Biomedical subjects

C H Lang

Publications and source records attributed to C H Lang.

At least 55 records · Page 3Linked to original sources

PubMed1998

Albumin synthesis and bone collagen formation in human immunodeficiency virus-positive subjects: differential effects of growth hormone administration.

Loss of lean tissue often accompanies human immunodeficiency virus (HIV) infection. Exogenous human recombinant GH (hrGH) has been shown to be beneficial in reversing this wasting. However, catabolic effects of hrGH on muscle protein metabolism have also been reported. Therefore, the responsiveness of other GH-sensitive tissues, including bone formation and albumin synthesis, has been examined. Anabolic activity in bone, from serum levels of carboxy-terminal propeptide of type I collagen, was stimulated by 2 weeks of hrGH in controls (56 +/- 15%, P = 0.002), patients with asymptomatic HIV (24 +/- 10%, not significant), patients with AIDS (47 +/- 7%, P < 0.001), and patients with AIDS and > 10% weight loss (21 +/- 12%, P = 0.02). Albumin synthesis, determined from the incorporation of L-[2H5]phenylalanine, was increased in response to hrGH in controls (23 +/- 7%, P < 0.05), HIV+ subjects (39 +/- 16%, P < 0.05), and patients with AIDS (25 +/- 7%, P < 0.01). Patients with AIDS and weight loss, however, did not increase albumin synthesis (-0.6 +/- 12%) in response to hrGH. The results indicate variable anabolic responses to hrGH. Bone collagen synthesis remained sensitive to hrGH, whereas, the anabolic action of hrGH on the synthesis of albumin diminished with severity of disease. However unlike muscle protein synthesis, albumin synthesis was not depressed below basal levels by hrGH.

Acquired Immunodeficiency Syndrome↗

PubMed1998

Modulation of the insulin-like growth factor system by chronic alcohol feeding.

Insulin-like growth factor (IGF)-I is a potent anabolic agent that plays an important role in regulating muscle protein balance. Alterations in one or more of the various components of the IGF system may be in part responsible for the muscle wasting that accompanies chronic alcohol consumption. The purpose of the present study was to characterize changes in the growth hormone-IGF axis produced by chronic alcohol consumption in rats. After 8 weeks of alcohol feeding, the IGF-I concentration was decreased in plasma (31%) as well as in the liver and skeletal muscle (40-50%), compared with pair-fed control animals. In addition, alcohol consumption decreased IGF-I mRNA abundance in liver and muscle (approximately 50%). IGF-I content in duodenum and kidney, however, was not altered by alcohol feeding. Concomitantly, the relative concentration of IGF binding protein (IGFBP)-1 was increased in plasma, liver, and muscle of alcohol-fed rats, compared with control values. In contrast, no changes in the plasma concentrations of IGFBP-2, -3, or -4 were detected in alcohol-fed rats at this time point Previous studies have indicated that elevations in glucocorticoids or decreases in insulin or growth hormone might be responsible for the decrease in IGF-I and/or the increase in IGFBP-1 in other catabolic conditions. However, there was no difference in the plasma concentrations of these hormones between alcohol-fed and control animals in this study. These data indicate that chronic alcohol feeding in rats decreases IGF-I and increases IGFBP-1 in the circulation and in skeletal muscle and that these changes appear to be independent of changes in classical hormonal regulators of the IGF system. The observed alterations in the IGF system are consistent with a reduction in the anabolic actions of IGF-I induced by chronic alcohol consumption.

Alcoholism↗

PubMed1997

Responsiveness of muscle protein synthesis to growth hormone administration in HIV-infected individuals declines with severity of disease.

