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F Q Nuttall

Publications and source records attributed to F Q Nuttall.

At least 73 records · Page 4Linked to original sources
PubMed1989

The importance of nucleoside triphosphate inhibition of liver glycogen synthase phosphatase activity.

The liver glycogen particle contains constitutive glycogen-synthase phosphatase activity which is inhibited by ATP-Mg in a concentration-dependent manner within the physiological range (I0.5 = 0.1 mM). Therefore, we determined whether other nucleoside triphosphate-magnesium complexes also inhibit synthase phosphatase activity. UTP-Mg, CTP-Mg and GTP-Mg were all found to be inhibitory. The maximum inhibition was 85-90% which was greater than that for ATP-Mg. The I0.5 for UTP-Mg was comparable to that of ATP-Mg but it was greater for CTP-Mg and for GTP-Mg. At in vivo physiological concentrations, both UTP and ATP are possible inhibitors of synthase phosphatase activity. In the presence of a saturating concentration of ATP-Mg, added UTP-Mg increased the inhibition suggesting the presence of at least two distinct nucleotide binding sites. Substitution of calcium for magnesium in an ATP complex had no effect on the I0.5, but increased the maximum inhibition. The present studies also suggest that in the multistep conversion of synthase D to synthase I, ATP-Mg inhibition occurs early in the sequence. Addition of glycogen, a known inhibitor of synthase phosphatase activity, to a reaction mixture containing 3 mM ATP-Mg did not further inhibit synthase phosphatase activity when added at concentrations up to 22 mg/ml. The latter data suggest that the presence of a nucleoside triphosphate may desensitize the phosphatase to glycogen inhibition. ATP-Mg and, to a lesser extent, UTP-Mg and CTP-Mg all stimulated phosphorylase phosphatase activity but GTP-Mg did not.

Adenosine Triphosphate↗
PubMed1989

An improved assay for hepatic glycogen synthase in liver extracts with emphasis on synthase R.

An assay for measurement of optimal amounts of glycogen synthase R, the physiologically active form of the enzyme, in liver tissue extracts is described. Tissue extracts enriched in synthase R had a pH profile different from those reported for synthase D and synthase I. In tissue extracts, synthase I had a broad pH optimum but maximal activity was present at pH 7.0-9.0. Synthase D had a sharp pH optimum at pH 8.5 and had little activity at pH 7.0, either in the presence or in the absence of glucose 6-phosphate (G6P). In extracts enriched in synthase R, the pH optimum was 7.0-8.0 without G6P, but 8.0 with G6P. The synthase R activity without G6P rapidly decreased at a higher pH. The proportion of synthase in the physiologically active form traditionally has been reported as an activity ratio based upon the activity in the presence and absence of G6P. The assay has been performed at a single pH. Because of the differences in pH profile, we recommend that the enzyme be measured at pH 7.0 in the absence of G6P and pH 8.5-8.8 in the presence of G6P. In previous assays the substrate UDP-Glc concentration used often has been less than saturating, and the G6P concentration generally has been excessive. A substrate concentration of 11 mM UDP-Glc was found to be necessary for maximal activity. A G6P concentration of 2 mM is adequate for measurement of the D form of the enzyme.

Animals↗
PubMed1989

Disposition of a glucose load in fed rats and rats adapted to a high-carbohydrate diet.

Current evidence suggests that, during the transition from the fasted to the fed state, liver glycogen is synthesized primarily from gluconeogenic precursors rather than from glucose unless the circulating glucose concentration is high. In the fed state the glucose concentration already is elevated. We aimed to determine whether administration of an additional oral glucose load (4 g/kg) to chow- or high-carbohydrate diet-adapted (CHO) rats would further increase the glucose concentration and result in increased direct glucose uptake. In the chow- and CHO-fed rats, 70 and 98% of the administered glucose was absorbed by 120 min. In the chow-fed rats the glucose concentration entering the liver increased by only 1.0 mM from 8.0 to 9.0 mM; no net hepatic glucose uptake was observed. In the CHO-adapted rats the entering glucose concentration increased transiently by 3.5 mM from 8.0 to 11.5 mM. This was associated with net glucose uptake, which continued until the entering glucose concentration fell below 9.5 mM, the entering glucose concentration threshold above which net glucose uptake was observed previously in fasted rats. Net hepatic glucose uptake could not be correlated with insulin or hepatic intracellular glucose concentrations. Net glycogen synthesis did not occur in either group. We could not account for the absorbed glucose by the rise in portal glucose concentrations or by increased muscle glycogen deposition. The fate of much of the absorbed glucose remains unknown.

