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Biomedical subjects

L Rossetti

Publications and source records attributed to L Rossetti.

At least 109 records · Page 6Linked to original sources
PubMed1994

The efficacy of the combination of l-moprolol and dipivefrin in reducing the intraocular pressure in primary open-angle glaucoma or in ocular hypertension.

BACKGROUND: In this double-blind prospective trial the efficacy of lowering the intraocular pressure of l-moprolol given alone and in combination with dipivefrin was tested. METHODS: Twenty-seven patients with primary open-angle glaucoma or ocular hypertension were randomly assigned to receive twice-daily l-moprolol eye drops or dipivefrin eye drops for 4 weeks; in a second phase of the trial, the combination of the two drugs was administered for 4 weeks. RESULTS: The results of this study indicated that l-moprolol and dipivefrin had an equivalent effect in lowering the intraocular pressure. The association of the two drugs caused a further reduction of intraocular pressure which was significant only in the group previously treated with dipivefrin alone. CONCLUSION: This trial demonstrated that the combination of l-moprolol and dipivefrin is an effective and safe treatment for elevated intraocular pressure.

Adrenergic beta-Antagonists↗
PubMed1994

Performance of diffractive multifocal intraocular lenses in extracapsular cataract surgery.

In a prospective, randomized clinical trial, 42 patients received a monofocal intraocular lens and 38 a multifocal lens after extracapsular cataract extraction. Patients were examined three, six, and 12 months after surgery. Uncorrected visual acuity was 20/40 or better in 57% of monofocal and 58% of multifocal patients; 12% and 52% had near uncorrected visual acuity of J1 to J2, respectively. Best corrected visual acuities were not significantly different. Forty-eight percent of the multifocal and 8% of the monofocal group did not require spectacle correction. On a patient satisfaction questionnaire, 60% of all patients reported discomfort when using spectacles for near vision. Patients in the multifocal group were more satisfied with their near vision than those in the monofocal group. The difference in satisfaction was not significantly different although more multifocal patients reported visual phenomena (e.g., glare, halos). Mean contrast sensitivity for the monofocal group and the multifocal group was 1.73 and 1.70, respectively. At low contrast sensitivities, the difference was not significant although the monofocal patients scored better.

Aged↗
PubMed1994

Mechanisms of fatty acid-induced inhibition of glucose uptake.

Increased plasma FFA reduce insulin-stimulated glucose uptake. The mechanisms responsible for this inhibition, however, remain uncertain. It was the aim of this study to determine whether the FFA effect was dose dependent and to investigate its mechanism. We have examined in healthy volunteers (13 male/1 female) the effects of three steady state plasma FFA levels (approximately 50, approximately 550, approximately 750 microM) on rates of glucose uptake, glycolysis (both with 3-3H-glucose), glycogen synthesis (determined with two independent methods), carbohydrate (CHO) oxidation (by indirect calorimetry), hepatic glucose output, and nonoxidative glycolysis (glycolysis minus CHO oxidation) during euglycemic-hyperinsulinemic clamping. Increasing FFA concentration (from approximately 50 to approximately 750 microM) decreased glucose uptake in a dose-dependent fashion (from approximately 9 to approximately 4 mg/kg per min). The decrease was caused mainly (approximately 2/3) by a reduction in glycogen synthesis and to a lesser extent (approximately 1/3) by a reduction in CHO oxidation. We have identified two independent defects in glycogen synthesis. The first consisted of an impairment of muscle glycogen synthase activity. It required high FFA concentration (approximately 750 microM), was associated with an increase in glucose-6-phosphate, and developed after 4-6 h of fat infusion. The second defect, which preceded the glycogen synthase defect, was seen at medium (approximately 550 microM) FFA concentration, was associated with a decrease in muscle glucose-6-phosphate concentration, and was probably due to a reduction in glucose transport/phosphorylation. In addition, FFA and/or glycerol increased insulin-suppressed hepatic glucose output by approximately 50%. We concluded that fatty acids caused a dose-dependent inhibition of insulin-stimulated glucose uptake (by decreasing glycogen synthesis and CHO oxidation) and that FFA and/or glycerol increased insulin-suppressed hepatic glucose output and thus caused insulin resistance at the peripheral and the hepatic level.

Adult↗
PubMed1994

Increased epinephrine and skeletal muscle responses to hypoglycemia in non-insulin-dependent diabetes mellitus.