This study was undertaken to determine if human recombinant growth hormone (hrGH, 6 mg/d for 2 wk) would stimulate muscle protein synthesis in AIDS wasting. Healthy controls were compared with patients who were HIV+, had AIDS without weight loss, and had AIDS with > 10% weight loss. Before hrGH, rates of skeletal muscle protein synthesis, measured with l-[2H5]phenylalanine, were the same in controls and in all stages of disease. Rates of myofibrillar protein degradation, however, assessed from urinary excretion of 3-methyl histidine, were higher in AIDS and AIDS wasting than in HIV+ or healthy individuals. The group with weight loss had significantly higher TNFalpha levels but not higher HIV viral loads. Muscle function, as determined by isokinetic knee extension and shoulder flexion, was significantly higher in controls than all infected individuals. After GH, rates of protein synthesis were stimulated 27% in controls, with a smaller increase (11%) in HIV+, and a significant depression (42%) in AIDS with weight loss, despite fourfold elevation in insulin-like growth factor-I in all groups. There was a significant correlation of hrGH-induced changes in muscle protein synthesis with severity of disease (P = 0.002). The results indicate increased basal muscle protein degradation and decreased responsiveness of muscle protein synthesis to GH in the later stages of disease.

Adult↗

PubMed1997

Insulin stimulates lipoprotein lipase activity and synthesis in adipocytes from septic rats.

Gram-negative sepsis suppresses lipoprotein lipase (LPL) activity in adipose tissue which contributes, in part, to the altered clearance of triglycerides. The suppression in LPL activity occurs when plasma insulin concentrations are elevated and insulin-stimulated glucose utilization is impaired. This study was planned to evaluate whether the presence of insulin resistance was responsible for the decrease in adipose LPL activity. Adipocytes were isolated from epididymal fat pads 24 h after inducing sepsis in male Lewis rats by intravenous injection of 4 x 10(8) colonies of live Escherichia coli/100 g body wt. The decrease in heparin-releasable (HR) LPL activity in adipocytes from the septic rats was evident at the time of isolation and maintained in a 20-h culture. After overnight incubation with insulin (10(-8) M), HR LPL activity was stimulated to a greater extent in adipocytes from septic rats (298%) than in adipocytes from control rats (88%). The insulin stimulation of LPL activity during sepsis could not be attributed to insulin-like growth factor-I (IGF-I) as adipocytes from septic rats appeared to be IGF-I resistant. Insulin-treatment (10(-8) M) increased LPL synthesis 99% in adipocytes from control rats and 136% in adipocytes from septic rats. Insulin treatment also led to a 65 and 62% increase in LPL mass in adipocytes from control and septic rats, respectively. These findings indicate that the sepsis-induced decrease in adipose LPL is not due to insulin resistance with respect to LPL. The insulin stimulation of LPL activity in adipocytes from septic rats appears to be mediated by an increase in LPL synthesis.

Adipocytes↗

PubMed1997

Involvement of capsaicin-sensitive nerves in regulating the hormone and glucose metabolic response to endotoxin.

This study investigated the role that sensory nerves play in mediating the hormone and glucose metabolic response to endotoxin [lipopolysaccharide (LPS)]. Adult rats were pretreated subcutaneously with capsaicin to selectively destroy primary sensory afferent nerve fibers. Ten days later, [3-3H]glucose was infused intravenously to assess whole body glucose flux before and after the intravenous injection of Escherichia coli LPS (100 micrograms/100 g body wt). Control animals responded to LPS with characteristic increases in the plasma concentration of glucose (91%) and lactate (threefold) and elevations in the rates of glucose appearance and disappearance (77%). In capsaicin-treated rats, the maximal LPS-induced increase in these parameters was attenuated by 50-60%. In addition, these animals were hypoglycemic at the conclusion of the experiment. Control animals demonstrated early and sustained elevations in circulating levels of corticosterone, glucagon, and catecholamines. In contrast, the early LPS-induced elevation in epinephrine and norepinephrine, and to a lesser extent glucagon, was completely absent or greatly impaired by capsaicin pretreatment. In a separate study, the epinephrine-induced increase in glucose flux was blunted by 75% in capsaicin-treated rats. These data indicate that sensory afferent neurons play a critical role in the early secretory response of glucagon and catecholamines, the maintenance of tissue catecholamine responsiveness, and the stimulation of glucose production after LPS.

