Biomedical subjects

L Rossetti

Publications and source records attributed to L Rossetti.

At least 91 records · Page 5Linked to original sources

PubMed1996

Age-related changes in body composition are associated with hepatic insulin resistance in conscious rats.

Age-dependent changes in body composition and hepatic ([3H]glucose) glucose metabolism were examined in 2-, 4-, and 14-mo-old (n = 26) conscious Sprague-Dawley rats. Hepatic glucose production (HGP) and hepatic glucose-6-phosphatase maximum velocity were decreased 18 and 30%, respectively, between 2 and 4 mo but were unchanged with further aging. However, between 4 and 14 mo, twofold higher plasma insulin levels were required to maintain similar HGP, suggesting that hepatic insulin resistance develops with age. Utilizing hepatic-pancreatic clamp technique, we showed that a much higher rate of insulin infusion (1.6 +/- 0.1 vs. 0.8 +/- 0.1 mU.kg-1.min-1) was needed to achieve similar plasma glucose levels and HGP. Furthermore, when 4-mo-old rats were infused with insulin at similar rates as the 14-mo-old rats, HGP was decreased by approximately 30%. Because hepatic insulin sensitivity was inversely related to the increase in body weight (r2 = 0.876) and free fatty acid levels (r2 = 0.843), we suggest that age-related changes in body composition may lead to the impairment of hepatic glucose metabolism.

Adipose Tissue↗

PubMed1996

Neural and pancreatic influences on net hepatic glucose uptake and glycogen synthesis.

The role of the liver nerves in the disposition of peripherally administered glucose was examined in seven hepatic innervated (HI) and nine hepatic denervated (HD) 42-h-fasted conscious dogs. After a 40-min basal period, there was a 4-h experimental period during which the hepatic glucose load was increased twofold via peripheral glucose infusion. Somatostatin was infused to suppress pancreatic endocrine secretion, and insulin and glucagon were infused intraportally to produce a fourfold increase in insulin and a gradual decrease (approximately 25%) in glucagon. The area under the curve of net hepatic glucose uptake (NHGU) during the glucose infusion period totaled 483 +/- 82 and 335 +/- 32 mg/kg in HD and HI, respectively (P < 0.05). The area under the curve of the hepatic fractional extraction of glucose was 27% greater in HD (P < 0.05). Net hepatic lactate output was similar in the two groups, and net hepatic glycogen synthesis was 3.8 +/- 0.8 vs. 2.7 +/- 0.5 mg.kg dog wt-1.min-1 in HD and HI, respectively (P = 0.13). The direct pathway of glycogen synthesis was responsible for 54-58% of net hepatic glycogen synthesis in both HI and HD (n = 6 for both). In summary 1) NHGU in response to peripheral glucose infusion was approximately 44% greater in HD than in HI, 2) net hepatic glycogen synthesis was enhanced by 41% in HD although the probability of this change was 0.13, and 3) the contribution of the direct pathway to glycogen synthesis was the same in HD and HI. These data are consistent with a role for the liver nerves in regulating the magnitude of NHGU in response to glucose administration. They also indicate that the absence of liver nerves may reduce glycogen turnover during glucose infusion.

Alanine↗

PubMed1996

Increased lipid oxidation but normal muscle glycogen response to epinephrine in humans with IDDM.

The effects of physiological increments in epinephrine and insulin on glucose production (GP), skeletal muscle glycogen metabolism, and substrate oxidation were studied in eight insulin-dependent diabetes mellitus (IDDM) and nine control subjects. Epinephrine was coinfused for the final 120 min of a 240-min euglycemic, hyperinsulinemic clamp. In both groups, insulin increased glucose uptake, glycogen synthesis, and whole body carbohydrate (CHO) oxidation and inhibited GP (by 70-80%) and lipid oxidation (by approximately 50%), whereas epinephrine antagonized the effect of insulin on glucose uptake and glycogen synthesis. In contrast, GP increased in IDDM subjects (P < 0.02) but remained suppressed by insulin in controls. CHO oxidation fell (1.37 +/- 0.25 vs. 2.08 +/- 0.32 mg.kg-1.min-1) and lipid oxidation increased to baseline in IDDM subjects, with increments in plasma free fatty acids (FFA) and glycerol. In contrast, in controls, plasma FFA and glycerol remained suppressed and lipid oxidation decreased further with epinephrine (P < 0.005). Epinephrine completely reversed insulin's activation of muscle glycogen synthase in both groups. Thus, during hyperinsulinemia, the hepatic response to epinephrine in IDDM subjects may be dependent on activation of lipid oxidation. Skeletal muscle glycogen metabolism is exquisitely sensitive to epinephrine despite the presence of hyperinsulinemia.