Acclimatization↗
PubMed1989

Effects of dose of ingested glucose on plasma metabolite and hormone responses in type II diabetic subjects.

Ten untreated type II (non-insulin-dependent) diabetic subjects were given 15, 25, 35, and 50 g glucose orally. Plasma glucose, insulin, C-peptide, glucagon, urea nitrogen, alpha-amino acid nitrogen, and lactate concentrations were measured, and net 5-h postprandial areas were calculated. The net glucose-area response to the ingested glucose dose (with the 0-time value as a constant baseline) was best described by a second-order polynomial equation, whereas insulin-area response was best described by a third-order equation. In a separate study, 5 untreated type II diabetic subjects were given only water, and the same metabolites and hormones were measured. Data from this study indicated that the baseline was not constant during the 5 h of study but decreased progressively. The net glucose-area and insulin-area responses to ingested glucose dose (with the decreasing baseline) were then best described by third-order equations. Glucagon, alpha-amino acid nitrogen, and lactate concentrations were exquisitely sensitive to a rise in glucose and insulin concentrations. These were all decreased with the lowest concentration of glucose used. At this dose of glucose, the increase in insulin was only 15 microU/ml.

Aged↗
PubMed1988

Regulation of glycogen synthesis in the liver.

The glycogen synthase-mediated reaction is rate-limiting for glycogen synthesis in the liver. Glycogen synthase has been purified essentially to homogeneity and has been shown to be a dimer composed of identical subunits. It is regulated by a phosphorylation-dephosphorylation mechanism, catalyzed by kinases and a phosphatase. The subunits of synthase D, the most phosphorylated form, each contain approximately 17 phosphates. The subunits of synthase I, the least phosphorylated form, each contain 14 phosphates. Thus, during the transition between these two forms, a net of three phosphoryl groups is added or removed. In synthase D, six of the phosphates are alkali-labile. In synthase I, three of the phosphates are alkali-labile. Therefore, all of the phosphorylation sites important in the interconversion of these two forms are alkali-labile (attached to serine or threonine residues). In short-term experiments using isolated hepatocytes, [32P]phosphate was only incorporated into the alkali-labile sites and the phosphate in these sites was shown to turn over rapidly. Glucose addition, which is known to reduce the proportion of synthase in the D form when assayed kinetically, also reduced the [32P]phosphate content. Glucagon addition, which increases the proportion of synthase in the D form, increased it. These changes do not appear to be site-specific. Ingestion or administration of fructose, or galactose, as well as glucose, result in a shift in synthase equilibrium in favor of the less phosphorylated forms. Possible mechanisms by which synthase phosphatase activity may be increased after ingestion of glucose or fructose, and thus shift the equilibrium in favor of the less phosphorylated forms, are discussed. The mechanism by which galactose may stimulate the phosphatase reaction is completely unknown.

Animals↗
PubMed1988

The effect of glucose on liver glycogen synthase phosphatase activity in the presence of ATP-Mg.

Glycogen particle synthase phosphatase activity is stimulated by glucose with an A0.5 of approximately 27 mM. The A0.5 is higher than the usual concentrations present in the liver. However, in vitro, certain methylxanthines such as caffeine or theophylline reduce the glucose A0.5 to approximately 10 mM, a concentration well within the normal range of liver glucose concentrations. Methylxanthines do not affect the maximum stimulation by glucose (2.3-fold greater than control rate). The phosphatase reaction also is inhibited by ATP-Mg (I0.5 = 0.1 mM). In the present studies, we have determined the interaction of these effectors. The presence of ATP-Mg at a concentration of 3 mM only slightly reduced the maximal stimulation by glucose. The A0.5 for glucose was unaffected (24 mM). The synergistic effect of caffeine with glucose also was not changed by the presence of ATP-Mg. The A0.5 for glucose was reduced to 11 mM, similar to that in the absence of ATP-Mg. In addition, maximum stimulation by glucose was unchanged. Similar results were obtained when theophylline replaced caffeine. We conclude that the ATP-Mg binding site on either the phosphatase or its substrate, synthase D, does not influence the glucose and methylxanthine binding sites. Effectively, ATP-Mg increased the range over which glucose stimulates the phosphatase activity. In the presence of ATP-Mg, the maximum stimulation by glucose is approximately 7-fold; whereas, in the absence of ATP-Mg it is approximately 2.3-fold. Thus, ATP-Mg may serve to increase the sensitivity of the synthase phosphatase reaction to glucose regulation under in vivo conditions.