We evaluated skeletal muscle counterregulation during hypoglycemia in nine subjects with non-insulin-dependent diabetes mellitus (NIDDM) (HbA1c 9.4 +/- 0.5%, nl < 6.2%) compared with six normal controls, matched for age (51 +/- 3 and 49 +/- 5 yr, respectively) and body mass index (27.3 +/- 1.2 and 27.0 +/- 2.1 kg/m2). After 60 min of euglycemia (plasma insulin approximately 140 microU/ml), plasma glucose was lowered to 62 +/- 2 mg/dl by 120 min. Hypoglycemia induced a 2.2-fold greater increase in plasma epinephrine in NIDDM (P < 0.001), while the plasma glucagon response was blunted (P < 0.01). Hepatic glucose output ([3H-3]glucose) suppressed similarly during euglycemia, but during hypoglycemia was greater in NIDDM (P < 0.005). Conversely, glucose uptake during euglycemia was 150% greater in controls (P < 0.01) and remained persistently higher than in NIDDM during hypoglycemia. In NIDDM, plasma FFA concentrations were approximately fivefold greater (P < 0.001), and plasma lactate levels were approximately 40% higher than in controls during hypoglycemia (P < 0.01); the rates of glycolysis from plasma glucose were similar in the two groups despite a 49% lower rate of glucose uptake in NIDDM (3.4 +/- 0.9 vs. 6.9 +/- 1.3 mg/kg per minute, P < 0.001). Muscle glycogen synthase activity fell by 42% with hypoglycemia (P < 0.01) in NIDDM but not in controls. In addition, glycogen phosphorylase was activated by 56% during hypoglycemia in NIDDM only (P < 0.01). Muscle glucose-6-phosphate concentrations rose during hypoglycemia by a twofold greater increment in NIDDM (P < 0.01). Thus, skeletal muscle participates in hypoglycemia counterregulation in NIDDM, directly by decreased removal of plasma glucose and, indirectly, by providing lactate for hepatic gluconeogenesis. Consequently, in addition to inherent insulin resistance in NIDDM, the enhanced plasma epinephrine response during hypoglycemia may partially offset impaired glucagon secretion and counteract the effects of hyperinsulinemia on liver, fat, and skeletal muscle.

Adult↗
PubMed1994

Relationship between morphometric optic disc parameters, sex and axial length.

Optic disc correlations were evaluated in normal eyes by means of computer-aided morphometry. Two hundred and thirty-five subjects (144 women and 91 men) entered the study. One eye per patient was randomly chosen for statistical analysis. Disc area (P < 0.05) and axial length (P < 0.0001) were statistically different between sexes. There was a correlation between axial length and both disc area (r for females = 0.55, P < 0.00001; r for males = 0.35, P < 0.0007) and refraction (r for females = 0.40, P < 0.00001; r for males = 0.50, P < 0.00001). The main findings of this investigation were that disc area is greater in male than in female eyes (thus clinically confirming the Ishi's and Quigley's previous observations of autopsy eyes) on the basis of axial length difference between the two sexes, and that disc size correlated with axial length. Disagreements in disc measurements reported in previous studies may be caused by differences in the male/female ratios of their samples.

Adult↗
PubMed1993

Role of glucokinase and glucose-6-phosphatase in the acute and chronic regulation of hepatic glucose fluxes by insulin.