Animals↗

PubMed1997

Ventromedial hypothalamic lesions impair glucoregulation in response to endotoxin.

The purpose of the present study was to determine the role of the ventromedial hypothalamus (VMH) in regulating counter-regulatory hormone release and the increase in glucose flux that is observed after injection of endotoxin [lipopolysaccharide (LPS)]. Bilateral lesions of the VMH were produced electrolytically 2 wk before the experiment; sham-operated rats served as controls. [3-3H]glucose was infused to assess whole body glucose flux before and for 4 h after intravenous injection of Escherichia coli LPS. In control rats, LPS increased the plasma concentrations of glucose and lactate and the rates of glucose appearance and disappearance. In these animals, LPS also produced sustained elevations in corticosterone, glucagon, and catecholamines. In contrast, the glucose metabolic response to LPS was attenuated by > 50% in VMH-lesioned rats. These changes were associated with a blunted increase in the plasma concentration of glucagon, epinephrine, and norepinephrine in VMH-lesioned rats compared with control animals. There was no difference in the plasma concentrations of corticosterone or TNF-alpha between the two groups after LPS or the responsiveness of sham- and VMH-lesioned rats to an infusion of either glucagon or epinephrine. These data indicate that the VMH plays a central role in regulating the secretion of glucagon and catecholamines and the stimulation of glucose flux after LPS.

Animals↗

PubMed1997

Differential role of glucocorticoids in mediating endotoxin-induced changes in IGF-I and IGFBP-1.

The purpose of the present study was to determine whether endogenous elevations in glucocorticoids mediate the changes in insulin-like growth factor (IGF) 1 and IGF binding protein (IGFBP) 1 levels in plasma and tissues observed after in vivo administration of lipopolysaccharide (LPS). In overnight-fasted male rats LPS injected via the tail vein decreased the IGF-I concentration in plasma, liver, and skeletal muscle (30-45%) and increased IGF-I content in kidney (approximately 3-fold). LPS also decreased IGF-I mRNA abundance in liver and muscle and increased gene expression in kidney. Concomitantly, IGFBP-1 levels in plasma, liver, and muscle were markedly elevated by LPS. All these changes were associated with a greater than fourfold elevation in plasma corticosterone. Pretreatment of rats with the glucocorticoid receptor antagonist RU-486 completely prevented or blunted the LPS-induced changes in IGF-I content in plasma, liver, muscle, and kidney. In liver and muscle RU-486 significantly attenuated the reduction in IGF-I mRNA abundance produced by LPS, but in kidney the LPS-induced increase in IGF-I mRNA was still evident. In contrast, pretreatment with RU-486 did not prevent or attenuate the LPS-induced increase in IGFBP-1 levels in plasma, liver, or muscle. These data suggest that glucocorticoids play a major role in regulating IGF-I mRNA and peptide content in tissues in response to LPS, but the increased IGFBP-1 in blood and tissues induced by LPS appears largely glucocorticoid independent.

Animals↗

PubMed1997

Acute alterations in growth hormone-insulin-like growth factor axis in humans injected with endotoxin.

The purpose of the present study was to characterize the acute changes in the insulin-like growth factor (IGF) system in humans after administration of endotoxin (lipopolysaccharide; LPS). Escherichia coli LPS (4 ng/kg) was injected intravenously into healthy adults, and serial blood samples were collected for the next 5 h; subjects injected with saline served as time-matched controls. LPS administration resulted in a gradual decrease in the total extractable IGF-I concentration, which was reduced by approximately 20% over the final 2 h of the experiment; levels of free IGF-I were not significantly altered. LPS also produced a marked but transient elevation in growth hormone (GH) concentration. IGF-binding protein (BP)-1 levels were elevated more than fivefold 2 h after LPS injection, and thereafter levels gradually returned toward baseline. IGFBP-2 concentration also increased after LPS injection, but the maximal increase (approximately 50% above basal) was observed during the final 2 h of the protocol. In contrast, IGFBP-3 levels did not vary over the period examined in response to LPS, and there was no apparent increase in number of BP-3 proteolytic fragments. Cortisol levels were increased early and remained two- to threefold above baseline throughout the protocol. No significant alterations in serum concentration of glucose or insulin were noted. LPS also produced an early elevation in tumor necrosis factor and a later increase in interleukin-6. These data indicate that the acute changes in the GH-IGF axis in humans in response to LPS are comparable with those observed in humans in other traumatic conditions and in animal models of endotoxemia and infection.