Adenosine Triphosphate↗
PubMed1988

The insulin and glucose responses to meals of glucose plus various proteins in type II diabetic subjects.

We previously have shown that ingested beef protein is just as potent as glucose in stimulating a rise in insulin concentration in type II diabetic patients. A synergistic effect was seen when given with glucose. Therefore, we considered it important to determine if other common dietary proteins also strongly stimulate an increase in insulin concentration when given with glucose. Seventeen type II (non-insulin-dependent) untreated diabetic subjects were given single breakfast meals consisting of 50 g glucose, or 50 g glucose plus 25 g protein in the form of lean beef, turkey, gelatin, egg white, cottage cheese, fish, or soy. The peripheral plasma concentrations of glucose, insulin, glucagon, alpha amino nitrogen, urea nitrogen, free fatty acids, and triglycerides were measured. Following ingestion of the meals containing protein, the plasma insulin concentration was increased further and remained elevated longer compared with the meal containing glucose alone. The relative area under the insulin response curve was greatest following ingestion of the meal containing cottage cheese (360%) and was least with egg white (190%) compared with that following glucose alone (100%). The glucose response was diminished following ingestion of the meals containing protein with the exception of the egg white meals. The peripheral glucagon concentration was decreased following ingestion of glucose alone and increased following all the meals containing protein. The alpha amino nitrogen concentration varied considerably. It was decreased after glucose alone, was unchanged after egg white ingestion, and was greatest after ingestion of gelatin. The free fatty acid concentration decrease was 4- to 8-fold greater after the ingestion of protein with glucose compared with ingestion of glucose alone.

Adult↗
PubMed1988

The paradoxical response of cardiac glycogen to oral casein hydrolysate in rats.

In fasted rats, casein hydrolysate administration resulted in a marked increase in glycogen synthase I activity, no change in phosphorylase a and a marked decrease in glycogen concentration. This occurred with doses as small as 0.5 g/kg body weight. The major reason for an increase in synthase I appeared to be the reduced glycogen concentration, although insulin may play a role early in the time course. The decrease in glycogen in the absence of a change in phosphorylase a most likely is due to a decrease in an allosteric inhibitor. The nature of this inhibitor is unknown.

Administration, Oral↗
PubMed1988

Relationship of hepatic glucose uptake to intrahepatic glucose concentration in fasted rats after glucose load.

Glucose concentration gradients across the liver and hepatic blood flow were measured to characterize the relationship of hepatic glucose uptake to hepatic glucose concentration for 240 min after administration of a large oral glucose load to fasted rats. Extraction of glucose occurred only transiently, from 20 to 80 min after glucose administration. The liver changed from net glucose output to net glucose removal only when the intracellular hepatic glucose concentration exceeded 12.5 mumol/ml water. Even when arteriovenous glucose concentrations gradients were compatible with net direct hepatic uptake of glucose, the hepatic glucose concentration always exceeded the inflow glucose concentration. These data indicate that direct glucose uptake occurred against a concentration gradient when the liver is considered as a whole. The hepatic intracellular-to-extracellular glucose concentration gradient changed very little, suggesting that this is not being regulated by glucose, insulin, or other effectors. The mechanism by which the hepatic glucose concentration and net hepatic glucose uptake versus output are coordinated is unknown. The rate of glycogen synthesis was linear for 120 min after administration of the glucose load. This occurred in the presence of direct uptake of glucose early in the time course and later in the presence of net glucose output by the liver. Net direct uptake of glucose by the liver could account for, at most, 37-55% of the glycogen formed. Fractional extraction of both lactate and alanine decreased after glucose was given, but net hepatic uptake of these metabolites could account for 33-49 and 7-10%, respectively, of the glycogen formed, depending on plasma versus blood water flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗
PubMed1988

Quantitative importance of dietary constituents other than glucose as insulin secretagogues in type II diabetes.

In seven type II (non-insulin-dependent) diabetic patients, given either 50 g glucose or a mixed meal potentially containing 61 g glucose as starch and sucrose, the postmeal plasma glucose area integrated over 4 h was less after the mixed meal. The insulin area was considerably greater (2.1-fold). The greater increase in insulin could be explained largely, but not entirely, by the protein and fructose in the mixed meal (85%) which, in addition to glucose, are known insulin secretagogues. The residual unexplained increase may be due to a synergistic interaction of these secretagogues, an unidentified insulin secretagogue, or by a reduced insulin removal rate. These possibilities remain to be explored.