Increased hepatic glucose production (HGP) is the major cause of fasting hyperglycemia in all forms of diabetes. Glucokinase (GK) and glucose-6-phosphatase (Glc-6-Pase) are the proximal and the distal enzymatic steps, respectively, in the regulation of HGP. We examined the impact of changes in GK and Glc-6-Pase activities on in vivo hepatic glucose fluxes in diabetic (D) and control (C) rats. In particular, the acute regulation by insulin was investigated using the euglycemic hyperinsulinemic clamp technique in conscious rats. In experimental diabetes (6 weeks): (a) GK mRNA was decreased by approximately 40%; (b) the Vmax of GK was markedly decreased (approximately 4 versus 9 mumol/g wet weight/min) and that of Glc-6-Pase was 2-fold increased (approximately 30 versus 15 mumol/g wet weight/min, D versus C), while (c) the Km of GK (approximately 10 mM) and Glc-6-Pase (approximately 1.5 mM) were unchanged. HGP was increased by 65% in diabetes and correlated highly with the ratio of Glc-6-Pase/GK (r = 0.81, p < 0.01). Following acute hyperinsulinemia (2 h): (a) GK mRNA increased by approximately 2-fold in both C and D; (b) GK Vmax did not change in C, but doubled to near-normal in D; (c) Glc-6-Pase Vmax decreased by 23% in C and by 34% in D; (d) the Km of GK decreased by approximately 40% (p < 0.01) in C. Acute hyperinsulinemia almost completely inhibited HGP in both C and D, and no correlation was demonstrated between HGP and the ratio of Glc-6-Pase/GK in these groups. Our data suggest that GK and Glc-6-Pase are important determinants of fasting HGP in diabetes. However, acute changes in Glc-6-Pase and GK activities can account for only a small portion of the in vivo inhibition of hepatic glucose flux by insulin, suggesting additional mechanisms for the short-term regulation of HGP.

Animals↗
PubMed1993

Is proper methodology associated with the use of a clinically relevant outcome measure? The case of randomized clinical trials on medical treatment of open-angle glaucoma.

OBJECTIVE: The aim of this study was to assess critically the published literature concerning medical treatment of primary open-angle glaucoma (POAG), and to see whether trial methodologic quality was related to a clinically relevant outcome measure. METHODS: We identified and reviewed the methodologic quality of 102 published randomized clinical trials (RCTs) on treatment of POAG using an explicit protocol and explored the association between selected aspects of design and conduct and the studies' clinical relevance. RESULTS: Our analysis revealed serious methodologic problems with the trials reviewed. Areas of major concern were: use of unsatisfactory or unspecified methods of randomization (89% of the trials reported no information), exclusion of some patients from the analysis (53% of the studies), failure to provide evidence of having estimated the number of patients needed to detect a prespecified treatment difference (96% failed to provide such an estimate), and incomplete description of patient characteristics (in 39% of the RCTs information on this item was insufficient). Within this generally unsatisfactory picture we found, however, that those studies adopting a double-masked design and those not excluding patients after randomization followed patients for longer periods of time and assessed treatment effectiveness using a clinically relevant outcome (that is, visual field changes) compared to other studies. CONCLUSIONS: For clinicians to make use of the results of clinical trials, future studies must be adequately designed and conducted. In particular, proper method of randomization, masking of the observers, and inclusion of all randomized patients in the analysis must be used. Of perhaps even greater importance is the need for trials to measure clinically relevant outcomes.

Clinical Protocols↗
PubMed1993

Randomized clinical trials on medical treatment of glaucoma. Are they appropriate to guide clinical practice?

A systematic quantitative and qualitative overview of published randomized clinical trials was undertaken to assess the yield of medical treatment on the outcome of patients with primary open angle glaucoma. Reports of 102 randomized clinical trials were published between 1975 and 1991, totalling about 5000 patients. Only 16% (16/102) of the trials were, however, properly designed (ie, comparing an active treatment with a placebo-treated or untreated control group) to answer the question of whether any medical treatment can effectively cure patients with primary open angle glaucoma. Pooled analysis showed a moderate yet statistically significant reduction in mean intraocular pressure (-4.9 mm Hg; 95% confidence interval [CI], -7.3 to -2.5 mm Hg); however, data on long-term visual field changes were available in only three randomized clinical trials, and their statistical combination failed to show a significant protective effect of active treatment (odds ratio, 0.75; 95% CI, 0.42 to 1.35). All of the remaining 86 randomized clinical trials looked at the effectiveness of one drug vs another in lowering intraocular pressure and were thus of no use in the overview. Practicing ophthalmologists should be aware that the effectiveness of pressure-lowering agents in the treatment of primary open angle glaucoma is still to be determined and that the vast majority of published trials are not appropriate to guide clinical practice. It is urgent to plan trials with end-point and follow-up duration that is fully relevant for the health of patients.

Clinical Protocols↗
PubMed1993

Multiple metabolic effects of CGRP in conscious rats: role of glycogen synthase and phosphorylase.