Adolescent↗

PubMed1997

Transient exposure of human myoblasts to tumor necrosis factor-alpha inhibits serum and insulin-like growth factor-I stimulated protein synthesis.

Tumor necrosis factor-alpha (TNF-alpha) induces cachexia and is postulated to be responsible for muscle wasting in several pathophysiological conditions. The purpose of the present study was to investigate whether exposure of human myoblasts to TNF-alpha could directly inhibit the ability of serum or insulin-like growth factor I (IGF-I) to stimulate protein synthesis as assessed by the incorporation of [3H]phenylalanine into protein. Serum and IGF-I stimulated protein synthesis dose dependently. Half-maximal stimulation of protein synthesis occurred at 05% serum and 8 ng/ml of IGF-I, respectively. TNF-alpha inhibited IGF-I-stimulated protein synthesis in a dose-dependent manner. Additionally, as little as 2 ng/ml of TNF-alpha impaired the ability of IGF-I to stimulate protein synthesis by 33% and, at a dose of 100 ng/ml, TNF-alpha completely prevented the increase in protein synthesis induced by either serum or a maximally stimulating dose of IGF-I. Inhibition of protein synthesis was independent of whether TNF-alpha and growth factors were added to cells simultaneously or if the cells were pretreated with growth factors. Exposure ofmyoblasts to TNF-alpha for 10 min completely inhibited serum-induced stimulation of protein synthesis. TNF-alpha inhibited protein synthesis up to 48 h after addition of the cytokine. TNF-alpha also inhibited serum-stimulated protein synthesis in human myoblasts that were differentiated into myotubes. In contrast, exposure of myoblasts to TNF-alpha had no effect on IGF-I binding and failed to alter the ability of either IGF-I or serum to stimulate [3H]thymidine uptake. These data indicate that transient exposure of myoblasts or myotubes to TNF-alpha inhibits protein synthesis. Thus, the anabolic actions of IGF-I on muscle protein synthesis may be impaired during catabolic conditions in which TNF-alpha is over expressed.

Cells, Cultured↗

PubMed1996

IL-6 stimulation of insulin-like growth factor binding protein (IGFBP)-1 production.

TNF alpha and IL-1 beta have previously been shown to increase the IGFBP-1 concentration in plasma and liver under in vivo conditions. The present study demonstrates that another inflammatory cytokine, IL-6, also elevates a 30- to 32-kDa IGF binding protein in the plasma of mice. Moreover, IL-6 produced dose- and time-dependent increases in IGFBP-1 production by HepG2 cells. The maximal IL-6-induced increase in IGFBP-1 was comparable to that observed with dexamethasone, and this increase was attenuated by diltiazem or dantrolene, both of which are known to reduce the cytosolic Ca2+ concentration. Finally, incubation of HepG2 cells with TNF alpha or IL-1 beta also increased IGFBP-1 in a dose-dependent manner. These results demonstrate that IGFBP-1 production is mediated directly by proinflammatory cytokines and suggest that this mechanism may be important for the upregulation of IGFBP-1 seen in catabolic conditions associated with overexpression of these cytokines.

Animals↗

PubMed1996

Contribution of excitatory amino acids to morphine-induced metabolic alterations.