Aged↗
PubMed1988

The high-carbohydrate diet in diabetes management.

In summary, the best diet for an insulin-requiring diabetic person is a diet that can be best integrated into the person's lifestyle, one that is best matched to an insulin regimen acceptable to that person, and one that leads to the best control of the 24-hour integrated blood glucose concentration. Should future research indicate that a very high-CHO, low-fat diet is of additional benefit to the patient, then the dietary recommendations to the patient should be altered accordingly. It should be understood that diabetes is a chronic disease that requires intensive effort by the patient if reasonable management is to be attained. We should not complicate this management unnecessarily by dietary intervention unless clear benefits can be observed. For the type II, noninsulin-requiring diabetic person, dietary recommendations are even less certain. Obese patients should be encouraged to lose weight and to maintain a more ideal body weight, but one should not be disappointed if the patient is unable to accomplish this. Medical indications for weight loss rarely have been sufficient motivation for patients to remain on a semistarvation diet. Should safe, effective anorexigenic drugs become available, they clearly would be the treatment of choice for these patients. The best weight-maintenance diet for type II diabetic persons remains to be determined. A high-CHO, low-fat diet would appear to be best, provided it results in a more normal average level of blood glucose. An increase in dietary soluble fiber also may be useful in reducing the serum cholesterol concentration. In such a diet, those CHO foods that raise the postprandial glucose concentration the least should be emphasized.

Blood Glucose↗
PubMed1987

Acute effects of ingestion of carbohydrate, protein, or fat on cardiac glycogen metabolism in rats.

Administration of large doses of insulin to intact rats has been shown to stimulate cardiac glycogen synthase phosphatase activity. This results in an activation of glycogen synthase. However, whether a more physiologic stimulus for insulin secretion also resulted in activation of synthase had not been studied. In the present study, rats were fed glucose, casein hydrolysate, or a mixed meal after a 24-hour fast as a means of physiologically stimulating insulin secretion. Lard was fed as a noninsulinotropic nutrient for comparative purposes. Plasma insulin was significantly increased by 15 minutes in rats given a mixed meal or glucose, but surprisingly, no change was observed in rats fed casein hydrolysate. As expected, no change in plasma insulin was observed in rats fed lard. Synthase phosphatase activity was stimulated in rats fed a mixed meal, glucose, or casein hydrolysate, but not in rats fed lard. Likewise, the proportion of synthase in the active (I) form was significantly increased in rats fed a mixed meal, glucose, or casein hydrolysate, but not in rats fed lard. The increase in phosphatase activity and the increased proportion of synthase in the active form following ingestion of casein hydrolysate was unexpected since this occurred in the absence of an increase in insulin. The proportion of phosphorylase in the active (a) form decreased in rats fed glucose, but remained unchanged in rats fed a mixed meal, casein hydrolysate, or lard. The cardiac glycogen concentration decreased dramatically in rats fed casein hydrolysate. Following the other meals, there was either no change or the decrease was modest.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Effects of graded intravenous doses of fructose on glycogen synthase in the liver of fasted rats.

We have examined in fasted rats the effects of graded doses of intravenous fructose (50 to 500 mg/kg) in order to determine potential mechanisms by which different concentrations of fructose reaching the liver may modify the activity of glycogen synthase (and phosphorylase). With increasing fructose doses the % synthase I increased threefold to a maximum at a dose of 125 mg/kg and then decreased progressively after higher fructose doses were given. The % phosphorylase a decreased by 30% to a minimum at a dose of 125 mg/kg but increased with higher doses to 370% of the control values. Both the % synthase I and the % phosphorylase a were elevated above the control values at fructose doses of 175 to 225 mg/kg. The increase in % synthase I after low doses of fructose occurred with a significant increase in glucose-6-P but no significant change in hepatic fructose, glucose, UDPglucose, ATP/Mg++, Pi, cAMP, plasma insulin, or glucagon concentrations. The reciprocal decrease in % synthase I and increase in % phosphorylase a occurred despite increases in glucose and glucose-6-P, at fructose doses resulting in no change in ATP/Mg++, Pi or cAMP, and only a small increase (0.39 mmol/L) in the fructose-1-P concentration. We propose that activation of synthase phosphatase by a rise in the glucose-6-P concentration is responsible for the increase in % synthase I after low doses of fructose. The mechanism by which higher fructose doses overcome the expected activation of synthase phosphatase by glucose and glucose-6-P and a decreased ATP/Mg++ ratio is uncertain.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Diet and diabetes, a brief overview: personal perspective.