Calcitonin gene-related peptide (CGRP) is a neuropeptide that is released at the neuromuscular junction in response to nerve excitation. To examine the relationship between plasma CGRP concentration and intracellular glucose metabolism in conscious rats, we performed insulin (22 pmol.kg-1.min-1) clamp studies combined with the infusion of 0, 20, 50, 100, 200, and 500 pmol.kg-1.min-1 CGRP (plasma concentrations ranging from 2 x 10(-11) to 5 x 10(-9) M). CGRP antagonized insulin's suppression of hepatic glucose production at plasma concentrations (approximately 10(-10) M) that are only two- to fivefold its basal portal concentration. Insulin-mediated glucose disposal was decreased by 20-32% when CGRP was infused at 50 pmol.kg-1.min-1 (plasma concentration 3 x 10(-10) M) or more. The impairment in insulin-stimulated glycogen synthesis in skeletal muscle accounted for all of the CGRP-induced decrease in glucose disposal, while whole body glycolysis was increased despite the reduction in total glucose uptake. The muscle glucose 6-phosphate concentration progressively increased during the CGRP infusions. CGRP inhibited insulin-stimulated glycogen synthase in skeletal muscle with a 50% effective dose of 1.9 +/- 0.36 x 10(-10) M. This effect on glycogen synthase was due to a reduction in enzyme affinity for UDP-glucose, with no changes in the maximal velocity. In vitro CGRP stimulated both hepatic and skeletal muscle adenylate cyclase in a dose-dependent manner. These data suggest that 1) CGRP is a potent antagonist of insulin at the level of muscle glycogen synthesis and hepatic glucose production; 2) inhibition of glycogen synthase is its major biochemical action in skeletal muscle; and 3) these effects are present at concentrations of the peptide that may be in the physiological range for portal vein and skeletal muscle. These data underscore the potential role of CGRP in the physiological modulation of intracellular glucose metabolism.

Adenylyl Cyclases↗
PubMed1993

Effect of hepatic nerves on disposition of an intraduodenal glucose load.

We examined the disposition of a continuous 4-h intraduodenal glucose infusion (8 mg.kg-1 x min-1, labeled with [1-13C]glucose and [3-3H]glucose) in nine conscious hepatic-denervated dogs. Cumulative net hepatic uptakes (in grams of glucose equivalents) were 13.7 +/- 2.5 glucose, 3.1 +/- 0.6 gluconeogenic amino acids, and 0.8 +/- 0.1 glycerol. Net hepatic glycogen synthesis totalled 11.0 +/- 0.9 g, 55-62% via the direct pathway. All values were similar to those in hepatic-innervated dogs. Glycogen synthase activity and rate of glycogen synthesis were positively correlated (r2 = 0.913, P < 0.05). Variability in net hepatic glycogen synthesis and the mass of glycogen synthesized via the indirect pathway was reduced in hepatic-denervated dogs (P < 0.05). In conclusion, the glycemic response and rate of net glycogen synthesis during an intraduodenal glucose infusion was no different in hepatic-denervated and -innervated dogs. Net hepatic glucose uptake was sufficient to account for all net hepatic glycogen synthesis and lactate production, consistent with an intrahepatic source of gluconeogenic precursors for glycogen synthesis via the indirect pathway. Hepatic nerves appear responsible for much of the variability in net hepatic glycogen synthesis and in the mass of glycogen synthesized via the indirect pathway in normal dogs.

Amino Acids↗
PubMed1993

Quantitation of glycolysis and skeletal muscle glycogen synthesis in humans.