Adult↗

PubMed1996

Glucosamine-induced inhibition of liver glucokinase impairs the ability of hyperglycemia to suppress endogenous glucose production.

Although the kinetic characteristics of hepatic glucokinase (GK) suggest its potential role as the hepatic "glucose sensor," its impact on the regulation of in vivo hepatic glucose production (HGP) is still controversial. Since decreased GK activity has been linked to experimental and human diabetes, we examined whether a moderate and transient inhibition of GK activity diminishes the ability of hyperglycemia to suppress HGP. We first determined the concentration of the competitive inhibitor, glucosamine (GlcN), which decreases hepatic GK activity by approximately 60% in vitro. GlcN was then infused into conscious rats to achieve a similar inhibition of the in vivo GK activity (plasma GlcN levels = approximately 2 mmol/l; rats infused with saline served as control, n = 20). To maintain equal plasma insulin and glucagon concentrations throughout the studies, somatostatin and insulin (basal replacement) were infused for 4 h. [3-(3H)]-glucose and [U-(14C)]-lactate were infused to measure HGP, gluconeogenesis, and glucose cycling (GC) during 2 h of euglycemia (glucose approximately 8 mmol/l) followed by 2 h of hyperglycemia (glucose approximately 18 mmol/l). Our results support the notion that hepatic GK activity is indeed decreased by GlcN in vivo. In fact, in response to hyperglycemia the "direct" pathway of hepatic glucose-6-phosphate (G-6-P) formation was approximately 40% lower with GlcN compared with saline infusion (37 +/- 3 vs. 63 +/- 3%; P < 0.001). Furthermore, while hyperglycemia stimulated GC by approximately 2.5-fold during saline infusion (from 3.0 +/- 0.6 to 7.7 +/- 1.4 mg.kg-1.min-1, P < 0.001, euglycemia vs. hyperglycemia), this increase was blunted in the presence of GlcN (4.6 +/- 0.6 mg.kg-1.min-1, P = NS). Finally, in the presence of GlcN, the hepatic concentration of G-6-P was decreased by approximately 40% compared with saline (234 +/- 38 and 390 +/- 24 nmol/g, P < 0.01). During the euglycemic studies, HGP was similar (12.6 +/- 0.6 and 11.3 +/- 0.2 mg .kg-1.min-1 with GlcN or saline infusion, respectively). However, while hyperglycemia per se suppressed HGP by approximately 65%, HGP was inhibited by approximately 38% and it was approximately twofold higher than in the saline-infused rats (7.8 +/- 0.8 and 4.0 +/- 0.3 mg.kg-1.min-1, P < 0.01) in the presence of GlcN-induced inhibition of hepatic GK. This increase in HGP was largely accounted for by the decreased inhibition of hepatic net glycogenolysis by hyperglycemia (3.3 +/- 0.8 and 1.1 +/- 0.3 mg.kg-1.min-1 with GlcN or saline infusion, respectively, P < 0.01). We conclude that intact GK activity is required for the normal suppression of HGP by hyperglycemia and its impairment may contribute to increased HGP in experimental and human diabetes.

Animals↗

PubMed1996

Increased hexosamine availability similarly impairs the action of insulin and IGF-1 on glucose disposal.

