synthase phosphatase stimulation was glucose concentration dependent even when phosphorylase a had been rapidly reduced to a low level. The estimated A0.5 for glucose stimulation of synthase phosphatase activity was 27 mM. An A0.5 for glucose stimulation of phosphorylase phosphatase activity could not be estimated since activity was still increasing with concentrations of glucose as high as 200 mM. In preparations from glucose-treated rats which contain virtually no phosphorylase a, glucose stimulation was still apparent but the A0.5 was increased modestly (36 mM). Stimulation of synthase phosphatase activity was specific for glucose. Several other monosaccharides and the polyhydric alcohol sorbitol were ineffective.

Animals↗

PubMed1984

Glucose stimulation of heart phosphorylase phosphatase activity in vitro and in vivo.

To determine the mechanism of the glucose stimulation, glucose or glucose-6-phosphate was added to dilute heart extracts in the presence or absence of AMP. The intracellular glucose, tissue glucose-6-phosphate, and tissue AMP concentrations were also determined in 24-h starved animals given glucose; 24-h starved animals given insulin as well as diabetic starved and diabetic starved insulin-treated animals were also studied. The A0.5 for glucose stimulation of cardiac phosphorylase phosphatase activity was approximately 1.2 mM. The A0.5 for glucose-6-phosphate was approximately 0.02 mM. The glucose-6-phosphate concentration in all animals exceeded the A0.5 by 10-fold. However, the intracellular glucose concentration in the glucose-treated, insulin-treated, diabetic, and diabetic insulin-treated rats was in the range of the A0.5 for stimulation of phosphorylase phosphatase activity. AMP completely inhibited phosphorylase phosphatase activity at a concentration of 0.2 mM. Physiological concentrations of glucose and glucose-6-phosphate partially reversed this inhibition. Administration of glucose or insulin resulted in an increase in intracellular glucose concentration, an increase in tissue glucose-6-phosphate and a decrease in tissue AMP concentrations. These data suggest that glucose may be a physiological regulator of phosphorylase phosphatase in heart muscle as it is in liver.

Adenosine Monophosphate↗

PubMed1984

Long-term weight regulation in treated hyperthyroid and hypothyroid subjects.

Body weight regulation after treatment was studied in 87 hyperthyroid and 18 hypothyroid subjects. Mean body weight was 83.9 percent of the premorbid weight at the time of initial treatment for hyperthyroidism and 102.5 percent at 96 months following treatment. Mean (+/- SD) post-treatment weight difference from baseline was 3.4 +/- 18.6 pounds at 96 months (n = 44). Early weight gain was greatest in subjects in whom thyroxine values normalized quickly. Hyperthyroid subjects from whom a body mass index could be calculated (n = 45) were divided into two groups. The obese group had a greater mean weight loss (35.2 +/- 15.0 pounds versus 21.2 +/- 9.9 pounds, p less than 0.001) and a lower weight (percent of baseline weight) at the time of treatment for hyperthyroidism (81.6 +/- 7.7 percent versus 86.0 +/- 5.1 percent, p less than 0.05). Subjects with thyroxine levels of 20 micrograms/dl or more had higher premorbid body weights and greater weight loss from baseline than subjects with thyroxine values below 20 micrograms/dl. Hypothyroid subjects showed a small decline in mean body weight over the first six months of treatment but returned to pretreatment weight by 24 months. In the absence of significant metabolic derangement, body weight is regulated within narrow limits over many years. Effective treatment of hyperthyroidism is accompanied by weight gain.

Adult↗

PubMed1984

Effect of prolonged starvation on glycogen synthase and glycogen synthase phosphatase activity in rat heart.