Previous studies have indicated that excitatory amino acids are involved in the analgesic and addictive properties of morphine. However, their role in the morphine-induced alterations in glucose metabolism is not known. This study assessed the contribution of NMDA receptor activation to the morphine-induced hormonal and metabolic alterations in conscious unrestrained chronically catheterized rats. Whole body glucose flux was assessed with a primed constant intravenous infusion of [3-3H]glucose in rats pretreated with the NMDA-receptor antagonist MK-801 (0.25 mg/kg, intraarterial) or an equal volume (1.5 ml) of sterile saline (0.9%) administered 15 min prior to i.c.v. injection of H2O (Con; 5 microliters) or morphine sulfate (80 micrograms). No significant alterations were noted in metabolic and hormonal parameters of H2O injected rats. i.c.v. morphine increased the plasma glucose concentration (60%), hepatic glucose production (Ra; 60%) and whole body glucose utilization (Rd; 53%), but did not alter the glucose metabolic clearance rate (MCR). MK-801 alone resulted in transient hyperglycemia (25%), stimulation of glucose Ra (60%) and glucose Rd (53%), and a significant (30%) increase in MCR. MK-801 pretreatment blunted the morphine-induced hyperglycemia and the increased glucose Ra and Rd. Morphine increased the plasma concentration of epinephrine (4-fold), norepinephrine (2-fold) and corticosterone (67%); however, no alterations in plasma insulin and glucagon were detected. MK-801 pretreatment, blunted the morphine-induced increase in corticosterone and norepinephrine, and elicited a significant rise in insulin concentrations. These results indicate that activation of the NMDA receptors contributes to the morphine-induced hyperglycemia and hormonal alterations. Furthermore, this response appears partially mediated by activation of sympathetic outflow and suppression of insulin release, which is blunted by inhibition of NMDA receptors.

Animals↗

PubMed1996

Double minutes in the papillary thyroid cancer cell line PTC-1113A.

The cell line PTC-1113A was established from a metastasizing recurrent papillary thyroid cancer. The cell line was growing as monolayer and showed a complex karyotype with chromosome numbers ranging from 30 to 140/metaphase. A proportion of metaphases contained double minutes and/or pulverized chromosomes. Extrachromosomal DNA seemed to originate from a B-group chromosome. A chromosome 4 painting probe hybridized to extrachromosomal material, representing double minutes (dmin) and possibly minutes. In addition, fluorescence in situ hybridization (FISH) with the chromosome 4 library detected a translocation chromosome and a pulverized chromosome originating from chromosome 4. PTC-1113A is, to our knowledge, the single papillary thyroid cancer cell line demonstrating evidence of gene amplification.

Aged↗

PubMed1996

Central opiate modulation of growth hormone and insulin-like growth factor-I.

The effects of central administration of morphine-sulfate (MOR:80 micrograms) and morphine-6-glucuronide (M6G:1 microgram) on the growth hormone (GH)/insulin-like growth factor (IGF) system were assessed. MOR and M6G were injected intracerebroventricularly (ICV) in chronically catheterized 24 h fasted rats; time-matched control animals received H2O (5 microliters). MOR increased plasma GH concentrations 3-fold 2 h after i.c.v. injection, and transiently increased the plasma concentration and liver content of IGF-I (60% and 90%, respectively) 30 min after i.c.v injection. M6G did not produce any significant alterations in plasma GH and IGF-I levels at the time-points measured. Both MOR and M6G increased the concentration of IGF binding protein-1 (IGFBP-1) in plasma and liver 2 h after injection. However, MOR showed 2- to 2.5-fold greater effect than M6G in stimulating plasma and liver IGFBP-1. MOR and M6G produced similar increases in plasma epinephrine (5-fold), norepinephrine (3-fold) and corticosterone (1.5-fold). Neither opiate significantly altered circulating insulin levels. These findings suggest that opiate modulation of GH and IGF may be hormone-independent and centrally modulated. We speculate that differential affinities of MOR and M6G to the different opiate receptor subtypes might be responsible for their distinct effects on GH/IGF-I system.

Animals↗

PubMed1996

Wasting in the acquired immune deficiency syndrome is associated with multiple defects in the serum insulin-like growth factor system.