Prolonged glucosamine (GlcN) infusion increases the skeletal muscle hexosamine concentration and induces peripheral insulin resistance in conscious rats. IGF-1 and insulin share common steps in signal transduction, and the action of IGF-1 on carbohydrate metabolism is preserved in certain insulin-resistant states. In our study, we attempted to delineate whether increased GlcN availability also impairs the effects of IGF-1 on glucose uptake (Rd), glycolysis, and glycogen synthesis. We performed euglycemic IGF-1 (5 and 15 microg x kg(-1) x min(-1)) and insulin (3 and 18 mU mg x kg(-1) x min(-1)) clamp studies at 0-2 h and 5-7 h in conscious rats (n = 44) during saline or GlcN infusions. GlcN infusion raised plasma GlcN levels to approximately 2.0 mmol/l and skeletal muscle uridinediphospho-n-acetylglucosamine to 80-150 nmol/g (approximately three- to fivefold over basal). During physiological hyperinsulinemia (3 mU x kg(-1) x min(-1), plasma insulin approximately 50 microU/ml), GlcN infusion caused comparable decreases in Rd (15.7 +/- 1.0 [5-7 h] vs. 21.7 +/- 2.3 [0-2 h] mg x kg(-1) x min(-1); P < 0.01) and glycogen synthesis (5.4 +/- 0.5 [5-7 h] vs. 10.4 +/- 1.9 [0-2 h] mg x kg(-1) x min(-1); P < 0.005). Furthermore, GlcN markedly decreased Rd by 7.8 +/- 1.2 mg x kg(-1) x min(-1) (18.7 +/- 0.7 [5-7 h] vs. 26.5 +/- 1.3 [0-2 h] mg x kg(-1) x min(-1); P < 0.001 vs. control) during IGF-1 (5 microg x kg(-1) x min(-1)) clamp studies. This decline was associated with a 26% decrease in the steady-state concentration of skeletal muscle Glc-6-P (286 +/- 45 vs. 386 +/- 36 nmol/g; P < 0.01) and was primarily caused by impaired glycogen synthesis (6.7 +/- 0.5 [5-7 h] vs. 13.9 +/- 0.9 [0-2 h] mg x kg(-1) x min(-1); P < 0.005). The effects of GlcN infusion on glucose disposal (percentage decrease in Rd) were correlated (r2 = 0.803; P < 0.01) with the skeletal muscle concentration of UDP-GlcNAc. To investigate whether IGF-1 can overcome GlcN-induced insulin resistance, GlcN and insulin (18 mU x kg(-1) x min(-1)) were infused for 7 h during euglycemic clamps, and IGF-1 (15 microg x kg(-1) x min(-1)) was superimposed during the final 2 h. GlcN infusion induced severe impairment of insulin action on Rd (39.4 +/- 3.2 [4-5 h] vs. 49.8 +/- 3.6 [1-2 h] mg x kg(-1) x min(-1); P < 0.05), which the addition of IGF-1 failed to improve (35.9 +/- 2.3 [6-7 h] vs. 39.4 +/- 3.2 [4-5 h] mg x kg(-1) x min(-1); P > 0.1). In summary, GlcN induced severe resistance to the actions of both insulin and IGF-1 on glucose uptake and glycogen synthesis, and IGF-1 was unable to overcome GlcN-induced insulin resistance. Thus, it is likely that GlcN causes peripheral insulin resistance acting at a site common to both IGF-1 and insulin signaling pathways.

Animals↗

PubMed1996

Oral vanadyl sulfate improves insulin sensitivity in NIDDM but not in obese nondiabetic subjects.

