Effect of intensive insulin therapy on the somatotropic axis of critically ill children.

CONTEXT: Intensive insulin therapy (IIT) improved outcome in the adult and pediatric intensive care unit (PICU) compared with conventional insulin therapy (CIT). IIT did not increase the anabolic hormone IGF-I in critically ill adults, but feeding in critically ill children and pediatric hormonal responses may differ. Twenty-five percent of the children with IIT experienced hypoglycemia, which may have evoked counterregulatory responses. OBJECTIVE: We hypothesized that IIT reactivates the somatotropic axis and anabolism in PICU patients. DESIGN: This was a preplanned subanalysis of a randomized controlled trial on IIT. PATIENTS: We studied 369 patients who stayed in PICU for at least 3 d (study 1) and 126 patients in a nested case-control study (study 2). MAIN OUTCOME MEASURES: Circulating insulin, C-peptide, GH, IGF-I, bioavailable IGF-I, IGF-binding protein (IGFBP)-1, IGFBP-3, and acid-labile subunit were analyzed upon admission and d 3. In the nested case-control study, the somatotropic axis, cortisol, and glucagon were analyzed before and after hypoglycemia. RESULTS: On d 3, C-peptide was more than 10-fold lower (P < 0.0001) in the IIT group than in the CIT group. IIT increased circulating GH (P = 0.04) and lowered bioavailable IGF-I (P = 0.002). IIT also decreased IGFBP-3 (P = 0.0005) and acid-labile subunit (P = 0.007), while increasing IGFBP-1 (P = 0.04) and the urea/creatinine ratio, a marker of catabolism (P = 0.03). In the nested case-control study, IGFBP-1 was increased after hypoglycemia, whereas the somatotropic axis and the counterregulatory hormones cortisol and glucagon did not change. CONCLUSIONS: Despite improved PICU outcome, IIT did not counteract the catabolic state of critical illness. Suppression of portal insulin may have resulted in lower bioavailable IGF-I.

Transient catabolic state with reduced IGF-I after antenatal glucocorticoids.

Glucocorticoid (GC) administration before preterm birth reduces neonatal morbidity but may restrain growth. Here we explored the effect of antenatal GC on nutrient substrates [glucose, FFA, amino acids (AA)], and on IGF-I and IGF-binding protein-1 (IGFBP-1). We analyzed umbilical vein (UV) plasma obtained at birth from 91 preterm newborns that received one course of GC (last exposure 1-1358 h before birth) and 49 newborns that did not. We found that recent GC exposure (-48 h) raised glucose, FFA, and AA concentrations, and the homeostasis model assessment of insulin resistance (HOMA-IR) index, but lowered IGF-I concentrations. The AA surge was greater in newborns with a birth weight z score <0 than in those with a z score >0. Although all AA were transiently increased, the increment was most robust for glutamine and alanine. Shorter duration since GC administration and lower IGF-I concentrations independently predicted AA levels. In conclusion, an antenatal course of GC elicited a transient catabolic state encompassing all nutrient substrates, and a temporary drop in IGF-I concentrations. These changes may explain the growth-inhibitory effects of repeated antenatal GC administration. Future research should clarify the role of IGF-I in the protein-catabolic response to GC.

Tissue deiodinase activity during prolonged critical illness: effects of exogenous thyrotropin-releasing hormone and its combination with growth hormone-releasing peptide-2.

Prolonged critical illness is characterized by reduced pulsatile TSH secretion, causing reduced thyroid hormone release and profound changes in thyroid hormone metabolism, resulting in low circulating T(3) and elevated rT(3) levels. To further unravel the underlying mechanisms, we investigated the effects of exogenous TRH and GH-releasing peptide-2 (GHRP-2) in an in vivo model of prolonged critical illness. Burn-injured, parenterally fed rabbits were randomized to receive 4-d treatment with saline, 60 microg/kg.h GHRP-2, 60 microg/kg.h TRH, or 60 microg/kg.h TRH plus 60 microg/kg.h GHRP-2 started on d 4 of the illness (n = 8/group). The activities of the deiodinase 1 (D1), D2, and D3 in snap-frozen liver, kidney, and muscle as well as their impact on circulating thyroid hormone levels were studied. Compared with healthy controls, hepatic D1 activity in the saline-treated, ill animals was significantly down-regulated (P = 0.02), and D3 activity tended to be up-regulated (P = 0.06). Infusion of TRH and TRH plus GHRP-2 restored the catalytic activity of D1 (P = 0.02) and increased T(3) levels back within physiological range (P = 0.008). D3 activity was normalized by all three interventions, but only addition of GHRP-2 to TRH prevented the rise in rT(3) seen with TRH alone (P = 0.02). Liver D1 and D3 activity were correlated (respectively, positively and negatively) with the changes in circulating T(3) (r = 0.84 and r = -0.65) and the T(3)/rT(3) ratio (r = 0.71 and r = -0.60). We conclude that D1 activity during critical illness is suppressed and related to the alterations within the thyrotropic axis, whereas D3 activity tends to be increased and under the joint control of the somatotropic and thyrotropic axes.