Rats were fasted 24, 48 or 72 hours to determine the effect of several days without food on glycogen synthase and synthase phosphatase activity in heart. The basal percentage of synthase I decreased gradually from approximately 20% in fed animals to approximately 6% in rats starved for 72 hours. Glycogen increased progressively from 4.6 mg/g wet weight in fed rats to 7.6 mg/g wet weight in 72-hour starved rats. Thus, there was an inverse relationship between the glycogen concentration and the basal percentage of synthase I. The total synthase phosphatase activity measured at a standardized glycogen concentration decreased 50% by 24 hours of starvation and then was unchanged up to 72 hours. The 50% decrease in phosphatase activity correlated directly with insulin concentration in rats fasted 24-72 hours. The rapid stimulatory effect of insulin on synthase activity observed in fed rats was delayed in rats starved 24 and 48 hours. This correlated with a progressively slower synthase phosphatase response to insulin. The stimulatory effect of insulin was lost completely in 72-hour fasted rats. The proposed mechanism for the delayed response in rats starved 24 and 48 hours and lack of response in rats starved 72 hours is insulin resistance. The mechanism remains to be elucidated.

Animals↗

PubMed1984

Metabolic effects of oral glucose in the liver of fasted rats.

Twenty-four-hour-fasted rats were given glucose (4 g/kg) by gavage. Glucose absorption and portal and peripheral plasma glucose, lactate, and insulin concentrations, as well as liver glucose, UDPglucose, glucose-6-P, lactate, ATP, and inorganic phosphate (Pi), and % glycogen synthase I and % phosphorylase a were measured at 10, 20, 30, 40, 60, and 120 min after the glucose was given. Liver and muscle glycogen also were measured. Ninety-one percent of the glucose load had disappeared from the gut in 2 h. Despite increased plasma glucose and insulin levels the liver continued to produce glucose. Lactate produced in the periphery was the major substrate for gluconeogenesis, and lactate utilization could account for the hepatic glycogen synthesized. Glucose ingestion did not affect lactate production by the splanchnic bed. In the liver glucose-6-P was transiently increased; UDP glucose decreased after glucose administration. ATP and Pi were unchanged. Glycogen synthase was activated by 20 min without a significant change in phosphorylase a. Hepatic glycogen increased linearly after 20 min. Total glucose storage as glycogen was similar in liver (20%) and muscle (19%). We could account for 41% of the glucose absorbed as glycogen, unmetabolized glucose, or glucose metabolites. Most of the remainder probably was oxidized.

Administration, Oral↗

PubMed1984

Metabolic effects of oral fructose in the liver of fasted rats.

Twenty-four-hour-fasted rats were given fructose (4 g/kg) by gavage. Fructose absorption and the portal vein, aorta, and hepatic vein plasma fructose, glucose, lactate, and insulin concentrations as well as liver fructose and fructose 1-P, glucose, glucose 6-P, UDPglucose, lactate, pyruvate, ATP, ADP, AMP, inorganic phosphate (Pi), cAMP, and Mg2+, and glycogen synthase I and phosphorylase alpha were measured at 10, 20, 30, 40, 60 and 120 min after gavage. Liver and muscle glycogen and serum uric acid and triglycerides also were measured. Fifty-nine percent of the fructose was absorbed in 2 h. There were modest increases in plasma and hepatic fructose, glucose, and lactate and in plasma insulin. Concentrations in the portal vein, aorta, and hepatic vein plasma indicate rapid removal of fructose and lactate by the liver and a modest increase in production of glucose. The source of the increase in plasma lactate is uncertain. Hepatic glucose 6-P increased twofold; UDPglucose rose transiently and then decreased below the control level. Fructose 1-P increased linearly to a concentration of 3.3 mumol/g wet wt by 120 min. There was no change in ATP, ADP, AMP, cAMP, Pi, or Mg2+. Serum triglycerides and uric acid were unchanged. Glycogen synthase was activated by 20 min without a change in phosphorylase alpha. This occurred with a fructose dose that did not significantly increase either the liver glucose or fructose concentrations. Liver glycogen increased linearly after 20 min, and glycogen storage was equal in liver (38.4%) and muscle (36.5%).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1983

Endogenous phosphates on liver glycogen synthase D and synthase I. Studies on the number and location.