We compared the effects of oral vanadyl sulfate (100 mg/day) in moderately obese NIDDM and nondiabetic subjects. Three-hour euglycemic-hyperinsulinemic (insulin infusion 30 mU / m / min) clamps were performed after 2 weeks of placebo and 3 weeks of vanadyl sulfate treatment in six nondiabetic control subjects (age 37 +/- 3 years; BMI 29.5 +/- 2.4 kg/m2 ) and seven NIDDM subjects (age 53 +/- 2 years; BMI 28.7 +/-1.8 kg/m2). Glucose turnover ([3-3 H]glucose), glycolysis from plasma glucose, glycogen synthesis, and whole-body carbohydrate and lipid oxidation were evaluated. Decreases in fasting plasma glucose (by approximately 1.7 mmol/l) and HbAlc (both P < 0.05) were observed in NIDDM subjects during treatment; plasma glucose was unchanged in control subjects. In the latter, the glucose infusion rate (GIR) required to maintain euglycemia (40.1 +/- 5.7 and 38.1 +/- 4.8 micromol / kg fat-free mass FFM / min) and glucose disposal (Rd) (41.7 +/- 5.7 and 38.9 +/-4.7 micromol / kg FFM / min were similar during placebo and vanadyl sulfate administration, respectively. Hepatic glucose output (HGO) was completely suppressed in both studies. In contrast, in NIDDM subjects, vanadyl sulfate increased GIR approximately 82% (17.3 +/- 4.7 to 30.9 +/- 2.7 micromol / kg FFM / min, P < 0.05); this improvement in insulin sensitivity was due to both augmented stimulation of Rd (26.0 +/-4.0 vs. 33.6 +/- 2.22 micromol / kg FFM / min, P < 0.05) and enhanced suppression of HGO (7.7 +/- 3.1 vs. 1.3 +/- 0.9 micromol / kg FFM / min, P < 0.05). Increased insulin-stimulated glycogen synthesis accounted for >80% of the increased Rd with vanadyl sulfate (P < 0.005), but plasma glucose flux via glycolysis was unchanged. In NIDDM subjects, vanadyl sulfate was also associated with greater suppression of plasma free fatty acids (FFAs) (P < 0.01) and lipid oxidation (P < 0.05) during clamps. The reduction in HGO and increase in Rd were both highly correlated with the decline in plasma FFA concentrations during the clamp period (P < 0.001). In conclusion, small oral doses of vanadyl sulfate do not alter insulin sensitivity in nondiabetic subjects, but it does improve both hepatic and skeletal muscle insulin sensitivity in NIDDM subjects in part by enhancing insulin's inhibitory effect on lipolysis. These data suggest that vanadyl sulfate may improve a defect in insulin signaling specific to NIDDM.

Administration, Oral↗

PubMed1996

Correlation between the progression of optic disc and visual field changes in glaucoma.

Visual field test and optic disc evaluation are the standard examination techniques used to detect the onset and progression of glaucoma. This explorative study was performed to assess the temporal correlation between visual field and optic disc changes in eyes with ocular hypertension and well-established glaucoma. Eighty-six hypertensive and 16 glaucomatous eyes were followed up for a period of up to 9 years (average 4.4 yrs) using kinetic and computerized static perimetry and optic disc manual morphometry. Perimetric changes were based on a series of strict criteria and optic disc changes were based as a reduction in the baseline rim area/disc area ratio (R/D) measurement exceeding the 99% confidence interval for intraobserver reproducibility (7.7%). Optic disc changes were found prior to visual field changes in four hypertensive eyes, whereas visual field changes were found prior to disc changes in six glaucomatous eyes (p = 0.042). The results of our explorative study suggest that quantitative optic disc analysis may be more sensitive than visual field examination in detecting early glaucomatous changes, whereas visual field examination may be more sensitive than quantitative optic disc analysis in detecting glaucomatous progressions in eyes with well established glaucoma.

Aged↗

PubMed1995

Effects of fasting on hepatic and peripheral glucose metabolism in conscious rats with near-total fat depletion.