Exogenous corticosteroids and in utero oxygenation modulate indices of fetal insulin secretion.

Low birth weight has long-term effects on glucose-insulin homeostasis. Factors that could mediate intra-uterine "programing" of glucose homeostasis include endogenous and exogenous glucocorticoids, adipose tissue-secreted factors such as adiponectin, and in utero hypoxia. Here, we studied 123 fetuses with gestational age (GA) between 25 and 37 wk and birth weight sd score (BW SDS) between -2.79 and 2.42. We measured proinsulin, C-peptide, insulin, and adiponectin in umbilical vein (UV) plasma and calculated the proinsulin to insulin ratio as a measure of beta-cell secretory function. These indices were related to GA, BW SDS, time since the last maternal betamethasone administration, and blood gas data. Insulin and C-peptide were correlated with BW SDS but not GA, whereas the proinsulin to insulin ratio was inversely correlated with BW SDS. The proinsulin to insulin ratio was raised (P = 0.002) in fetuses with UV PO(2) less than or equal to 21.3 mm Hg (i.e. the 50th percentile) compared with those with PO(2) more than 21.3 mm Hg, inferring that in utero hypoxia engenders beta-cell secretory dysfunction. Proinsulin, insulin, and C-peptide were markedly but transiently (<24 h) elevated after maternal betamethasone administration, returning thereafter to concentrations measured in noncorticosteroid-treated fetuses. However, there was considerable variability within the less than 24-h betamethasone group: the indices of insulin secretion were related to UV PO(2), suggesting that hypoxia attenuates the responsiveness of fetal beta-cells to corticosteroids. Adiponectin was not related to any of the insulin indices. In conclusion, we have identified two environmental signals that modulate fetal insulin output: maternal corticosteroids produce a transient surge in fetal insulin synthesis and secretion, whereas in utero hypoxia disturbs the insulin secretory process.

Neuroendocrine tumor markers and enterochromaffin-like cell hyper/dysplasia in type 1 diabetes.

OBJECTIVE: Parietal cell antibodies (PCAs) are found in 20% of type 1 diabetic patients, denoting autoimmune gastritis and pernicious anemia, which may predispose to enterochromaffin-like (ECL) cell hyper/dysplasia and gastric carcinoid tumors. We evaluated whether chromogranin A (CgA), 5-hydroxyindole acetic acid (5-HIAA), and neuron-specific enolase (NSE) contribute to screening for ECL cell hyper/dysplasia. RESEARCH DESIGN AND METHODS: Sera from 93 type 1 diabetic patients (53 men and 40 women, 31 PCA(+) and 62 PCA(-), aged 45 +/- 13 years) were analyzed for PCAs by indirect immunofluorescence and for CgA, NSE, and gastrin by radioimmunoassay. Urinary 5-HIAA was tested by high-performance liquid chromatography. Corpus atrophy and ECL cell proliferation were assessed in gastric biopsies. RESULTS: PCA(+) patients had higher gastrin (P < 0.0001) and CgA levels (P = 0.003) and were more prone to autoimmune gastritis (odds ratio [OR] 17, P < 0.0001) and ECL cell hyper/dysplasia (OR = 23, P = 0.005) than PCA(-) subjects. ECL cell hyper/dysplasia was present in seven PCA(+) patients who showed higher CgA levels (P < 0.0001) than subjects without ECL cell hyper/dysplasia, but NSE and 5-HIAA levels were similar. CgA levels correlated with gastrinemia (r = 0.50, P < 0.0001), PCA titer (r = 0.42, P = 0.001), and 5-HIAA levels (r = 0.38, P = 0.012). Logistic regression identified the CgA level (beta = 0.01, P = 0.027) as an independent risk factor for ECL cell hyper/dysplasia when PCA, CgA, 5-HIAA, NSE, gastrin, sex, and age were tested. Multivariate linear regression demonstrated that CgA level was determined by ECL cell density (r = 0.59, P < 0.0001) and gastrin level (r = 0.67, P = 0.02). One PCA(+) patient with elevated gastrin, CgA, and 5-HIAA levels had a gastric carcinoid tumor. CONCLUSIONS: PCA(+) patients, particularly those with high gastrin and CgA levels, risk developing ECL cell hyper/dysplasia. The determination of CgA, but not NSE and 5-HIAA, may complement histology in evaluating ECL cell mass.

Endocrine and metabolic effects of growth hormone (GH) compared with GH-releasing peptide, thyrotropin-releasing hormone, and insulin infusion in a rabbit model of prolonged critical illness.