Over the past several years there has been renewed interest in the dietary management of persons with diabetes. Many of the older concepts are being questioned and dietary recommendations are being revised. A uniform concensus regarding the best diet for insulin-requiring diabetic persons is not available. In my opinion, the best diet, considering our state of knowledge and the limitations imposed by current treatment modalities, is a diet that is most acceptable to the patient as long as it is nutritionally adequate. Once a diet is decided upon, constancy of carbohydrate (CHO) content for each meal is emphasized. A diet low in fat and containing approximately 50-60% CHO is desirable but is not as important as patient compliance. A stable reduction in the plasma glucose concentration in these patients should be the overwhelming objective. Dietary management of non-insulin requiring diabetic persons remains uncertain and controversial. Much more scientific data are needed before dietary recommendations can be made. Nevertheless, one can educate patients regarding CHO containing foods which have a large effect on the postmeal glucose concentration (cooked potatoes and cereal products such as bread and breakfast cereals) and those which produce a smaller effect (milk and milk products, fruits, vegetables, table sugar, and honey). With the interest in the dietary management of diabetic patients at the present time, I look forward to rapid progress in this field and resolution of the current controversies.

Combined Modality Therapy↗
PubMed1987

Oral protein hydrolysate causes liver glycogen depletion in fasted rats pretreated with glucose.

Studies in rats indicated that the major physiologic stimulus for synthesis of liver glycogen is a rise in the portal glucose concentration after ingestion of a meal. Conversely, glycogen degradation in the liver is stimulated by a rise in portal glucagon concentration. In humans, ingestion of carbohydrate lowers the concentration of circulating glucagon, whereas protein stimulates an increase in peripheral glucagon concentration. Little is known about the effects of these nutrients on glucagon concentrations in the rat. Therefore, we studied the effects of oral protein administration to 24-h-fasted rats pretreated with glucose for 2 h to test the effect of two potent but potentially opposite signals for glycogen metabolism. An increase in liver glycogen concentration was observed in fasted rats given oral glucose, as expected. Removal of glucose by the liver could not account for the glycogen synthesized, indicating that most glycogen formed was derived from gluconeogenesis. In addition, the apparent intracellular and extracellular glucose concentrations were not in equilibrium. A small amount of glucose may have been taken up against a concentration gradient. The portal glucagon was not significantly decreased. Oral protein administration to the rats pretreated with glucose resulted in a rapid and dramatic decrease in liver glycogen concentration. This was associated with an increase in the portal glucagon concentration, no change in insulin concentration, a slight increase in liver cAMP concentration, an increase in the active form of phosphorylase, and a decrease in the active form of synthase. Glycogenolysis could account for the glucose released into the circulation from the liver after protein administration.

Animals↗
PubMed1987

Ultrastructural relationship of quadriceps muscle degeneration with a distant peroneal nerve conduction in human myotonia dystrophica.

The association of motor nerve conduction velocity (MNCV) to (1) duration of symptoms, (2) deep tendon reflex responses, (3) clinical muscle atrophy, and (4) ultrastructure of quadriceps muscle was studied in 18 patients with myotonia dystrophica of Steinert and nine normal controls. These patients had neither diabetes mellitus nor any other type of muscle dystrophy. Ultrastructural features of muscle fibers and intercellular spaces between atrophic fibers provided a basis for identifying degenerative changes and evaluating them semi-quantitatively. Our study indicates presence of an association between the pattern of muscle degeneration and both MNCV (correlation coefficients, gamma = +0.60) and duration of symptoms (gamma = -0.62), but not between MNCV and duration of symptoms (gamma = +0.28). Further analysis of the association between the degeneration of quadriceps and the MNCV of a distant peroneal nerve (which does not innervate quadriceps) suggested that the systemic nerve degeneration occurred in some groups of myotonia patients. Our study indicates that while in some patients the muscle degeneration may have been associated with the impairment of neurogenic elements, in others it occurred in the absence of any MNCV abnormality. Our findings favor the role of both neuropathic and myopathic factors in the muscle degeneration seen in myotonia dystrophica.

Adult↗