Experimental diabetes and fasting are both associated with hypoinsulinaemia and share several other metabolic features. We investigated hepatic and peripheral glucose metabolism in young rats after near-total depletion of their fat mass. Conscious rats were fasted for 72 h (n = 13), while 6 h-fasted animals (n = 14) served as controls. Rats were studied either during saline infusion or insulin (18 m-units/kg per min)-clamp studies. In fasting, despite a 2-fold increase in hepatic glucose-6-phosphatase (Glc-6-Pase) Vmax. (from 16 +/- 2 mumol/g of liver per min in control; P < 0.001), the basal hepatic glucose production (HGP) decreased by 47% [from 88 +/- 3 mumol/kg lean body mass (LBM) per min in control; P < 0.01]. The decreased HGP in fasting was associated with a 70% decrease in the hepatic levels of glucose 6-phosphate (Glc-6-P) (from 366 +/- 53 nmol/g wet wt. in control; P < 0.01). Thus Glc-6-Pase activity assayed in the presence of the Glc-6-P levels found in vivo was decreased by 44%. During hyperinsulinaemia, peripheral glucose uptake was decreased by 15% with 3 days of fasting (from 272 +/- 17 mumol/kg LBM per min in control; P < 0.01). This was completely accounted for by a 42% decrease in whole-body glycolysis (P < 0.01), while the rate of glycogen synthesis was unchanged. Thus fasting (after near-total fat depletion) differs from experimental diabetes because: (1) despite markedly increased Glc-6-Pase, HGP is decreased in fasting, due to a marked decrease in the substrate level (Glc-6-P) in vivo; and (2) the impairment in peripheral insulin sensitivity in fasting is due to a decrease in the glycolytic, and not the glycogen-synthetic, pathway.

Animals↗

PubMed1995

Glycogen synthase activity in two rat models of hypertension.

Several studies on both humans and animal models have reported a pathogenetic relationship among hyperinsulinism, insulin resistance, and hypertension. We have previously evaluated whole body glucose disposal and insulin sensitivity in different models of hypertensive rats, showing an increase rather than an impairment of glucose metabolism, which in turn was due to an improved ability of insulin to channel the absorbed glucose towards the nonoxidative disposal. Aiming to confirm our previous findings we performed the direct assay of skeletal muscle glycogen synthase on tissue samples from the previous clamp studies, as a rate limiting step enzyme of glycogen synthesis, under conditions of physiologic hyperinsulinemia and euglycemia. Glycogen synthase was assayed on samples from rectus muscle tissues of spontaneously hypertensive rats and high sodium, one kidney, one figure-8 hypertensive rats. Compared to controls, our data show an increased activity of glycogen synthase in the hypertensive animals, which is consistent with the increased glycogen synthesis previously reported. In conclusion, under our experimental conditions, hypertension and chronic hyperadrenergism are associated with an increased ability of insulin to stimulate glucose uptake and disposal. These latter effects are mainly due to an increase in nonoxidative disposal and glycogen synthase activity.

Animals↗

PubMed1995

Relationship between changes in body composition and insulin responsiveness in models of the aging rat.

Increased body weight (BW) is one of several confounding factors that may contribute to the development of insulin resistance in human aging. Therefore aging-associated increase in BW was determined by 3H2O in Sprague-Dawley (S-D, n = 40) rats and was highly correlated with increased lean body mass (LBM), fat mass (FM), and plasma insulin and free fatty acid (FFA) levels (r2 > 0.850, P < 0.01 for all). Insulin (18 mU.kg-1.min-1) responsiveness (Rd; 270 +/- 10 mumol.kg LBM-1.min-1, P < 0.01) decreased by 17% between 2 and 4 mo but did not decline further at 14 mo. This decrease was inversely correlated with the increase in FM between 2 and 4 mo (r2 = 0.522, P < 0.05). The decline in Rd was accompanied by an approximately 20% decrease in glycolytic rate by 4 mo (P < 0.01) and in glycogen synthesis rate at 14 mo (P < 0.01) compared with 2-mo rats. Thus early impairment in intracellular glucose metabolism occurred concomitantly with an initial, rapid, and disproportionate increase in FM compared with LBM. Further increases in FM after 4 mo of age were not associated with a further decrease in insulin responsiveness in either S-D or Fischer 344 aging rats.

Aging↗

PubMed1995

Quantitation of hepatic glucose fluxes and pathways of hepatic glycogen synthesis in conscious mice.