We measured the net rates of skeletal muscle glycogen synthesis and glycolysis (conversion of [3-3H]glucose to 3H2O) in healthy overnight-fasted volunteers. Two studies were performed. In study 1, seven subjects participated in two paired infusions under basal conditions of either [2-3H]glucose (H2) or [3-3H]glucose (H3). Total glucose uptake (Rd) and rates of whole body 3H2O formation (3H2O Ra) were measured. With H2, Rd and 3H2O Ra were similar. With H3, 3H2O Ra, equal to glycolysis, was 65% of Rd. In study 2, six different subjects underwent a 3-h, 40 mU.m-2 x min-1 euglycemic insulin clamp. [6,6-2H2]glucose was infused throughout and H3 was infused during the last hour of the study. Open muscle biopsies were obtained at 150 and 180 min. Glycogen synthesis was assessed by three independent means: 1) direct measurement, as 3H disintegrations per minute in isolated muscle glycogen per plasma H3 specific activity; 2) extrapolation from the activity of glycogen synthase assayed in the presence of the concentrations of glucose 6-phosphate and UDP-glucose measured in the biopsy; and 3) the difference between Rd and glycolysis. Despite a wide range in Rd [24.5-58.8 mumol.kg fat-free mass (FFM)-1 x min-1] and glycolysis (14.2-26.1), the three methods yielded similar results of 20.0 +/- 3.9, 22.5 +/- 3.7, and 20.6 +/- 3.7 mumol.kg FFM-1 x min-1 and correlated highly with each other (r2 = 0.92-0.96). Our results (study 1) indicate that the rate of plasma tritiated water formation reflects the intracellular detritiation of tritiated glucose. Under hyperinsulinemic conditions (study 2) the net rate of muscle glycogen synthesis can be accurately estimated from the glycogen synthase activity and from the difference between total glucose uptake and glycolysis. Thus, at high physiological plasma insulin concentrations resulting in submaximal stimulation of muscle glycogen synthesis, the latter can be accurately measured in humans.

Adult↗
PubMed1993

Mechanism by which hyperglycemia inhibits hepatic glucose production in conscious rats. Implications for the pathophysiology of fasting hyperglycemia in diabetes.

To examine the relationship between the plasma glucose concentration (PG) and the pathways of hepatic glucose production (HGP), five groups of conscious rats were studied after a 6-h fast: (a) control rats (PG = 8.0 +/- 0.2 mM); (b) control rats (PG = 7.9 +/- 0.2 mM) with somatostatin and insulin replaced at the basal level; (c) control rats (PG = 18.1 +/- 0.2 mM) with somatostatin, insulin replaced at the basal level, and glucose infused to acutely raise plasma glucose by 10 mM; (d) control rats (PG = 18.0 +/- 0.2 mM) with somatostatin and glucose infusions to acutely reproduce the metabolic conditions of diabetic rats, i.e., hyperglycemia and moderate hypoinsulinemia; (e) diabetic rats (PG = 18.4 +/- 2.3 mM). All rats received an infusion of [3-3H]glucose and [U-14C]lactate. The ratio between hepatic [14C]UDP-glucose sp act (SA) and 2X [14C]-phosphoenolpyruvate (PEP) SA (the former reflecting glucose-6-phosphate SA) measured the portion of total glucose output derived from PEP-gluconeogenesis. In control rats, HGP was decreased by 58% in hyperglycemic compared to euglycemic conditions (4.5 +/- 0.3 vs. 10.6 +/- 0.2 mg/kg.min; P < 0.01). When evaluated under identical glycemic conditions, HGP was significantly increased in diabetic rats (18.9 +/- 1.4 vs. 6.2 +/- 0.4 mg/kg.min; P < 0.01). In control rats, hyperglycemia increased glucose cycling (by 2.5-fold) and the contribution of gluconeogenesis to HGP (91% vs. 45%), while decreasing that of glycogenolysis (9% vs. 55%). Under identical plasma glucose and insulin concentrations, glucose cycling in diabetic rats was decreased (by 21%) and the percent contribution of gluconeogenesis to HGP (73%) was similar to that of controls (84%). These data indicate that: (a) hyperglycemia causes a marked inhibition of HGP mainly through the suppression of glycogenolysis and the increase in glucokinase flux, with no apparent changes in the fluxes through gluconeogenesis and glucose-6-phosphatase; under similar hyperglycemic hypoinsulinemic conditions: (b) HGP is markedly increased in diabetic rats; however, (c) the contribution of glycogenolysis and gluconeogenesis to HGP is similar to control animals.

Animals↗
PubMed1993

Skeletal muscle glycogenolysis is more sensitive to insulin than is glucose transport/phosphorylation. Relation to the insulin-mediated inhibition of hepatic glucose production.