Synthase D and synthase I of high specific activity have been isolated from rabbit liver, with subunit Mr = 78,000 and 85,000, respectively. Minor bands of Mr = 78,000 and 71,000 were also observed, and these were shown to be proteolytic products containing synthase activity. Incubation with trypsin resulted in no activity changes, but there was a conversion of synthase I to the Mr = 78,000 species. Incubation with chymotrypsin produced no change in total synthase activity, but both enzymes were converted to the Mr = 71,000 species. Synthase I, after chymotrypsin treatment, became dependent on glucose-6-P for activity. Kinetic studies indicated that the chymotrypsin-treated synthase D and synthase I were not the same species. Synthase D contained 5.7 mol of alkali-labile phosphate/subunit and synthase I, 2.9 mol/subunit. With trypsin treatment there was little loss of phosphate from synthase. With chymotrypsin treatment, there was a loss of 3.1 and 1.5 mol of phosphate/subunit from synthase D and I, respectively. Some conversion to synthase I still occurred when chymotrypsin-treated synthase D was incubated with crude extract, suggesting that the phosphates which remained were still removable by synthase phosphatase. The presence of additional alkali-stable phosphates was indicated when the synthase samples were ashed. The total phosphates were 17.3 mol/subunit for synthase D and 13.4 mol/subunit for synthase I. Our results indicate that the liver synthase enzymes are highly phosphorylated and extremely susceptible to endogenous and exogenous proteolysis. The alkali-labile phosphates are distributed in chymotrypsin-sensitive as well as chymotrypsin-insensitive sites. Both sites are involved in the conversion of synthase D to synthase I.

Animals↗

PubMed1983

Impotence in medical clinic outpatients.

One thousand one hundred eighty men in a medical outpatient clinic were screened as to the presence of impotence. Four hundred one men (34%) were impotent, and of those, 188 (47%) chose to be examined for their problem. After a comprehensive evaluation the following diagnoses were obtained: medication effect, 25%; psychogenic, 14%; neurological, 7%; urologic, 6%; primary hypogonadism, 10%; secondary hypogonadism, 9%; diabetes mellitus, 9%; hypothyroidism, 5%; hyperthyroidism, 1%; hyperprolactinemia, 4%; miscellaneous, 4%; and unknown causes, 7%. The mean age of the impotent patients was 59.4 years, and the prevalence of alcoholism was 7%. Luteinizing hormone, follicle-stimulating hormone, testosterone, thyroxine, triiodothyronine (T3), T3 resin uptake, and prolactin studies were necessary to diagnose individual cases. We conclude that erectile dysfunction is a common and often overlooked problem in middle-aged men followed in a medical clinic.

Alcoholism↗

PubMed1983

Response of liver glycogen synthase and phosphorylase to in vivo glucose and glucose analogues.

Glucose causes a rapid increase in the proportion (%) of glycogen synthase in the active (I) form and a rapid decrease in the proportion of phosphorylase in the active (a) form in both fed and fasted rats. The changes in synthase I and phosphorylase a are more rapid in fasted animals. With graded doses of glucose, the maximal decrease in phosphorylase a occurred at a dose that was considerably smaller than that required to maximally stimulate an increase in % synthase I. Thus, in the intact animal a dissociation between the effects of glucose on the synthase and phosphorylase systems was observed. Sorbitol, mannose, galactose, and arabinose all stimulated an increase in synthase I but did not significantly affect the proportion of phosphorylase in the a form. The % synthase I was not significantly affected by a number of other glucose homologues, pentoses, or three-carbon gluconeogenic substrates. The ketoses fructose and mannoheptulose both caused a striking increase in % phosphorylase a and a decrease in % synthase I, i.e., results opposite to those of glucose. The mechanism by which fructose induces these changes is not known, but the mannoheptulose effects may be accounted for by a rise in liver cAMP concentration.

Animals↗