Mice were studied with the euglycemic hyperinsulinemic and the hyperglycemic clamp techniques after a 6-h fast: 1) euglycemic (6.7 +/- 0.2 mM) hyperinsulinemia (approximately 800 microU/ml); 2) hyperglycemic (15.3 +/- 0.4 mM) hyperinsulinemia (approximately 800 microU/ml). All mice received an infusion of [3-3H]glucose and [U-14C]lactate. Basal hepatic glucose production (HGP) averaged approximately 170 mumol.kg-1.min-1 in both groups. During euglycemic and hyperglycemic hyperinsulinemia, HGP decreased by 53% (to 76.7 +/- 11.1 mumol.kg-1.min-1; P < 0.01) and 74% (to 43.3 +/- 7.2 mumol.kg-1.min-1; P < 0.01), respectively. Hyperglycemia increased glucose cycling (by 2.1-fold; P < 0.01) and the contribution of gluconeogenesis to HGP (88 vs. 43%; P < 0.01) while decreasing that of glycogenolysis (12 vs. 57%; P < 0.01). The percentage of neosynthetized hepatic glycogen formed via the direct pathway was markedly increased during hyperglycemia (53 +/- 2% vs. 23 +/- 3%; P < 0.01): These data indicate that the assessment of hepatic glucose fluxes can be accomplished in conscious unrestrained mice and that, in the presence of hyperinsulinemia, hyperglycemia causes 1) a further inhibition of HGP mainly via inhibition of glycogenolysis and increase in hepatic glucose cycling; and 2) about a fivefold stimulation in the direct pathway of hepatic glycogen formation.

Animals↗

PubMed1995

Oral vanadyl sulfate improves hepatic and peripheral insulin sensitivity in patients with non-insulin-dependent diabetes mellitus.

We examined the in vivo metabolic effects of vanadyl sulfate (VS) in non-insulin-dependent diabetes mellitus (NIDDM). Six NIDDM subjects treated with diet and/or sulfonylureas were examined at the end of three consecutive periods: placebo for 2 wk, VS (100 mg/d) for 3 wk, and placebo for 2 wk. Euglycemic hyperinsulinemic (30 mU/m2.min) clamps and oral glucose tolerance tests were performed at the end of each study period. Glycemic control at baseline was poor (fasting plasma glucose 210 +/- 19 mg/dl; HbA1c 9.6 +/- 0.6%) and improved after treatment (181 +/- 14 mg/dl [P < 0.05], 8.8 +/- 0.6%, [P < 0.002]); fasting and post-glucose tolerance test plasma insulin concentrations were unchanged. After VS, the glucose infusion rate during the clamp was increased (by approximately 88%, from 1.80 to 3.38 mg/kg.min, P < 0.0001). This improvement was due to both enhanced insulin-mediated stimulation of glucose uptake (rate of glucose disposal [Rd], +0.89 mg/kg.min) and increased inhibition of HGP (-0.74 mg/kg.min) (P < 0.0001 for both). Increased insulin-stimulated glycogen synthesis (+0.74 mg/kg.min, P < 0.0003) accounted for > 80% of the increased Rd after VS, and the improvement in insulin sensitivity was maintained after the second placebo period. The Km of skeletal muscle glycogen synthase was lowered by approximately 30% after VS treatment (P < 0.05). These results indicate that 3 wk of treatment with VS improves hepatic and peripheral insulin sensitivity in insulin-resistant NIDDM humans. These effects were sustained for up to 2 wk after discontinuation of VS.

Administration, Oral↗

PubMed1995

In vivo glucosamine infusion induces insulin resistance in normoglycemic but not in hyperglycemic conscious rats.