Treatment with recombinant human GH (rhGH) increases the mortality of critical illness. We postulated that combined GH-releasing peptide-2 (GHRP-2), TRH, and insulin infusion is a less toxic anabolic strategy through a putative inability to overstimulate the GH axis and a capacity to normalize thyroid hormone concentrations while foregoing excessive hyperglycemia. Burn-injured, parenterally fed, New Zealand White rabbits were randomized to receive 4-d treatment with saline (n=8); 60 microg/kg.h GHRP-2 and 60 microg/kg.h TRH, i.v. (n=9); or 3.5 mg/kg rhGH, s.c. (n=7). In the GHRP-2+TRH group, insulin was adjusted to maintain blood glucose below 180 mg/dl. Endocrine function and biochemical organ system function markers were studied. Animals were killed for assay of deiodinase activity in snap-frozen liver. Mortality, organ system function, hyperglycemia, and insulin requirement were equal in the three groups. GHRP-2+TRH increased pulsatile rabbit GH (rGH) and TSH release on d 1. After 4 d, rGH secretion and T4 and T3 concentrations were elevated, with a significant increase in hepatic activity of type 1 deiodinase and a decrease in type 3 deiodinase. Exogenous rhGH suppressed endogenous rGH secretion and increased IGF-I more than GHRP-2+TRH without altering thyroid hormone levels. Unlike GHRP-2+TRH, rhGH down-regulated liver type 3 deiodinase and did not affect type 1 deiodinase. We conclude that in experimentally induced critical illness, GHRP-2+TRH reactivated the GH and TSH axes and altered liver deiodinase activity, driving T4 to T3 conversion. In contrast to the human model, high dose rhGH was not rapidly lethal in this rabbit model. Whether this is explained by lack of rhGH-induced insulin resistance and hyperglycemia remains unclear.

Metabolic, endocrine, and immune effects of stress hyperglycemia in a rabbit model of prolonged critical illness.

Stress hyperglycemia is frequent in critically ill patients. The aim of this study was to investigate the effect of blood glucose control with insulin on endocrine, metabolic, and immune function in an animal model of severe injury. Seventy-two hours after alloxan injection and exogenous insulin infusion combined with continuous iv parenteral nutrition, male New Zealand White rabbits received a burn injury and were allocated to a normoglycemic (n = 17) or hyperglycemic (n = 13) group. In the normoglycemic group, blood glucose levels were kept between 3.3 and 6.1 mmol/liter by insulin infusion, whereas in the hyperglycemic group blood glucose levels were maintained at 13.8-16.6 mmol/liter. Blood was drawn for biochemical analysis at regular time points. At 24 and 72 h after burn injury, immune function of monocytes was assessed in vitro. Maintenance of normoglycemia with exogenous insulin after severe trauma to a large extent prevented weight loss, lactic acidosis, and hyponatremia. Furthermore, within 3 d after injury, the intervention improved phagocytosis of monocytes investigated in fresh cells by more than a mean 150% (P = 0.006) and after 24-h incubation with or without lipopolysaccharide by more than a mean 4-fold (P = 0.001) and 2-fold (P = 0.05), respectively. Oxidative killing after 24-h incubation was also improved by 2-fold (P = 0.05), but no effect on chemotaxis was detected. Concomitantly, inflammation and stress-induced growth hormone hypersecretion were suppressed. Prevention of catabolism, acidosis, excessive inflammation, and impaired innate immune function may explain previously documented beneficial effects of intensive insulin therapy on outcome of critical illness.

A novel in vivo rabbit model of hypercatabolic critical illness reveals a biphasic neuroendocrine stress response.

High doses of GH, used to induce anabolism in prolonged critically ill patients, unexpectedly increased mortality. To further explore underlying mechanisms, a valid animal model is needed. Such a model is presented in this study. Seven days after arterial and venous cannulae placement, male New Zealand White rabbits were randomly allocated to a control or a critically ill group. To induce prolonged critical illness, a template controlled 15% deep dermal burn injury was imposed under combined general and regional (paravertebral) anesthesia. Subsequently, critically ill rabbits received supplemental analgesia and were parenterally fed with glucose, insulin, amino acids, and lipids. On d 1 and d 8 after randomization, acute and chronic spontaneous hormonal profiles of GH, TSH, and PRL secretion were obtained by sampling blood every 15 min for 7 h. Furthermore, GH, TSH, and PRL responses to an iv bolus of GH-releasing peptide 2 (GHRP-2) + TRH were documented on d 0, 1, and 8. Hemodynamic status and biochemical parameters were evaluated on d 0, 1, 3, 5, and 8, after which animals were killed and relative wet weight and water content of organs was determined. Compared with controls, critically ill animals exhibited transient metabolic acidosis on d 1 and weight loss, organ wasting, systolic hypertension, and pronounced anemia on d 8. On d 1, pulsatile GH secretion doubled in the critically ill animals compared with controls, and decreased again on d 8 in the presence of low plasma IGF-I concentrations from d 1 to d 8. GH responses to GHRP-2 + TRH were elevated on d 1 and increased further on d 8 in the critically ill animals. Mean TSH concentrations were identical in both groups on d 1 and 8, in the face of dramatically suppressed plasma T(4) and T(3) concentrations in the critically ill animals. PRL secretion was impaired in the critically ill animals exclusively on d 8. TSH and PRL responses to GHRP-2 and TRH were increased only on d 1. In conclusion, this rabbit model of acute and prolonged critical illness reveals several of the clinical, biochemical, and endocrine manifestations of the human counterpart.