OBJECTIVE: The aim of this investigation was to characterize the GH-IGF axis of patients with AIDS associated wasting. A special emphasis was placed on determining whether IGF binding proteins (IGFBPs) of patients who have lost more than 10% of their ideal body mass are structurally different from the IGFBPs of patients with no weight loss. DESIGN AND PATIENTS: A cross-sectional study of 11 AIDS patients was performed to determine whether the IGF system is abnormal in AIDS patients with wasting. Seven additional AIDS patients were followed longitudinally to determine whether AIDS patients experience long-term changes to their IGF system. MEASUREMENTS: Serum levels of GH and IGF-I were measured by radioimmunoassay, IGF-II was measured by radioreceptor assay, and IGFBP-1 was measured by an enzyme linked immunoassay. IGFBP-3 and IGFBP-3 protease activity were measured by ligand blotting and a BP-3 protease assay, respectively. IGFBP-3 ternary complex formation and IGFBP-1 phosphovariants were analysed by non-denaturing PAGE. RESULTS: AIDS patients who had lost more than 10% of their ideal body mass demonstrated a 55% reduction in serum IGF-I (81 vs 179 micrograms/l) and a 70% reduction in IGF-II (226 vs 776 micrograms/l), compared to healthy HIV negative subjects. IGF-I levels were depressed, in some patients, despite high serum levels of GH. AIDS patients who had lost more than 10% of their ideal body mass had low levels of IGFBP-3 and a reduced ability to form the IGFBP-3 ternary complex. The IGFBP-3 ternary complex could be restored only upon addition of pure IGFBP-3 and acid labile subunit to serum. Serum IGFBP-1 was increased more than threefold compared to control subjects (90 vs 24 micrograms/l). IGFBP-1 was present as a free phosphoprotein in AIDS patients with low levels of IGF-I and in a bound form when serum IGF-I levels were normal. Changes in the GH-IGF axis were sustained for up to 25 months in AIDS patients with wasting. CONCLUSIONS: AIDS wasting is associated with a GH resistant state that results in low levels of serum IGF-I, IGF-II and IGFBP-3, elevated levels of phosphorylated IGFBP-1, and a reduced ability to form the IGFBP-3 ternary complex.

Acquired Immunodeficiency Syndrome↗

PubMed1996

Regulation of the acid-labile subunit of the insulin-like growth factor ternary complex in patients with insulin-dependent diabetes mellitus and severe burns.

OBJECTIVE: Little information is available regarding the regulation of serum acid-labile subunit (ALS) in human disease. We have studied alterations in serum ALS of the insulin-like growth factor (IGF) ternary complex in children with untreated insulin-dependent diabetes mellitus (IDDM) and subjects with severe burns before and after insulin therapy. In addition, we have investigated the effect of insulin plus GH on serum ALS in burn patients. DESIGN: Serum samples were obtained from children with newly diagnosed and untreated IDDM before the initiation of insulin therapy and 1 month thereafter. Serum samples were also obtained from adult patients with severe burns who were on a continuous infusion of a carbohydrate-rich enteral diet via nasogastric and duodenal catheters under basal conditions, after a 1-week period of continuous insulin infusion, and after an additional week of insulin plus recombinant GH. PATIENTS: Twenty children and adolescents with untreated IDDM, aged 1.2-16 years, and 6 young adult patients with severe burns aged 17-28 years were studied longitudinally. Control sera were obtained from age, sex and pubertal status matched subjects (for children with IDDM) and from fed healthy adults. MEASUREMENTS: Serum insulin, GH, cortisol and IGF-I were measured by radioimmunoassay, and serum ALS levels were assessed by Western immunoblot before and after treatment periods. RESULTS: Serum ALS levels were lower in untreated children with IDDM (69 +/- 6% of control children). Insulin therapy significantly increased serum ALS (79 +/- 5%, P < 0.05) in these children. Patients with severe burns also had lower serum ALS levels (79 +/- 10% of control adults). After one week of insulin therapy serum ALS levels increased to 90 +/- 15% of control values (P < 0.05). Addition of GH to insulin therapy for another week did not significantly further increase serum ALS levels (95 +/- 27%). Serum IGF-I concentrations increased nearly 2.5-fold in diabetic subjects and fourfold in burn subjects at the end of the study periods. There were no proteolytic fragments of ALS in the sera studied. The deglycosylation pattern of ALS did not differ between diabetic and control sera. CONCLUSION: Serum ALS levels were diminished in children with untreated IDDM and were partially restored after the initiation of insulin therapy. Serum ALS levels were also diminished in patients with severe burn injury and restored by insulin treatment. Addition of GH to insulin therapy did not significantly increase serum ALS levels over levels obtained during insulin therapy alone. These decreases in serum ALS were smaller than the decrease in serum IGF-I concentrations in both conditions, suggesting that IGF-I is the limiting factor for the ternary complex formation in the catabolic states. Insulin may regulate circulating ALS levels in catabolic states and helps to restore the IGF system.