The effects of minimal increments in plasma insulin concentrations on hepatic glucose production and glucose uptake, skeletal muscle net glycogen synthesis and glycogenolysis, glycogen synthase and phosphorylase activity, glucose-6-phosphate and uridinediphosphoglucose (UDPG) concentrations were examined in 24-h and in 6-h fasted conscious rats. Insulin was infused for 120 min at rates of 1.5, 3, 6, 12, 24, and 108 pmol/kg per min in 24-h fasted rats and at rates of 3, 6, 9, 12, 36, and 108 pmol/kg per min in 6-h fasted rats while endogenous insulin release was inhibited by SRIF infusion and plasma glucose was maintained at the basal level. All rats received an infusion of [3-3H]glucose. The portion of the muscle glucose-6-phosphate (G6P) pool derived from net glycogenolysis was estimated from the ratio of specific activities of muscle UDPG and plasma glucose. Minimal increments in the circulating insulin levels, which did not stimulate glucose uptake, caused: (a) the increase in skeletal muscle glycogen synthase activity and the decrease in the rate of muscle glycogenolysis and in the G6P concentration; (b) the inhibition of hepatic glucose production. Net muscle glycogen synthesis was not stimulated despite submaximal activation of glycogen synthase, and its onset correlated with the rise in muscle G6P levels. Thus, insulin's inhibition of muscle glycogenolysis is the most sensitive insulin action on skeletal muscle and its dose-response characteristics resemble those for the inhibition of hepatic glucose production. These findings indicate that skeletal muscle glycogen synthase may play a major role in carbohydrate homeostasis even under postabsorptive (basal insulin) conditions and support the notion that insulin may exert some of its effects on the liver through an indirect or peripheral mechanism.

Animals↗
PubMed1992

In vivo insulin action in genetic models of hypertension.

Insulin resistance has been described in nonobese subjects with essential hypertension. At present it is unknown whether hypertension per se may lead to the onset of insulin resistance. To examine this question we studied in vivo insulin action in two rat models of genetic hypertension. Four groups of conscious rats were studied: Milan hypertensive (MHS), Milan normotensive (MNS), spontaneously hypertensive (SHR), and Wistar-Kyoto (WKY). Mean arterial pressure was increased in SHR vs. WKY in both the fed (184 +/- 5 vs. 126 +/- 6 mmHg; P less than 0.001) and fasting (160 +/- 5 vs. 129 +/- 5; P less than 0.001) states. During high-dose insulin clamps, total body glucose uptake (mg.kg-1.min-1) was similar in MNS (28.7 +/- 1.4) vs. MHS (33.6 +/- 3.0) and in WKY (34.6 +/- 1.8) vs. SHR (35.7 +/- 2.4). During low-dose insulin clamps, suppression of hepatic glucose production (3.5 +/- 0.6 vs. 3.0 +/- 0.5 mg.kg-1.min-1) and stimulation of glycolysis (12.9 +/- 0.8 vs. 14.4 +/- 1.5 mg.kg-1.min-1) were similar in WKY vs. SHR, whereas glucose uptake (24.6 +/- 1.9 vs. 18.3 +/- 1.2 mg.kg-1.min-1; P less than 0.01) and muscle glycogenic rate (10.2 +/- 1.1 vs. 6.5 +/- 1.1 mg.kg-1.min-1; P less than 0.05) were increased in SHR vs. WKY. In conclusion, 1) feeding markedly augments blood pressure in hypertensive but not in normotensive rats, and 2) hepatic and muscle insulin sensitivity are normal or increased in two different rat models of genetic hypertension. These results provide evidence that high blood pressure per se does not invariably lead to the development of insulin resistance.

Animals↗
PubMed1992

Increased insulin sensitivity in the high sodium one-kidney, one figure-8 hypertensive rat.

This study examines the relation between sympathetic activity and in vivo insulin-mediated glucose metabolism in a rat model of acquired hypertension. Two groups of conscious, unrestrained rats were studied in the postabsorptive state: sham-operated normotensive rats (n = 10) and renal-wrapped hypertensive rats (n = 10). Mean arterial pressure was increased in the hypertensive compared with the normotensive group in the fed (184 +/- 9 versus 144 +/- 6 mm Hg; p less than 0.01) and in the fasting (147 +/- 8 versus 112 +/- 7 mm Hg; p less than 0.01) state. After a 24-hour fast, hepatic glucose production, plasma glucose, insulin, and norepinephrine concentrations were similar in the two groups. Blood pressure did not change in either group during the 3-milliunits/kg.min euglycemic insulin clamp study; however, plasma norepinephrine concentration rose significantly in hypertensive (207 +/- 24 versus 329 +/- 11 pg/ml; p less than 0.05) but not in normotensive rats (229 +/- 23 versus 267 +/- 27 pg/ml; p = NS). During the insulin clamp study, the hepatic glucose production was similar in the hypertensive (3.8 +/- 0.8 mg/kg.min) compared with the normotensive (4.0 +/- 0.3 mg/kg.min) rats. Insulin-mediated glucose uptake was significantly higher in hypertensive than in normotensive rats (33.0 +/- 0.7 versus 25.8 +/- 0.8; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Predominant role of gluconeogenesis in the hepatic glycogen repletion of diabetic rats.