To test the hypothesis that increased flux through the hexosamine biosynthetic pathway can induce insulin resistance in skeletal muscle in vivo, we monitored glucose uptake, glycolysis, and glycogen synthesis during insulin clamp studies in 6-h fasted conscious rats in the presence of a sustained (7-h) increase in glucosamine (GlcN) availability. Euglycemic (approximately 7 mM) insulin (approximately 2,500 pM) clamps with saline or GlcN infusions were performed in control (CON; plasma glucose [PG] = 7.4 +/- 0.2 mM), diabetic (D; PG = 19.7 +/- 1.1), and phlorizin-treated (3-wk) diabetic rats (D + PHL; PG = 7.6 +/- 0.9). 7-h euglycemic hyperinsulinemia with saline did not significantly decrease Rd (360-420 min = 39.2 +/- 3.6 vs. 60-120 min = 42.2 +/- 3.7 mg/kg.min; P = NS). GlcN infusion raised plasma GlcN concentrations to approximately 1.2 mM and increased muscle and liver UDP-GlcNAc levels by 4-5-fold in all groups. GlcN markedly decreased Rd in CON (360-420 min = 30.4 +/- 1.3 vs. 60-120 min = 44.1 +/- 3.5 mg/kg.min; P < 0.01) and D + PHL (360-420 min = 29.4 +/- 2.5 vs. 60-120 min = 43.8 +/- 2.9 mg/kg.min; P < 0.01), but not in D (5-7 h = 21.5 +/- 0.8 vs. 0-2 h = 24.3 +/- 1.1 mg/kg.min; P = NS). Thus, increased GlcN availability induces severe skeletal muscle insulin resistance in normoglycemic but not in chronically hyperglycemic rats. The lack of additive effects of GlcN and chronic hyperglycemia (experimental diabetes) provides support for the hypothesis that increased flux through the GlcN pathway in skeletal muscle may play an important role in glucose-induced insulin resistance in vivo.

Animals↗

PubMed1995

Counterregulation of hypoglycemia. Skeletal muscle glycogen metabolism during three hours of physiological hyperinsulinemia in humans.

We examined the role of skeletal muscle in counterregulation of hypoglycemia (3.4 +/- 0.1 mmol/l) in 12 nondiabetic individuals (age 26 +/- 1 years, body mass index 24.2 +/- 0.7 kg/m2) during physiological hyperinsulinemia (280 +/- 25 pmol/l) compared with euglycemia (4.8 +/- 0.1 mmol/l). During hypoglycemia, hepatic glucose output (3-[3H]-glucose) was greater (7.72 +/- 2.72 mumol.kg-1.min-1, P < 0.01), glucose uptake was approximately 49% lower (21.20 +/- 3.55 mumol.kg-1.min-1, P < 0.005), and glucose clearance was reduced (P < 0.002) compared with euglycemia. Rates of flux of plasma-derived glucosyl units through glycolysis were similar in the two experiments, while glycogen synthetic rates were significantly reduced during hypoglycemia (P < 0.01) and accounted entirely for the reduction in glucose disposal. The insulin-induced activation of skeletal muscle glycogen synthase (reflected by Km decline by approximately 50% from 0.408 +/- 0.056 mmol/l and fractional velocity increase by approximately twofold from 21.8 +/- 2.7%) was completely abolished in hypoglycemia. In concert, glycogen phosphorylase activity increased during hypoglycemia by approximately 40% (P = 0.0001). Hypoglycemia resulted in seven- to eightfold increments in plasma epinephrine (P < 0.0001) and growth hormone (P < 0.001) and 40-60% increments in plasma glucagon (P < 0.005) and cortisol (P < 0.05). We conclude that, in this model of mild hypoglycemia of moderate duration, the majority of the glucose made available during the counterregulatory process (approximately 60-70%) is due to the limitation of glucose disposal, mostly via decreased glycogen synthetic activity in skeletal muscle.

Adult↗

PubMed1995

[Long-term prognosis after coronary angioplasty in relation to the presence of modifiable factors of coronary risk].

Short-term outcome after coronary angioplasty is mainly determined by restenosis, while long-term outcome is determined by new events due to incomplete revascularization, by atherosclerosis progression and by late-restenosis. The aim of this study is to assess if correctly treated coronary risk factors are predictors of poor prognosis after coronary angioplasty. Two-hundred and twenty six patients (209 males, 17 females, mean age 56 +/- 9 years) with successful coronary angioplasty were treated for coronary risk factors. New events (death, myocardial infarction, repeat angioplasty, bypass surgery) were recorded. Ischemia was evaluated by serial exercise tests. The mean follow-up was 31 +/- 12 months. Survival was 99.5% at 1 year and 97.4% after 5 years; "event free survival" was 84.6% at 1 year and 65.9% after 5 years; "ischemia free survival" was 84.6% at 1 year and 44.8% after 5 years. "Ischemia free survival" was higher in patients with single coronary angioplasty and in patients with infarct-related vessel angioplasty. Smoke addiction, diabetes, hypercholesterolemia and hypertension were not significantly correlated with "ischemia free survival". Smokers and diabetics had a trend towards a less favorable 5 year outcome, but without statistical differences. In conclusion, this study shows that correctly treated coronary risk factors do not worsen prognosis after coronary angioplasty.