Acute Disease↗

PubMed1996

Insulin treatment normalizes reduced free insulin-like growth factor-I concentrations in diabetic children.

OBJECTIVE: We have recently demonstrated multiple aberrations in the GH-IGF axis in the sera of children with untreated insulin-dependent diabetes mellitus (IDDM) which were restored after insulin replacement. However, the net result of these alterations in the IGF system on the concentrations of free/biologically available IGF-I in the serum have not been examined directly in diabetic children. In the present study, the effect of diabetes and subsequent insulin replacement on the circulating free IGF-I concentrations are assessed. DESIGN: Fasting venous serum samples were obtained longitudinally, before and at various times after the initiation of insulin treatment in untreated diabetic subjects. SUBJECTS: Ten prepubertal, aged (mean +/- SEM) 6.3 +/- 1.0 years, and six adolescent, aged 12.7 +/- 1.1 years, subjects with newly diagnosed and untreated IDDM, and age and pubertal status-matched control children and adolescents were recruited. METHODS: The serum samples were collected before initiating insulin treatment and 12-24 h, 1 week, and 1 month thereafter in subjects with IDDM. Insulin doses ranged from 0.5 to 1.2 U/kg/day. MEASUREMENTS: Free IGF-I concentration was assayed by a recently developed two-site immunoradiometric assay. Total IGF-I was measured by radioimmunoassay after acid-ethanol extraction of binding proteins. Differences in free and total IGF-I concentrations in IDDM subjects before and during insulin treatment were analysed by repeated measures analysis of variance followed by pairwise multiple comparisons test. In seven subjects with IDDM, where serum IGFBP-1 and IGFBP-3 concentrations, and IGFBP-3 protease activity had also been measured in a previous study, the relationship between these variables and circulating free IGF-I concentrations were examined by linear regression analysis. RESULTS: Free IGF-I concentrations in prepubertal subjects with IDDM were 0.9 +/- 0.2, 1.5 +/- 0.3, 1.6 +/- 0.3 and 2.5 +/- 0.4 micrograms/l before, 1 day, 1 week and 1 month after insulin treatment, respectively. Free IGF-I concentrations of control prepubertal children were 2.6 +/- 0.5 micrograms/l. Pubertal subjects had higher free IGF-I concentrations than prepubertal subjects but demonstrated a similar type of pattern; before insulin 2.3 +/- 1.1, 1 day 3.8 +/- 1.3, 1 week 3.7 +/- 0.6, 1 month 6.5 +/- 1.5 vs pubertal controls 7.7 +/- 2.0 micrograms/l. Total IGF-I concentrations were also reduced in untreated diabetic subjects and showed a slower pattern of normalization than free IGF-I concentrations. Free IGF-I concentrations correlated positively with total IGF-I and negatively with IGFBP-1 concentrations. There was no significant correlation between free IGF-I and either serum IGFBP-3 concentrations or IGFBP-3 protease activity. CONCLUSION: Alterations in the IGF system during untreated IDDM lead to a reduction in circulating free IGF-I concentrations which is restored progressively during insulin treatment. An increase in free IGF-I precedes that of total IGF-I suggesting that the former is a more sensitive indicator of the metabolic status. An inverse correlation between free IGF-I and IGFBP-1 supports the hypothesis that IGFBP-1 plays an important role in the acute modulation of free IGF-I levels.