Liver glycogen formation can occur via the direct (glucose----glucose-6-phosphate----glycogen) or indirect (glucose----C3 compounds----glucose-6-phosphate----glycogen) pathways. In the present study we have examined the effect of hyperglycemia on the pathways of hepatic glycogenesis, estimated from liver uridine diphosphoglucose (UDPglucose) specific activities, and on peripheral (muscle) glucose metabolism in awake, unstressed control and 90% pancreatectomized, diabetic rats. Under identical conditions of hyperinsulinemia (approximately 550 microU/ml), 2-h euglycemic (6 mM) and hyperglycemic (+5.5 mM and +11 mM) clamp studies were performed in combination with [3-3H,U-14C]glucose, [6-3H,U-14C]glucose, or [3-3H]glucose and [U-14C]lactate infusions under postabsorptive conditions. Total body glucose uptake and muscle glycogen synthesis were decreased in diabetic vs. control rats during all the clamp studies, whereas glycolytic rates were similar. By contrast, hyperglycemia determined similar rates of liver glycogen synthesis in both groups. Nevertheless, in diabetic rats, the contribution of the direct pathway to hepatic glycogen repletion was severely decreased, whereas the indirect pathway was markedly increased. After hyperglycemia, hepatic glucose-6-phosphate concentrations were increased in both groups, whereas UDPglucose concentrations were reduced only in the control group. These results indicate that in the diabetic state, under hyperinsulinemic conditions, hyperglycemia normally stimulates liver glycogen synthesis through a marked increase in the indirect pathway, which in turn may compensate for the reduction in the direct pathway. The increase in the hepatic concentrations of both glucose-6-phosphate and UDPglucose suggests the presence, in this diabetic rat model, of a compensatory "push" mechanism for liver glycogen repletion.

Animals↗
PubMed1992

Hyperglycemia markedly enhances skeletal muscle glycogen synthase activity in diabetic, but not in normal conscious rats.

Both hyperinsulinemia and hyperglycemia stimulate skeletal muscle glucose uptake. However, the intracellular metabolic fate of the phosphorylated glucose may be different when the prevalent stimulus for glucose uptake is hyperinsulinemia or hyperglycemia. To define the impact of hyperglycemia on the intracellular glucose disposal, we studied control and diabetic conscious rats under four experimental conditions: 1) basal insulin and basal glucose; 2) basal insulin and high glucose; 3) high insulin and basal glucose; and 4) high insulin and high glucose. Under both basal insulin (130 pM) and high insulin (2500 pM), hyperglycemia (15 mM) increased glucose uptake and muscle and liver glycogen synthesis similarly in control and diabetic rats. Hyperglycemia resulted in a more significant decline in the muscle G-6-P concentration in diabetic rats than in control rats, suggesting activation of intracellular glucose metabolism. The diabetic skeletal muscle glycogen synthase was severely resistant to insulin stimulation compared with control (FV0.1 = 0.31 +/- 0.04 vs. 0.49 +/- 0.03; Km = 0.19 +/- 0.05 vs. 0.10 +/- 0.01 mM; P < 0.01), but it was markedly responsive to glucose stimulation under both basal (FV0.1 = 0.38 +/- 0.03 vs. 0.21 +/- 0.03; Km = 0.10 +/- 0.01 vs. 0.35 +/- 0.08 mM) and high insulin (FV0.1 = 0.65 +/- 0.07 vs. 0.31 +/- 0.04; Km = 0.11 +/- 0.02 vs. 0.19 +/- 0.05 mM). By contrast, in control rats, hyperglycemia did not exert any stimulatory effect on skeletal muscle glycogen synthase. Thus, some metabolic alteration associated with the diabetic state renders the skeletal muscle glycogen synthase selectively responsive to glucose stimulation. This may represent a compensatory mechanism for the severe impairment in insulin's activation of this enzyme in diabetes.

Animals↗