Aged↗

PubMed1995

Glucose toxicity: the implications of hyperglycemia in the pathophysiology of diabetes mellitus.

Non-insulin-dependent diabetes mellitus (NIDDM) results from a disruption of normal glucose homeostasis, primarily insulin secretion and hepatic and peripheral insulin action. However, chronic hyperglycemia has been shown in animal models to contribute to impaired insulin secretion as well as to peripheral insulin resistance. Consequently, stringent control measures aimed at ameliorating chronically elevated blood glucose levels may help lessen the cellular "toxic" effect of hyperglycemia.

Animals↗

PubMed1994

Reproducibility of retinal nerve fiber layer evaluation by dynamics scanning laser ophthalmoscopy.

Scanning laser ophthalmoscopy is a laser-based image acquisition technique, which greatly improves the quality of the examination of the fundus and the retinal nerve fiber layer. To assess retinal nerve fiber layer imaging by scanning laser ophthalmoscopy and evaluate intra- and interobserver reproducibility in the classification of retinal nerve fiber layer defects, three independent observers evaluated on two separate occasions the videotaped images of 150 eyes of 80 consecutive patients with ocular hypertension or glaucoma. Ophthalmoscopy was performed using argon blue light (488 nm), confocal apertures of 3 to 1 mm, and 40-degree and 20-degree field angles. Of 150 eyes, 20 (13.3%) were excluded from the study because of the poor quality of the images (clinically significant cataract or myopic peripapillary atrophy). The retinal nerve fiber layer was evaluated qualitatively according to a standard classification: normal pattern, slit, wedge, and diffuse defects. Intraobserver reproducibility, evaluated by kappa statistic, was excellent (> or = 0.75): observer A = 0.78 (95% confidence limits, 0.67-0.88); observer B = 0.84 (95% confidence limits, 0.72-0.96); and observer C = 0.79 (95% confidence limits, 0.67-0.91). Interobserver reproducibility was also excellent in all cases: observers A-B = 0.84 (95% confidence limits, 0.71-0.98); observers A-C = 0.76 (95% confidence limits, 0.65-0.87); and observers B-C = 0.80 (95% confidence limits, 0.69-0.92). Kappa values ranged between 0.59 and 0.69 for intraobserver reproducibility and between 0.55 and 0.69 for interobserver reproducibility when using only those eyes in which abnormalities were noted by at least one observer.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1994

Altered body composition and increased frequency of diverse malignancies in insulin-like growth factor-II transgenic mice.

The physiological role of insulin-like growth factor (IGF) II (IGF-II) in adult humans is poorly understood. Rather high levels of IGF-II persist in adult human serum, whereas, in rodents, IGF-II levels are very low. To investigate the physiological and carcinogenic effects of persistently elevated IGF-II in adults, we have produced two lines of transgenic mice in which high levels of IGF-II (20- or 30-fold increase above normal) are persistently maintained in the blood. The transgene is driven by the major urinary protein promoter, and it is highly expressed in the liver and perputial glands in both lines. The adult transgenic mice are smaller than controls, and their body composition is altered. Their lean body mass is reduced by 5-8%, whereas fat mass is reduced between 44 and 77%. The mice expressing the highest level of IGF-II (30x) develop hypoglycemia and hypoinsulinemia and IGF-I levels are normal. Mice in the lower expression line (20-fold elevated IGF-II) develop hypoglycemia progressively over their lifetime. Mice from both lines also develop a diverse spectrum of tumors at a higher frequency than controls after 18 months of age, and the most frequent types of tumors are hepatocellular carcinomas and lymphomas. Squamous cell carcinoma, sarcoma, and thyroid carcinomas also occurred in our test group. The long latent period before tumors arise and the wide spectrum of tumor types suggest that IGF-II may function primarily as a tumor progression factor in mice via autocrine and endocrine mechanisms of action.

Animals↗