Adolescent↗

PubMed1996

Pyruvate dehydrogenase inactivity is not responsible for sepsis-induced insulin resistance.

OBJECTIVE: To determine whether activation of pyruvate dehydrogenase with dichloroacetate can reverse sepsis-induced insulin resistance in humans or rats. DESIGN: Prospective, controlled study. SETTING: Intensive care unit (ICU) and laboratory at a university medical center. SUBJECTS: Nine patients were admitted to the ICU with Gram-negative sepsis, confirmed by cultures. In addition, chronically instrumented, Sprague-Dawley rats, either controls or with live Escherichia coli-induced sepsis. INTERVENTIONS: Hyperinsulinemic euglycemic clamp, with or without coadministration of dichloroacetate. MEASUREMENTS AND MAIN RESULTS: In humans, a primed, constant infusion of [6,6-2H2]glucose was used to determine endogenous glucose production and whole-body glucose disposal. Septic humans exhibited impaired maximal insulin-stimulated glucose utilization (39.5 +/- 2.7 mumol/kg/min), despite complete suppression of endogenous glucose production. In rats, a primed, constant infusion of [3-3H]glucose was used to determine endogenous glucose production and whole-body glucose disposal. Tissue glucose uptake in vivo was determined by [14C]-2-deoxyglucose uptake. Maximal, whole-body, insulin-stimulated glucose utilization was 205 +/- 11 and 146 +/- 9 mumol/kg/min in control and septic rats, respectively. The defect was specific to skeletal muscle and heart. Stimulation of pyruvate dehydrogenase with dichloroacetate caused a 50% decrease in plasma lactate concentration but failed to improve whole-body insulin-stimulated glucose utilization in either the septic human or rat. Dichloroacetate reversed the impairment of insulin-stimulated myocardial glucose uptake in septic rats, but did not influence skeletal muscle glucose uptake either under basal conditions or during insulin stimulation. CONCLUSIONS: Activation of pyruvate dehydrogenase with dichloroacetate does not ameliorate the impairment of whole-body, insulin-stimulated glucose uptake in septic humans or rats, or reverse the specific defect in insulin-mediated skeletal muscle glucose uptake by septic rats. Therefore, the decreased pyruvate dehydrogenase activity associated with sepsis does not appear to mediate sepsis-induced insulin resistance during insulin-stimulated glucose uptake at either the whole-body or tissue level.

APACHE↗

PubMed1996

IGF-I stimulates muscle glucose uptake during sepsis.

The purpose of the present study was to determine whether insulin-like growth factor (IGF)-I would increase whole body and muscle glucose uptake in septic rats that are known to be insulin resistant. Animals were infused with either saline, low-dose IGF-I, high-dose IGF-I, or a maximally stimulating dose of insulin for 2 h, and the glucose metabolic response was assessed using a euglycemic clamp in combination with [3-3H]glucose. Under basal conditions, sepsis increased the rates of whole body glucose uptake, glycolysis, and hepatic glucose production. Under euglycemic hyperinsulinemic conditions, septic rats demonstrated a marked insulin resistance as evidenced by the impaired rate of insulin-stimulated glucose uptake and muscle glycogen synthesis. In contrast, the infusion of either dose of IGF-I increased total glucose uptake, glycolysis, and glycogen synthesis in both control and septic rats to the same extent. Furthermore, there was no difference in the IGF-I stimulation of glucose uptake (as determined by [14C]-2-deoxyglucose) in the gastrocnemius, soleus, and heart between control and septic rats. These results indicate that the glucose metabolic response to IGF-I is intact in insulin-resistant septic rats.

Animals↗